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Daniel Boakye1,2, Viola Walter1, Uwe M Martens3, Jenny Chang-Claude4, Michael Hoffmeister1, Lina Jansen1,*, Hermann Brenner1,5,6,* 1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; 2Medical Faculty Heidelberg, Heidelberg University, Heidelberg, Germany; 3SLK-Clinics, Cancer Center Heilbronn-Franken, Heilbronn, Germany; 4Unit of Genetic Epidemiology, Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; 5Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; 6German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany*These authors contributed equally to this workCorrespondence: Hermann BrennerDivision of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 581, Heidelberg 69120, GermanyTel +49 622 142 1300Fax +49 622 142 1302Email h.brenner@dkfz.deIntroduction: Propensity score methods are increasingly used to address confounding related to treatment selection in observational studies. Studies estimating the effect of chemotherapy in colon cancer (CC) patients, however, often lacked information on pertinent comorbidities and functional status (FS). We assessed to what extent comorbidities and FS impact treatment decisions in colorectal cancer patients and explain the benefit of chemotherapy in stage III CC patients.Methods: Stage II-III colorectal cancer patients diagnosed in 2003–2014 and recruited into a population-based study were included (N=1102). Associations of comorbidity and FS with treatment patterns were examined with multivariable logistic regression. The contribution of lower comorbidity and higher FS to the benefit of chemotherapy was estimated with propensity score weighted Cox models in 430 stage III CC patients who were followed over a median time of 4.7 years.Results: In stage II (high-risk) and III CC patients, Charlson comorbidity scores 1, 2 and 3+ were associated with 57%, 66% and 70% lower odds of chemotherapy use, respectively. In combination with older age and poor FS, comorbidity was associated with 97% and 83% decreased odds of adjuvant chemotherapy use in CC and rectal cancer patients, respectively. In stage III CC patients, lower comorbidity and higher FS explained 38% and 24% of the overall and disease-specific survival benefits of chemotherapy, respectively. Selection bias was observed even in the comprehensive models, as chemotherapy was still associated with substantially higher non-disease-specific survival (hazard ratio (HR): 0.66; 95% confidence interval (CI): 0.46–0.92), especially in patients

Background: Patients with gastro-oesophageal adenocarcinoma with tumour-positive lymph nodes (ypN+) or positive surgical margins (R1) following neoadjuvant chemotherapy and resection are at high risk of recurrence. Adjuvant nivolumab is effective in oesophageal/oesophagogastric junction cancer and residual pathological disease following chemoradiation and surgery. Immune checkpoint inhibition has shown efficacy in advanced gastro-oesophageal cancer. We hypothesised that nivolumab/ipilimumab would be more effective than adjuvant chemotherapy in high-risk (ypN+ and/or R1) patients with gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and resection., Patients and Methods: VESTIGE was an academic international, multicentre, open-label, randomised phase II trial evaluating the efficacy of adjuvant nivolumab/ipilimumab versus chemotherapy in gastro-oesophageal adenocarcinoma at high risk of recurrence. Patients were randomised 1 : 1 to receive standard adjuvant chemotherapy (same regimen as neoadjuvant) or nivolumab 3 mg/kg intravenously (i.v.) every 2 weeks plus ipilimumab 1 mg/kg i.v. every 6 weeks for 1 year. Key inclusion criteria included ypN+ and/or R1 status after neoadjuvant chemotherapy plus surgery. The primary endpoint was disease-free survival in the intent-to-treat population. Secondary endpoints included overall survival, locoregional and distant failure rates, and safety according to National Cancer Institute Common Terminology Criteria for Adverse Events v5.0., Results: The independent Data Monitoring Committee reviewed data from 189 of the planned 240 patients in June 2022 and recommended stopping recruitment due to futility. At the time of final analysis, median follow-up was 25.3 months for 195 patients (98 nivolumab/ipilimumab and 97 chemotherapy). Median disease-free survival for the nivolumab/ipilimumab group was 11.4 months [95% confidence interval (CI) 8.4-16.8 months] versus 20.8 months (95% CI 15.0-29.9 months) for the chemotherapy group, hazard ratio 1.55 (95% CI 1.07-2.25, one-sided P = 0.99). The 12-month disease-free survival rates were 47.1% and 64.0%, respectively. There were no toxicity concerns or excess early discontinuations., Conclusion: Nivolumab/ipilimumab did not improve disease-free survival compared with chemotherapy in patients with ypN+ and/or R1 gastro-oesophageal adenocarcinoma following neoadjuvant chemotherapy and surgery., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Advanced cancer treatments increase survival rates and with that the importance of Quality of Life (QoL). QoL is well studied in trials, but the transition to standard care is little. For this reason, we identified the challenges for a regular integration to conceptualize an applicable solution together with patients and health professionals (HP). We conducted two meetings based on the design thinking method. Two Physicians, one employee of cancer counseling centers, one psycho-oncologists, and five patients were included. Based on the discussions a system was conceptualized to solve current thresholds. All participants had experience with the documentation of QoL, but none had shared it digitally from home. Therefore, the main threshold was the lack of system for data transition between agents, followed by lack of time for HP and acceptance of QoL for patients. HP were mainly interested in data on the trend of QoL whereas patients preferred information on their activity, energy level and social contacts. The conceptualized solution is based on a health app on the patients' side with a browser-based implementation for HP. Within the system, automatized data interpretation, alarm systems, support information, standardized input fields as an orientation for documentation with expandable options for specific restrictions as well as interinstitutional networking for HP to better refer patients to others was wished for. This article describes the concept of such a system developed with HP and patients. Implementation and transfer to clinical care has yet to be done.

Current treatment outcome of patients with glioblastoma (GBM) remains poor. Following standard therapy, recurrence is universal with limited survival. Tumors from 173 GBM patients are analysed for somatic mutations to generate a personalized peptide vaccine targeting tumor-specific neoantigens. All patients were treated within the scope of an individual healing attempt. Among all vaccinated patients, including 70 treated prior to progression (primary) and 103 treated after progression (recurrent), the median overall survival from first diagnosis is 31.9 months (95% CI: 25.0-36.5). Adverse events are infrequent and are predominantly grade 1 or 2. A vaccine-induced immune response to at least one of the vaccinated peptides is detected in blood samples of 87 of 97 (90%) monitored patients. Vaccine-specific T-cell responses are durable in most patients. Significantly prolonged survival is observed for patients with multiple vaccine-induced T-cell responses (53 months) compared to those with no/low induced responses (27 months; P = 0.03). Altogether, our results highlight that the application of personalized neoantigen-targeting peptide vaccine is feasible and represents a promising potential treatment option for GBM patients., (© 2024. The Author(s).)

Background: The aim of this trial was to investigate the addition of the anti-SLAMF7 monoclonal antibody elotuzumab to lenalidomide, bortezomib, and dexamethasone (RVd) in induction and consolidation therapy as well as to lenalidomide maintenance treatment in transplant-eligible patients with newly diagnosed multiple myeloma., Methods: GMMG-HD6 was a phase 3, randomised trial conducted at 43 main trial sites and 26 associated trial sites throughout Germany. Adult patients (aged 18-70 years) with previously untreated, symptomatic multiple myeloma, and a WHO performance status of 0-3, with 3 being allowed only if caused by myeloma disease and not by comorbid conditions, were randomly assigned 1:1:1:1 to four treatment groups. Induction therapy consisted of four 21-day cycles of RVd (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m 2 subcutaneously on days 1, 4, 8, and 11]; and dexamethasone 20 mg orally on days 1, 2, 4, 5, 8, 9, 11, 12, and 15 for cycles 1-2) or, RVd induction plus elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1-2, and on days 1 and 11 for cycles 3-4; E-RVd). Autologous haematopoietic stem-cell transplantation was followed by two 21-day cycles of either RVd consolidation (lenalidomide 25 mg orally on days 1-14; bortezomib 1·3 mg/m 2 subcutaneously on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 2, 8, 9, 15, and 16) or elotuzumab plus RVd consolidation (with elotuzumab 10 mg/kg intravenously on days 1, 8, and 15) followed by maintenance with either lenalidomide (10 mg orally on days 1-28 for cycles 1-3; thereafter, up to 15 mg orally on days 1-28; RVd/R or E-RVd/R group) or lenalidomide plus elotuzumab (10 mg/kg intravenously on days 1 and 15 for cycles 1-6, and on day 1 for cycles 7-26; RVd/E-R or E-RVd/E-R group) for 2 years. The primary endpoint was progression-free survival analysed in a modified intention-to-treat (ITT) population. Safety was analysed in all patients who received at least one dose of trial medication. This trial is registered with ClinicalTrials.gov, NCT02495922, and is completed., Findings: Between June 29, 2015, and on Sept 11, 2017, 564 patients were included in the trial. The modified ITT population comprised 559 (243 [43%] females and 316 [57%] males) patients and the safety population 555 patients. After a median follow-up of 49·8 months (IQR 43·7-55·5), there was no difference in progression-free survival between the four treatment groups (adjusted log-rank p value, p=0·86), and 3-year progression-free survival rates were 69% (95% CI 61-77), 69% (61-76), 66% (58-74), and 67% (59-75) for patients treated with RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R, respectively. Infections (grade 3 or worse) were the most frequently observed adverse event in all treatment groups (28 [20%] of 137 for RVd/R; 32 [23%] of 138 for RVd/E-R; 35 [25%] of 138 for E-RVd/R; and 48 [34%] of 142 for E-RVd/E-R). Serious adverse events (grade 3 or worse) were observed in 68 (48%) of 142 participants in the E-RVd/E-R group, 53 (39%) of 137 in the RVd/R, 53 (38%) of 138 in the RVd/E-R, and 50 (36%) of 138 in the E-RVd/R (36%) group. There were nine treatment-related deaths during the study. Two deaths (one sepsis and one toxic colitis) in the RVd/R group were considered lenalidomide-related. One death in the RVd/E-R group due to meningoencephalitis was considered lenalidomide and elotuzumab-related. Four deaths (one pulmonary embolism, one septic shock, one atypical pneumonia, and one cardiovascular failure) in the E-RVd/R group and two deaths (one sepsis and one pneumonia and pulmonary fibrosis) in the E-RVd/E-R group were considered related to lenalidomide or elotuzumab, or both., Interpretation: Addition of elotuzumab to RVd induction or consolidation and lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma did not provide clinical benefit. Elotuzumab-containing therapies might be reserved for patients with relapsed or refractory multiple myeloma., Funding: Bristol Myers Squibb/Celgene and Chugai., Competing Interests: Declaration of interests EKM reports consulting or advisory role with Bristol Myers Squibb (BMS)/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi Aventis, Stemline, and Takeda; honoraria from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi Aventis, Stemline, and Takeda; research funding from Sanofi Aventis; and travel accommodation and expenses from BMS/Celgene, GlaxoSmithKline, Janssen-Cilag, Sanofi Aventis, Stemline, and Takeda. HG reports support for the present manuscript from BMS/Celgene, Chugai, and HD6 funding; consulting or advisory role with Amgen, BMS, Janssen, Sanofi, and Adaptive Biotechnology; honoraria from Amgen, BMS, Chugai, GlaxoSmithKline, Janssen, Novartis, Sanofi, and Pfizer; research funding from Amgen, BMS, Celgene, GlycoMimetics, GlaxoSmithKline, Heidelberg Pharma, Hoffmann-La Roche, Karyopharm, Janssen, Incyte Corporation, Millenium Pharmaceuticals, Molecular Partners, Merck Sharp and Dohme, MorphoSys, Pfizer, Sanofi, Takeda, and Novartis; travel accommodations and expenses from Amgen, BMS, GlaxoSmithKline, Janssen, Novartis, Sanofi, and Pfizer; and grants or provision of Investigational Medicinal Products from Amgen, Array Biopharma/Pfizer, BMS/Celgene, Chugai, Dietmar-Hopp-Foundation, Janssen, Johns Hopkins University, Mundipharma, and Sanofi. MHä reports consulting or advisory role with Novartis, BMS/Celgene, Gilead Sciences, Sanofi/Aventis, Roche, Amgen, SOBI, Janssen, Takeda, GlaxoSmithKline, Jazz Pharmaceuticals, Bayer Vital, and BMS. RF reports Honoraria from Amgen, BMS/Celgene, Janssen, Sanofi, and Takeda; and travel accommodations and expenses from BMS/Celgene, Janssen, and GSK. MM reports consulting or Advisory Role with Janssen, BMS, Abbvie, Sanofi, GlaxoSmithKline, Oncopeptides, Takeda, and Stemline; honoraria from Amgen, BMS, GlaxoSmithKline, Janssen, and Takeda; and travel accommodations and expenses from Amgen. JD reports honoraria from Sanofi, BMS, Janssen, AstraZeneca, Beigene; and travel accommodation and expenses from Amgen, BMS, Beigene, and Amgen. CM reports Consulting or Advisory Role from Celgene, BMS, and Janssen. CS reports consulting or advisory role from BMS, GlaxoSmithKline, Janssen, Pfizer, Roche, and Takeda; honoraria from Amgen, BMS/GlaxoSmithKline, Janssen, MSD, Novartis, Roche, Sanofi, and Takeda; research funding from Janssen, and Takeda; and travel accommodation and expenses from BMS, Janssen, Sanofi Aventis, and Takeda. RS reports consulting or advisory role with BMS/Celgene, GlaxoSmithKline, Janssen, Kite/Gilead, and Sanofi; and honoraria from Amgen, BMS/Celgene, GlaxoSmithKline, Janssen, Kite/Gilead, Sanofi, and Takeda. IvM reports consulting or advisory role with Sanofi, Amgen, Janssen, Takeda, Stemline, GSK, BMS, Oncopeptides, Pfizer, and AstraZeneca. PR reports honoraria from BMS and travel accommodation and expenses from BMS. UG reports consulting or advisory role with Amgen, Boehringer Ingelheim, BMS, Celtrion, Ipsen, Sanofi, and MSD; and honoraria from Amgen, AstraZeneca, and Novartis. SK reports travel accommodation and expenses from AbbVie. UMM reports consulting or advisory role with Sanofi-Aventis, BMS, Roche, GSK, Novartis, Pierre Fabre, MSD, and Guardant Health; and travel accommodation and expenses from Pierre Fabre, Ipsen, and Janssen. CK reports travel accommodation and expenses from European Hematology Association. KCW reports consulting or advisory role with Abbvie, Amgen, Adaptive Biotech, BMS/Celgene, BeiGene, Janssen, GlaxoSmithKline, Karyopharm, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Takeda, and Menarini; honoraria from Abbvie, Amgen, Adaptive Biotech, Astra Zeneca, BMS/Celgene, BeiGene, Janssen, GlaxoSmithKline, Karyopharm, Novartis, Oncopeptides, Pfizer, Roche Pharma, Sanofi, Stemline, Takeda, and Menarini; and research funding from Abbvie, Amgen, BMS/Celgene, Janssen, GlaxoSmithKline, Sanofi, and Takeda. MSR reports consulting or advisory role with BMS, Amgen, GSK, Janssen, Sanofi, Pfizer, AbbVie, Novartis, and Roche; research funding from Sanofi; travel accommodation and expenses from BMS, AbbVie, Janssen, Sanofi, GSK; Honoraria from BMS, Janssen, GSK, AbbVie, and Sanofi; and receipt of equipment, materials, drugs, medical writing, gifts or other services from Novartis, Sanofi. HJS reports consulting or advisory role with Amgen, AstraZeneca, BMS/Celgene, Genzyme, GSK, Janssen Cilag, Oncopeptides, Pfizer, Sanofi, and Stemline; honoraria from Abbvie, Amgen, AstraZeneca, BMS/Celgene, Genzyme, GSK, Janssen Cilag, Oncopeptides, Pfizer, Roche, Sanofi, Stemline, and Takeda; and travel accommodation and expenses from Amgen, BMS/Celgene, Janssen Cilag, and Sanofi. All other authors declare no competing interests., (Copyright © 2024 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.)

Background: The treatment for cancer can have a negative impact not only on physical well-being but also on mental health and the quality of life (QoL). Health apps enable the monitoring of different parameters, but to date, there are only few that support patients with cancer and none that focuses on the assessment of QoL. Furthermore, patients as stakeholders are often only integrated at the late stage of the development process, if at all., Objective: The aim of this research was to develop and evaluate a smartphone app (Lion-App) to enable patients with cancer to autonomously measure the QoL with an iterative, user-centered approach., Methods: Patients with cancer were involved in a 3-stage process from conceptualization to the point when the app was available on the tester's private device. First, focus groups with members (N=21) of cancer support groups were conducted to understand their expectations and needs. Thereafter, individual tests were performed. After developing a prototype that incorporated findings from the focus groups, a second test cycle was conducted, followed by a beta test lasting 2 months. In our app, the QoL can be assessed via a patient diary and an integrated questionnaire. Through all stages, usability was evaluated using the modular extended version of the User Experience Questionnaire (UEQ+), including the calculation of a key performance indicator (KPI). If possible, the impact of sex on the results was evaluated. As part of the beta test, usage rates as well as age-dependent differences were also assessed., Results: A total of 21 participants took part in the initial 3 focus groups. In the subsequent usability testing (N=18), 17 (94%) participants rated their impression through the UEQ+, with a mean KPI of 2.12 (SD 0.64, range: -3 to 3). In the second usability test (N=14), the mean KPI increased to 2.28 (SD=0.49). In the beta test, the usage rate of 19 participants was evaluated, of whom 14 (74%) also answered the UEQ+ (mean KPI 1.78, SD 0.84). An influence of age on the number of questionnaire responses in Lion-App was observed, with a decrease in responses with increasing age (P=.02). Sex-dependent analyses were only possible for the first usability test and the beta test. The main adjustments based on user feedback were a restructuring of the diary as well as integration of a shorter questionnaire to assess the QoL., Conclusions: The iterative, user-centered approach for development and usability testing resulted in positive evaluations of Lion-App. Our app was rated as suitable for everyday use to monitor the QoL of patients with cancer. Initial results indicated that the sex and age of participants seem to play only a minor role., (©Chantal N L Beutter, Katharina Zeller, Uwe M Martens, Bettina Pfleiderer, Christian Fegeler. Originally published in JMIR Cancer (https://cancer.jmir.org), 26.09.2023.)

Background: Acute myeloid leukaemia with mutated NPM1 is associated with high CD33 expression and intermediate-risk cytogenetics. The aim of this study was to evaluate intensive chemotherapy with or without the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin in participants with newly diagnosed, NPM1-mutated acute myeloid leukaemia., Methods: This open-label, phase 3 trial was conducted at 56 hospitals in Germany and Austria. Eligible participants were 18 years or older and had newly diagnosed NPM1-mutated acute myeloid leukaemia and an Eastern Cooperative Oncology Group performance status of 0-2. Participants were randomly assigned, using age as a stratification factor (18-60 years vs >60 years), 1:1 to the two treatment groups using allocation concealment; there was no masking of participants and investigators to treatment groups. Participants received two cycles of induction therapy (idarubicin, cytarabine, and etoposide) plus all-trans retinoic acid (ATRA) followed by three consolidation cycles of high-dose cytarabine (or an intermediate dose for those older than 60 years) and ATRA, without or with gemtuzumab ozogamicin (3 mg/m 2 administered intravenously on day 1 of induction cycles 1 and 2, and consolidation cycle 1). The primary endpoints were short-term event-free survival and overall survival in the intention-to-treat population (overall survival was added as a co-primary endpoint after amendment four of the protocol on Oct 13, 2013). The secondary endpoints were event-free survival with long-term follow-up, rates of complete remission, complete remission with partial haematological recovery (CRh), and complete remission with incomplete haematological recovery (CRi), cumulative incidences of relapse and death, and number of days in hospital. This trial is registered with ClinicalTrials.gov (NCT00893399) and has been completed., Findings: Between May 12, 2010, and Sept 1, 2017, 600 participants were enrolled, of which 588 (315 women and 273 men) were randomly assigned (296 to the standard group and 292 to the gemtuzumab ozogamicin group). No difference was found in short-term event-free survival (short-term event-free survival at 6-month follow-up, 53% [95% CI 47-59] in the standard group and 58% [53-64] in the gemtuzumab ozogamicin group; hazard ratio [HR] 0·83; 95% CI 0·65-1·04; p=0·10) and overall survival between treatment groups (2-year overall survival, 69% [63-74] in the standard group and 73% [68-78] in the gemtuzumab ozogamicin group; 0·90; 0·70-1·16; p=0·43). There was no difference in complete remission or CRi rates (n=267 [90%] in the standard group vs n=251 [86%] in the gemtuzumab ozogamicin group; odds ratio [OR] 0·67; 95% CI 0·40-1·11; p=0·15) and complete remission or CRh rates (n=214 [72%] vs n=195 [67%]; OR 0·77; 0·54-1·10; p=0·18), whereas the complete remission rate was lower with gemtuzumab ozogamicin (n=172 [58%] vs n=136 [47%]; OR 0·63; 0·45-0·80; p=0·0068). Cumulative incidence of relapse was significantly reduced by gemtuzumab ozogamicin (2-year cumulative incidence of relapse, 37% [95% CI 31-43] in the standard group and 25% [20-30] in the gemtuzumab ozogamicin group; cause-specific HR 0·65; 0·49-0·86; p=0·0028), and there was no difference in the cumulative incidence of death (2-year cumulative incidence of death 6% [4-10] in the standard group and 7% [5-11] in the gemtuzumab ozogamicin group; HR 1·03; 0·59-1·81; p=0·91). There were no differences in the number of days in hospital across all cycles between treatment groups. The most common treatment-related grade 3-4 adverse events were febrile neutropenia (n=135 [47%] in the gemtuzumab ozogamicin group vs n=122 [41%] in the standard group), thrombocytopenia (n=261 [90%] vs n=265 [90%]), pneumonia (n=71 [25%] vs n=64 [22%]), sepsis (n=85 [29%] vs n=73 [25%]). Treatment-related deaths were documented in 25 participants (4%; n=8 [3%] in the standard group and n=17 [6%] in the gemtuzumab ozogamicin group), mostly due to sepsis and infections., Interpretation: The primary endpoints of the trial of event-free survival and overall survival were not met. However, an anti-leukaemic efficacy of gemtuzumab ozogamicin in participants with NPM1-mutated acute myeloid leukaemia is shown by a significantly lower cumulative incidence of relapse rate, suggesting that the addition of gemtuzumab ozogamicin might reduce the need for salvage therapy in these participants. The results from this study provide further evidence that gemtuzumab ozogamicin should be added in the standard of care treatment in adults with NPM1-mutated acute myeloid leukaemia., Funding: Pfizer and Amgen., Competing Interests: Declaration of interests HD declares being in an advisory role for Abbvie, Agios, Amgen, Astellas, AstraZeneca, Berlin-Chemie, Bristol Myers Squibb, Celgene, Daiichi Sankyo, GEMoaB, Gilead, Janssen, Jazz Pharmaceuticals, Novartis, Servier, Stemline, and Syndax; and research funding from Abbvie, Agios, Amgen, Astellas, Bristol Myers Squibb, Jazz Pharmaceuticals, Kronos-Bio, Novartis, and Pfizer. WF declares a membership on an entity's board of directors or advisory committee for AbbVie, Amgen, ARIAD/Incyte, Celgene, Jazz Pharmaceuticals, MorphoSys, Stemline, Clinigen, Novartis, and Pfizer; patents and royalties from Amgen; support for meeting attendance from Amgen, Daiichi Sankyo, Gilead, Jazz Pharmaceuticals, and Servier; and research funding from Amgen and Pfizer. MWMK declares being in an advisory role for Abbvie, Bristol Myers Squibb, Jazz Pharmaceuticals, Kura-Oncology, and Pfizer; speakers honoraria from Abbvie and Gilead; travel support from Abbvie, Celgene, and Daiichi Sankyo; and research funding from Kura-Oncology. TS declares being in an advisory role for Abbvie, Astellas, Celgene, Janssen, Jazz Pharmaceuticals, Novartis, Takeda, Pfizer Bristol Myers Squibb, and Telix Pharma; speakers honoraria from Abbvie, Astellas, Celgene, Janssen, Jazz Pharmaceuticals, and Novartis; research funding from Jazz Pharmaceuticals and Bristol Myers Squibb; and travel support from Jazz Pharmaceuticals and Medac. KM declares being on an advisory role and paid for lectures for Bristol Myers Squibb; and travel support from Amgen, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Pfizer, and Roche. ML declares being in an advisory role for AbbVie, Astex Pharmaceuticals, Janssen, Pfizer, Otsuka, and Syros; and research funding from Aristopharm, Cheplapharm, Janssen, and TEVA. KG declares being in an advisory role for Abbvie, BMS, and Servier. LF declares being in an advisory role for AbbVie, Amgen, Medac, Novartis, and Takeda; and research funding from Abbvie, Kite, and Speaker's Bureau for Celgene. EK reports speaker honoraria from Abbvie, Astellas, Celgene/BMS, Jazz, Novartis, and Servier; and being in an advisory or consultancy role for Abbvie, Astellas, Celgene/BMS, Jazz, and Servier. GW reports consultancy for Clinigen and Novartis; and honoraria from Novartis, Gilead, and Takeda. JS reports being in an advisory role and honoraria from AbbVie, Bayer, BMS, Janssen, Novartis, Pfizer, and Sanofi. RG reports being in an advisory role for Abbvie, Astra Zeneca, BMS, Celgene, Daiichi Sankyo, Gilead, Janssen, Merck, MSD, Novartis, Roche, Sanofi, and Takeda. BH reports being in an advisory role for Bristol Myers Squibb, Celgene, Novartis, and Sanofi. UMM reports being in an advisory role for BMS and Sanofi. SM-S reports being in an advisory role for Amgen, BMS/Celgene, Jazz Pharmaceuticals, and Novartis. SK-S reports consultancy for Abbvie, Jazz Pharmaceuticlas, and Pfizer. LB reports being in an advisory role for Abbvie, Amgen, Astellas, Bristol-Myers Squibb, Celgene, Daiichi Sankyo, Gilead, Hexal, Janssen, Jazz Pharmaceuticals, Menarini, Novartis, Pfizer, Sanofi, and Seattle Genetics; and research funding from Bayer and Jazz Pharmaceuticals. FT reports being in an advisory role for Abbvie, Astellas, Bristol Myers Squibb/Celgene, Jazz Pharmaceuticals, Novartis, and Pfizer. MH reports being in an advisory role for Abbvie, BMS/Celgene, Daiichi Sankyo, Jazz Pharmaceuticals, Novartis, Pfizer, Roche, and Tolremo; honoraria from Jazz Pharmaceuticals, Janssen, and Novartis; and research funding to institution from Astellas, Bayer Pharma, BergenBio, Daiichi Sankyo, Jazz Pharmaceuticals, Karyopharm, Novartis, Pfizer, and Roche. PP reports being in an advisory role for Abbvie, Agios, Astellas, Astex Pharmaceuticals, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, Otsuka Pharma, Pfizer, and Sunesis; speakers bureau for Abbvie, Agios, Astellas, Bristol Myers Squibb, Celgene, Jazz Pharmaceuticals, Novartis, and Pfizer; and travel support for Abbvie, Bristol Myers Squibb, Celgene, Janssen, Novartis, and Takeda. VIG reports being in an advisory role for Abbvie and Pfizer; and speakers bureau for Pfizer and Janssen. RFS reports consulting for or an advisory board membership with Astellas, Daiichi Sankyo, Novartis, and Pfizer; research funding from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, PharmaMar, and Roche; and travel, accommodations, and expenses covered by Daiichi Sankyo. KD reports being in an advisory role for Amgen, Bristol Myers Squibb, Celgene, Daiichi Sankyo, Janssen, Jazz Pharmaceuticals, Novartis, and Roche; and research funding from Agios, Astex, Astellas, Bristol Myers Squibb, Celgene, and Novartis. AG reports being in an advisory role for Celgene, JAZZ Pharmaceuticals, and Novartis. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Precision oncology, defined as treatment of patients with targeted therapies matched to specific molecular alterations, has entered routine clinical practice. Particularly in patients with advanced cancer or hematologic malignancies, for whom no further standard therapies are available, this approach is increasingly applied as last resort option outside of the approved indication. However, data on patient outcomes are not systematically collected, analyzed, reported, and shared. We have initiated the INFINITY registry to provide evidence from routine clinical practice to fill this knowledge gap., Methods: INFINITY is a retrospective, non-interventional cohort study conducted at approximately 100 sites in Germany (office-based oncologists/hematologists and hospitals). We aim to include 500 patients with advanced solid tumors or hematologic malignancies who received a non-standard targeted therapy based on potentially actionable molecular alterations or biomarkers. INFINITY aims to provide insights into the use of precision oncology in routine clinical practice within Germany. We systematically collect details on patient and disease characteristics, molecular testing, clinical decision-making, treatment, and outcome., Discussion: INFINITY will provide evidence on the current biomarker landscape driving treatment decisions in routine clinical care. It will also provide insights on effectiveness of precision oncology approaches in general, and of specific drug class/alteration matches used outside their approved indications., Trial Registration: The study is registered at ClinicalTrials.gov, NCT04389541., (© 2023. The Author(s).)

Quality of life (QoL) is affected by environmental influences and varies between patients. A combined measurement through Patient Reported Outcomes (PROs) and Patient Generated Data (PGD) may enhance the detection of QoL impairments by a longitudinal survey. Leveraging different approaches of QoL measurement techniques, the challenge is to combine data in a standardized, interoperable way. We developed an app (Lion-App) to semantically annotate data from sensor systems as well as PROs to be merged in an overall analysis of QoL. A FHIR implementation guide was defined for a standardized assessment. To access sensor data the interfaces of Apple Health or Google Fit are used instead of integrating various provider directly into the system. Since QoL cannot be collected exclusively via sensor values, a combination of PROs and PGD is necessary. PGD enable a progression of QoL which offers more insight into personal limitations whereas PROs give insight about personal burden. The use of FHIR enables structured exchange of data while personalized analyses might improve therapy and outcome.

UBA1 is an X-linked gene and encodes an ubiquitin-activating enzyme. Three somatic mutations altering the alternative start codon (M41) in UBA1 in hematopoietic precursor cells have recently been described, resulting in a syndrome of severe inflammation, cytopenias, and the presence of intracellular vacuoles in hematopoietic precursors - termed VEXAS syndrome, a predominantly male disease. Here we present a patient with clinical features of VEXAS who harbored two novel somatic variants in UBA1 (I894S and N606I). To better understand the clinical relevance and biological consequences of non-M41 (UBA1 non-M41 ) variants, we analyzed the whole genome and transcriptome data of 4168 patients with hematological malignancies and detected an additional 16 UBA1 non-M41 putative somatic variants with a clear sex-bias in patients with myeloid malignancies. Patients diagnosed with myeloid malignancies carrying UBA1 non-M41 putative somatic variants either had vacuoles or immunodysregulatory symptoms. Analysis of the transcriptome confirmed neutrophil activation in VEXAS patients compared to healthy controls but did not result in a specific transcriptomic signature of UBA1 M41 patients in comparison with MDS patients. In summary, we have described multiple putative novel UBA1 non-M41 variants in patients with various hematological malignancies expanding the genomic spectrum of VEXAS syndrome., (© 2023. The Author(s).)

Background: The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs)., Patients and Methods: A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate., Results: From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection., Conclusions: CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery., Clinical Trial Number: ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results., Competing Interests: Disclosure IH reports honoraria from Celgene/BMS and Roche. JTS reports honoraria from AstraZeneca, Bayer, Celgene/BMS, MorphoSys, Roche, and Shire. EG reports honoraria from AstraZeneca, Celgene/BMS, MSD, Sanofi, and Servier. GS reports grants and honoraria from AstraZeneca, AURIKAMED, BeiGene, Eisai, Celgene/BMS, Deutsche Röntgengesellschaft, Isofol Medical, Janssen-Cilag, Lilly, Medizinwelten-Services GmbH, MOLOGEN, Novartis, Nutricia, Roche, Sanofi, Servier, and Shire. UMM reports honoraria from Amgen, Celgene/BMS, Lilly, Pierre-Fabre, Roche, and Sanofi. DW reports grants and honoraria from AstraZeneca, Bayer, Celgene/BMS, Eisai, Falk, Incyte, Ipsen, Novartis, Roche, Servier, Shire, and Sirtex. MF reports honoraria from Celgene/BMS, Falk, MSD, Roche and Servier. FK reports grants and honoraria from Celgene/BMS. SB reports grants and honoraria from Astra-Zeneca, Celgene/BMS, Fresenius, Incyte, Janssen-Cilag and Servier. TJE reports honoraria from Astra-Zeneca, Bayer, Celgene/BMS, Ipsen, Lilly, MSD, Roche, and Servier. RK reports employment by AIO-Studien-gGmbH. FA reports grants from the Interdisciplinary Center for Clinical Research (IZKF) Würzburg, Germany. AS reports grants from Deutsche Krebsgesellschaft (DKG). VH reports grants, honoraria, and nonfinancial support from Amgen, Astra-Zeneca, Baxalta, Boehringer-Ingelheim, Celgene/BMS, Halozyme, Lilly, Merck, MSD, Novartis, OncoSil, Pierre-Fabre, Roche, Sanofi, Servier, Shire, Sirtex, Taiho, and Terumo. VK reports grants and honoraria from Amgen, Astra-Zeneca, Celgene/BMS, MSD, and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The analysis of circulating tumor DNA (ctDNA) is at the threshold of implementation into standard care for colorectal cancer (CRC) patients. However, data about the clinical utility of liquid profiling (LP), its acceptance by clinicians, and its integration into clinical workflows in real-world settings remain limited. Here, LP tests requested as part of routine care since 2016 were retrospectively evaluated. Results show restrained request behavior that improved moderately over time, as well as reliable diagnostic performance comparable to translational studies, with an overall agreement of 91.7%. Extremely low ctDNA levels at < 0.1% in over 20% of cases, a high frequency of concomitant driver mutations (in up to 14% of cases), and ctDNA levels reflecting the clinical course of disease were revealed. However, certain limitations hampering successful translation of ctDNA into clinical practice were uncovered, including the lack of clinically relevant ctDNA thresholds, appropriate time points of LP requests, and integrative evaluation of ctDNA, imaging, and clinical findings. In conclusion, these results highlight the potential clinical value of LP for CRC patient management and demonstrate issues that need to be addressed for successful long-term implementation in clinical workflows., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Background: Colorectal cancer (CRC) survivors generally have a higher healthcare utilization (HCU) than the general population due to cancer burden. However, it is unclear which factors are associated with this increased uptake. Our study aimed to (1) compare CRC-related and non-CRC visits to general practitioners (GPs) and medical specialists (MSs) by comorbidities, and (2) assess whether HCU differs by demographic, clinical, and psychological factors., Methods: We used data from a German population-based cohort of 1,718 survivors of stage I-III CRC diagnosed in 2003 through 2010 who provided information on HCU at 5-year follow-up. Multivariable linear regression was used to calculate least-square means of CRC-related and non-CRC HCU according to the Charlson comorbidity index and comorbidity cluster, adjusting for relevant demographic, clinical, and psychological characteristics., Results: A higher comorbidity level was associated with more CRC-related MS visits and non-CRC GP visits. In addition to being strongly associated with non-CRC GP visits, comorbidity clusters were associated with CRC-related GP and MS visits, but their association varied by specific cardiometabolic comorbidities. HCU was less dependent on prognostic factors for CRC, such as age and tumor stage, but was strongly associated with disease recurrence, depression, and emotional functioning., Conclusions: Comorbidities, rather than age or tumor stage, were related to HCU, suggesting that CRC survivors use healthcare mainly for reasons other than cancer 5 years postdiagnosis. Improved communication between primary and tertiary healthcare providers could enhance the medical care of cancer survivors with complex health needs and thereby also reduce healthcare costs.

The ability to detect minimal residual disease (MRD) after a curative-intent surgery or treatment is of paramount importance, because it offers the possibility to help guide the clinical decisions related adjuvant therapy. Thus, the earlier MRD is detected, the earlier potentially beneficial treatment can be proposed to patients who might need it. Liquid biopsies, and in particular the next-generation sequencing of circulating tumor DNA (ctDNA) in the blood, have been the focus of an increasing amount of research in the past years. The ctDNA detection at advanced cancer stages is practicable for several solid tumors, and complements molecular information on acquired therapy resistance. In the context of MRD, it is by definition more challenging to detect ctDNA, but it is technically achievable and provides information on treatment response and probability of relapse significantly earlier than standard imaging methods. The clinical benefit of implementing this new technique in the routine is being tested in interventional clinical trials at the moment. We propose here an update of the current use of ctDNA detection by NGS as a tool to assess the presence of MRD and improve adjuvant treatment of solid tumors. We also discuss the main limitations and medium-term perspectives of this process in the clinic.

To date, more than 160 million people have been infected with COVID-19 worldwide. In the present study, we investigated the history of SARS-CoV-2 infection among 3067 healthcare workers (HCW) in a German COVID-19 treatment center during the early phase of the pandemic (July 2020) based on the seroprevalence of SARS-CoV-2 antibodies and self-reported previous PCR results. The results demonstrate a low prevalence of SARS-CoV-2 infection ( n = 107 [3.5%]) with no increased risk for employees with a high level of patient exposure in general or working in COVID-19-confined areas in particular. This suggests that the local hygiene standards implemented in our hospital during the first wave of COVID-19 pandemic were effective in preventing patient-to-HCW transmission. No evidence for highly mobile staff serving as a vector for SARS-CoV-2 transmission could be found. In addition, impairment of smell and/or taste was strongly associated with SARS-CoV-2 history.

Background: Head and neck squamous cell carcinomas (HNSCCs) are common malignancies caused by carcinogens, including tobacco and alcohol, or infection with human papillomavirus (HPV). Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway are effective against unresectable recurrent/metastatic HNSCC. Here, we explored the safety and efficacy of anti-PD-1 therapy in at-risk resectable HPV-positive and HPV-negative HNSCC in the neoadjuvant setting., Methods: The phase I/II CheckMate 358 trial in virus-associated cancers assessed neoadjuvant nivolumab in patients with previously untreated, resectable HPV-positive or HPV-negative HNSCC. Patients received nivolumab 240 mg intravenously on days 1 and 15, with surgery planned by day 29. Safety/tolerability (primary endpoint) was assessed by monitoring adverse events (AEs) and surgical delays. Radiographic response was measured before surgery using RECIST v1.1, adapted for a single post-nivolumab evaluation. Pathologic specimens were examined for treatment response using immune-based criteria., Results: From November 2015 to December 2017, 52 patients with AJCC (seventh edition) stage III-IV resectable HNSCC received neoadjuvant nivolumab (26 HPV-positive, 26 HPV-negative). Any-grade treatment-related AEs (TRAEs) occurred in 19 patients (73.1%) and 14 patients (53.8%) in the HPV-positive and HPV-negative cohorts, respectively; grade 3-4 TRAEs occurred in five (19.2%) and three patients (11.5%), respectively. No patient had a protocol-defined TRAE-related surgical delay (>4 weeks). Thirty-eight patients were reported as undergoing complete surgical resection, 10 had a planned post-nivolumab biopsy instead of definitive surgery due to a protocol misinterpretation, and four did not undergo surgery or biopsy, including two with tumor progression. Radiographic response rates in 49 evaluable patients were 12.0% and 8.3% in the HPV-positive and HPV-negative cohorts, respectively. There were no complete pathologic responses by site or central review in operated patients. Among 17 centrally evaluable HPV-positive tumors, one (5.9%) achieved major pathological response and three (17.6%) achieved partial pathologic response (pPR); among 17 centrally evaluable HPV-negative tumors, one (5.9%) achieved pPR., Conclusions: Neoadjuvant nivolumab was generally safe and induced pathologic regressions in HPV-positive (23.5%) and HPV-negative (5.9%) tumors. Combinatorial neoadjuvant treatment regimens, and continued postoperative therapy for high-risk tumors, are warranted in future trials to enhance the efficacy of this approach., Trial Registration Number: ClinicalTrials.gov NCT02488759; https://clinicaltrials.gov/ct2/show/NCT02488759., Competing Interests: Competing interests: RLF reports consulting or advisory from Bristol Myers Squibb (BMS), MedImmune, Merck, Lilly, Pfizer, Amgen, EMD Serono, PPD, Bain Capital Life Sciences, GlaxoSmithKline, Iovance Biotherapeutics, Numab Therapeutics AG, Oncorus, Ono Pharmaceutical, Regeneron, Novasenta, Aduro Biotech, MacroGenics, Nanobiotix, Torque Therapeutics, Lifescience Dynamics, Sanofi, and Zymeworks, Inc; and research funding from BMS, MedImmune, Merck, Tesaro, Novasenta, VentiRx, and AstraZeneca/MedImmune. WCS reports consulting from BMS and Regeneron. RL reports personal and institutional research funding from BMS. AG has nothing to disclose. UMM reports consulting and advisory from MSD Oncology, Roche, BMS, and Celgene; and travel accommodations from BMS, Celgene, Amgen, and Pierre Fabre. CK has nothing to disclose. WS reports honoraria from BMS and Array BioPharma; consulting or advisory from BMS, Novartis, Regeneron, ION Pharma, and Merck; research funding from Novartis, Merck, and Genentech; and institutional research funding from BMS. CHC reports consulting or advisory fees from BMS, CUE Biopharma, Ignyta, Mirati Therapeutics, and Sanofi; research funding from BMS, Ignyta, Lilly, Regeneron, IRX Therapeutics, and Lion Biotechnologies; and travel accommodation expenses from Mirati Therapeutics. LAD reports institutional expert input forum payments from MSD BV Netherlands; and institutional speaker fee payment from BMS. HG has nothing to disclose. SIC has nothing to disclose. LV has nothing to disclose. JMT reports consulting and advisory from BMS, MedImmune, Merck, Compugen, and Akoya Biosciences, and stock options from Akoya Biosciences. JES has nothing to disclose. JL reports employment and stock ownership from BMS. BL reports employment and stock ownership from BMS. TC reports employment and stock ownership from BMS. AB reports employment and stock ownership from BMS. SLT reports consulting or advisory from Five Prime Therapeutics, Immunocore, and Merck; travel accommodations from Five Prime Therapeutics, Merck, and BMS; research funding from BMS; stock ownership by her spouse in Tizona Therapeutics, DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Trieza Therapeutics, and Dracen Pharmaceuticals; consulting or advisory by her spouse in DNAtrix, RAPT, WindMIL, Dragonfly Therapeutics, Ervaxx, Amgen, AstraZeneca, Immunomic Therapeutics, Janssen Oncology, and Dynavax Technologies; royalties by her spouse in WindMIL, Immunomic Therapeutics, Arbor Pharmaceuticals, BMS, and NexImmune; and research funding by her spouse from Compugen., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Health-related quality of life (HR-QoL) as a parameter for patient well-being is becoming increasingly important.[1] Nevertheless, it is mainly used as an endpoint in studies rather than as an indicator for adjustments in therapy. In this paper we will present an approach to gradually integrate quality of life (QoL) as a control element into the care delivery of oncology., Concept: Acceptance, usability, interoperability and data protection were identified and integrated as key indicators for the development. As an initial approach, a questionnaire tool was developed to provide patients a simplified answering of questionnaires and physicians a clearer presentation of the results., Implementation: As communication standard HL7 FHIR was used and known security concepts like OpenID Concept were integrated. In a usability study, first results were achieved by asking patients in the waiting room to answer a questionnaire, which will be discussed with the physician in the appointment. This study was conducted in 2019 at theSLK Clinics Heilbronn and achieved 86% participation of all respondents with an average age of 67 years., Discussion: Although the evaluation study could prove positive results in usability and acceptance, it is necessary to aim for longitudinal surveys in order to include QoL as a control element in the therapy. However, a longitudinal survey through questionnaires leads to decreasing compliance and increasing response bias. [2] For this reason, the concept needs to be expanded. With sensors a continuous monitoring can be carried out and the data can be mapped to the individual, interpreted by machine learning., Conclusion: Questionnaires are a concept that has been successfully applied in studies for years. However, since care delivery poses different challenges, the integration of new concepts is inevitable. The authors are currently working on an extension of the use of questionnaires with patient generated data through sensors.

Background: Lipegfilgrastim has been shown to be non-inferior to pegfilgrastim for reduction of the duration of severe neutropenia (DSN) in breast cancer patients. This open-label, non-inferiority study assessed the efficacy and safety of lipegfilgrastim versus pegfilgrastim in elderly patients with aggressive B cell non-Hodgkin lymphoma (NHL) at high risk for chemotherapy-induced neutropenia., Patient and Methods: One hundred and one patients (median age, 75 years) were randomized to lipegfilgrastim or pegfilgrastim (6 mg/cycle) during six cycles of R-CHOP21., Results: Lipegfilgrastim was non-inferior to pegfilgrastim for the primary efficacy endpoint, reduction of DSN in cycle 1. In the per-protocol population, mean (standard deviation) DSN was 0.8 (0.92) and 0.9 (1.11) days in the two groups, respectively; the adjusted mean difference between groups was - 0.3 days (95% confidence interval, - 0.70 to 0.19). Non-inferiority was also demonstrated in the intent-to-treat population. The incidence of severe neutropenia in cycle 1 was 51% (21/41) in the lipegfilgrastim group and 52% (23/44) in the pegfilgrastim group. Very severe neutropenia (ANC < 0.1 × 10 9 /L) in cycle 1 was reported by 5 (12%) patients in the lipegfilgrastim group and 8 (18%) patients in the pegfilgrastim group. However, over all cycles, febrile neutropenia (strict definition) was reported by only 1 (2%) patient in each treatment group (during cycle 1 in the lipegfilgrastim group and cycle 6 in the pegfilgrastim group). The mean time to absolute neutrophil count recovery (defined as ≥ 2.0 × 10 9 /L) was 8.3 and 9.4 days in the two groups, respectively. Serious adverse events occurred in 46% of patients in each group; none were considered treatment-related. Eight patients died during the study (2 in the lipegfilgrastim group, 5 in the pegfilgrastim group, and 1 who died before starting study treatment). No deaths occurred during the treatment period, and all were considered to be related to the underlying disease., Conclusions: This study shows lipegfilgrastim to be non-inferior to pegfilgrastim for the reduction of DSN in elderly patients with aggressive B cell NHL receiving myelosuppressive chemotherapy, with a comparable safety profile., Trial Registration Number: ClinicalTrials.gov identifier NCT02044276; EudraCT number 2013-001284-23.

Background: In the era of personalized medicine, cancer care is subject to major changes and innovations. It is unclear, however, to what extent implementation of such innovations and their impact on patient outcomes differ by health insurance type. This study compared provision of treatment and survival outcomes among patients with colorectal cancer (CRC) who had statutory health insurance (SHI) versus private health insurance (PHI) in Germany., Methods: We analyzed patterns of CRC treatment (surgery, chemotherapy/radiotherapy, and targeted therapy) and survival in a large cohort of patients who were diagnosed with CRC in 2003 through 2014 and were observed for an average of 6 years. Associations of type of health insurance with treatment administration and with overall, CRC-specific, and recurrence-free survival were investigated using multivariable logistic and Cox proportional hazards models, respectively., Results: Of 3,977 patients with CRC, 427 (11%) had PHI. Although type of health insurance was not associated with treatment administration in patients with stage I-III disease, those with stage IV disease with PHI more often received targeted therapy (65% vs 40%; odds ratio, 2.43; 95% CI, 1.20-4.91), with differences decreasing over time because of catch-up of uptake rates in patients with SHI. Median overall survival was longer in patients with PHI than in those with SHI (137.0 vs 114.9 months; P=.010), but survival advantages were explained to a large extent by differences in sociodemographic factors. In patients with stage IV disease, survival advantages of PHI were nonsignificant and were restricted to the early years after diagnosis., Conclusions: We observed major differences in uptake of targeted therapy between patients with PHI and those with SHI but no differences in patient survival after adjusting for relevant sociodemographic, clinical, and tumor characteristics. Further studies are needed on factors associated with the uptake of therapeutic innovations and their impact on patient survival by health insurance type.

Purpose: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints., Methods: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively., Results: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site., Conclusions: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.

Purpose: Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer commonly driven by the Merkel cell polyomavirus (MCPyV). The programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) immunosuppressive pathway is often upregulated in MCC, and advanced metastatic MCC frequently responds to PD-1 blockade. We report what we believe to be the first trial of anti-PD-1 in the neoadjuvant setting for resectable MCC., Methods: In the phase I/II CheckMate 358 study of virus-associated cancer types, patients with resectable MCC received nivolumab 240 mg intravenously on days 1 and 15. Surgery was planned on day 29. Tumor regression was assessed radiographically and microscopically. Tumor MCPyV status, PD-L1 expression, and tumor mutational burden (TMB) were assessed in pretreatment tumor biopsies., Results: Thirty-nine patients with American Joint Committee on Cancer stage IIA-IV resectable MCC received ≥ 1 nivolumab dose. Three patients (7.7%) did not undergo surgery because of tumor progression (n = 1) or adverse events (n = 2). Any-grade treatment-related adverse events occurred in 18 patients (46.2%), and grade 3-4 events in 3 patients (7.7%), with no unexpected toxicities. Among 36 patients who underwent surgery, 17 (47.2%) achieved a pathologic complete response (pCR). Among 33 radiographically evaluable patients who underwent surgery, 18 (54.5%) had tumor reductions ≥ 30%. Responses were observed regardless of tumor MCPyV, PD-L1, or TMB status. At a median follow-up of 20.3 months, median recurrence-free survival (RFS) and overall survival were not reached. RFS significantly correlated with pCR and radiographic response at the time of surgery. No patient with a pCR had tumor relapse during observation., Conclusion: Nivolumab administered approximately 4 weeks before surgery in MCC was generally tolerable and induced pCRs and radiographic tumor regressions in approximately one half of treated patients. These early markers of response significantly predicted improved RFS. Additional investigation of these promising findings is warranted.

Background: Comorbidities and old age independently compromise prognosis of patients with colorectal cancer (CRC). The impact of comorbidities could thus be considered as conveying worse prognosis already at younger ages, but evidence is lacking on how much worsening of prognosis with age is advanced to younger ages in comorbid versus noncomorbid patients. We aimed to quantify, for the first time, the impact of comorbidities on CRC prognosis in "age advancement" of worse prognosis., Methods: A total of 4,602 patients aged ≥30 years who were diagnosed with CRC in 2003 through 2014 were recruited into a population-based study in the Rhine-Neckar region of Germany and observed over a median period of 5.1 years. Overall comorbidity was quantified using the Charlson comorbidity index (CCI). Hazard ratios and age advancement periods (AAPs) for comorbidities were calculated from multivariable Cox proportional hazards models for relevant survival outcomes., Results: Hazard ratios for CCI scores 1, 2, and ≥3 compared with CCI 0 were 1.25, 1.53, and 2.30 (P<.001) for overall survival and 1.20, 1.48, and 2.03 (P<.001) for disease-free survival, respectively. Corresponding AAP estimates for CCI scores 1, 2, and ≥3 were 5.0 (95% CI, 1.9-8.1), 9.7 (95% CI, 6.1-13.3), and 18.9 years (95% CI, 14.4-23.3) for overall survival and 5.5 (95% CI, 1.5-9.5), 11.7 (95% CI, 7.0-16.4), and 21.0 years (95% CI, 15.1-26.9) for disease-free survival. Particularly pronounced effects of comorbidity on CRC prognosis were observed in patients with stage I-III CRC., Conclusions: Comorbidities advance the commonly observed deterioration of prognosis with age by many years, meaning that at substantially younger ages, comorbid patients with CRC experience survival rates comparable to those of older patients without comorbidity. This first derivation of AAPs may enhance the empirical basis for treatment decisions in patients with comorbidities and highlight the need to incorporate comorbidities into prognostic nomograms for CRC.

Purpose: This trial investigated the addition of panitumumab to triplet chemotherapy with fluorouracil/folinic acid, oxaliplatin, and irinotecan (FOLFOXIRI) in a two-to-one randomized, controlled, open-label, phase II trial in patients with untreated RAS wild-type (WT) metastatic colorectal cancer., Patients and Methods: The primary end point was objective response rate (ORR) according to RECIST (version 1.1). The experimental arm (modified FOLFOXIRI [mFOLFOXIRI] plus panitumumab) was considered active if the ORR was ≥ 75%. The experimental ORR was compared with an estimated ORR of 60% based on historical data, verified by a randomized control group (FOLFOXIRI). The power of the trial was 80%, with a potential type I error of 0.05. Secondary end points included secondary resection rate, toxicity, progression-free survival, and overall survival., Results: A total of 63 patients were randomly assigned to the experimental arm and 33 patients to the control arm. The ORR of the mFOLFOXIRI plus panitumumab arm exceeded 75% and was higher when compared with that of FOLFOXIRI (87.3% v 60.6%; odds ratio, 4.469; 95% CI, 1.61 to 12.38; P = .004). The secondary resection rate was improved with the addition of panitumumab (33.3% v 12.1%; P = .02). Progression-free survival was similar in the study arms, whereas overall survival showed a trend in favor of the panitumumab-containing arm (hazard ratio for death, 0.67; 95% CI, 0.41 to 1.11; P = .12)., Conclusion: The addition of panitumumab to mFOLFOXIRI in patients with RAS WT metastatic colorectal cancer improved the ORR and rate of secondary resection of metastases and represents a treatment option in selected and fit patients in need of highly active first-line therapy. Future studies should determine whether the addition of panitumumab to mFOLFOXIRI prolongs survival.

Background: Chemotherapy underuse in elderly patients (aged ≥75 years) with colon cancer has been reported in previous studies. However, these studies were mostly registry-based and limited in their potential to consider underlying reasons of such undertreatment. This study aimed to evaluate patient and hospital determinants of chemotherapeutic treatment in patients with stage III colon cancer, with a particular focus on age and underlying reasons for nontreatment of elderly patients., Methods: A total of 629 patients with stage III colon cancer who were diagnosed in 2003 through 2012 and recruited into a population-based study in the Rhine-Neckar region of Germany were included. Information on sociodemographic and lifestyle factors, comorbidities, and treatment was collected from patient interviews and physicians. Patient (with an emphasis on age) and hospital factors were evaluated for their associations with administration of adjuvant chemotherapy overall and of oxaliplatin specifically using multivariable logistic regression., Results: Administration of chemotherapy decreased from 94% in patients aged 30 to 64 years to 51% in those aged ≥75 years. A very strong decline in chemotherapy use with age persisted even after comprehensive adjustment for multiple patient factors-including comorbidities-and hospital factors and was also seen among patients without any major comorbidities. Between 2005 and 2008, and 2009 and 2012, chemotherapy administration in patients aged ≥75 years decreased from 60% to 41%. Among chemotherapy recipients, old age was also strongly associated with higher odds of nonadministration of oxaliplatin. The 2 most commonly reported reasons for chemotherapy nonreceipt among the study population were patient refusal (30%) and old age (24%)., Conclusions: Age was the strongest predictor of chemotherapy underuse, irrespective of comorbidities and even in patients without comorbidities. Such underuse due just to older age in otherwise healthy patients deserves increased attention in clinical practice to ensure that elderly patients also get the best possible care. Patients' refusal as the most frequent reason for chemotherapy nonreceipt also warrants further investigation to exclude misinformation as underlying cause.

The aim of this randomized phase-II study was to evaluate the effect of substituting cytarabine by azacitidine in intensive induction therapy of patients with acute myeloid leukemia (AML). Patients were randomized to four induction schedules for two cycles: STANDARD (idarubicin, cytarabine, etoposide); and azacitidine given prior (PRIOR), concurrently (CONCURRENT), or after (AFTER) therapy with idarubicin and etoposide. Consolidation therapy consisted of allogeneic hematopoietic-cell transplantation or three courses of high-dose cytarabine followed by 2-year maintenance therapy with azacitidine in the azacitidine-arms. AML with CBFB-MYH11, RUNX1-RUNX1T1, mutated NPM1, and FLT3-ITD were excluded and accrued to genotype-specific trials. The primary end point was response to induction therapy. The statistical design was based on an optimal two-stage design applied for each arm separately. During the first stage, 104 patients (median age 62.6, range 18-82 years) were randomized; the study arms PRIOR and CONCURRENT were terminated early due to inefficacy. After randomization of 268 patients, all azacitidine-containing arms showed inferior response rates compared to STANDARD. Event-free and overall survival were significantly inferior in the azacitidine-containing arms compared to the standard arm (p < 0.001 and p = 0.03, respectively). The data from this trial do not support the substitution of cytarabine by azacitidine in intensive induction therapy.

Background: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma. This study reports on the safety and efficacy of the docetaxel-based triplet FLOT (fluorouracil plus leucovorin, oxaliplatin and docetaxel) as a perioperative therapy for patients with locally advanced, resectable tumours., Methods: In this controlled, open-label, phase 2/3 trial, we randomly assigned 716 patients with histologically-confirmed advanced clinical stage cT2 or higher or nodal positive stage (cN+), or both, resectable tumours, with no evidence of distant metastases, via central interactive web-based-response system, to receive either three pre-operative and three postoperative 3-week cycles of 50 mg/m 2 epirubicin and 60 mg/m 2 cisplatin on day 1 plus either 200 mg/m 2 fluorouracil as continuous intravenous infusion or 1250 mg/m 2 capecitabine orally on days 1 to 21 (ECF/ECX; control group) or four preoperative and four postoperative 2-week cycles of 50 mg/m 2 docetaxel, 85 mg/m 2 oxaliplatin, 200 mg/m 2 leucovorin and 2600 mg/m 2 fluorouracil as 24-h infusion on day 1 (FLOT; experimental group). The primary outcome of the trial was overall survival (superiority) analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01216644., Findings: Between Aug 8, 2010, and Feb 10, 2015, 716 patients were randomly assigned to treatment in 38 German hospitals or with practice-based oncologists. 360 patients were assigned to ECF/ECX and 356 patients to FLOT. Overall survival was increased in the FLOT group compared with the ECF/ECX group (hazard ratio [HR] 0·77; 95% confidence interval [CI; 0.63 to 0·94]; median overall survival, 50 months [38·33 to not reached] vs 35 months [27·35 to 46·26]). The number of patients with related serious adverse events (including those occurring during hospital stay for surgery) was similar in the two groups (96 [27%] in the ECF/ECX group vs 97 [27%] in the FLOT group), as was the number of toxic deaths (two [<1%] in both groups). Hospitalisation for toxicity occurred in 94 patients (26%) in the ECF/ECX group and 89 patients (25%) in the FLOT group., Interpretation: In locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma, perioperative FLOT improved overall survival compared with perioperative ECF/ECX., Funding: The German Cancer Aid (Deutsche Krebshilfe), Sanofi-Aventis, Chugai, and Stiftung Leben mit Krebs Foundation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Olaparib (Lynparza [AstraZeneca, Cambridge, UK], formerly referred to as AZD2281 or KU0059436) is an oral poly(ADP-ribose) polymerase (PARP) inhibitor. It is rationally designed to act as a competitive inhibitor of NAD + at the catalytic site of PARP1 and PARP2, both members of the PARP family of enzymes that are central to the repair of DNA single-strand breaks (SSBs) mediated via the base excision repair (BER) pathway. Inhibition of the BER pathway by olaparib leads to the accumulation of unrepaired SSBs, which leads to the formation of deleterious double-strand breaks (DSBs). In cells with an intact homologous recombination (HR) pathway, these DSBs can be repaired effectively. However, in tumors with homologous recombination repair deficiencies, olaparib causes synthetic lethality through the combination of two molecular events that are otherwise nonlethal when occurring in isolation. Olaparib is already approved for the treatment of patients with recurrent ovarian cancer and a BRCA mutation, and it has been shown to provide clinically meaningful benefits among such patients. It has also shown promising activity in patients with metastatic breast or prostate cancer and a germline BRCA mutation. Besides its usage as a single agent, olaparib can also act either as a chemo- and/or radiosensitizer, due to its ability to potentiate the cytotoxic effects of these therapeutic agents. However, a clear patient benefit for the latter application has not been demonstrated yet.

One of the most challenging issues in oncology research and treatment is identifying oncogenic drivers within an individual patient's tumor which can be directly targeted by a clinically available therapeutic drug. In this context, gene fusions as one important example of genetic aberrations leading to carcinogenesis follow the widely accepted concept that cell growth and proliferation are driven by the accomplished fusion (usually involving former proto-oncogenes) and may therefore be successfully inhibited by substances directed against the fusion. This concept has already been established with oncogenic gene fusions like BCR-ABL in chronic myelogenous leukemia (CML) or anaplastic lymphoma kinase (ALK) in lung cancer, including special tyrosine kinase inhibitors (TKIs) which are able to block the activation of the depending downstream proliferation pathways and, consequently, tumor growth. During the last decade, the NTRK1, 2, and 3 genes, encoding the TRKA, B, and C proteins, have attracted increasing attention as another significant and targetable gene fusion in a variety of cancers. Several TRK inhibitors have been developed, and one of them, Larotrectinib (formerly known as LOXO-101), represents an orally available, selective inhibitor of the TRK receptor family that has already shown substantial clinical benefit in both pediatric and adult patients harboring an NTRK gene fusion over the last few years.

Purpose: Studies investigating combinations of anti-epidermal growth factor receptor monoclonal antibodies such as panitumumab or cetuximab with standard chemoradiation therapy protocols in rectal cancer have yielded disappointing results. Because of the supposed negative interaction of epidermal growth factor receptor inhibition and chemoradiation therapy, we conducted a phase 2 study using single-agent panitumumab in combination with radiation therapy in patients with RAS wild-type locally advanced rectal cancer., Methods and Materials: Patients with RAS wild-type locally advanced (clinical stage II or III) rectal cancer localized 0 to 12 cm from the anus were eligible for study participation. The primary objective of the study was to determine pathologic complete response (pCR). Secondary objectives comprised assessing the safety, surgical morbidity, clinical response, tumor downstaging, and tumor regression grading according to Dworak., Results: A total of 54 patients with a median age of 58 years were treated. In 3.7% of patients, pCR was achieved. Downstaging of the primary tumor or lymph nodes was seen in 65% of patients. No grade ≥2 hematologic toxicity was seen. The most common grade ≥3 nonhematologic toxicities were skin toxicity (24%) and diarrhea (10%)., Conclusions: Panitumumab in combination with radiation therapy as neoadjuvant treatment for locally advanced rectal cancer showed a favorable toxicity profile but failed to meet the predefined pCR rate to justify further clinical trials., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Importance: Surgical resection has a potential benefit for patients with metastatic adenocarcinoma of the stomach and gastroesophageal junction., Objective: To evaluate outcome in patients with limited metastatic disease who receive chemotherapy first and proceed to surgical resection., Design, Setting, and Participants: The AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial is a prospective, phase 2 trial of 252 patients with resectable or metastatic gastric or gastroesophageal junction adenocarcinoma. Patients were enrolled from 52 cancer care centers in Germany between February 1, 2009, and January 31, 2010, and stratified to 1 of 3 groups: resectable (arm A), limited metastatic (arm B), or extensive metastatic (arm C). Data cutoff was January 2012, and the analysis was performed in March 2013., Interventions: Patients in arm A received 4 preoperative cycles of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) followed by surgery and 4 postoperative cycles. Patients in arm B received at least 4 cycles of neoadjuvant FLOT and proceeded to surgical resection if restaging (using computed tomography and magnetic resonance imaging) showed a chance of margin-free (R0) resection of the primary tumor and at least a macroscopic complete resection of the metastatic lesions. Patients in arm C were offered FLOT chemotherapy and surgery only if required for palliation. Patients received a median (range) of 8 (1-15) cycles of FLOT., Main Outcomes and Measures: The primary end point was overall survival., Results: In total, 238 of 252 patients (94.4%) were eligible to participate. The median (range) age of participants was 66 (36-79) years in arm A (n = 51), 63 (28-79) years in arm B (n = 60), and 65 (23-83) years in arm C (n = 127). Patients in arm B (n = 60) had only retroperitoneal lymph node involvement (27 patients [45%]), liver involvement (11 [18.3%]), lung involvement (10 [16.7%]), localized peritoneal involvement (4 [6.7%]), or other (8 [13.3%]) incurable sites. Median overall survival was 22.9 months (95% CI, 16.5 to upper level not achieved) for arm B, compared with 10.7 months (95% CI, 9.1-12.8) for arm C (hazard ratio, 0.37; 95% CI, 0.25-0.55) (P < .001). The response rate for arm B was 60% (complete, 10%; partial, 50%), which is higher than the 43.3% for arm C. In arm B, 36 of 60 patients (60%) proceeded to surgery. The median overall survival was 31.3 months (95% CI, 18.9-upper level not achieved) for patients who proceeded to surgery and 15.9 months (95% CI, 7.1-22.9) for the other patients., Conclusions and Relevance: Patients with limited metastatic disease who received neoadjuvant chemotherapy and proceeded to surgery showed a favorable survival. The AIO-FLOT3 trial provides a rationale for further randomized clinical trials., Trial Registration: clinicaltrials.gov identifier: NCT00849615.

Background: Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer., Methods: Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA., Results: Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m 2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively)., Conclusion: Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation.

Background: Docetaxel-based chemotherapy is effective in metastatic gastric and gastro-oesophageal junction adenocarcinoma, but has not yet been evaluated in the context of resectable patients. Here we report findings from the phase 2 part of the phase 2/3 FLOT4 trial, which compared histopathological regression in patients treated with a docetaxel-based triplet chemotherapy versus an anthracycline-based triplet chemotherapy before surgical resection., Methods: In this randomised, open-label, phase 2/3 study, eligible participants were recruited from 28 German oncology centres. Patients with resectable gastric or gastro-oesophageal junction cancer who had clinical stage cT2 or higher, nodal positive (cN+) disease, or both were randomly assigned (1:1) to either three preoperative and three postoperative 3-week cycles of intravenous epirubicin 50 mg/m 2 on day 1, intravenous cisplatin 60 mg/m 2 on day 1, and either fluorouracil 200 mg/m 2 as continuous intravenous infusion or capecitabine 1250 mg/m 2 orally (two doses of 625 mg/m 2 per day) on days 1 to 21 (ECF/ECX group) or four preoperative and four postoperative 2-week cycles of docetaxel 50 mg/m 2 , intravenous oxaliplatin 85 mg/m 2 , intravenous leucovorin 200 mg/m 2 , and fluorouracil 2600 mg/m 2 as a 24 h infusion, all on day 1 (FLOT group). Randomisation was done centrally with an interactive web-response system based on a sequence generated with blocks (block size 2) stratified by Eastern Cooperative Oncology Group performance status, location of primary tumour, age, and nodal status. No masking was done. Central assessment of pathological regression was done according to the Becker criteria. The primary endpoint was pathological complete regression (tumour regression grade TRG1a) and was analysed in the modified intention-to-treat population, defined as all patients who were randomly assigned to treatment excluding patients who had surgery but did not provide resection specimens for central evaluation. The study (including the phase 3 part) has completed enrolment, but follow-up is ongoing and this is an interim analysis. The trial is registered with ClinicalTrials.gov, number NCT01216644., Findings: Between Aug 18, 2010, and Aug 10, 2012, 300 patients (152 patients in the ECF/ECX group; 148 patients in the FLOT group) were enrolled into the phase 2 part of the study, 265 of whom (137 in the ECF/ECX group; 128 in the FLOT group) were assessable on a modified intention-to-treat basis. 119 (93%) of 128 patients in the FLOT group and 126 (92%) of 137 patients in the ECF/ECX group were given all planned preoperative cycles of treatment. FLOT was associated with significantly higher proportions of patients achieving pathological complete regression than was ECF/ECX (20 [16%; 95% CI 10-23] of 128 patients vs eight [6%; 3-11] of 137 patients; p=0·02). 44 (40%) of 111 patients in the ECF/ECX group and 30 (25%) of 119 patients in the FLOT group had at least one serious adverse event involving a perioperative medical or surgical complication. The most common non-surgical grade 3-4 adverse events were neutropenia (52 [38%] of 137 patients in the ECF/ECX group vs 67 [52%] of 128 patients in the FLOT group), leucopenia (28 [20%] vs 36 [28%]), nausea (23 [17%] vs 12 [9%]), infection (16 [12%] vs 15 [12%]), fatigue (19 [14%] vs 11 [9%]), and vomiting (13 [10%] vs four [3%])., Interpretation: Perioperative FLOT was active and feasible to administer, and might represent an option for patients with locally advanced, resectable gastric or gastro-eosophageal junction adenocarcinoma., Funding: None., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Persistent polyclonal B lymphocytosis (PPBL) is a benign hematological disorder characterized by a selective expansion of circulating polyclonal marginal zone (MZ)-like B cells. Previous reports demonstrated that cases of PPBL showed poor activation, proliferation and survival of B cells in vitro, yet the underlying defect remains unknown. Here we report for the first time an attenuated activation of the canonical NF-κB (nuclear factor of kappa light polypeptide gene enhancer in B cells) and mitogen-activated protein kinase/extracellular signal-regulated kinase pathway after CD40 stimulation. This defect was selective, as alternative NF-κB signaling after CD40 stimulation and both B-cell receptor- and Toll-like receptor 9-mediated activation remained unaffected. Reduced canonical NF-κB activation resulted in decreased IκBα and CD40 expression in resting cells. In PPBL patients, expression of Bcl-xL in MZ-like B cells did not increase upon activation, consistent with the high apoptosis rates of PPBL-derived B cells that were observed in vitro. The B-cell phenotype of mice with selective knockouts of early components of the CD40 signaling pathway resembles PPBL, but sequencing corresponding genes in sorted MZ-like B cells of PPBL patients did not reveal relevant genetic alterations. Nevertheless, the frequently observed mutations in early signaling components of the NF-κB pathway in MZ lymphomas underline the relevance of our findings for the pathogenesis of PPBL.

Objectives: Today, hospitals and other health care-related institutions are accumulating a growing bulk of real world clinical data. Such data offer new possibilities for the generation of disease models for the health economic evaluation. In this article, we propose a new approach to leverage cancer registry data for the development of Markov models. Records of breast cancer patients from a clinical cancer registry were used to construct a real world data driven disease model., Methods: We describe a model generation process which maps database structures to disease state definitions based on medical expert knowledge. Software was programmed in Java to automatically derive a model structure and transition probabilities. We illustrate our method with the reconstruction of a published breast cancer reference model derived primarily from clinical study data. In doing so, we exported longitudinal patient data from a clinical cancer registry covering eight years. The patient cohort (n=892) comprised HER2-positive and HER2-negative women treated with or without Trastuzumab., Results: The models generated with this method for the respective patient cohorts were comparable to the reference model in their structure and treatment effects. However, our computed disease models reflect a more detailed picture of the transition probabilities, especially for disease free survival and recurrence., Conclusions: Our work presents an approach to extract Markov models semi-automatically using real world data from a clinical cancer registry. Health care decision makers may benefit from more realistic disease models to improve health care-related planning and actions based on their own data., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Records of female breast cancer patients were selected from a clinical cancer registry and separated into three cohorts according to HER2-status (human epidermal growth factor receptor 2) and treatment with or without Trastuzumab (a humanized monoclonal antibody). Propensity score matching was used to balance the cohorts. Afterwards, documented information about disease events (recurrence of cancer, metastases, remission of local/regional recurrences, remission of metastases and death) found in the dataset was leveraged to calculate the annual transition probabilities for every cohort.

Clinical cancer registries are a valuable data source for health services research (HSR). HSR is in need of high quality routine care data for its evaluations. However, the secondary use of routine data - such as documented cancer cases in a disease registry - poses new challenges in terms of data quality, IT-management, documentation processes and data privacy. In the clinical cancer registry Heilbronn-Franken, real-world data from the Giessen Tumor Documentation System (GTDS) was utilized for analyses of patients' disease processes and guideline adherence in follow-up care. A process was developed to map disease state definitions to fields of the GTDS database and extract patients' disease progress information. Thus, the disease process of sub-cohorts could be compared to each other, e.g., comparison of disease free survival of HER2 (human epidermal growth factor receptor 2)-positive and -negative women who were treated with Trastuzumab, a targeted therapy applied in breast cancer. In principle, such comparisons are feasible and of great value for HSR as they depict a routine care setting of a diverse patient cohort. Yet, local documentation practice, missing flow of information from external health care providers or small sub-cohorts impede the analyses of clinical cancer registries data bases and usage for HSR.

Background: Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and continues to be a major healthcare concern. Molecular heterogeneity of CRC is believed to be one of the main factors responsible for the considerable variability in treatment response. With the recent development of powerful genomic technologies, novel insights in tumor biology of CRC have now been provided, facilitating the recognition of new molecular subtypes with prognostic and predictive implications., Purpose: The purpose of this review article is to summarize current knowledge about genomic, epigenomic, and proteomic characteristics of CRC, as well as their implications for biomarker identification and individualized targeted therapy., Conclusion: Supplementing the findings from several previous studies, the Cancer Genome Atlas (TCGA) project recently finalized the systematic characterization of CRC resulting in the first tumor dataset with complete molecular measurements at DNA, RNA, and protein levels. The challenge now is to translate these findings into a robust and reproducible CRC classification system linking molecular features of the tumor to precision medicine.

Background: Integrins are involved in tumour progression and metastasis, and differentially expressed on colorectal cancer (CRC) cells. Abituzumab (EMD 525797), a humanised monoclonal antibody targeting integrin αν heterodimers, has demonstrated preclinical activity. This trial was designed to assess the tolerability of different doses of abituzumab in combination with cetuximab and irinotecan (phase I) and explore the efficacy and tolerability of the combination versus that of cetuximab and irinotecan in patients with metastatic CRC (mCRC) (phase II part)., Methods: Eligible patients had KRAS (exon 2) wild-type mCRC and had received prior oxaliplatin-containing therapy. The trial comprised an initial safety run-in using abituzumab doses up to 1000 mg combined with a standard of care (SoC: cetuximab plus irinotecan) and a phase II part in which patients were randomised 1 : 1 : 1 to receive abituzumab 500 mg (arm A) or 1000 mg (arm B) every 2 weeks combined with SoC, or SoC alone (arm C). The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall survival (OS), response rate (RR) and tolerability. Associations between tumour integrin expression and outcomes were also assessed., Results: Phase I showed that abituzumab doses up to 1000 mg were well tolerated in combination with SoC. Seventy-three (arm A), 71 (arm B) and 72 (arm C) patients were randomised to the phase II part. Baseline characteristics were balanced. PFS was similar in the three arms: arm A versus SoC, hazard ratio (HR) 1.13 [95% confidence interval (CI) 0.78-1.64]; arm B versus SoC, HR 1.11 (95% CI 0.77-1.61). RRs were also similar. A trend toward improved OS was observed: arm A versus SoC, HR 0.83 (95% CI 0.54-1.28); arm B versus SoC, HR 0.80 (95% CI 0.52-1.25). Grade ≥3 treatment-emergent adverse events were observed in 72%, 78% and 67% of patients. High tumour integrin αvβ6 expression was associated with longer OS in arms A [HR 0.55 (0.30-1.00)] and B [HR 0.41 (0.21-0.81)] than in arm C., Conclusion: The primary PFS end point was not met, although predefined exploratory biomarker analyses identified subgroups of patients in whom abituzumab may have benefit. The tolerability of abituzumab combined with cetuximab and irinotecan was acceptable. Further study is warranted. CLINICALTRIALS.GOV IDENTIFIER: NCT01008475., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Survival time prediction at the time of diagnosis is of great importance to make decisions about treatment and long-term follow-up care. However, predicting the outcome of cancer on the basis of clinical information is a challenging task. We now examined the ability of ten different data mining algorithms (Perceptron, Rule Induction, Support Vector Machine, Linear Regression, Naïve Bayes, Decision Tree, k-nearest Neighbor, Logistic Regression, Neural Network, Random Forest) to predict the dichotomous attribute "5-year-survival" based on seven attributes (sex, UICC-stage, etc.) which are available at the time of diagnosis. For this study we made use of the nationwide German research data set on colon cancer provided by the Robert Koch Institute. To assess the results a comparison between data mining algorithms and physicians' opinions was performed. Therefore, physicians guessed the survival time by leveraging the same seven attributes. The average accuracy of the physicians' opinion was 59%, the average accuracy of the machine learning algorithms was 67.7%.

Telomerase inhibition causes progressive telomere shortening and cellular senescence, which constitutes a universal barrier to tumor growth and therefore an attractive target for tumor therapy. To expand our previous studies, we investigated the global effects of telomere dysfunction on the proteome of tumor cells in order to find novel senescence biomarkers. Telomerase-deficient HCT-116 cell clones were analyzed by a quantitative proteomic approach using isotope-coded protein labeling (ICPL) and nanoflow-HPLC-MS/MS. Stringent reduction of the extensive proteomic data from this tumor cell model revealed a list of 59 markers including proteins identified in our former studies and a number of novel proteins involved in tumorigenesis and metastasis such as SFN, S100A4, ANXA2, and LGALS1. A loss of the chromatin protein HMGB2 was demonstrated not only in various telomerase-inhibited clones of different tumor cell lines, but also in normal human fibroblasts undergoing replicative senescence and in aging telomerase knockout mice. Impressively, a coherent and dense network of protein-protein interactions for the bulk of the markers and their implementation in signaling pathways involving key regulators for tumorigenesis were revealed. These results have an impact on the understanding of telomere- and senescence-related signal transduction in tumor cells in consideration of the general lack of senescence markers., Biological Significance: Induction of cellular senescence constitutes a potent concept for tumor therapy which interferes with immortalization and additional hallmarks of cancer. The application of a powerful quantitative proteomic approach using isotope-coded protein labeling to an approved model for senescence represented by telomerase inhibited tumor cells led to the identification of novel candidate biomarkers for telomere dysfunction and replicative senescence. Thereby, the identified markers not only fit in the context of the investigated processes with a relevance for additional hallmarks of cancer but are also involved in a strong interaction network and integrated in canonical pathways centered around key cancer-relevant proteins. These potential markers alone or in combination will significantly extend the view on telomere-associated signal transduction in tumor cells and contribute to the field of cellular senescence and aging in consideration of the general lack of biomarkers in this regard., (© 2013.)

Analysis of tumor-infiltrating lymphocytes (TIL) in primary human colorectal cancer (CRC) by in situ immunohistochemical staining supports the hypothesis that the adaptive immune response influences the course of human CRC. Specifically, high densities of TILs in the primary tumor are associated with good prognosis independent of other prognostic markers. However, the prognostic role of TILs in metastatic CRC lesions is unknown, as is their role in response or resistance to conventional chemotherapy. We analyzed the association of TIL densities at the invasive margin of CRC liver metastases with response to chemotherapy and progression-free survival in a set of 101 large section samples. High-resolution automated microscopy on complete tissue sections was used to objectively generate cell densities for CD3, CD8, granzyme B, or FOXP3 positive immune cells. A predictive scoring system using TIL densities was developed in a training set and tested successfully in an independent validation set. TIL densities at the invasive margin of liver metastases allowed the prediction of response to chemotherapy with a sensitivity of 79% and specificity of 100%. The association of high density values with longer progression-free survival under chemotherapy was statistically significant. Overall, these findings extend the impact of the local immune response on the clinical course from the primary tumor also to metastatic lesions. Because detailed quantification of TILs in metastatic lesions revealed a strong association with chemotherapy efficacy and prognosis, we suggest that the developed scoring system may be used as a predictive tool for response to chemotherapy in metastatic CRC., (©2011 AACR.)