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Background: Both aflibercept and bevacizumab-based regimens are available II-line treatment options for patients with metastatic colorectal cancer (mCRC). However, no head-to-head trials established the optimal anti-angiogenic strategy for this setting., Methods: We launched a multicenter, retrospective, observational study to assess and compare clinical efficacy of II-line treatments for patients with mCRC. Patients with KRAS/NRAS/BRAF-wild type and KRAS/NRAS mutant tumors were also analyzed separately., Findings: 348 patients were included, of whom 153 and 195 were treated with bevacizumab- and aflibercept-based regimens, respectively. Patients treated with aflibercept showed an increased risk of death (corrected [co]-HR 1.92, 95 %CI: 1.37-2.68), of disease progression/death (co-HR 1.43, 95 %CI: 1.12-1.82) and a decreased objective response rate (ORR) (21.5 % vs 34.7 %, p=0.007) in comparison to bevacizumab. Patients treated with II-line bevacizumab were more frequently treated in the third line setting after disease progression (91.1 % vs 68.5 %, p<0.0001). In the KRAS/NRAS mutant cohort, treatment with bevacizumab was associated with longer overall survival (OS) (18.0 months vs 12.5 months, p=0.0069), but similar progression free survival (PFS) (p=0.32) and ORR (p=0.57). In the KRAS/NRAS, BRAF wild type cohort, patients treated with bevacizumab achieved longer OS (20.2 months vs 10.6 months, p=0.013), PFS (8.4 months vs 3.7 months, p=0.0002), and higher ORR (48.6 % vs 15.0 %, p=0.0016), compared to those treated with aflibercept. The results were independently confirmed with inverse probability of treatment weighting and with fixed multivariable Cox-regressions., Conclusion: These findings support the use of bevacizumab-based over aflibercept-based regimens as II-line treatment in mCRC, especially in KRAS/NRAS and BRAF wild type tumors., Competing Interests: Disclosure The authors disclose no conflicts of interest in relation to the published work. Alessio Cortellini received grants for consultancies/advisory boards: BMS, MSD, OncoC4, IQVIA, Roche, GSK, AstraZeneca, Access Infinity, Ardelis Health and REGENERON. He also received speaker fees from AstraZeneca, EISAI, MSD, SANOFI/REGENERON and Pierre-Fabre., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: As an extended analysis of the COVID-DELAY study, we aimed to assess the impact of the COVID-19 pandemic on diagnosis, staging, and survival outcomes among patients with colorectal cancer (CRC) diagnosis performed from 2019 to 2022., Methods: All consecutive newly diagnosed CRC patients referred to 11 Italian Oncology Departments between March and December 2019, 2020, 2021, and 2022 were enrolled. Access rate, demographics, diagnostic-therapeutic temporal intervals, and first-line progression-free survival (PFS) and OS among metastatic patients were assessed., Results: Compared to 2019 (n = 690), an initial global reduction in new CRC cases in 2020 (n = 564, -18.3%) was observed, followed by a progressive increase in new CRC diagnoses in 2021 (n = 748, + 8.4%) and 2022 (n = 756, + 9.6%); a higher rate of TNM stage IV tumors was diagnosed in 2020 (35.4%) and 2021 (31.0%) compared to 2019 (29.6%), with normalization in 2022 (26.4%) (P < .001). Not clinically relevant differences between histological diagnosis and first oncological examination, cytohistological diagnosis and systemic treatment start, first oncological appointment and systemic treatment start, treatment start and first radiological assessment between 2020 and 2021-2022 years were found. After propensity score matching according to the year of diagnosis, median OS was significantly worse in 2020, 2021, and 2022 compared to 2019 (27.6 vs 24.8 vs not reached vs 38.9 months, respectively) (P < .001). Concordantly, the median PFS was significantly worse with each passing year: 13.0 vs 11.1 vs 9.2 vs 7.2 months in 2019, 2020, 2021, and 2022, respectively (P = .00027)., Conclusions: A progressive normalization in the rate of new CRC diagnosis as well as TNM stages at diagnosis, in 2021 and 2022 compared to 2020 and 2019, was found. The increase in new CRC cases might have affected some diagnostic-therapeutic time intervals in 2021-2022 years compared to 2020. Significantly, compared to the pre-pandemic phase, pandemic years were independently associated with worse PFS and OS outcomes in patients affected by metastatic disease., (© The Author(s) 2024. Published by Oxford University Press.)

Background: In the TOPAZ-1, patients with biliary tract cancers (BTC) and recurrence within 6 months after surgery were excluded, even if this event is frequently observed in clinical practice. Our study aimed to assess if the efficacy of cisplatin-gemcitabine-durvalumab (CGD) in this population is comparable to that reported in the phase 3 trial., Methods: The study cohort included patients with BTC who underwent surgery on the primary tumor, experienced disease recurrence occurring ≤6 months or >6 months after surgery or after the end of adjuvant therapy and started CGD. The primary objectives were overall survival (OS) and progression free survival (PFS)., Results: A total of 178 patients were enrolled. No significant differences were observed between early and late relapse groups in OS (23.4 months vs not reached; HR 1.26; 95% CI, 0.67-2.37; P = .45) and PFS [7.0 months vs 9.8 months; HR 1.3(95% CI, 0.9-2.1) P = .13]. Overall response rate and disease control rate (P = .33 and P = .62) were comparable between the 2 groups, as the overall safety profile. In addition, we compared survival outcomes between the selected population and a historical cohort of patients with BTC treated with cisplatin-gemcitabine (CG) and found that despite the absence of statistical significance, CGD showed an outcome trend compared with CG regardless of the time of recurrence after surgery or adjuvant chemotherapy [(CG ≤ 6 vs CGD ≤ 6 months: HR 0.59, 95%CI, 0.35-1.01, P = .05; HR 0.70; 95%CI, 0.46-1.06, P = .09, OS and PFS, respectively) and (CG > 6 vs. CGD > 6 months: HR 0.50; 95%CI, 0.29-0.88, P = 0.0165; HR 0.54; 95%CI, 0.35-0.84, P = .0068, OS and PFS, respectively)]., Conclusion: Our analysis suggests that CGD retains its efficacy independently of the timing of relapse after surgery or completion of adjuvant treatment in patients with advanced BTC., (© The Author(s) 2024. Published by Oxford University Press.)

Background & Aims: Atezolizumab/bevacizumab (A/B) is now a standard first-line treatment for advanced hepatocellular carcinoma (HCC), but the optimal second-line regimen is not known. We evaluated real-world treatment patterns and outcomes to investigate factors associated with post-progression survival (PPS)., Methods: In this multicenter, international, retrospective study, we examined clinical characteristics and outcomes of patients with advanced HCC who progressed on first-line A/B. The primary outcome of PPS was defined as time from first radiographic progression on A/B to death., Results: A total of 406 patients alive after progression on first-line A/B were included in the final analysis, of whom 45.3% (n = 184) received best supportive treatment (BST) and 54.7% (n = 222) continued active systemic treatment. In the second line, 155 patients were treated with tyrosine kinase inhibitors (TKIs), 45 with immune checkpoint inhibitor (IO)-based regimens, and 3 had missing data. Median PPS of the whole cohort (mPPS) was 6.0 months (95% CI 5.2-7.2). On multivariate Cox regression analysis, absence of portal vein tumor thrombus, ECOG <2, and continued active treatment were predictors of better PPS. mPPS was significantly longer for patients who continued active treatment vs. BST (9.7 vs. 2.6 months; HR 0.41, p < 0.001). In the second-line setting, patients treated with TKIs had a numerically shorter mPPS compared to those treated with IO (8.4 vs. 14.9 months; HR 1.37, p = 0.256)., Conclusions: Continuation of active therapy after A/B progression was independently associated with better survival even after adjusting for baseline disease characteristics. mPPS with IO-based therapy exceeded a year, suggesting that IO continuation post-progression may retain benefit. The precise sequencing of TKI and IO regimens warrants further investigation., Impact and Implications: There is currently a lack of level 1 data on second-line treatment options for patients with advanced hepatocellular carcinoma who progress after frontline atezolizumab plus bevacizumab, as all second-line approvals were established during the frontline sorafenib era. Our study aims to fill in some of the knowledge gap by investigating real-world patient outcomes in the second-line treatment setting. Findings from this study show that patients who continued active treatment had improved post-progression survival compared to those who received best supportive care, and medication regimens incorporating tyrosine kinase inhibitors as well as immunotherapy agents were active. These results can help inform clinicians of possible treatment options for patients who progress after frontline atezolizumab plus bevacizumab while we await maturing data from randomized-controlled trials., Competing Interests: Celina Ang has received compensation for participating in advisory boards for Bayer and Caris Life Sciences. Lorenz Balcar has served as a speaker for Chiesi and Gilead. Ciro Celsa has received speaker fees or been on the advisory boards of AstraZeneca, MSD/Eisai, Ipsen and has received travel support from Roche. Hong Jae Chon holds consulting or advisory roles with Eisai, Roche, Bayer, ONO, MSD, BMS, Celgene, Sanofi, Servier, AstraZeneca, SillaJen, Menarini, and GreenCross Cell, and has received research grants from Roche, Dong-A ST, and Boryung Pharmaceuticals. Alessio Cortellini received grants for consultancies/advisory boards: BMS, MSD, OncoC4, IQVIA, Roche, GSK, AstraZeneca, Access Infinity, Ardelis Health and REGENERON. He also received speaker fees from AstraZeneca, EISAI, MSD, SANOFI/REGENERON and Pierre-Fabre. Antonio D’Alessio received educational support for congress attendance from Roche, and consultancy fees from Roche, Astrazeneca, and Chugai. Johann von Felden received honoraria from Roche and AstraZeneca. Friedrich Foerster has received honoraria for lectures from AstraZeneca, Lilly, MSD, Pfizer and Roche. He has served as advisory board member to AstraZeneca, BMS, Eisai and Roche and has received travel support from Merck KGaA and Servier. Peter Galle reports honoraria for advisory boards and lectures from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen. Wei-Fan Hsu received speaker fees from AstraZeneca, Eisai, and Roche. Ahmed O Kaseb received research support from Genentech, BMS, Merck, Eisai, Exelixis, AdaptImmune and Tvardi and has been on the advisory board/has received honoraria from/been a consultant for: Genentech, BMS, Merck, Eisai, Exelixis. Masatoshi Kudo has received lecture fees from Eisai and Chugai and has served as an advisor for Roche, BMS, Ono, AstraZeneca, MSD, and Eisai. Neehar Parikh has served as a consultant or advisor for Genentech, Astra Zeneca, Exact Sciences, Eisai, Fujifilm Medical, and Gilead. Matthias Pinter received speaker honoraria from Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he is a consultant/advisory board member for AstraZeneca, Bayer, BMS, Eisai, Ipsen, Lilly, MSD, and Roche; he received grants from AstraZeneca, Bayer, BMS, Eisai, and Roche; he received travel support from Bayer, BMS, Ipsen, and Roche. Tiziana Pressiani received consulting fees from Bayer, Ipsen, and AstraZeneca; institutional research funding from Roche, Bayer, Astra Zeneca; travel expenses from Roche. Lorenza Rimassa received consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks. Anwaar Saeed reports a leadership role with Autem therapeutics, Exelixis, KAHR medical and Bristol-Myers Squibb; consulting or advisory board role with AstraZeneca, Bristol-Myers Squibb, Merck, Exelixis, Pfizer, Xilio therapeutics, Taiho, Amgen, Autem therapeutics, KAHR medical, and Daiichi Sankyo; institutional research funding from AstraZeneca, Bristol-Myers Squibb, Merck, Clovis, Exelixis, Actuate therapeutics, Incyte Corporation, Daiichi Sankyo, Five prime therapeutics, Amgen, Innovent biologics, Dragonfly therapeutics, Oxford Biotherapeutics, Arcus therapeutics, and KAHR medical; and participation as a data safety monitoring board chair for Arcus therapeutics. Bernhard Scheiner received grant support from AstraZeneca and Eisai, speaker honoraria from Eisai as well as travel support from AbbVie, AstraZeneca, Ipsen and Gilead. Kornelius Schulze received honoraria from MSD, Roche, and AstraZeneca. Amit Singal has served as a consultant or been on advisory boards for Genentech, AstraZeneca, Eisai, Bayer, Exelixis, Merck, Boston Scientific, Sirtex, HistoSonics, FujiFilm Medical Sciences, Exact Sciences, Glycotest, and Roche. Susanna V Ulahannan reports advisory board roles with Eisai, Astra Zeneca, and IGM biosciences. She has received institutional support for research from AbbVie, Adlai Nortye, Artios Pharma, ArQule, Inc, Astra Zeneca, Atreca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Ciclomed, Eisai, Erasca, Evelo Biosciences, Exelexis, G1 Therapeutics, GlaxoSmithKline, IGM biosciences, Immunitas Therapeutics, Incyte, Isofol, Jazz Pharmaceuticals, Klus Pharma, Macrogenics, Merck, Mersana Therapeutics, Omega Therapeutics, OncoMed Pharmaceuticals, Pfizer, Purple, Regeneron, Revolution Medicines, Synermore Biologics, Takeda, Tarveda Therapeutics, Tesaro, Tempest Therapeutics, Theradex, Totos Medicines, Tvardi Therapeutics, Vigeo Therapeutics Inc. Arndt Vogel reports consultancy, speaker and advisory roles at: AstraZeneca, Amgen, BeiGene, Böhringer Mannheim, BMS, EISAI, Incyte, Ipsen, MSD, PierreFabre, Roche, Servier, and Tahio. Arndt Weinmann received compensations as a member of scientific advisory boards for AstraZeneca, Bayer, BMS, MSD, Eisai, Servier and Sanofi. He served as a speaker for Leo Pharma, Eisai, Ipsen, Abbvie, AstraZeneca and Roche and received travel support from Merck and Servier. Reports no COI: Claudia AM Fulgenzi, Joshua Glover, Yi-Hsiang Huang, Angelo Pirozzi, Giulia F Manfredi, Yehia Mohamed, Naoshi Nishida, Alessandro Parisi, Natascha Roehlen, Martin Schönlein, Marianna Silletta, Bernardo Stefanini, Y. Linda Wu, Meng Wu. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2024 The Authors.)

Importance: Whether patients with Child-Pugh class B (CP-B) cancer with unresectable hepatocellular carcinoma (uHCC) benefit from active anticancer treatment vs best supportive care (BSC) is debated., Objective: To evaluate the association of immune checkpoint inhibitor (ICI)-based therapies vs BSC with overall survival (OS) of patients with uHCC and CP-B liver dysfunction., Design, Setting, and Participants: This retrospective, multicenter, international clinical case series examined data of patients with CP-B with uHCC who were receiving first-line ICI-based regimens from September 2017 to December 2022 whose data were extracted from an international consortium and compared with a cohort of patients with CP-B receiving BSC. Patients were treated in tertiary care centers across Europe, US, and Asia in routine clinical practice. After applying the inclusion criteria, 187 and 156 patients were left in the ICI and BSC groups, respectively. The propensity score was calculated for the following variables: age, alpha-fetoprotein levels, Child-Pugh score, extrahepatic spread, portal vein tumor thrombosis, cirrhosis, ascites, and baseline Eastern Cooperative Oncology Group performance status., Exposures: Patients in the ICI group received first-line systemic therapy with either atezolizumab plus bevacizumab (A+B) (n = 141) or nivolumab (n = 46)., Main Outcomes and Measures: OS in the inverse probability of treatment weighting (IPTW) populations was the main outcome, and it was estimated with Kaplan-Meier method; univariable Cox regression test was used to make comparisons between the 2 groups., Results: The median age was 66 (IQR, 61-72) and 73 (IQR, 66-81) years in the ICI (33 women [18%]) and BSC groups (41 women [26%]), respectively. In the IPTW populations, median OS was significantly longer in the ICI group (7.50 months; 95% CI, 5.62-11.15) compared with BSC (4.04 months; 95% CI, 3.03-5.03; hazard ratio, 0.59; 95% CI, 0.43-0.80; P < .001). Multivariable analysis confirmed that ICI exposure was associated with a reduction of approximately 50% in the risk of death (hazard ratio, 0.55; 95% CI, 0.35-0.86; P < .001), and the presence of portal vein tumor thrombosis, an Eastern Cooperative Oncology Group performance score of greater than 1, and alpha-fetoprotein levels of 400 ng/mL or greater were associated with increased risk of death., Conclusions and Relevance: The results of this case series provide comparative evidence of improved survival in association with ICI treatment compared with BSC in patients with uHCC with CP-B liver dysfunction.

Background: The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC). To understand this combination's real-world efficacy and tolerability, we conducted a global multicenter retrospective analysis of its first-line treatment outcomes., Methods: We included patients with unresectable, locally advanced, or metastatic BTC treated with durvalumab, gemcitabine, and cisplatin at 39 sites in 11 countries (Europe, the United States, and Asia). The primary endpoint was overall survival (OS)., Results: 666 patients were enrolled. Median OS was 15.1 months and median PFS was 8.2 months. The investigator-assessed overall response rate was 32.7 %, with stable disease in 45.2 % of patients. High baseline CEA levels, ECOG PS > 0, metastatic disease, and NLR > 3 were associated with poor survival. Any grade adverse events (AEs) occurred in 92.9 % of patients (grade >2: 46.6 %). Immune-related AEs (irAEs) occurred in 20.0 % (grade >2: 2.5 %). Three deaths (0.5 %) were deemed treatment-related, none linked to immunotherapy. Common irAEs were rash (8.2 % all grades; 0.3 % grade >2), itching (10.3 % all grades; 0.2 % grade >2), and hypothyroidism (5.1 % all grades; 0.3 % grade >2). Durvalumab discontinuation rate due to AEs was 1.5 %. ESMO-recommended genes were analyzed and no outcome differences were found. A comparative analysis with a historical cohort of patients treated with chemotherapy alone confirmed the positive survival impact of durvalumab in combination with cisplatin/gemcitabine., Conclusion: This first global real-world analysis largely confirmed the TOPAZ-1 findings, supporting gemcitabine, cisplatin, and durvalumab as a first-line standard of care for patients with advanced BTC., Competing Interests: Declaration of Competing Interest LR reports consulting fees from AbbVie, AstraZeneca, Basilea, Bayer, Elevar Therapeutics, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Jazz Pharmaceuticals, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, BMS, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Zymeworks. ACG reports consulting fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, IQVIA, MSD, Roche, Servier; lecture fees from AstraZeneca, Bayer, BMS, Eisai, Incyte, Ipsen, Roche, Servier; travel expenses from AstraZeneca; research grants (to Institution) from AstraZeneca, Eisai. SLC serves an advisory member for AstraZeneca, MSD, Eisai, BMS, Ipsen, and Hengrui, received research funds from MSD, Eisai, Ipsen, SIRTEX, and Zailab, and honoraria from AstraZeneca, Eisai, Roche, Ipsen, and MSD. TP received consulting fees from Bayer, Ipsen, and AstraZeneca; institutional research funding from Roche, Bayer, and AstraZeneca; travel expenses from Roche. CB received honoraria as speaker (Astrazeneca, Incyte, Servier) and consultant (Incyte, Servier, Boehringer Ingelheim, Astrazeneca), received research funds (Avacta, Medannex, Servier) and her spouse is an employee of Astrazeneca. M. Ikeda reports honoraria from AstraZeneca, Chugai Pharma, Eisai, Incyte, Lilly Japan, MSD, Novartis, Ono Pharmaceutical, Takeda, Teijin Pharma, Nihon Servier, Taiho and research funding from AstraZeneca, Bayer, Bristol-Myers Squibb, Chiome Bioscience, Chugai, Eisai, Eli Lilly Japan, Delta-Fly Pharma, Invitae, J-Pharma, Merck biopharma, Merus N.V., MSD, Novartis, Nihon Servier, Ono, Syneos Health, and Rakuten Medical. GWP: Advisories and/or Speaker fees: Servier, Bayer, Roche Amgen, Merck, MSD, BMS, Sanofi, Lilly, Astra Zeneca, Astellas, Pierre-Fabre, Incyte, Arcus, CECOG. F. F. has received travel support from Ipsen, Abbvie, Astrazeneca and speaker’s fees from AbbVie, MSD, Ipsen, Astrazeneca. LP: Advisory role: AstraZeneca, Servier, Travel expenses: AstraZeneca, Ipsen. GG: Consulting Fees: Astra Zeneca, MSD, Servier, Seagen, Bayer, Amgen, Novartis, Ipsen, BMS. Travel Expenses: Astra Zeneca, Servier, Bayer, Novartis. S.L. reports research funding (to Institution) from Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche, Servier; personal honoraria as invited speaker from Amgen, Astra Zeneca, Bristol-Myers Squibb, Incyte, GSK, Lilly, Merck Serono, MSD, Pierre-Fabre, Roche, Servier; participation in advisory board for Amgen, Astellas, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, GSK, Incyte, Lilly, Merck Serono, MSD, Servier, Takeda, Rottapharm. JD received consulting fees and/or speaker honoraria from Amgen, AstraZeneca, Bayer, BMS, Eisai, Need Inc., Ipsen, Lilly, MediMix, Merck, MSD, Novartis, Roche and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: To identify barriers between health and communication in oncology in order to promote the best possible practice. The areas of communication to be focused on are communication directly with the patient, communication within the scientific community, and communication with the media., Material and Methods: A working group including eminent experts from the national mass media, healthcare system, and patients' advocacy has been established on behalf of the Italian Association of Medical Oncology (AIOM), with the aim of developing suitable recommendations for the best communication in oncology. A literature search has been conducted selecting primary studies related to the best practices applied to communication in oncology. Subsequent to having identified the most representative statements, through a consensus conference using the RAND/University of California Los Angeles modified Delphi method, the panel evaluated the relevance of each statement to support useful strategies to develop effective communication between oncologist physicians and patients, communication within the scientific community, and communication with media outlets, including social media., Results: A total of 292 statements have been extracted from 100 articles. Following an evaluation of relevance, it was found that among the 142 statements achieving the highest scores, 30 of these have been considered of particular interest by the panel., Conclusions: This consensus and the arising document represent an attempt to strengthen the strategic alliance between key figures in communication, identifying high-impact recommendations for the management of communication in oncology with respect to patients, the wider scientific community, and the media., (© 2024. The Author(s).)

Background and Aims: Unlike other malignancies, hepatic functional reserve competes with tumor progression in determining the risk of mortality from hepatocellular carcinoma (HCC). However, the relative contribution of hepatic decompensation over tumor progression in influencing overall survival (OS) has not been assessed in combination immunotherapy recipients., Approach and Results: From the AB-real observational study (n = 898), we accrued 571 patients with advanced/unresectable hepatocellular carcinoma, Child-Pugh A class treated with frontline atezolizumab + bevacizumab (AB). Hepatic decompensation and tumor progression during follow-up were studied in relationship to patients' OS using a time-dependent Cox model. Baseline characteristics were evaluated as predictors of decompensation in competing risks analysis. During a median follow-up of 11.0 months (95% CI: 5.1-19.7), 293 patients (51.3%) developed tumor progression without decompensation, and 94 (16.5%) developed decompensation. In multivariable time-dependent analysis, decompensation (HR: 19.04, 95% CI: 9.75-37.19), hepatocellular carcinoma progression (HR: 9.91, 95% CI: 5.85-16.78), albumin-bilirubin (ALBI) grade 2/3 (HR: 2.16, 95% CI: 1.69-2.77), and number of nodules >3(HR: 1.63, 95% CI: 1.28-2.08) were independently associated with OS. Pretreatment ALBI grade 2/3 (subdistribution hazard ratio [sHR]: 3.35, 95% CI: 1.98-5.67) was independently associated with decompensation, whereas viral etiology was protective (sHR: 0.55, 95% CI: 0.34-0.87). Among patients with viral etiology, effective antiviral treatment was significantly associated with a lower risk of decompensation (sHR: 0.48, 95% CI: 0.25-0.93)., Conclusions: Hepatic decompensation identifies patients with the worst prognosis following AB and is more common in patients with baseline ALBI >1 and nonviral etiology. Effective antiviral treatment may protect from decompensation, highlighting the prognostic disadvantage of patients with nonviral etiologies and the importance of multidisciplinary management to maximize OS., (Copyright © 2024 American Association for the Study of Liver Diseases.)

Background: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting., Material and Methods: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included., Results: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs., Conclusions: These results confirm the effectiveness and safety of pemigatinib in a real-world setting., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background & Aims: Immune-related liver injury (irLI) is commonly observed in patients with cancer treated with immune checkpoint inhibitors (ICIs). We aimed to compare the incidence, clinical characteristics, and outcomes of irLI between patients receiving ICIs for hepatocellular carcinoma (HCC) vs. other solid tumours., Methods: Two separate cohorts were included: 375 patients with advanced/unresectable HCC, Child-Pugh A class treated with first-line atezolizumab+bevacizumab from the AB-real study, and a non-HCC cohort including 459 patients treated with first-line ICI therapy from the INVIDIa-2 multicentre study. IrLI was defined as a treatment-related increase of aminotransferase levels after exclusion of alternative aetiologies of liver injury. The incidence of irLI was adjusted for the duration of treatment exposure., Results: In patients with HCC, the incidence of any grade irLI was 11.4% over a median treatment exposure of 4.4 months (95% CI 3.7-5.2) vs. 2.6% in the INVIDIa-2 cohort over a median treatment exposure of 12.4 months (95% CI 11.1-14.0). Exposure-adjusted-incidence of any grade irLI was 22.1 per 100-patient-years in patients with HCC and 2.1 per 100-patient-years in patients with other solid tumours (p <0.001), with median time-to-irLI of 1.4 and 4.7 months, respectively. Among patients who developed irLI, systemic corticosteroids were administered in 16.3% of patients with HCC and 75.0% of those without HCC (p <0.001), and irLI resolution was observed in 72.1% and 58.3%, respectively (p = 0.362). In patients with HCC, rates of hepatic decompensation and treatment discontinuation due to irLI were 7%. Grade 1-2 irLI was associated with improved overall survival only in patients with HCC (hazard ratio 0.53, 95% CI 0.29-0.96)., Conclusions: Despite higher incidence and earlier onset, irLI in patients with HCC is characterised by higher rates of remission and lower requirement for corticosteroid therapy (vs. irLI in other solid tumours), low risk of hepatic decompensation and treatment discontinuation, not negatively affecting oncological outcomes., Impact and Implications: Immune-related liver injury (irLI) is common in patients with cancer receiving immune checkpoint inhibitors (ICIs), but whether irLI is more frequent or it is associated with a worse clinical course in patients with hepatocellular carcinoma (HCC), compared to other tumours, is not known. Herein, we compared characteristics and outcomes of irLI in two prospective cohorts including patients treated with ICIs for HCC or for other oncological indications. irLI is significantly more common and it occurs earlier in patients with HCC, also after adjustment for duration of treatment exposure. However, outcomes of patients with HCC who developed irLI are not negatively affected in terms of requirement for corticosteroid therapy, hepatic decompensation, treatment discontinuation and overall survival., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: While PLD-Trabectedin is an approved treatment for relapsed platinum-sensitive ovarian cancer, its efficacy and tolerability has so far not been tested extensively in patients who progress after poly ADP-ribose polymerase inhibitor (PARPi) treatment., Methodology: This multicenter, retrospective analysis had the objective of comparing patients receiving PLD-Trabectedin after being treated with PARP-I (cases) with PARPi-naïve patients. Descriptive and survival analyses were performed for each group., Results: Data from 166 patients were collected, composed of 109 cases and 57 controls. In total, 135 patients were included in our analyses, composing 46 controls and 89 cases. The median PFS was 11 months (95% IC 10-12) in the control group vs. 8 months (95% IC 6-9) in the case group ( p value 0.0017). The clinical benefit rate was evaluated, with an HR for progression of 2.55 (1.28-5.06) for the case group ( p value 0.008), persisting when adjusted for BRCA and line with treatment. We compared hematological toxicity, gastro-intestinal toxicity, hand-foot syndrome (HFS), fatigue, and liver toxicity, and no statistically significant disparity was noted, except for HFS with a p value of 0.006. The distribution of G3 and G4 toxicities was also equally represented., Conclusion: The MITO39 study showed a statistically significant difference in terms of PFS, suggesting that previous exposure to PARPi might inhibit the efficacy of PLD-Trabectedin. Regarding tolerability, no remarkable disparity was noted; PLD-Trabectedin was confirmed to be a well-tolerated scheme in both groups. To our knowledge, these are the first data regarding this topic, which we deem to be of great relevance in the current landscape.

Background & Aims: Sex-related differences in the immune pathogenesis of hepatocellular carcinoma (HCC), particularly related to oestrogen-dependent secretion of pro-tumourigenic cytokines, are well-known. Whether sex influences the efficacy and safety of immunotherapy is not known., Methods: We performed a restricted maximum likelihood random effects meta-analysis of five phase III trials that evaluated immune checkpoint inhibitors (ICIs) in advanced HCC and reported overall survival (OS) hazard ratios (HRs) stratified by sex to evaluate sex-related differences in OS. In a real-world cohort of 840 patients with HCC from 22 centres included between 2018 and 2023, we directly compared the efficacy and safety of atezolizumab + bevacizumab (A+B) between sexes. Radiological response was reported according to RECIST v1.1. Uni- and multivariable Cox regression analyses were performed for OS and progression-free survival (PFS)., Results: In the meta-analysis, immunotherapy was associated with a significant OS benefit only in male (pooled HR 0.79; 95% CI 0.73-0.86) but not in female (pooled HR 0.85; 95% CI 0.70-1.03) patients with HCC. When directly comparing model estimates, no differences in the treatment effect between sexes were observed. Among 840 patients, 677 (81%) were male (mean age 66 ± 11 years), and 163 (19%) were female (mean age 67 ± 12 years). Type and severity of adverse events were similar between the two groups. OS and PFS were comparable between males and females upon uni- and multivariable analyses (aHR for OS and PFS: 0.79, 95% CI 0.59-1.04; 1.02, 95% CI 0.80-1.30, respectively). Objective response rates (24%/22%) and disease control rates (59%/59%) were also similar between sexes., Conclusion: Female phase III trial participants experienced smaller OS benefit following ICI therapy for advanced HCC, while outcomes following A+B treatment were comparable between sexes in a large real-world database. Based on the ambiguous sex-related differences in survival observed here, further investigation of sex-specific clinical and biologic determinants of responsiveness and survival following ICIs are warranted., Impact and Implications: While immune checkpoint inhibitors have emerged as standard of care for the treatment of hepatocellular carcinoma, there are conflicting reports on whether the efficacy of cancer immunotherapy differs between females and males. Our study suggests ambiguous sex-related differences in outcomes from immunotherapy in hepatocellular carcinoma. Further investigation of sex-specific clustering in clinicopathologic and immunologic determinants of responsiveness to immune checkpoint inhibitor therapy should be prioritised., Systematic Review Registration: PROSPERO CRD42023429625., Competing Interests: The authors have nothing to disclose regarding the work under consideration for publication. The following authors disclose conflicts of interests outside the submitted work: L.B. has nothing to disclose. B.Sc. received travel support from AbbVie, AstraZeneca, Gilead and Ipsen as well as grant support from AstraZeneca. C.A.M.F. has nothing to disclose. A.D. is supported by the National Institute for Health Research (NIHR) Imperial BRC, by grant funding from the European Association for the Study of the Liver (2021 Andrew Burroughs Fellowship) and from Cancer Research UK (RCCPDB- Nov21/100008). A.D. received educational support for congress attendance and consultancy fees from Roche. K.P. has nothing to disclose. M.B.R. has nothing to disclose. E.L.M. is a salaried employee of Berry Consultants. J.C. has nothing to disclose. N.N. has nothing to disclose. P.-C.L. has nothing to disclose. L.W. has nothing to disclose. C.A. has nothing to disclose. A.K. has nothing to disclose. An.S. has nothing to disclose. B.St. has nothing to disclose. A.Ca. has nothing to disclose. T.P. has nothing to disclose. Y.I.A. has nothing to disclose. S.C. has nothing to disclose. B.W. has nothing to disclose. A.P. has nothing to disclose. Y.-H.H. has nothing to disclose. S.P. has nothing to disclose. C.V. has nothing to disclose. F.S. has nothing to disclose. G.M. has nothing to disclose. D.B. has nothing to disclose. A.V. has nothing to disclose. J.v.F. has received advisory board fees from Roche. K.S. has nothing to disclose. M.S. has nothing to disclose. M.T. served as a speaker and/or consultant and/or advisory board member for Albireo, BiomX, Falk, Boehringer Ingelheim, Bristol-Myers Squibb, Falk, Genfit, Gilead, Hightide, Intercept, Janssen, MSD, Novartis, Phenex, Pliant, Regulus, Siemens and Shire, and received travel support from AbbVie, Falk, Gilead, and Intercept as well as grants/research support from Albireo, Alnylam, Cymabay, Falk, Gilead, Intercept, MSD, Takeda, and UltraGenyx. He is also co-inventor of patents on the medical use of 24-norursodeoxycholic acid. Ad.S. is supported by grant funding from CRUK, served as a speaker for Merck and Chugai and received grants from Histosonics, Transgene, Oncolytics and Theolytics. H.W. has received lecture and consulting fees from AstraZeneca, Roche, and Eisai. F.P. has received honoraria for advisory board or lecturing from Astrazeneca, Bayer, Bracco, ESAOTE, EISAI, Exact Sciences, GE, IPSEN, MSD, Roche, Samsung, Siemens Healthineers. P.R.G. received honoraria from Bayer, Boston Scientific, AstraZeneca, Adaptimmune, BMS, Eisai, MSD, Sirtex, Lilly, Roche, Guerbet, Ipsen and Daiichi-Sankyo. R.S. has nothing to disclose. M.K. received lecture fees from Eli Lilly, Bayer, Eisai, Chugai, Takeda, AstraZeneca as well as grant support from Taiho, Otsuka, EA Pharma, AbbVie, Eisai, Chugai, GE Healthcare; and acts on advisory boards from Chugai, Roche, AstraZeneca, Eisai. A.G.S. has served as a consultant or on advisory boards for Genentech, AztraZeneca, Eisai, Exelixis, Bayer, Boston Scientific, FujiFilm Medical Sciences, Exact Sciences, Roche, Glycotest, Freenome, and GRAIL. Dr. Singal’s research is conducted with support from National Cancer Institute R01 MD012565 and R01 CA256977. A.I. has nothing to disclose. S.V.U. has served on advisory boards for Eisai, Astra Zeneca, IgM biosciences and received institutional support for research from AbbVie, Inc, Adlai Nortye, ArQule, Inc, AstraZeneca, Atreca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene Corporation, Ciclomed LLC, Erasca, Evelo Biosciences, Inc, Exelexis, G1 Therapeutics, Inc, GlaxoSmithKline GSK, IGM biosciences, Incyte, Isofol, Klus Pharma, Inc, Macrogenics, Merck Co. Inc, Mersana Therapeutics, OncoMed Pharmaceuticals, Inc, Pfizer, Regeneron, Inc, Revolution Medicines, Inc, Synermore Biologics Co, Takeda, Tarveda Therapeutics, Tesaro, Tempest, Vigeo Therapeutics Inc. (all funds to institution). N.D.P. serves as a consultant for Exact Sciences, Eli Lilly, Freenome, Astra Zeneca and has served on advisory boards of Genentech, Eisai, Bayer, Exelixis, Wako/Fujifilm and has received research funding from Bayer, Target Pharmasolutions, Exact Sciences, and Glycotest. A.Co. served as consultant/advisory role for AstraZeneca, BMS, MSD, Roche, IQVIA and OncoC4. He also received speaker’s fees from AstraZeneca, Pierre-Fabre, EISAI. A.K. has nothing to disclose. L.R. reports consulting fees from AstraZeneca, Basilea, Bayer, BMS, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Servier, Taiho Oncology, Zymeworks; lecture fees from AstraZeneca, Bayer, Eisai, Gilead, Incyte, Ipsen, Merck, Serono, Roche, Sanofi, Servier; travel expenses from AstraZeneca; research grants (to Institution) from Agios, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. H.J.C. has nothing to disclose. D.J.P. is supported by grant funding from the Wellcome Trust Strategic Fund (PS3416) and acknowledges grant support from the Cancer Treatment and Research Trust (CTRT); the NIHR Imperial Biomedical Research Centre; and the AIRC MFAG Grant No. 25697, Associazione Italiana per la Ricerca sul Cancro Foundation, Milan, Italy. D.J.P. acknowledges the following COIs: Lecture fees: Bayer Healthcare, Astra Zeneca, EISAI, Bristol-Myers-Squibb, Roche, Ipsen; Travel expenses: Bristol-Myers-Squibb, Roche, Bayer Healthcare; Consulting fees: Mina Therapeutics, Boeringer Ingelheim, Ewopharma, EISAI, Ipsen, Roche, H3B, Astra Zeneca, DaVolterra, Mursla, Avammune Therapeutics, LiFT Biosciences, Exact Sciences; Research funding (to institution): MSD, BMS, GSK. M.P. served as a speaker and/or consultant and/or advisory board member for Astra Zeneca, Bayer, Bristol-Myers Squibb, Eisai, Ipsen, Lilly, MSD, and Roche, and received travel support from Bayer, Bristol-Myers Squibb, Ipsen, and Roche. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Coastal areas frequently face critical conditions due to the lack of adequate forms of land use planning, environmental management and inappropriate coastal risk management, sometimes leading to unexpected and undesired environmental effects. Risk management also involves cultural aspects, including perception. However, the acknowledgement of risk perception by stakeholders and local communities, as one of the social pillars of risk analysis, is often lacking. Starting from an overview of the risk concept and the related approaches to be addressed, the paper investigates the evolution of coastal risk management with a focus on the Italian case study. Despite the design and adoption of national policies to deal with coastal risks, coastal management still shows in Italy a fragmented and poorly coordinated approach, together with a general lack of attention to stakeholder involvement. Recent efforts in the design of plans aiming at reducing risks derived from climate change and mitigating their impacts (National Strategy on Climate Change Adaptation; National Climate Change Adaptation Plan; National Recovery and Resilience Plan activities) should be effective in updating knowledge about climate change risks and in supporting national adaptation policies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Hypovitaminosis D can have a negative prognostic impact in patients with cancer. Vitamin D has a demonstrated role in T-cell-mediated immune activation. We hypothesized that systematic vitamin D repletion could impact clinical outcomes in patients with cancer receiving immune-checkpoint inhibitors (ICIs)., Methods: We planned a prospective observational study (PROVIDENCE) to assess serum vitamin D levels in patients with advanced cancer receiving ICIs (cohort 1 at treatment initiation, cohort 2 during treatment) and the impact of systematic repletion on survival and toxicity outcomes. In an exploratory analysis, we compared the clinical outcomes of cohort 1 with a control cohort of patients followed at the participating centers who did not receive systematic vitamin D repletion., Results: Overall, 164 patients were prospectively recruited in the PROVIDENCE study. In cohort 1, consisting of 101 patients with 94.1% hypovitaminosis (≤ 30 ng/ml) at baseline, adequate repletion with cholecalciferol was obtained in 70.1% at the three months re-assessment. Cohort 2 consisted of 63 patients assessed for vitamin D at a median time of 3.7 months since immunotherapy initiation, with no patients having adequate levels (> 30 ng/ml). Even in cohort 2, systematic supplementation led to adequate levels in 77.8% of patients at the three months re-assessment. Compared to a retrospective control group of 238 patients without systematic vitamin D repletion, PROVIDENCE cohort 1 showed longer overall survival (OS, p = 0.013), time to treatment failure (TTF, p = 0.017), and higher disease control rate (DCR, p = 0.016). The Inverse Probability of Treatment Weighing (IPTW) fitted multivariable Cox regression confirmed the significantly decreased risk of death (HR 0.55, 95%CI: 0.34-0.90) and treatment discontinuation (HR 0.61, 95%CI: 0.40-0.91) for patients from PROVIDENCE cohort 1 in comparison to the control cohort. In the context of longer treatment exposure, the cumulative incidence of any grade immune-related adverse events (irAEs) was higher in the PROVIDENCE cohort 1 compared to the control cohort. Nevertheless, patients from cohort 1 experienced a significantly decreased risk of all grade thyroid irAEs than the control cohort (OR 0.16, 95%CI: 0.03-0.85)., Conclusion: The PROVIDENCE study suggests the potential positive impact of early systematic vitamin D supplementation on outcomes of patients with advanced cancer receiving ICIs and support adequate repletion as a possible prophylaxis for thyroid irAEs., (© 2023. The Author(s).)

Despite the introduction of targeted (BRAFi/MEKi) and immune checkpoint inhibitors (ICIs) has significantly reduced the recurrence rate and improved the overall survival (OS) of patients with Stage III and IV melanoma, only a percentage will benefit of durable disease control. The aim of this study was to examine whether the levels of circulating tumour DNA (ctDNA) in plasma of advanced melanoma patients undergoing BRAFi/MEKi or ICIs vary according to the patients' survival outcomes (i.e. progression-free survival (PFS) and OS) and disease progression. Plasma samples of Stage III-IV melanoma patients were collected at baseline (treatment initiation) and thereafter every 3 months. Circulating BRAF V600E/K and NRAS Q61R/K mutations were analysed through droplet digital PCR (ddPCR, Bio-Rad) in a total of 177 plasma samples from 48 melanoma patients (19 Stage III, 29 Stage IV). Baseline ctDNA concentration was significantly associated with OS (HR = 1.003, 95% CI = 1.000-1.006, p = 0.043) and PFS (HR = 1.004, 95% CI = 1.000-1.007, p = 0.029) independent of clinical-prognostic confounders. For each unit increase in the ∆ctDNA (concentration difference between the last follow-up and baseline) there was a 24% increased risk of disease progression, irrespective of treatment type and stage at diagnosis (OR = 1.24, 95% CI = 1.03-1.49, p = 0.020, AUC = 0.93). Patients with reduction of ctDNA level from baseline to the last follow-up had longer OS (HR = 0.14; 95% CI = 0.05-0.44, p = 0.001) and PFS (HR = 0.08; 95% CI = 0.03-0.27, p < 0.0001) compared to patients with increased ctDNA, including adjustment for confounding factors. Our findings suggest that variation of ctDNA over time during melanoma treatment reflects the clinical outcome and tumour response to therapy and might be helpful in clinical monitoring., (© 2023 The Authors. Experimental Dermatology published by John Wiley & Sons Ltd.)

In recent years, poly (ADP-ribose) polymerase (PARP) inhibition has become a promising therapeutic option for several tumors, especially for those harboring a BRCA 1-2 mutation or a deficit in the homologous recombination repair (HRR) pathway. Nevertheless, to date, PARP inhibitors are still not largely used for thoracic malignancies neither as a single agent nor in combination with other treatments. Recently, a deeper understanding of HRR mechanisms, alongside the development of new targeted and immunotherapy agents, particularly against HRR-deficient tumors, traced the path to new treatment strategies for many tumor types including lung cancer and malignant pleural mesothelioma. The aim of this review is to sum up the current knowledge about cancer-DNA damage response pathways inhibition and to update the status of recent clinical trials investigating the use of PARP inhibitors, either as monotherapy or in combination with other agents for the treatment of thoracic malignancies. We will also briefly discuss available evidence on Poly(ADP-Ribose) Glycohydrolase (PARG) inhibitors, a novel promising therapeutic option in oncology., Competing Interests: Professor Rossana Berardi reports grants from Lilly, grants from MSD, grants from Otsuka, grants from BI, grants from GSK, grants from Italfarmaco, grants from Roche, grants from AZ, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2023 Parisi et al.)

Background: Real-life spectrum and survival implications of immune-related adverse events (irAEs) in patients treated with extended interval dosing (ED) immune checkpoint inhibitors (ICIs) are unknown., Methods: Characteristics of 812 consecutive solid cancer patients who received at least 1 cycle of ED monotherapy (pembrolizumab 400 mg Q6W or nivolumab 480 mg Q4W) after switching from canonical interval dosing (CD; pembrolizumab 200 mg Q3W or nivolumab 240 mg Q2W) or treated upfront with ED were retrieved. The primary objective was to compare irAEs patterns within the same population (before and after switch to ED). irAEs spectrum in patients treated upfront with ED and association between irAEs and overall survival were also described., Results: A total of 550 (68%) patients started ICIs with CD and switched to ED. During CD, 225 (41%) patients developed any grade and 17 (3%) G3 or G4 irAEs; after switching to ED, any grade and G3 or G4 irAEs were experienced by 155 (36%) and 20 (5%) patients. Switching to ED was associated with a lower probability of any grade irAEs (adjusted odds ratio [aOR] = 0.83, 95% confidence interval [CI] = 0.64 to 0.99; P = .047), whereas no difference for G3 or G4 events was noted (aOR = 1.55, 95% CI = 0.81 to 2.94; P = .18). Among patients who started upfront with ED (n = 232, 32%), 107 (41%) developed any grade and 14 (5%) G3 or G4 irAEs during ED. Patients with irAEs during ED had improved overall survival (adjusted hazard ratio [aHR] = 0.53, 95% CI = 0.34 to 0.82; P = .004 after switching; aHR = 0.57, 95% CI = 0.35 to 0.93; P = .025 upfront)., Conclusions: Switching ICI treatment from CD and ED did not increase the incidence of irAEs and represents a safe option also outside clinical trials., (© The Author(s) 2023. Published by Oxford University Press.)

. Early warning scores for clinical deterioration in pediatric patients: a literature review., Introduction: An early recognition of clinical worsening (the manifestation of signs and symptoms resulting in physiological instability) in pediatric inpatients may prevent the evolution towards cardiorespiratory arrest. In recent decades, several tools known as PEWS (Pediatric Early Warning Scores), have been developed, aiming to reduce in-hospital morbidity and mortality., Objective: To describe efficacy, sensitivity and specificity of the available tools for early detection of clinical worsening in children, based on literature review., Methods: Systematic review through the consultation of PubMed and Google Scholar, cross-combining Mesh terms and free text words., Results: Out of 266 analysed papers, 34 were included in this review: 23 retrospective observational studies, 8 reviews, 1 reliability study, and 2 pilot studies. Overall, 23 main PEWS with sufficient evidence of efficacy were described (11 track and trigger and 12 aggregate). Ranges of sensibility and specificity were available only for 18 PEWS. It is not possible to recognize a gold standard, however, some PEWS are better in terms of validity and efficacy in different clinical settings. Internationally, the BPEWS (Brighton Pediatric Early Warning Score) is the most commonly adopted tool, able to identify clinical worsening of in-hospital children almost 11 hours before cardiac arrest., Conclusions: Although with limited evidence, validated PEWS have shown good ability to prevent the risk of clinical worsening by reducing adverse events. Further studies and greater standardization according to the clinical context are still needed.

Background: In metastatic pancreatic ductal adenocarcinoma (mPDAC), first line treatment options usually include combination regimens of folinic acid, 5-fluorouracil (5-FU), irinotecan, and oxaliplatin (FOLFIRINOX or mFOLFIRINOX) or gemcitabine based regimens such as in combination with albumin-bound paclitaxel (GEM + nab-PTX). After progression, multiple regimens including NALIRI + 5-FU and folinic acid, FOLFIRINOX, 5-FU-based oxaliplatin doublets (OFF, FOLFOX, or XELOX), or 5-FU-based monotherapy (FL, capecitabine, or S-1) are considered appropriate by major guidelines. This network meta-analysis (NMA) aimed to compare the efficacy of different treatment strategies tested as second-line regimens for patients with mPDAC after first-line gemcitabine-based systemic treatment., Methods: Randomized phase II and III clinical trials (RCTs) were included if they were published or presented in English. Trials of interest compared two active systemic treatments as second-line regimens until disease progression or unacceptable toxicity. We performed a Bayesian NMA with published hazard ratios (HRs) and 95%confidence intervals (CIs) to evaluate the comparative effectiveness of different second-line therapies for mPDAC. The main outcomes of interest were overall survival (OS) and progression free survival (PFS), secondary endpoints were grade 3-4 toxicities. We calculated the relative ranking of agents for each outcome as their surface under the cumulative ranking (SUCRA). A higher SUCRA score meant a higher ranking for efficacy outcomes., Results: A NMA of 9 treatments was performed for OS (n = 2521 patients enrolled). Compared with 5-FU + folinic acid both irinotecan or NALIRI + fluoropyrimidines had a trend to better OS (HR = 0.76, 95%CI 0.21-2.75 and HR = 0.74, 95%CI 0.31-1.85). Fluoropyrimidines + folinic acid + oxaliplatin were no better than the combination without oxaliplatin. The analysis of treatment ranking showed that the combination of NALIRI + 5-FU + folinic acid was most likely to yield the highest OS results (SUCRA = 0.7). Furthermore, the NMA results indicated that with the highest SUCRA score (SUCRA = 0.91), NALIRI + 5-FU + folinic acid may be the optimal choice for improved PFS amongst all regimens studied., Conclusions: According to the NMA results, NALIRI + 5-FU, and folinic acid may represent the best second-line treatment for improved survival outcomes in mPDAC. Further evidence from prospective trials is needed to determine the best treatment option for this group of patients., (© 2023. The Author(s).)

Purpose: Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice., Methods: We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR 28 ) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis., Results: By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR 28 demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively; P = .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR 28 (odds ratio [OR], 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls., Conclusion: Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19.

Background: COVID-19 sequelae can affect about 15% of patients with cancer who survive the acute phase of SARS-CoV-2 infection and can substantially impair their survival and continuity of oncological care. We aimed to investigate whether previous immunisation affects long-term sequelae in the context of evolving variants of concern of SARS-CoV-2., Methods: OnCovid is an active registry that includes patients aged 18 years or older from 37 institutions across Belgium, France, Germany, Italy, Spain, and the UK with a laboratory-confirmed diagnosis of COVID-19 and a history of solid or haematological malignancy, either active or in remission, followed up from COVID-19 diagnosis until death. We evaluated the prevalence of COVID-19 sequelae in patients who survived COVID-19 and underwent a formal clinical reassessment, categorising infection according to the date of diagnosis as the omicron (B.1.1.529) phase from Dec 15, 2021, to Jan 31, 2022; the alpha (B.1.1.7)-delta (B.1.617.2) phase from Dec 1, 2020, to Dec 14, 2021; and the pre-vaccination phase from Feb 27 to Nov 30, 2020. The prevalence of overall COVID-19 sequelae was compared according to SARS-CoV-2 immunisation status and in relation to post-COVID-19 survival and resumption of systemic anticancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974., Findings: At the follow-up update on June 20, 2022, 1909 eligible patients, evaluated after a median of 39 days (IQR 24-68) from COVID-19 diagnosis, were included (964 [50·7%] of 1902 patients with sex data were female and 938 [49·3%] were male). Overall, 317 (16·6%; 95% CI 14·8-18·5) of 1909 patients had at least one sequela from COVID-19 at the first oncological reassessment. The prevalence of COVID-19 sequelae was highest in the pre-vaccination phase (191 [19·1%; 95% CI 16·4-22·0] of 1000 patients). The prevalence was similar in the alpha-delta phase (110 [16·8%; 13·8-20·3] of 653 patients, p=0·24), but significantly lower in the omicron phase (16 [6·2%; 3·5-10·2] of 256 patients, p<0·0001). In the alpha-delta phase, 84 (18·3%; 95% CI 14·6-22·7) of 458 unvaccinated patients and three (9·4%; 1·9-27·3) of 32 unvaccinated patients in the omicron phase had sequelae. Patients who received a booster and those who received two vaccine doses had a significantly lower prevalence of overall COVID-19 sequelae than unvaccinated or partially vaccinated patients (ten [7·4%; 95% CI 3·5-13·5] of 136 boosted patients, 18 [9·8%; 5·8-15·5] of 183 patients who had two vaccine doses vs 277 [18·5%; 16·5-20·9] of 1489 unvaccinated patients, p=0·0001), respiratory sequelae (six [4·4%; 1·6-9·6], 11 [6·0%; 3·0-10·7] vs 148 [9·9%; 8·4-11·6], p=0·030), and prolonged fatigue (three [2·2%; 0·1-6·4], ten [5·4%; 2·6-10·0] vs 115 [7·7%; 6·3-9·3], p=0·037)., Interpretation: Unvaccinated patients with cancer remain highly vulnerable to COVID-19 sequelae irrespective of viral strain. This study confirms the role of previous SARS-CoV-2 immunisation as an effective measure to protect patients from COVID-19 sequelae, disruption of therapy, and ensuing mortality., Funding: UK National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust., Competing Interests: Declaration of interests AC has received consulting fees from MSD, Bristol Myers Squibb, AstraZeneca, and Roche, and speakers' fee from AstraZeneca, MSD, Novartis, and Eisai. ML acted as a consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, and Seagen, and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen, and Sandoz outside the submitted work. AG declares consulting or advisory roles for Roche, MSD, Eli Lilly, Pierre Fabre, Eisai, and Daichii Sankyo; speakers' fees for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, AstraZeneca, Celgene, and Daichii Sankyo; and research funds from Eisai, Eli Lilly, and Roche. CM-V has received travel grants and other honoraria from Bristol Myers Squibb, MSD, Novartis, and Roche. JB has declared consulting or advisory roles for MSD and AstraZeneca, and support for attending meetings and travel from GlaxoSmithKline. OM reports personal fees from Grupo Pacifico, Kyowa Kirin, Roche, and ROVI, and travel support from Almirall, Kyowa Kirin, and Sanofi. JT reports personal financial interest in the form of scientific consultancy roles for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; stocks in Oniria Therapeutics; and educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource. LRi reports receiving consulting fees from Amgen, ArQule, AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Servier, Taiho Oncology, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi, and Servier; travel expenses from AstraZeneca; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. AD'A has received educational support for congress attendance and consultancy fees from Roche. DJP has received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, and the Falk Foundation; travel expenses from Bristol Myers Squibb and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; and institutional research funding from MSD and Bristol Myers Squibb. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Genomics has greatly improved how patients with cancer are being treated; however, clinical-grade genomic biomarkers for chemotherapies are currently lacking. Using whole-genome analysis of 37 patients with metastatic colorectal cancer (mCRC) treated with the chemotherapy trifluridine/tipiracil (FTD/TPI), we identified KRAS codon G12 (KRAS G12 ) mutations as a potential biomarker of resistance. Next, we collected real-world data of 960 patients with mCRC receiving FTD/TPI and validated that KRAS G12 mutations were significantly associated with poor survival, also in analyses restricted to the RAS/RAF mutant subgroup. We next analyzed the data of the global, double-blind, placebo-controlled, phase 3 RECOURSE trial (n = 800 patients) and found that KRAS G12 mutations (n = 279) were predictive biomarkers for reduced overall survival (OS) benefit of FTD/TPI versus placebo (unadjusted interaction P = 0.0031, adjusted interaction P = 0.015). For patients with KRAS G12 mutations in the RECOURSE trial, OS was not prolonged with FTD/TPI versus placebo (n = 279; hazard ratio (HR) = 0.97; 95% confidence interval (CI) = 0.73-1.20; P = 0.85). In contrast, patients with KRAS G13 mutant tumors showed significantly improved OS with FTD/TPI versus placebo (n = 60; HR = 0.29; 95% CI = 0.15-0.55; P < 0.001). In isogenic cell lines and patient-derived organoids, KRAS G12 mutations were associated with increased resistance to FTD-based genotoxicity. In conclusion, these data show that KRAS G12 mutations are biomarkers for reduced OS benefit of FTD/TPI treatment, with potential implications for approximately 28% of patients with mCRC under consideration for treatment with FTD/TPI. Furthermore, our data suggest that genomics-based precision medicine may be possible for a subset of chemotherapies., (© 2023. The Author(s).)

The growing groundwater withdrawal rates in coastal aquifers in arid/semi-arid regions exacerbate seawater intrusion and saltwater upconing by causing groundwater salinization and potential adverse and cascading effects to related groundwater-depending systems. This study aims to highlight the dynamics of groundwater salinization in time and space by comparing the efficacy of statistical (hierarchical cluster and factor analyses) and hydrogeochemical (hydrogeochemical facies evolution) methods. Multi-temporal groundwater samples collected from the monitoring well network in the study area (Salento Aquifer, Puglia region, Southern Italy) have been considered to recognize such dynamics. By comparing the spatial and temporal evolution of water clusters, factor scores, and hydrogeochemical facies, the proposed methodological approach enables the identification of zones characterized by low dynamics of freshening and intrusion processes (with invariant features during the investigated period), which correspond to groundwater recharge areas and zones subject to groundwater salinization respectively. On the contrary, a high spatial and temporal variability of salinization dynamics typifies the zones subject to alternation of groundwater characteristics. These results allow outlining a preliminary hazard map related to groundwater salinization processes, which might be a useful tool for policymakers and stakeholders involved in groundwater management of coastal aquifers. Results suggest that generally, a thoughtful understanding of limitations concerning the aquifer heterogeneity and anisotropy, distribution and density of control points, and depth of sampling is crucial for handling the study outcomes, especially for the aims of management., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: There is compelling need for novel biomarkers to predict response to PARP inhibitors (PARPi) in BRCA wild-type (WT) ovarian cancer (OC)., Methods: MITO 37 is a multicenter retrospective study aiming at correlating Ki67 expression at diagnosis with a clinical outcome following platinum treatment and PARPi maintenance. Clinical data were collected from high grade serous or endometroid BRCAWT OC treated with niraparib or rucaparib maintenance between 2010-2021 in 15 centers. Ki67 expression was assessed locally by certified pathologists on formalin-fixed paraffin embedded (FFPE) tissues. Median Ki67 was used as a cut-off., Results: A total of 136 patients were eligible and included in the analysis. Median Ki67 was 45.7% (range 1.0-99.9). The best response to platinum according to median Ki67 was 26.5% vs. 39.7% complete response (CR), 69.1% vs. 58.8% partial response (PR), 4.4% vs. 1.5% stable disease (SD). The best response to PARPi according to median Ki67 was 19.1% vs. 36.8% CR, 26.5% vs. 26.5% PR, 26.5 vs. 25% SD, 27.9% vs. 16.2% progressive disease (PD). No statistically significant differences in progression free survival (PFS) and overall survival (OS) were identified between low and high Ki67. PFS and OS are in line with registration trials., Conclusions: Ki67 at diagnosis did not discriminate responders to PARPi., Competing Interests: The authors declare no conflict of interest.

For decades, chemoradiotherapy for early-stage disease and systemic chemotherapy for advanced disease have represented the mainstay of treatment for anal cancer. Over the last few years, however, the advent of immunotherapy has opened interesting therapeutic perspectives, with the establishment of new standards of care, and the development of clinical trials that may further shape the treatment algorithm for this tumour. In this review article, we discuss the rationale behind the use of immunotherapy for anal cancer and provide an overview of the available clinical data and ongoing efforts to build on these., Competing Interests: Conflict of interest statement Rita Saúde-Conde - Travel grants: MSD.Francesco Sclafani - Consultancy, advisory role, honoraria: AMAL Therapeutics, Bayer, BMS, Dragonfly Therapeutics, Merck, Nordic Pharma, Roche, Servier. Research funding: Amgen (inst), AstraZeneca (Inst), Bayer (Inst), BMS (Inst), Roche (Inst), Sanofi (Inst). Travel grants: Amgen, Bayer, Lilly, Servier. Leadership role: Co-Chair EORTC Task Force Colon, Rectum, Anal Canal., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Colorectal cancer (CRC) patients frequently develop liver metastases. Different treatment strategies are available according to the timing of appearance, the burden of metastatic disease, and the performance status of the patient. Systemic treatment (ST) represents the cornerstone of metastatic disease management. However, in select cases, combined ST and surgical resection can lead to remarkable survival outcomes. In the present multicentric cohort study, we explored the efficacy of a conversion strategy in a selected population of left-sided RAS/BRAF wild-type CRC patients with liver-limited metastatic disease. Methods: The primary endpoint was to compare survival outcomes of patients undergoing ST not leading to surgery, liver resection after conversion ST, and hepatic resection with perioperative ST. Furthermore, we explored survival outcomes depending on whether the case was discussed within a multidisciplinary team. Results: Between 2012 and 2020, data from 690 patients respecting the inclusion criteria were collected. Among these, 272 patients were deemed eligible for the analysis. The conversion rate was 24.1% of cases. Fifty-six (20.6%) patients undergoing surgical resection after induction treatment (i.e., ultimately resectable) had a significant survival advantage compared to those receiving systemic treatment not leading to surgery (176 pts, 64.7%) (5-year OS 60.8% and 11.7%, respectively, Log Rank test p < 0.001; HR = 0.273; 95% CI: 0.16−0.46; p < 0.001; 5-year PFS 22.2% and 6.3%, respectively, Log Rank test p < 0.001; HR = 0.447; 95% CI: 0.32−0.63; p < 0.001). There was no difference in survival between ultimately resectable patients and those who had liver resection with perioperative systemic treatment (potentially resectable—40 pts) (5-year OS 71.1%, Log Rank test p = 0.311. HR = 0.671; 95% CI: 0.31−1.46; p = 0.314; 5-year PFS 25.7%, Log Rank test p = 0.305. HR = 0.782; 95% CI: 0.49−1.25; p = 0.306). Conclusions: In our selected population of left-sided RAS/BRAF wild-type colorectal cancer patients with liver-limited disease, a conversion strategy was confirmed to provide a survival benefit. Patients not deemed surgical candidates at the time of diagnosis and patients judged resectable with perioperative systemic treatment have similar survival outcomes.

This work investigates a statistical approach analysing data from monitoring activities on marine-coastal areas for environmental quality determination and surveillance. Analyses were performed on a database of the Environmental Protection and Prevention Agency of the Puglia Region. As, Cr, Ni, and Pb concentration values in marine sediments and biota from 2013 to 2015 and 2017 were processed to investigate different contaminant characteristics. Hierarchical cluster analysis identified three contaminant distribution classes with (1) highest Cr, Ni, and Pb concentrations, (2) highest As concentration, and (3) lowest contaminants concentration. The Kruskal-Wallis and Friedman tests showed that contaminant distributions were statistically different when considering the monitoring years and classes. However, statistical similarities resulted during the 2013-2017 and 2014-2015 periods. Spearman's coefficients displayed positive correlations among the pollutants in each matrix and mainly negative correlations for matrices comparison. This methodology aims to provide a practical support for monitoring to identify potential environmental deterioration over time and correlations with specific contamination sources., (© 2022. The Author(s).)

Angiogenesis, a hallmark of cancer, plays a fundamental role in colorectal cancer (CRC). Anti-angiogenic drugs and chemotherapy represent a standard of care for treating metastatic disease. Immune checkpoint inhibitors (ICIs) have changed the therapeutic algorithm of many solid tumors. However, the efficacy of ICIs is limited to mCRC patients carrying microsatellite instability (MSI-H), which represent approximately 3-5% of mCRC. Emerging evidence suggests that anti-angiogenic drugs could exhibit immunomodulatory properties. Thus, there is a strong rationale for combining anti-angiogenics and ICIs to improve efficacy in the metastatic setting. Our review summarizes the pre-clinical and clinical evidence regarding the combination of anti-angiogenics and ICIs in mCRC to deepen the possible application in daily clinical practice.

Few data from randomized clinical trials (RCTs) investigating the efficacy of post-induction strategies after the first-line treatment with anti-Epidermal Growth Factor Receptor (EGFR) in patients with metastatic colorectal cancer (mCRC) are available. A systematic review and metanalysis might therefore be useful to highlight and even strengthen these data. A literature search in Pubmed, Embase, American Society of Clinical Oncology (ASCO) Annual Meetings, ASCO Gastrointestinal Symposia, and European Society for Medical Oncology (ESMO) Congresses was performed. The search included RCTs of patients with mCRC treated with an initial period of cytotoxic chemotherapy (CT) in association with anti-EGFR (ie, panitumumab or cetuximab) as first-line regimen, and then switched to one of the following strategies: observation; maintenance with anti-EGFR, fluoropyrimidine (FP), or both; or continuing the induction regimen until disease progression or unacceptable toxicity. Outcomes of interest included overall survival (OS) and progression-free survival (PFS). The overall effect was pooled using the Mantel-Haenszel method fixed-effect model or the DerSimonian-Laird method random-effect model according to heterogeneity (I 2 ). Analysis was performed on June 9, 2021. 7 studies (all phase II trials), including 1038 patients, were considered eligible for the meta-analysis. In all studies, CT (induction or maintenance with FP) + anti-EGFR until disease progression or unacceptable toxicity prolonged OS (HR = 0.72 [95%CI 0.61-0.86]; P < .01) and PFS (HR = 0.76, 95%CI 0.68-0.85; P < .01) compared to other agents (FP ± bevacizumab) or observation. Subgroup analyses for OS and PFS were performed according to type of maintenance therapy (containing or not containing single-agent anti-EGFR). Within patients evaluable for OS, CT + anti-EGFR combinations continued until disease progression were able to decrease the risk of death by 32% (HR 0.68; 95% CI 0.56-0.84; P < .01) and the risk of progression by 25% (HR 0.75; 95% CI 0.65-0.85; P < .01) over no maintenance or maintenance with anti-EGFR alone. Conversely, combination of CT + anti-EGFR were no better over anti-EGFR with FP in term of OS (HR = 0.81 [95%CI 0.60-1.09]; P = .17) and PFS (HR = 0.81 [95% 0.64, 1.01]; P = .06). Maintenance treatment with anti-EGFR + FP might be regarded as the better option following anti-EGFR based induction treatment in RAS wild-type mCRC, in terms of efficacy. This effect might be particularly amplified in left-sided BRAF wild-type mCRC patients. A higher level of evidence coming from phase III trials is auspicable., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: BRAF and MEK inhibitors target therapies (TT) and AntiPD1 immunotherapies (IT) are available first-line treatments for BRAF v600 mutant metastatic melanoma patients. ECOG PS (E), baseline LDH (L), and baseline number of metastatic sites (N) are well-known clinical prognostic markers that identify different prognostic categories of patients. Direct comparison between first-line TT and IT in different prognostic categories could help in first line treatment decision., Methods: This is a retrospective analysis conducted in 14 Italian centers on about 454 metastatic melanoma patients, divided in 3 groups: group A-patients with E = 0, L within normal range, and N less than 3; group B-patients not included in group A or C; group C-patients with E > 0, L over the normal range, and N more than 3. For each prognostic group, we compared TT and IT in terms of progression free survival (PFS), overall survival (OS), and disease control rate (DCR)., Results: In group A, results in 140 TT and 36 IT-treated patients were, respectively, median PFS 35.5 vs 11.6 months (HR (95% CI) 1.949 (1.180-3.217) p value 0.009); median OS not reached vs 55 months (HR (95% CI) 1.195 (0.602-2.373) p value 0.610); DCR 99% vs 75% p value <0.001). In group B, results in 196 TT and 38 IT-treated patients were, respectively, median PFS 11.5 vs 5 months (HR 1.535 (1.036-2.275) p value 0.033); median OS 19 vs 20 months (HR 0.886 (0.546-1.437) p value 0.623); DCR 85% vs 47% p value <0.001). In group C, results in 41 TT and 3 IT-treated patients were, respectively, median PFS 6.4 vs 1.8 months (HR 4.860 (1.399-16) p value 0.013); median OS 9 vs 5 months (HR 3.443 (0.991-11.9) p value 0.052); DCR 66% vs 33% p value 0.612)., Conclusions: In good prognosis, group A-TT showed statistically significant better PFS than IT, also in a long-term period, suggesting that TT can be a good first line option for this patient category. It is only in group B that we observed a crossing of the survival curves after the 3rd year of observation in favor of IT. Few patients were enrolled in group C, so few conclusions can be made on it., Competing Interests: RMa, PF, AN, SM, MF, FDR, MDT, ETT, FC, AM, NP, FM, MB, MT, MS, AP, MO, IS declare that they received financial support for congress participation, advisory board, scientific advice from BMS, MSD, Novartis, Pierre fabre, La Roche, Sanofi, Ipsen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marconcini, Fava, Nuzzo, Manacorda, Ferrari, De Rosa, De Tursi, Tanda, Consoli, Minisini, Pimpinelli, Morgese, Bersanelli, Tucci, Saponara, Parisi, Ocelli, Bazzurri, Massaro, Morganti, Ciardetti and Stanganelli.)

Aim: The aim of the current study is to investigate the impact of primary compared to secondary chemotherapy-induced nausea and vomiting (CINV) prophylaxis with NK1 receptor antagonists (NK1-RA) in patients affected by gastrointestinal malignancies and treated with oxaliplatin- and/or irinotecan-based doublet or triplet regimens., Study Design and Methods: Clinical data of patients affected by gastrointestinal malignancies, treated with an oxaliplatin and/or irinotecan-based doublet or triplet regimen as neo/adjuvant or advanced-line treatment, and who received NK1-RA as primary (from the first cycle of treatment) or secondary (after the onset of CINV with a previous regimen with 5HT3-RA and dexamethasone) prophylaxis for CINV, were retrospectively collected in an observational study involving 16 Italian centers. A propensity score matching was performed by taking into account the following stratification factors: sex (male vs. female), age (< vs. ≥70 years old), overweight (body mass index, BMI < vs. ≥25), underweight (BMI < vs. ≥19), disease spread (early vs. advanced/metastatic), tumor type (esophagogastric cancer vs. the rest, hepatobiliary tumor vs. the rest, colorectal cancer vs. the rest), type of NK1-RA used as primary/secondary prophylaxis (netupitant-palonosetron vs. fosaprepitant/aprepitant), concomitant use of opioids (yes vs. no), concomitant use of antidepressant/antipsychotic drugs (yes vs. no), Eastern Cooperative Oncology Group (ECOG) performance status at the start of NK1-RA treatment (0 vs. 1-2), and intensity of chemotherapy regimen (doublet vs. triplet)., Results: Among 409 patients included from January 2015 to January 2022 and eligible for analysis, 284 (69%) and 125 (31%) were treated with NK1-RA as primary and secondary antiemetic prophylaxis, respectively. After matching, primary NK1-RA use was not associated with higher rates of protection from emesis regardless the emesis phase (acute phase, p = 0.34; delayed phase, p = 0.14; overall phase, p = 0.80). On the other hand, a lower rate of relevant nausea (p = 0.02) and need for rescue antiemetic therapy (p = 0.000007) in the overall phase was found in primary NK1-RA users. Furthermore, a higher rate of both complete antiemetic response (p = 0.00001) and complete antiemetic protection (p = 0.00007) in the overall phase was more frequently observed in primary NK1-RA users. Finally, chemotherapy delays (p = 0.000009) and chemotherapy dose reductions (p = 0.0000006) were less frequently observed in primary NK1-RA users., Conclusion: In patients affected by gastrointestinal malignancies, a primary CINV prophylaxis with NK1-RA, 5HT3-RA, and dexamethasone might be appropriate, particularly in those situations at higher risk of emesis and in which it is important to avoid dose delays and/or dose reductions, keeping a proper dose intensity of chemotherapy drugs., Competing Interests: APa reported receiving advisory board fees from GSK, Servier, Pharmamar. RG reported receiving fees from Amgen and Servier and advisory board fees from Amgen, Servier, Bayer and Merck-Serono. LS reported receiving fees from Pierre-Fabre, AstraZeneca, Bayer, Servier, Merck, Amgen. APe reported receiving fees from Eli-Lilly, MSD, BMS, Merck, Servier. BD has received fees from Ipsen, Eisai, Eli Lilly, AstraZeneca, Sanofi, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Bayer, Roche, and Amgen; and has received non-financial support from Ipsen, BMS. MG reported receiving fees by Amgen, Merck, Eli-Lilly, Servier, Italfarmaco. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Parisi, Giampieri, Mammarella, Felicetti, Salvatore, Bensi, Maratta, Strippoli, Filippi, Satolli, Petrillo, Daniele, De Tursi, Di Marino, Giordano, Landriscina, Vitale, Zurlo, Dell’Aquila, Tomao, Depetris, Di Pietro, Zoratto, Ciardiello, Pensieri, Garrone, Galassi, Ferri, Berardi and Ghidini.)

Background: Although SARS-CoV-2 vaccines immunogenicity in patients with cancer has been investigated, whether they can significantly improve the severity of COVID-19 in this specific population is undefined., Methods: Capitalizing on OnCovid (NCT04393974) registry data we reported COVID-19 mortality and proxies of COVID-19 morbidity, including post-COVID-19 outcomes, according to the vaccination status of the included patients., Results: 2090 eligible patients diagnosed with COVID-19 between 02/2020 and 11/2021 were included, of whom 1930 (92.3%) unvaccinated, 91 (4.4%) fully vaccinated and 69 (3.3%) partially vaccinated. With the exception of a higher prevalence of patients from the UK (p = 0.0003) and receiving systemic anticancer therapy at COVID-19 diagnosis (p = 0.0082) among fully vaccinated patients, no demographics/oncological features were associated with vaccination status. The 14-days case fatality rate (CFR) (5.5% vs 20.7%, p = 0.0004) and the 28-days CFR (13.2% vs 27.4%, p = 0.0028) demonstrated a significant improvement for fully vaccinated patients in comparison with unvaccinated patients. The receipt of prior full vaccination was also associated with reduced symptomatic COVID-19 (79.1% vs 88.5%, p = 0.0070), need of COVID-19 oriented therapy (34.9% vs 63.2%, p < 0.0001), complications from COVID-19 (28.6% vs 39.4%, p = 0.0379), hospitalizations due to COVID-19 (42.2% vs 52.5%, p = 0.0007) and oxygen therapy requirement (35.7% vs 52%, p = 0.0036). Following Inverse Probability Treatment Weighting (IPTW) procedure no statistically significant difference according to the vaccination status was confirmed; however, all COVID-19 related outcomes were concordantly in favour of full vaccination. Among the 1228 (58.8%) patients who underwent a formal reassessment at participating centres after COVID-19 resolution, fully vaccinated patients experienced less sequelae than unvaccinated patients (6.7% vs 17.2%, p = 0.0320)., Conclusions: This analysis provides initial evidence in support of the beneficial effect of SARS-CoV-2 vaccines against morbidity and mortality from COVID-19 in patients with cancer., Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: As corresponding author of the abovementioned manuscript, I declare on behalf of my co-authors the following conflict of interests: David J Pinato received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS.Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations, and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb.Matteo Lambertini acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work.Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca.Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche.Gianluca Gaidano has declared consulting/advisory role for Janssen, Abbvie, Astra-Zeneca and BeiGene, and speaker fees from Janssen and Abbvie.Lorenza Rimassa received consulting fees from Taiho Oncology, Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks.Joseph Tabernero reported consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics and TheraMyc. He also reported speaker's fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). He also declared institutional research support from Amgen Inc, Array Biopharma Inc, AstraZeneca Pharmaceuticals LP, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International SA, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Janssen-Cilag SA, MedImmune, Menarini, Merck Health KGAA, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica SA, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA Inc, Spanish Association Against Cancer Scientific Foundation and Cancer Research UK.Alessio Cortellini received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers' fee from AstraZeneca, MSD, Novartis and Eisai.All remaining authors have declared no conflicts of interest.London, April 18th, 2022., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Fifteen percent of patients with cancer experience symptomatic sequelae, which impair post-COVID-19 outcomes. In this study, we investigated whether a proinflammatory status is associated with the development of COVID-19 sequelae., Methods: OnCovid recruited 2795 consecutive patients who were diagnosed with Severe Acute Respiratory Syndrome Coronavirus 2 infection between February 27, 2020, and February 14, 2021. This analysis focused on COVID-19 survivors who underwent a clinical reassessment after the exclusion of patients with hematological malignancies. We evaluated the association of inflammatory markers collected at COVID-19 diagnosis with sequelae, considering the impact of previous systemic anticancer therapy. All statistical tests were 2-sided., Results: Of 1339 eligible patients, 203 experienced at least 1 sequela (15.2%). Median baseline C-reactive protein (CRP; 77.5 mg/L vs 22.2 mg/L, P < .001), lactate dehydrogenase (310 UI/L vs 274 UI/L, P = .03), and the neutrophil to lymphocyte ratio (NLR; 6.0 vs 4.3, P = .001) were statistically significantly higher among patients who experienced sequelae, whereas no association was reported for the platelet to lymphocyte ratio and the OnCovid Inflammatory Score, which includes albumin and lymphocytes. The widest area under the ROC curve (AUC) was reported for baseline CRP (AUC = 0.66, 95% confidence interval [CI]: 0.63 to 0.69), followed by the NLR (AUC = 0.58, 95% CI: 0.55 to 0.61) and lactate dehydrogenase (AUC = 0.57, 95% CI: 0.52 to 0.61). Using a fixed categorical multivariable analysis, high CRP (odds ratio [OR] = 2.56, 95% CI: 1.67 to 3.91) and NLR (OR = 1.45, 95% CI: 1.01 to 2.10) were confirmed to be statistically significantly associated with an increased risk of sequelae. Exposure to chemotherapy was associated with a decreased risk of sequelae (OR = 0.57, 95% CI: 0.36 to 0.91), whereas no associations with immune checkpoint inhibitors, endocrine therapy, and other types of systemic anticancer therapy were found., Conclusions: Although the association between inflammatory status, recent chemotherapy and sequelae warrants further investigation, our findings suggest that a deranged proinflammatory reaction at COVID-19 diagnosis may predict for sequelae development., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: The omicron (B.1.1.529) variant of SARS-CoV-2 is highly transmissible and escapes vaccine-induced immunity. We aimed to describe outcomes due to COVID-19 during the omicron outbreak compared with the prevaccination period and alpha (B.1.1.7) and delta (B.1.617.2) waves in patients with cancer in Europe., Methods: In this retrospective analysis of the multicentre OnCovid Registry study, we recruited patients aged 18 years or older with laboratory-confirmed diagnosis of SARS-CoV-2, who had a history of solid or haematological malignancy that was either active or in remission. Patient were recruited from 37 oncology centres from UK, Italy, Spain, France, Belgium, and Germany. Participants were followed up from COVID-19 diagnosis until death or loss to follow-up, while being treated as per standard of care. For this analysis, we excluded data from centres that did not actively enter new data after March 1, 2021 (in France, Germany, and Belgium). We compared measures of COVID-19 morbidity, which were complications from COVID-19, hospitalisation due to COVID-19, and requirement of supplemental oxygen and COVID-19-specific therapies, and COVID-19 mortality across three time periods designated as the prevaccination (Feb 27 to Nov 30, 2020), alpha-delta (Dec 1, 2020, to Dec 14, 2021), and omicron (Dec 15, 2021, to Jan 31, 2022) phases. We assessed all-cause case-fatality rates at 14 days and 28 days after diagnosis of COVID-19 overall and in unvaccinated and fully vaccinated patients and in those who received a booster dose, after adjusting for country of origin, sex, age, comorbidities, tumour type, stage, and status, and receipt of systemic anti-cancer therapy. This study is registered with ClinicalTrials.gov, NCT04393974, and is ongoing., Findings: As of Feb 4, 2022 (database lock), the registry included 3820 patients who had been diagnosed with COVID-19 between Feb 27, 2020, and Jan 31, 2022. 3473 patients were eligible for inclusion (1640 [47·4%] were women and 1822 [52·6%] were men, with a median age of 68 years [IQR 57-77]). 2033 (58·5%) of 3473 were diagnosed during the prevaccination phase, 1075 (31·0%) during the alpha-delta phase, and 365 (10·5%) during the omicron phase. Among patients diagnosed during the omicron phase, 113 (33·3%) of 339 were fully vaccinated and 165 (48·7%) were boosted, whereas among those diagnosed during the alpha-delta phase, 152 (16·6%) of 915 were fully vaccinated and 21 (2·3%) were boosted. Compared with patients diagnosed during the prevaccination period, those who were diagnosed during the omicron phase had lower case-fatality rates at 14 days (adjusted odds ratio [OR] 0·32 [95% CI 0·19-0·61) and 28 days (0·34 [0·16-0·79]), complications due to COVID-19 (0·26 [0·17-0·46]), and hospitalisation due to COVID-19 (0·17 [0·09-0·32]), and had less requirements for COVID-19-specific therapy (0·22 [0·15-0·34]) and oxygen therapy (0·24 [0·14-0·43]) than did those diagnosed during the alpha-delta phase. Unvaccinated patients diagnosed during the omicron phase had similar crude case-fatality rates at 14 days (ten [25%] of 40 patients vs 114 [17%] of 656) and at 28 days (11 [27%] of 40 vs 184 [28%] of 656) and similar rates of hospitalisation due to COVID-19 (18 [43%] of 42 vs 266 [41%] of 652) and complications from COVID-19 (13 [31%] of 42 vs 237 [36%] of 659) as those diagnosed during the alpha-delta phase., Interpretation: Despite time-dependent improvements in outcomes reported in the omicron phase compared with the earlier phases of the pandemic, patients with cancer remain highly susceptible to SARS-CoV-2 if they are not vaccinated against SARS-CoV-2. Our findings support universal vaccination of patients with cancer as a protective measure against morbidity and mortality from COVID-19., Funding: National Institute for Health and Care Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust., Competing Interests: Declaration of interests DJP has received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, Eisai, and Falk Foundation; travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; and research funding (to their institution) from MSD and BMS. MLa has acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen, and Gilead; and has received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen, Libbs, Knight, and Sandoz. FM has received consulting fees from Eli Lilly, MSD, Takeda, and Roche; and travel support from Sanofi. SP reported that their spouse is employed by AstraZeneca. ASa has received consulting fees from Arqule, Sanofi, and Incyte; speaker's fees from Takeda, BMS, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Eli Lilly, Sandoz, Eisai, Novartis, Bayer, and MSD; and participation on data monitoring committees for BMS, Servier, Gilead, Pfizer, Eisai, Bayer, and MSD. FG has received consulting fees from Novocure, BMS, PharmaMar, and Novartis; speaker's fees from Novocure; travel support from MSD, Novocure, BMS, Boehringer Ingelheim, PharmaMar, Novartis, and Pierre Fabre; and participation on a data safety monitoring board for MSD, BMS, PharmaMar and Novartis. JH has a leadership role with Blood Cancer UK. NS-G has received speakers' fees from Amgen. GG has received consulting fees or had an advisory role for Janssen, AbbVie, AstraZeneca, Roche, Incyte, and BeiGene, and reported speaker fees from Janssen and AbbVie. LRi has received consulting fees from Taiho Oncology, Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, and Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, and Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, and Zymeworks. JT reports consulting fees from Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Scandion Oncology, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, and TheraMyc; speaker's fees from Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education, and Physicians Education Resource; and institutional research support from Amgen, Array Biopharma, AstraZeneca Pharmaceuticals, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho Pharma USA, Spanish Association Against Cancer Scientific Foundation, and Cancer Research UK. MB has received speakers' fee from Eisai pharma, Gilead Sciences, Merck, and ViiV; and has had leadership roles in the European AIDS Clinical Society, UNAIDS, WHO, and The European Hematology Association/ European Society of Medical Oncology. AC has received consulting fees from MSD, BMS, AstraZeneca, and Roche; and speakers' fee from AstraZeneca, MSD, Novartis, and Eisai. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: A significant proportion of patients with cancer who recover from Coronavirus Disease 2019 (COVID-19) may experience COVID-19 sequelae in the early post-infection phase, which negatively affect their continuity of care and oncological outcome. The long-term prevalence and clinical impact of the post-COVID-19 syndrome in patients with cancer are largely unknown., Methods: In this study, we describe the time course of COVID-19 sequelae in patients with non-advanced cancers enrolled in the OnCovid registry., Results: Overall, 186 patients were included, with a median observation period of 9.9 months (95%CI:8,8-11.3) post-COVID-19 resolution. After a median interval of 2.3 months post-COVID-19 (interquartile range: 1.4-3.7), 31 patients (16.6%) reported ≥1 sequelae, including respiratory complications (14, 7.6%), fatigue (13, 7.1%), neuro-cognitive sequelae (7, 3.8%). The vast majority of the patients were not vaccinated prior to COVID-19. COVID-19-related sequelae persisted in 9.8% and 8% of patients 6 and 12 months after COVID-19 resolution. Persistence of sequelae at first oncological follow-up was associated with history of complicated COVID-19 (45.2% vs 24.8%, p = 0.0223), irrespective of oncological features at COVID-19 diagnosis., Conclusion: This study confirms for the first time that, in a largely unvaccinated population, post-COVID-19 syndrome can affect a significant proportion of patients with non-advanced cancer who recovered from the acute illness. COVID-19 sequelae may persist up to 12 months in some patients, highlighting the need for dedicated prevention and supportive strategies., Competing Interests: Conflict of interest statement Alessio Cortellini received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Eisai. David J Pinato received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS. Aleix Prat has declared personal honoraria from Pfizer, Roche, MSD Oncology, Eli Lilly, and Daiichi Sankyo; travel, accommodations and expenses paid by Daiichi Sankyo; research funding from Roche and Novartis; and consulting/advisory role for NanoString Technologies, Amgen, Roche, Novartis, Pfizer and Bristol-Myers Squibb. Matteo Lambertini acted as consultant for Roche, Novartis, Lilly, AstraZeneca, Exact Sciences, MSD, Pfizer, Seagen and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, Ipsen and Sandoz outside the submitted work. Thomas Newsom-Davis has declared consulting/advisory role for Amgen, Bayer, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, MSD, Novartis, Otsuka, Pfizer, Roche, and Takeda; speakers fees from AstraZeneca, MSD, Roche, Takeda and travel, accommodations and expenses paid by AstraZenca, BMS, Boehringer Ingelheim, Lilly, MSD, Otsuka, Roche, and Takeda. Joan Brunet has declared consulting/advisory role for MSD and Astra Zeneca. Alessandra Gennari has declared consulting/advisory role for Roche, MSD, Eli Lilly, Pierre Fabre, EISAI, and Daichii Sankyo; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, Astra Zeneca, Celgene, and Daichii Sankyo; research funds: EISAI, Eli Lilly, and Roche. CMV has received travel grants and other honoraria from BMS, MSD, Novartis and Roche. Gianluca Gaidano has declared consulting/advisory role for Janssen, Abbvie, Astra-Zeneca and BeiGene, and speaker fees from Janssen and Abbvie. Lorenza Rimassa received consulting fees from Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, BMS, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, MSD, Nerviano Medical Sciences, Roche, Sanofi, Zymeworks; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, Sanofi; travel expenses from Ipsen; and institutional research funding from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, MSD, Nerviano Medical Sciences, Roche, Zymeworks. All remaining authors have declared no conflicts of interest., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

HER2 is considered one of the most traditional prognostic and predictive biomarkers in breast cancer. Literature data confirmed that the addition of pertuzumab to a standard neoadjuvant chemotherapy backbone (either with or without anthracyclines), in patients with human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC), leads to a higher pathological complete response (pCR) rate, which is known to correlate with a better prognosis. In this retrospective analysis, 47 consecutive patients with HER2-positive EBC received sequential anthracyclines and taxanes plus trastuzumab (ATH) or pertuzumab, trastuzumab and docetaxel (THP). Despite the limited sample size, this monocentric experience highlights the efficacy (in terms of pCR) and safety of THP in the neoadjuvant setting of HER2-positive EBC as an anthracycline-free approach. Given the role of PIK3CA as a prognostic and therapeutic target in breast cancer, tumors were also analyzed to assess the PIK3CA mutational status. Thirty-eight out of forty-seven patients were evaluated, and PIK3CA variants were identified in 21% of tumor samples: overall, one mutation was detected in exon 4 (2.6%), two in exon 9 (5.3%) and four in exon 20 (10.5%). Of note, one sample showed concurrent mutations in exons 9 (codon 545) and 20 (codon 1047). Among patients reaching pCR (n = 13), 38.5% were PIK3CA mutants; on the other hand, among those lacking pCR (n = 25), just 12% showed PIK3CA variants. Regarding THP-treated mutant patients (n = 5), 80% reached pCR (three hormone-receptor-negative, one hormone-receptor-positive). Interestingly, the only patient not achieving pCR had a tumor with two co-occurring PIK3CA mutations. In conclusion, this study provides new evidence about the efficacy and good safety profile of THP, compared to the ATH regimen, as an anthracycline-free neoadjuvant treatment of HER2-positive EBC. Further studies on larger/multicentric cohorts are planned for more in-depth analysis to confirm our molecular and clinical results.

The assessment of RAS and BRAF mutational status is one of the main steps in the diagnostic and therapeutic algorithm of metastatic colorectal cancer (mCRC). Multiple mutations in the BRAF and RAS pathway are described as a rare event, with concurrent variants in KRAS and BRAF genes observed in approximately 0.05% of mCRC cases. Here, we report data from a case series affected by high-risk stage III and stage IV CRC and tested for RAS and BRAF mutation, treated at our Medical Oncology Unit. The analysis of KRAS , NRAS (codons 12, 13, 59, 61, 117, 146), and BRAF (codon 600) hotspot variants was performed in 161 CRC tumors from August 2018 to September 2021 and revealed three (1.8%) patients showing mutations in both KRAS and BRAF (V600E), including two cases with earlier CRC and one with metastatic disease. We also identified one patient (0.6%) with a mutation in both KRAS and NRAS genes and another one (0.6%) with a double KRAS mutation. Notably, the latter was characterized by aggressive behavior and poor clinical outcome. The mutational status, pathological features, and clinical history of these five CRC cases are described. Overall, this study case series adds evidence to the limited available literature concerning both the epidemiological and clinical aspects of CRC cases characterized by the presence of concurrent RAS/BRAF variants. Future multicentric studies will be required to increase the sample size and provide additional value to results observed so far in order to improve clinical management of this subgroup of CRC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Zelli, Parisi, Patruno, Cannita, Ficorella, Luzi, Compagnoni, Zazzeroni, Alesse and Tessitore.)

Background: Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published., Aim and Methods: To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS)., Results: Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months)., Conclusion: Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients' quality of life without compromising the continuity and efficacy of antineoplastic therapy., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Importance: Whether the severity and mortality of COVID-19 in patients with cancer have improved in terms of disease management and capacity is yet to be defined., Objective: To test whether severity and mortality from COVID-19 among patients with cancer have improved during the course of the pandemic., Design, Setting, and Participants: OnCovid is a European registry that collects data on consecutive patients with solid or hematologic cancer and COVID-19. This multicenter case series study included real-world data from 35 institutions across 6 countries (UK, Italy, Spain, France, Belgium, and Germany). This update included patients diagnosed between February 27, 2020, and February, 14, 2021. Inclusion criteria were confirmed diagnosis of SARS-CoV-2 infection and a history of solid or hematologic cancer., Exposures: SARS-CoV-2 infection., Main Outcomes and Measures: Deaths were differentiated at 14 days and 3 months as the 2 landmark end points. Patient characteristics and outcomes were compared by stratifying patients across 5 phases (February to March 2020, April to June 2020, July to September 2020, October to December 2020, and January to February 2021) and across 2 major outbreaks (February to June 2020 and July 2020 to February 2021)., Results: At data cutoff, 2795 consecutive patients were included, with 2634 patients eligible for analysis (median [IQR] age, 68 [18-77] years ; 52.8% men). Eligible patients demonstrated significant time-dependent improvement in 14-day case-fatality rate (CFR) with estimates of 29.8% (95% CI, 0.26-0.33) for February to March 2020; 20.3% (95% CI, 0.17-0.23) for April to June 2020; 12.5% (95% CI, 0.06-22.90) for July to September 2020; 17.2% (95% CI, 0.15-0.21) for October to December 2020; and 14.5% (95% CI, 0.09-0.21) for January to February 2021 (all P < .001) across the predefined phases. Compared with the second major outbreak, patients diagnosed in the first outbreak were more likely to be 65 years or older (974 of 1626 [60.3%] vs 564 of 1008 [56.1%]; P = .03), have at least 2 comorbidities (793 of 1626 [48.8%] vs 427 of 1008 [42.4%]; P = .001), and have advanced tumors (708 of 1626 [46.4%] vs 536 of 1008 [56.1%]; P < .001). Complications of COVID-19 were more likely to be seen (738 of 1626 [45.4%] vs 342 of 1008 [33.9%]; P < .001) and require hospitalization (969 of 1626 [59.8%] vs 418 of 1008 [42.1%]; P < .001) and anti-COVID-19 therapy (1004 of 1626 [61.7%] vs 501 of 1008 [49.7%]; P < .001) during the first major outbreak. The 14-day CFRs for the first and second major outbreaks were 25.6% (95% CI, 0.23-0.28) vs 16.2% (95% CI, 0.13-0.19; P < .001), respectively. After adjusting for country, sex, age, comorbidities, tumor stage and status, anti-COVID-19 and anticancer therapy, and COVID-19 complications, patients diagnosed in the first outbreak had an increased risk of death at 14 days (hazard ratio [HR], 1.85; 95% CI, 1.47-2.32) and 3 months (HR, 1.28; 95% CI, 1.08-1.51) compared with those diagnosed in the second outbreak., Conclusions and Relevance: The findings of this registry-based study suggest that mortality in patients with cancer diagnosed with COVID-19 has improved in Europe; this improvement may be associated with earlier diagnosis, improved management, and dynamic changes in community transmission over time.

The treatment of cutaneous and subcutaneous localizations from breast cancer (BC) is still a therapeutic challenge. Electrochemotherapy (ECT) is one of the available options, and it is characterized by the association between the administration of a chemotherapic agent (Bleomycin) with the temporary raise of permeability of the cellular membrane induced by the local administration of electrical impulses (electroporation). ECT represents an effective therapy for loco-regional control of this disease. This study aimed to investigate the predictive factors of response in cutaneous and subcutaneous localizations from breast cancer treated with ECT. We decided to evaluate the response to this treatment in 55 patients who underwent ECT between January 2013 and March 2020 at our Institute. We performed a monocentric retrospective cohort study. ECT was administered following the ESOPE (European Standard Operative Procedure of Electrochemotherapy) guidelines, a set of criteria updated in 2018 by a panel of European experts on ECT who defined the indications for selecting the patients who can benefit from the ECT treatment and the ones for technically performing the procedure. The responses were evaluated with the RECIST criteria (Response Evaluation Criteria in Solid Tumor). We found after 12 weeks of treatment a complete response (CR) in 64% of our patients. From the analysis divided for subgroups of covariates is emerged that lower BMI, reduced body surface, and absence of previous radiation treatment could be predictive for a better complete response. This study suggests that the efficacy of the ECT treatment is related to the concurrent systemic therapies while administering ECT. The association between ECT and immunotherapy has offered better results than the association between ECT and chemotherapy (p-value = 0.0463). So, ECT is a valuable tool in the treatment of cutaneous and subcutaneous metastases from breast cancer and its efficacy in local control of these lesions improves when it is well planned in a therapeutic scenario., Competing Interests: Author FT was employed by company IGEA S.p.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Russano, Del Fiore, Di Prata, Pasqual, Marconato, Campana, Spina, Gianesini, Collodetto, Tropea, Dall’Olmo, Carraro, Parisi, Galuppo, Scarzello, De Terlizzi, Rastrelli and Mocellin.)

Background: Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin. The incidence of the disease has undergone a significant increase in recent years, which is caused by an increase in the average age of the population and in the use of immunosuppressive therapies. MCC is an aggressive pathology, which metastasizes early to the lymph nodes. These characteristics impose an accurate diagnostic analysis of the regional lymph node district with radiography, clinical examination and sentinel node biopsy. In recent years, there has been a breakthrough in the treatment of the advanced pathology thanks to the introduction of monoclonal antibodies acting on the PD-1/PD-L1 axis. This study aimed to describe the clinico-pathological characteristics, treatment strategies and prognostic factors of MCC., Methods: A retrospective cohort study was conducted involving 143 consecutive patients who were diagnosed and/or treated for MCC. These patients were referred to the Veneto Institute of Oncology IOV-IRCCS and to the University Hospital of Padua (a third-level center) in the period between December 1991 and January 2020. In the majority of cases, diagnosis took place at the IOV. However, some patients were diagnosed elsewhere and subsequently referred to the IOV for a review of the diagnosis or to begin specific therapeutic regimens., Results: 143 patients, with an average age of 71 years, were affected mainly with autoimmune and neoplastic comorbidities. Our analysis has shown that age, autoimmune comorbidities and the use of therapy with immunomodulating drugs (which include corticosteroids, statins and beta-blockers) are associated with a negative prognosis. In this sense, male sex is also a negative prognostic factor., Conclusions: Autoimmune and neoplastic comorbidities were frequent in the studied population. The use of drugs with immunomodulatory effects was also found to be a common feature of the population under examination. The use of this type of medication is considered a negative prognostic factor. The relevance of a multidisciplinary approach to the patient with MCC is confirmed, with the aim of assessing the risks and benefits related to the use of immunomodulating therapy in the individual patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Rastrelli, Del Fiore, Russo, Tartaglia, Dal Monico, Cappellesso, Nicolè, Piccin, Fabozzi, Biffoli, Di Prata, Ferrazzi, Dall’Olmo, Vecchiato, Spina, Russano, Bezzon, Cingarlini, Mazzarotto, Parisi, Scarzello, Pigozzo, Brambullo, Tropea, Vindigni, Bassetto, Bertin, Gregianin, Dei Tos, Cavallin, Alaibac, Chiarion-Sileni and Mocellin.)

Background: The medium-term and long-term impact of COVID-19 in patients with cancer is not yet known. In this study, we aimed to describe the prevalence of COVID-19 sequelae and their impact on the survival of patients with cancer. We also aimed to describe patterns of resumption and modifications of systemic anti-cancer therapy following recovery from SARS-CoV-2 infection., Methods: OnCovid is an active European registry study enrolling consecutive patients aged 18 years or older with a history of solid or haematological malignancy and who had a diagnosis of RT-PCR confirmed SARS-CoV-2 infection. For this retrospective study, patients were enrolled from 35 institutions across Belgium, France, Germany, Italy, Spain, and the UK. Patients who were diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, and entered into the registry at the point of data lock (March 1, 2021), were eligible for analysis. The present analysis was focused on COVID-19 survivors who underwent clinical reassessment at each participating institution. We documented prevalence of COVID-19 sequelae and described factors associated with their development and their association with post-COVID-19 survival, which was defined as the interval from post-COVID-19 reassessment to the patients' death or last follow-up. We also evaluated resumption of systemic anti-cancer therapy in patients treated within 4 weeks of COVID-19 diagnosis. The OnCovid study is registered in ClinicalTrials.gov, NCT04393974., Findings: 2795 patients diagnosed with SARS-CoV-2 infection between Feb 27, 2020, and Feb 14, 2021, were entered into the study by the time of the data lock on March 1, 2021. After the exclusion of ineligible patients, the final study population consisted of 2634 patients. 1557 COVID-19 survivors underwent a formal clinical reassessment after a median of 22·1 months (IQR 8·4-57·8) from cancer diagnosis and 44 days (28-329) from COVID-19 diagnosis. 234 (15·0%) patients reported COVID-19 sequelae, including respiratory symptoms (116 [49·6%]) and residual fatigue (96 [41·0%]). Sequelae were more common in men (vs women; p=0·041), patients aged 65 years or older (vs other age groups; p=0·048), patients with two or more comorbidities (vs one or none; p=0·0006), and patients with a history of smoking (vs no smoking history; p=0·0004). Sequelae were associated with hospitalisation for COVID-19 (p<0·0001), complicated COVID-19 (p<0·0001), and COVID-19 therapy (p=0·0002). With a median post-COVID-19 follow-up of 128 days (95% CI 113-148), COVID-19 sequelae were associated with an increased risk of death (hazard ratio [HR] 1·80 [95% CI 1·18-2·75]) after adjusting for time to post-COVID-19 reassessment, sex, age, comorbidity burden, tumour characteristics, anticancer therapy, and COVID-19 severity. Among 466 patients on systemic anti-cancer therapy, 70 (15·0%) permanently discontinued therapy, and 178 (38·2%) resumed treatment with a dose or regimen adjustment. Permanent treatment discontinuations were independently associated with an increased risk of death (HR 3·53 [95% CI 1·45-8·59]), but dose or regimen adjustments were not (0·84 [0·35-2·02])., Interpretation: Sequelae post-COVID-19 affect up to 15% of patients with cancer and adversely affect survival and oncological outcomes after recovery. Adjustments to systemic anti-cancer therapy can be safely pursued in treatment-eligible patients., Funding: National Institute for Health Research Imperial Biomedical Research Centre and the Cancer Treatment and Research Trust., Competing Interests: Declaration of interests DJP reports lecture fees from ViiV Healthcare, Bayer Healthcare, Bristol Myers Squibb, Roche, Eisai, and Falk Foundation; travel expenses from Bristol Myers Squibb and Bayer Healthcare; consulting fees from Mina Therapeutics, Eisai, Roche, DaVolterra, and Astra Zeneca; and research funding (to institution) from Merck Sharp and Dohme and Bristol Myers Squibb, outside of the submitted work. MLa acted as consultant for Roche, Novartis, Lilly, and AstraZeneca, outside of the submitted work, and received speaker honoraria from Roche, Novartis, Lilly, Pfizer, Takeda, and Sandoz, outside of the submitted work. EF reports research funding to institution from Pfizer, outside of the submitted work, and travel expenses from Lilly, Novartis, Pfizer, and Esai, outside of the submitted work. TN-D reports consulting fees from Amgen, Bayer, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck Sharp and Dohme, Novartis, Otsuka, Pfizer, Roche, and Takeda, outside of the submitted work; speakers fees from AstraZeneca, Merck Sharp and Dohme, Roche, and Takeda, outside of the submitted work; and travel, accommodation, and expenses from AstraZenca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck Sharp and Dohme, Otsuka, Roche, and Takeda, outside of the submitted work. JB reports consulting fees for Merck Sharp and Dohme and Astra Zeneca, outside of the submitted work. APr reports personal honoraria from Pfizer, Roche, Merck Sharp and Dohme Oncology, Eli Lilly, and Daiichi Sankyo, outside of the submitted work; travel, accommodations, and expenses by Daiichi Sankyo, outside of the submitted work; research funding (to institution) from Roche and Novartis, outside of the submitted work; and consulting fees from NanoString Technologies, Amgen, Roche, Novartis, Pfizer, and Bristol-Myers Squibb, outside of the submitted work. APar reports consulting fees from Takeda and Novartis, outside of the submitted work. MT reports travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, and Takeda, outside of the submitted work; and honoraria as a medical writer from Novartis and Amgen, outside the submitted work. AG reports consulting fees from Roche, Merck Sharp and Dohme, Eli Lilly, Pierre Fabre, Eisai, and Daichii Sankyo, outside the submitted work; speakers bureau for Eisai, Novartis, Eli Lilly, Roche, Teva, Gentili, Pfizer, AstraZeneca, Celgene, and Daichii Sankyo, outside the submitted work; research funds (to institution) from Eisai, Eli Lilly, and Roche, outside the submitted work; support for attending meetings or travel from Bristol-Myers Squibb, Merck Sharp and Dohme, Novartis, and Roche, outside the submitted work; and personal research funding from Associazione Italiana per la Ricerca sul Cancro Foundation UPO aging project, outside the submitted work. GG reports personal research funding outside of the submitted work from Associazione Italiana per la Ricerca sul Cancro Foundation, outside the submitted work; consulting fees from Janssen, Abbvie, AstraZeneca, and BeiGene, outside the submitted work; and speaker fees from Janssen and Abbvie, outside the submitted work. LR reports consulting fees from Servier, Amgen, ArQule, AstraZeneca, Basilea, Bayer, Bristol Myers Squibb, Celgene, Eisai, Exelixis, Genenta, Hengrui, Incyte, Ipsen, IQVIA, Lilly, Merck Sharp and Dohme, Nerviano Medical Sciences, Roche, Sanofi, and Zymeworks, outside the submitted work; lecture fees from AbbVie, Amgen, Bayer, Eisai, Gilead, Incyte, Ipsen, Lilly, Merck Serono, Roche, and Sanofi, outside the submitted work; travel expenses from Ipsen, outside the submitted work; and institutional research funding (to institution) from Agios, ARMO BioSciences, AstraZeneca, BeiGene, Eisai, Exelixis, Fibrogen, Incyte, Ipsen, Lilly, Merck Sharp and Dohme, Nerviano Medical Sciences, Roche, and Zymeworks, outside the submitted work. JT reports having a scientific consultancy role for Array Biopharma, AstraZeneca, Avvinity, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma, Ikena Oncology, IQVIA, Lilly, Menarini, Merck Serono, Merus, Merck Sharp and Dohme, Mirati, Neophore, Novartis, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Seattle Genetics, Servier, Taiho, Tessa Therapeutics, and TheraMyc, outside of the submitted work; educational collaboration with Imedex, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource, outside of the submitted work; and institutional financial interest in form of financial support for clinical trials or contracted research for Amgen, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX, Hutchison MediPharma International, Janssen-Cilag, MedImmune, Menarini, Merck Healt, Merck Sharp and Dohme, Merus, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, Taiho, Spanish Association Against Cancer Scientific Foundation, and Cancer Research UK, outside the submitted work. ACo reports consulting fees from Merck Sharp and Dohme, Bristol Myers Squibb, AstraZeneca, and Roche, outside the submitted work; and speaker fees from AstraZeneca, Merck Sharp and Dohme, Novartis, and Astellas, outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Doublets plus antiepidermal growth factor receptors monoclonal antibodies (EGFRi) are widely considered the preferable first-line regimen in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC), resulting superior in terms of activity and efficacy compared to doublets plus bevacizumab. However, data comparing doublet plus EGFRi and triplet plus bevacizumab are lacking, and the relative benefit of an intensive regimen plus an antiangiogenic backbone in this population is debated., Methods: This multicenter, retrospective study aimed at evaluating clinicians' attitude to triplet-bevacizumab and doublet-EGFRi as first-line regimen in patients with left-sided RAS/BRAF wild-type mCRC treated in clinical practice at 22 Oncology Units from March 2012 to October 2020. A random case-control matching was performed to compare activity (ORR), and effectiveness (PFS, OS, secondary resection rate of metastases with curative intent) between triplet-bevacizumab and doublet-EGFRi, on the basis of ECOG-PS, age, gender, and burden of disease., Results: A total of 718 patients were consecutively treated with doublet-EGFRi (686, 95.5%) or triplet-bevacizumab (32, 4.5%). After case-control matching, median PFS was 13.6 (95% CI, 8.9-31.7) and 16.1 (95% CI, 12.1-36.8) months (P= .621), while median OS was 30.2 (95% CI, 14.4-69.5) and 38.1 (95% CI, 33.1-101.1) months (P= .0283) in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. The ORR was 65.6% and 90.6% (P= .016), while the secondary resection rate was 18.8% and 46.9% (P= .016), in the doublet-EGFRi and the triplet-bevacizumab cohort, respectively. Triplet-bevacizumab was associated with a higher incidence of G3/G4 neutropenia (25.0% vs. 12.5%, P= .041)., Conclusion: Although a doublet-EGFRi remains the recommended upfront regimen in patients with left-sided RAS and BRAF wild-type mCRC, our real life data suggest a triplet-bevacizumab might be at least equally active and effective in properly selected cases., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Few data regarding post-induction management following first-line anti-epidermal growth factor receptor (EGFR)-based doublet regimens in patients with left-sided RAS/BRAF wild-type metastatic colorectal cancer (mCRC) are available., Methods: This multicenter, retrospective study aimed at evaluating clinicians' attitude, and the safety and effectiveness of post-induction strategies in consecutive patients affected by left-sided RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR as first-line regimen, who did not experience disease progression within 6 months from induction initiation, at 21 Italian and 1 Spanish Institutions. The measured clinical outcomes were: progression-free survival (PFS), overall survival (OS), adverse events, and objective response rate (ORR)., Results: At the data cutoff, among 686 consecutive patients with left-sided RAS/BRAF wild-type mCRC treated with doublet plus anti-EGFR as first-line regimen from March 2012 to October 2020, 355 eligible patients have been included in the present analysis. Among these, 118 (33.2%), 66 (18.6%), and 11 (3.1%) received a maintenance with 5-fluorouracil/leucovorin (5FU/LV)+anti-EGFR, anti-EGFR, and 5FU/LV, respectively, while 160 (45.1%) patients continued induction treatment (non-maintenance) until disease progression, unacceptable toxicity, patient decision, or completion of planned treatment. The median period of follow-up for the overall population was 33.7 months (95%CI = 28.9-35.6). The median PFS values of the 5FU/LV+anti-EGFR, anti-EGFR, 5FU/LV, and non-maintenance cohorts were 16.0 (95%CI = 14.3-17.7, 86 events), 13.0 (95%CI = 11.4-14.5, 56 events), 14.0 (95%CI = 8.1-20.0, 8 events), and 10.1 months (95%CI = 9.0-11.2, 136 events), respectively ( p < 0.001). The median OS values were 39.6 (95%CI = 31.5-47.7, 43 events), 36.1 (95%CI = 31.6-40.7, 36 events), 39.5 (95%CI = 28.2-50.8, 4 events), and 25.1 months (95%CI = 22.6-27.6, 99 events), respectively ( p < 0.001). After adjusting for key covariates, a statistically significant improvement in PFS in favor of 5FU/LV+anti-EGFR (HR = 0.59, 95%CI = 0.44-0.77, p < 0.001) and anti-EGFR (HR = 0.71, 95%CI = 0.51-0.98, p = 0.039) compared to the non-maintenance cohort was found. Compared to the non-maintenance cohort, OS was improved by 5FU/LV+anti-EGFR (HR = 0.55, 95%CI = 0.38-0.81, p = 0.002) and, with marginal significance, by anti-EGFR (HR = 0.67, 95%CI = 0.51-0.98, p = 0.051). No difference was found in ORR. Any grade non-hematological and hematological events were generally higher in the non-maintenance compared to the maintenance cohorts., Conclusion: Among the treatment strategies following an anti-EGFR-based doublet first-line induction regimen in patients affected by left-sided RAS/BRAF wild-type mCRC treated in a "real-life" setting, 5FU/LV+anti-EGFR resulted the most adopted, effective, and relatively safe regimen., Competing Interests: AlP reported receiving advisory board fees from GSK. AC reported receiving consulting/advisory board fees from AstraZeneca, MSD, Roche, and BMS and speakers’ fee from Novartis, Astellas, MSD, and AstraZeneca. AnP reported receiving fees from Eli-Lilly, MSD, and Servier. RG reported receiving fees from Amgen and Servier and advisory board fees from Amgen, Servier, Bayer, and Merck-Serono. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Parisi, Cortellini, Venditti, Filippi, Salvatore, Tortora, Ghidini, Nigro, Gelsomino, Zurlo, Fulgenzi, Lombardi, Roselló Keränen, Depetris, Giampieri, Morelli, Di Marino, Di Pietro, Zanaletti, Vitale, Garajova, Spinelli, Zoratto, Roberto, Petrillo, Aimar, Patruno, D’Orazio, Ficorella, Ferri and Porzio.)

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

Background: Melanoma of unknown primary (MUP), accounts for up to 3% of all melanomas and consists of a histologically confirmed melanoma metastasis to either lymph nodes, (sub)cutaneous tissue, or visceral sites without any evidence of a primary cutaneous, ocular, or mucosal melanoma. This study aimed to investigate the characteristics, treatment strategies, and prognostic factors of MUP patients, in order to shed some light on the clinical behavior of this malignancy., Methods: All the consecutive patients with a diagnosis of MUP referring to our institutions between 1985 and 2018 were considered in this retrospective cohort study. The records of 173 patients with a suspected diagnosis of MUP were retrospectively evaluated for inclusion in the study. Patient selection was performed according to the Das Gupta criteria, and a total of 127 MUP patients were finally included in the study, representing 2.7% of the patients diagnosed with melanoma skin cancer at our institutions during the same study period. A second cohort of all consecutive 417 MKP patients with AJCC stages IIIB-IV, referring tions in the period considered (1985-2018), was included in the study to compare survival between MUP and MKP patients. All the diagnoses were based on histopathologic, cytologic and immunohistochemical examination of the metastases. All tumors were re-staged according to the 2018 American Joint Committee on Cancer (AJCC) 8 th Edition., Results: Median follow-up was 32 months (IQR: 15-84). 3-year progression-free survival (PFS) was 54%, while 3-year overall survival (OS) was 62%. Worse OS and PFS were associated with older age (P = 0.0001 for OS; P = 0.008 for PFS), stage IV (P < 0.0001 for OS; P = 0.0001 for PFS) and higher Charlson Comorbidity Index (P < 0.0001 for OS and P = 0.01 for PFS). Patients with lymph node disease showed longer PFS (P = 0.001) and OS (P = 0.0008) than those with (sub)cutis disease. Complete lymph node dissection (CLND) was the most common surgical treatment; a worse OS in these patients was associated with the number of positive lymph nodes (P = 0.01), without significant association with the number of retrieved lymph nodes (P = 0.79). Survival rates were lower in patients undergoing chemotherapy (CT) and target therapy (TT), and higher in those receiving immunotherapy (IT). 417 patients with AJCC stages IIIB-IV of Melanoma Known Primary (MKP) were included for the survival comparison with MUP. 3-year PFS rates were 54 and 58% in MUP and MKP, respectively (P = 0.30); 3-year OS rates were 62 and 70% in MUP and MKP, respectively (P = 0.40)., Conclusions: The most common clinical scenario of our series was a male patient around 59 years with lymph node disease. We report that CLND associated with IT was the best treatment in terms of survival outcome. In the current era of IT and TT for melanoma, new studies have to clarify the impact of novel drugs on MUP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Del Fiore, Rastrelli, Dall’Olmo, Cavallin, Cappellesso, Vecchiato, Buja, Spina, Parisi, Mazzarotto, Ferrazzi, Grego, Rotondi, Benna, Tropea, Russano, Filoni, Bassetto, Tos, Alaibac, Rossi, Pigozzo, Sileni and Mocellin.)

Despite the paradigmatic shift occurred in recent years for defined molecular subtypes in the metastatic setting treatment, colorectal cancer (CRC) still remains an incurable disease in most of the cases. Therefore, there is an urgent need for new tools and biomarkers for both early tumor diagnosis and to improve personalized treatment. Thus, liquid biopsy has emerged as a minimally invasive tool that is capable of detecting genomic alterations from primary or metastatic tumors, allowing the prognostic stratification of patients, the detection of the minimal residual disease after surgical or systemic treatments, the monitoring of therapeutic response, and the development of resistance, establishing an opportunity for early intervention before imaging detection or worsening of clinical symptoms. On the other hand, preclinical and clinical evidence demonstrated the role of gut microbiota dysbiosis in promoting inflammatory responses and cancer initiation. Altered gut microbiota is associated with resistance to chemo drugs and immune checkpoint inhibitors, whereas the use of microbe-targeted therapies including antibiotics, pre-probiotics, and fecal microbiota transplantation can restore response to anticancer drugs, promote immune response, and therefore support current treatment strategies in CRC. In this review, we aim to summarize preclinical and clinical evidence for the utilization of liquid biopsy and gut microbiota in CRC.

Background: Despite the increase in chances of cure for early breast cancer (EBC) patients, approximately 20-45% of them will experience a disease recurrence, particularly bone metastases in 60-80% of cases, which occur more frequently in luminal subtypes. Endocrine therapy (ET) has always been the milestone of adjuvant treatment for hormone receptor-positive EBC patients, leading to indubitable reduction of disease recurrence risk. However, adjuvant aromatase inhibitors (AIs) therapy may promote a progressive decrease in bone mineral density (BMD), which can lead to osteoporosis. The increased bone resorption associated with osteoporosis may provide fertile soil for cancer growth and accelerate the development of bone metastases., Patients and Methods: In this single-institution cohort study, we performed a retrospective analysis of "luminal-like" EBC patients who experienced bone recurrence after a subsequent disease free interval. The aim of the study was to evaluate the median time to skeletal recurrence (TSkR)., Results: 143 patients experienced bone recurrence. Median TSkR was 54 months (95%CI: 45-65). Among patients who received adjuvant AIs median TSkR was 35 months (95%CI: 25-54), while among patients who did not was 61 months (95%CI: 50-80) (HR = 1.45 [95%CI: 0.97-2.17], p = 0.0644). After adjusting for TNM stage (AJCC 8th edition), adjuvant AIs treatment was significantly related to a shorter TSkR (HR = 1.60 [95%CI: 1.06-2.42], p = 0.0244). Adjuvant Tamoxifen, adjuvant AIs/Tamoxifen and no-treatment did not revealed to be associated to TSkR., Conclusions: In this cohort of EBC patients with bone recurrence, AIs treatment seems to be related to a shorter TSkR. AIs-induced bone resorption might represent the underlying mechanism.