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Purpose: In recent times, "ringing the bell" at the end of cancer treatment has attracted the attention of health care providers with regard to how this experience impacts patients' mental and emotional health. In this context, a study was conducted at a radiation oncology center in Santiago, Chile, to assess the perceived valorization of patients toward "ringing the bell" at the end of their treatment. It was further determined whether this experience had a positive or negative impact on their mental health., Methods and Materials: Two hundred thirty-six patients were invited to respond to a printed anonymous survey that used a Likert scale to evaluate their perceived valorization of "ringing the bell" after radiation therapy. In this survey, patients were also asked questions regarding their background to examine possible trends related to different lifestyles and socioeconomic status., Results: The results showed that 93.6% of participants classified the experience as "positive" or "very positive." There were 6 "negative" responses out of 708 (0.8%) to the 3 questions regarding perceived valorization of the experience and no "very negative" responses., Conclusions: "Ringing the bell" at the end of radiation therapy can be considered a psychological comfort that positively impacts patients' mental health. No trends related to socioeconomic status were observed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Clever Hans effect occurs when machine learning models rely on spurious correlations instead of clinically relevant features and poses significant challenges to the development of reliable artificial intelligence (AI) systems in medical imaging. This scoping review provides an overview of methods for identifying and addressing the Clever Hans effect in medical imaging AI algorithms. A total of 173 papers published between 2010 and 2024 were reviewed, and 37 articles were selected for detailed analysis, with classification into two categories: detection and mitigation approaches. Detection methods include model-centric, data-centric, and uncertainty and bias-based approaches, while mitigation strategies encompass data manipulation techniques, feature disentanglement and suppression, and domain knowledge-driven approaches. Despite the progress in detecting and mitigating the Clever Hans effect, the majority of current machine learning studies in medical imaging do not report or test for shortcut learning, highlighting the need for more rigorous validation and transparency in AI research. Future research should focus on creating standardized benchmarks, developing automated detection tools, and exploring the integration of detection and mitigation strategies to comprehensively address shortcut learning. Establishing community-driven best practices and leveraging interdisciplinary collaboration will be crucial for ensuring more reliable, generalizable, and equitable AI systems in healthcare., Competing Interests: Declarations. Ethics Approval: This study is a literature review and does not involve human or animal participants, nor does it include any original data collection. Therefore, ethics committee approval was not required. Consent to Participate: As this study is a literature review and does not involve the collection of new data from human or animal subjects, obtaining consent to participate was not applicable. Consent for Publication: This study is a literature review and does not involve individual data or images from participants. Therefore, obtaining consent to publish is not applicable. Conflict of Interest: The authors declare no competing interests., (© 2024. The Author(s) under exclusive licence to Society for Imaging Informatics in Medicine.)

Introduction: Minimal important change estimates (MIC) are useful for interpreting results of clinical research with quality of life (QoL) as an endpoint. For the European Organisation for Research and Treatment of Cancer head and neck cancer module, the EORTC QLQ-HN43, no such thresholds are established., Methods: Head and neck cancer patients under active treatment (n = 503) from 15 countries completed the EORTC QLQ-HN43 three times (t1: before treatment, t2: three months after t1, t3: six months after t1). A subgroup completed a Subjective Significance Questionnaire (SSQ), indicating experienced change from the previous time point in four QoL domains. QoL was assumed to deteriorate after t1 and improve again until t3. The MIC was established using the average of mean differences in SSQ groups (MIC mean ) and estimates based on logistic regressions (MIC predict ). Additionally, minimal detectable changes (MDC) were computed using 0.5 standard deviation and standard error of the mean., Results: For swallowing, speech, dry mouth, and global QoL, the MIC for deterioration were 13, 14, 26, and 10 respectively. The MIC for improvement were 8 (swallowing), 6 (dry mouth), and 5 (global QoL); no MIC for speech improvement can be presented because of insufficient correlation between change score and anchor. The MDC estimates for deterioration were 15, 14, 15, and 11. For improvement, the MDC estimates were 13, 14, 14, and 11., Conclusions: Our results underline that no single MIC or MDC can be applied to all EORTC QLQ-HN43 scales, and that the MIC for deterioration seems larger than those for improvement., Competing Interests: Declaration of Competing Interest Authors declare they have no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study reported a case of an arachnoid cyst of the sphenoid bone causing orbital signs and symptoms in a 58-year-old man with progressive proptosis and nonspecific discomfort in the OS. Orbital MRI showed a 3-cm homogeneous cyst within the left greater wing of the sphenoid bone. To the best of our knowledge, this is the first report of an intradiploic arachnoid cyst in the sphenoid bone with atypical radiological features, causing clinical symptoms, and managed through an eyelid approach, achieving a complete resolution with no complications., Competing Interests: The authors have no financial or conflicts of interest to disclose., (Copyright © 2024 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.)

Millicharged particles appear in several extensions of the standard model, but have not yet been detected. These hypothetical particles could be produced by an intense proton beam striking a fixed target. We use data collected in 2020 by the SENSEI experiment in the MINOS cavern at the Fermi National Accelerator Laboratory to search for ultrarelativistic millicharged particles produced in collisions of protons in the NuMI beam with a fixed graphite target. The absence of any ionization events with 3 to 6 electrons in the SENSEI data allow us to place world-leading constraints on millicharged particles for masses between 30 to 380 MeV. This work also demonstrates the potential of utilizing low-threshold detectors to investigate new particles in beam-dump experiments, and motivates a future experiment designed specifically for this purpose.

Background: Immunotherapy-based combinations have emerged as standard therapies for patients with metastatic renal cell carcinoma (mRCC). Pembrolizumab, a PD-1 inhibitor, combined with epacadostat, an indoleamine 2,3-deoxygenase 1 selective inhibitor, demonstrated promising antitumor activity in a phase 1 study in advanced solid tumors, including mRCC., Methods: KEYNOTE-679/ECHO-302 was a randomized, open-label, parallel-group, multicenter, phase 3 study (NCT03260894) that compared pembrolizumab plus epacadostat with sunitinib or pazopanib as first-line treatment for mRCC. Eligible patients had histologically confirmed locally advanced or metastatic clear cell RCC and had not received systemic therapy. Patients were randomly assigned 1:1 to pembrolizumab 200 mg IV every 3 weeks plus epacadostat 100 mg orally twice daily versus sunitinib 50 mg orally once daily (4 weeks on treatment followed by 2 weeks off treatment) or pazopanib 800 mg orally once daily. Original dual primary end points were progression-free survival and overall survival. Enrollment was stopped when a phase 3 study in melanoma of pembrolizumab plus epacadostat compared with pembrolizumab monotherapy did not meet its primary end point. This protocol was amended, and primary end point was changed to investigator-assessed objective response rate (ORR) per RECIST 1.1., Results: One-hundred-twenty-nine patients were randomly assigned to receive pembrolizumab plus epacadostat (n = 64) or sunitinib/pazopanib (n = 65). Median (range) follow-up, defined as time from randomization to data cutoff, was 10.3 months (2.2-14.3) and 10.3 months (2.7-13.8) in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. ORRs were similar between pembrolizumab plus epacadostat (31.3% [95% CI 20.2-44.1] and sunitinib/pazopanib (29.2% [18.6-41.8]). Grade 3-5 treatment-related adverse events occurred in 34.4% and 42.9% of patients in the pembrolizumab plus epacadostat and sunitinib/pazopanib arms, respectively. One patient in the sunitinib/pazopanib arm died of septic shock (not treatment-related). Circulating kynurenine levels decreased in the pembrolizumab plus epacadostat arm, but not to levels observed in healthy subjects., Conclusions: ORRs were similar between pembrolizumab plus epacadostat and sunitinib/pazopanib as first-line treatment in patients with mRCC. Safety and tolerability appeared similar between treatment arms; no new safety concerns were identified. Antitumor responses observed in patients with RCC receiving pembrolizumab plus epacadostat may be driven primarily by pembrolizumab., Clinical Trial Registration: ClinicalTrials.gov; NCT03260894 ., (© 2023. The Author(s).)

Population aging represents a critical issue for global cancer care, notably in low- and middle-income countries (LMIC). Latin America is a large region composed of 21 countries with notable diversity in both human development and access to quality healthcare. Thus, it is necessary to understand how care for older individuals is being delivered in such large and diverse regions of the world. This review describes the recent advances made in Mexico, Brazil, and Chile, focusing on the creation and implementation of educational, research, and clinical activities in geriatric oncology. These initiatives intend to change healthcare professionals' perceptions about the care for older adults and to improve the way older patients are being treated., Competing Interests: Declaration of Competing Interest Enrique Soto-Perez-de-Celis reports receiving payments for honoraria from Lactealis. The other authors have no conflicts of interest to disclose., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: Uncomplicated Staphylococcus aureus bacteremia remains a leading cause of morbidity and mortality in hospitalized patients. Current guidelines recommend a minimum of 14 days of treatment., Objective: To evaluate the efficacy and safety of short versus usual antibiotic therapy in adults with uncomplicated S . aureus bacteremia (SAB)., Methods: We developed a search strategy to identify systematic review and meta-analysis of non-randomized studies (NRS), comparing short versus usual or long antibiotic regimens for uncomplicated SAB in MEDLINE, Embase, and the Cochrane Register up to June 2023. The risk of bias was assessed using the ROBINS I tool. The meta-analysis was performed using Review Manager software with a random effect model., Results: Six NRS with a total of 1700 patients were included. No significant differences were found when comparing short versus prolonged antibiotic therapy as defined by the authors for 90-day mortality [odds ratio (OR): 1.09; 95% confidence interval (CI): 0.82-1.46, p : 0.55; I 2  = 0%] or 90-day recurrence or relapse of bacteremia [OR: 0.72; 95% CI: 0.31-1.68, p : 0.45; I 2  = 26%]. Sensitivity analysis showed similar results when comparing a predefined duration of <14 days versus ⩾14 days and when excluding the only study with a high risk of bias., Conclusion: Shorter-duration regimens could be considered as an alternative option for uncomplicated SAB in low-risk cases. However, based on a small number of studies with significant methodological limitations and risk of bias, the benefits and harms of shorter regimens should be analyzed with caution. Randomized clinical trials are needed to determine the best approach regarding the optimal duration of therapy., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: In the randomized, controlled, phase III KEYNOTE-061 trial, second-line pembrolizumab did not significantly prolong overall survival (OS) versus paclitaxel in patients with PD-L1-positive (combined positive score ≥1) advanced gastric/gastroesophageal junction (G/GEJ) cancer but did elicit a longer duration of response and offered a favorable safety profile. This prespecified exploratory analysis was conducted to evaluate associations between tumor gene expression signatures and clinical outcomes in the phase III KEYNOTE-061 trial., Methods: Using RNA sequencing data obtained from formalin-fixed, paraffin-embedded baseline tumor tissue samples, we evaluated the 18-gene T-cell-inflamed gene expression profile (Tcell inf GEP) and 10 non-Tcell inf GEP signatures (angiogenesis, glycolysis, granulocytic myeloid-derived suppressor cell (gMDSC), hypoxia, monocytic MDSC (mMDSC), MYC, proliferation, RAS, stroma/epithelial-to-mesenchymal transition/transforming growth factor-β, WNT). The association between each signature on a continuous scale and outcomes was analyzed using logistic (objective response rate (ORR)) and Cox proportional hazards regression (progression-free survival (PFS) and OS). One-sided (pembrolizumab) and two-sided (paclitaxel) p values were calculated for Tcell inf GEP (prespecified α=0.05) and the 10 non-Tcell inf GEP signatures (multiplicity-adjusted; prespecified α=0.10)., Results: RNA sequencing data were available for 137 patients in each treatment group. Tcell inf GEP was positively associated with ORR (p=0.041) and PFS (p=0.026) for pembrolizumab but not paclitaxel (p>0.05). The Tcell inf GEP-adjusted mMDSC signature was negatively associated with ORR (p=0.077), PFS (p=0.057), and OS (p=0.033) for pembrolizumab, while the Tcell inf GEP-adjusted glycolysis (p=0.018), MYC (p=0.057), and proliferation (p=0.002) signatures were negatively associated with OS for paclitaxel., Conclusions: This exploratory analysis of tumor Tcell inf GEP showed associations with ORR and PFS for pembrolizumab but not for paclitaxel. Tcell inf GEP-adjusted mMDSC signature was negatively associated with ORR, PFS, and OS for pembrolizumab but not paclitaxel. These data suggest myeloid-driven suppression may play a role in resistance to PD-1 inhibition in G/GEJ cancer and support a strategy of considering immunotherapy combinations which target this myeloid axis., Trial Registration Number: NCT02370498., Competing Interests: Competing interests: KS: reports receiving research funding paid to his institution from Astellas Pharma, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai Pharma, MSD, Amgen, Eisai, and Medi Science; consulting fees for advisory role from Eli Lilly and Company, Bristol Myers Squibb, Takeda Pharmaceuticals, Pfizer, Ono Pharmaceutical, Novartis, AbbVie, Daiichi Sankyo, Taiho Pharmaceutical, GlaxoSmithKline, Amgen, Boehringer Ingelheim, MSD, Astellas, Guardant Health Japan, and Janssen; and honoraria for lectures from Bristol Myers Squibb, Takeda Pharmaceuticals, and Janssen. MDB: reports participation on a data safety monitoring board/advisory board for MDS. MM: reports no disclosures. M-HR: reports receiving consulting fees from Ono Pharmaceutical, Bristol Myers Squibb, MSD, Eli Lilly, Taiho, Novartis, AstraZeneca, and Daiichi Sankyo. CC: reports receiving payment or honoraria from MSD and Roche, and other financial or nonfinancial interests paid to his institution for participating as a principal investigator or subinvestigator for MSD, Medivation, AstraZeneca, Roche, Astellas Pharma, Bristol Myers Squibb, GlaxoSmithKline, Athenex, Daiichi Sankyo, and Sanofi. TO: reports no disclosures. HCC: reports receiving study material and medical writing support for the present work from Merck; grants or contracts paid to his institution by Eli Lilly, GSK, MSD, Merck Serono, Bristol Myers Squibb/Ono Pharmaceutical, Taiho, Amgen, BeiGene, Incyte, and Zymeworks; consulting fees from Taiho, Celltrion Healthcare, MSD, Eli Lilly, Bristol Myers Squibb/Ono Pharmaceutical, Merck-Serono, Beigene/Amgen, and Zymeworks; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Merck Serono and Eli Lilly; and participation on a data safety monitoring board or advisory board for MSD. KM: reports receiving research funding paid to his institution from Solasia Pharma, Merck Serono, Daiichi Sankyo, Parexel International, Pfizer, MSD, Amgen, Ono Pharmaceutical, Astellas, Sanofi, Taiho, and Eisai; consulting fees from AstraZeneca, Ono Pharmaceutical, and Amgen; honoraria for lectures from Ono Pharmaceutical, Taiho, Bristol Myers Squibb, and Eli Lilly; and participation on an advisory board for Ono Pharmaceutical, Amgen, AstraZeneca, Eli Lilly, and Takeda. EG: reports no disclosures. RSM: reports no disclosures. WM: reports no disclosures. ZW: reports receiving support for the present work from Merck; grants paid to his institution from Novartis, Bristol Myers Squibb, Plexxikon, and Arcus; consulting fees from AstraZeneca, Arcus, Amgen, Bristol Myers Squibb, Novartis, Eli Lilly, Bayer, Daiichi, Merck, and Astellas; support for attending meetings and/or travel from Amgen; and participation on a data safety monitoring board or advisory board for Mirati and Pfizer. C-SS: employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, New Jersey, USA. JK: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. MN: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. RC: employee of Merck Sharp & Dohme, a subsidiary of Merck & Co., Rahway, New Jersey, USA, and has stock in Merck & Co., Rahway, New Jersey, USA; and reports a pending patent (WO 2020/167619) related to the application of Angiogenesis and mMDSC gene expression-based biomarker of tumor response to PD-1 antagonists. ZAC: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. AL: employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, New Jersey, USA, and has stock in Merck & Co., Inc., Rahway, NJ, USA. MÖ: reports no disclosures., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There are currently two authorized vaccines against herpes zoster (HZ) that have been shown to be safe and effective in its prevention: Zostavax, a zoster vaccine live (ZVL), and Shingrix, a recombinant zoster Vaccine (RZV). Because ophthalmologists work with vision-threatening complications of zoster, such as herpes zoster ophthalmicus (HZO), they are in a good position to advocate for vaccination. Our aim was to determine the current knowledge among Spanish ophthalmologists about the effectiveness of the available vaccines against HZ. A Google Forms questionnaire was created and used as the survey platform for this study. It was an anonymous online survey of 16 questions, which was shared among Spanish ophthalmologists in-training and consultants from 27 April 2022 to 25 May 2022. The survey was completed by a total of 206 ophthalmologists of all subspecialties. We obtained responses from 17 of the 19 regions of Spain. Fifty-five percent of the respondents agreed that HZ is a frequent cause of vision loss. However, 27% of the professionals were unaware of the existence of vaccines against HZ and 71% of them did not know in which cases it could be indicated. Only nine ophthalmologists (4%) had ever suggested vaccination against HZ to their patients. Despite this, 93% considered it important to recommend vaccination against HZ if it proved to be safe and effective. Considering the sequelae, complications, and the existence of safe and effective vaccines against HZ, vaccination of the target population could be considered an important public health measure. We are convinced that it is time for ophthalmologists to take an active role in HZO prevention.

The use of curved layers in fused filament fabrication could lead to various advantages in surface finishing and mechanical properties. Here, the influence of three different structural and manufacturing parameters (volume fraction, raster arrangement, and the use of curved or planar layers) on the mechanical properties of lattice structures under three-point bending is studied. Two different raster arrangements were considered, i.e., those with rasters at planes parallel to the principal axes of the samples and those diagonally arranged, all at four different volume fractions. All different samples were additively manufactured using planar and curved layers. Samples were further dimensionally inspected to refine the computational models before their analysis via finite element simulations. The linear elastic region of the load-displacement curves was further analyzed numerically via finite element models. Predictions with finite element models resulted in good agreement with errors below 10%. Samples with diagonal rasters were 70% softer than those parallel to the principal axes.

Worldwide, gastric cancer (GC) is the fifth most commonly diagnosed malignancy. It has a reduced prevalence but has maintained its poor prognosis being the fourth leading cause of deaths related to cancer. The highest mortality rates occur in Asian and Latin American countries, where cases are usually diagnosed at advanced stages. Overall, GC is viewed as the consequence of a multifactorial process, involving the virulence of the Helicobacter pylori ( H. pylori ) strains, as well as some environmental factors, dietary habits, and host intrinsic factors. The tumor microenvironment in GC appears to be chronically inflamed which promotes tumor progression and reduces the therapeutic opportunities. It has been suggested that inflammation assessment needs to be measured qualitatively and quantitatively, considering cell-infiltration types, availability of receptors to detect damage and pathogens, and presence or absence of aggressive H. pylori strains. Gastrointestinal epithelial cells express several Toll-like receptors and determine the first defensive line against pathogens, and have been also described as mediators of tumorigenesis. However, other molecules, such as cytokines related to inflammation and innate immunity, including immune checkpoint molecules, interferon-gamma pathway and NETosis have been associated with an increased risk of GC. Therefore, this review will explore innate immune activation in the context of premalignant lesions of the gastric epithelium and established gastric tumors., Competing Interests: Conflict-of-interest statement: Dr. F. Villarroel-Espindola has received compensation from Ilico SpA. and Gebrax-Chile for consulting services. Other authors declare having no conflict of interests, neither real nor perceivable, in relation to this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective: 2-[ 18 F]fluoro-2-deoxy- d -glucose PET/computed tomography ([ 18 F]FDG-PET/CT) is a widely used imaging method in the management of diffuse large B-cell lymphomas (DLBCL). Our aim was to investigate the prognostic performance of different PET biomarkers in a multicenter setting., Methods: We investigated baseline volumetric values [metabolic tumor volume (MTV) and total lesion glycolysis (TLG), also normalized for body weight] segmented with three different methods [>SUV4 (glob4); 41% isocontour (41pc), and a gradient-based lesion growing algorithm (grad)] and interim parameters [Deauville score, maximal standardized uptake value (ΔSUVmax), modified qPET, and ratio PET (rPET)] alongside clinical parameters (stage, revised International Prognostic Index), using 24-month progression-free survival as the clinical endpoint. Receiver operating characteristics analyses were performed to define optimal cutoff points for the continuous PET parameters., Results: A total of 107 diffuse large B-cell lymphoma patients were included (54 women; mean age: 53.7 years). MTV and TLG calculations showed good correlation among glob4, 41pc, and grad methods; however, optimal cutoff points were markedly different.Significantly different PFS was observed between low- and high-risk groups according to baseline MTV, body weight-adjusted (bwa) MTV, TLG, bwaTLG, as well as interim parameters Deauville score, ΔSUVmax, mqPET, and rPET. Univariate Cox regression analyses showed hazard ratios (HRs) lowest for bwaMTVglob4 (HR = 2.3) and highest for rPET (HR = 9.09). In a multivariate Cox-regression model, rPET was shown to be an independent predictor of PFS ( P  = 0.041; HR = 9.15). Combined analysis showed that ΔSUVmax positive patients with high MTV formed a group with distinctly poor PFS (35.3%)., Conclusion: Baseline MTV and TLG values and optimal cutoff points achieved with different segmentation methods varied markedly and showed a limited prognostic impact. Interim PET/CT parameters provided more accurate prognostic information with semiquantitative 'Deauville-like' parameters performing best in the present study., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Introduction: A high prevalence of advanced breast cancer (BC) is a common scenario in Latin America. In Peru, the frequency of BC at Stages III/IV is ≈50% despite implementation of a programme for breast cancer screening (BCS) along the country. We carried out a study to assess the feasibility and develop an instrument to evaluate the knowledge, barriers and perception about BCS in a nationwide pilot study in Peru among candidates for BCS., Methods: We conducted a systematic review of 2,558 reports indexed in PubMed, Scopus, Web of Science, Medline-Ovid and EMBASE, regarding to our study theme. In total, 111 were selected and a 51-items survey was developed (eight items about sociodemographic characteristics). Patients were recruited in public hospitals or private clinics, in rural and urban areas of nine departments of Peru., Results: We surveyed 488 women from: Lima (150), Cajamarca (93), Ica (59), Arequipa (56), Loreto (48), Ancash (38), Junín (15), Puerto Maldonado (15) and Huancavelica (14); 27.9% of them were from rural areas. The mean of age was 53.3 years (standard deviation ± 9.1). Regarding education level, 29.8% had primary, 33.2% secondary and 37.0% higher education. In total, 28.7% of women did not know the term 'mammogram' and 47.1% reported never receiving a BCS (36.9% from urban and 73.5% from rural population). In women that underwent BCS, only 67% knew it is for healthy women. In total, 54.1% of patients had low levels of knowledge about risk factors for BC (i.e. 87.5% of women respond that injuries in the breast produce cancer). Cultural, economic and geographic barriers were significantly associated with having a mammogram where 56.9% of participants considered a cost ≤ 7 USD as appropriate. Mammogram was perceived as too painful for 54.9% of women. In addition, women with a self-perception of low-risk for BC and a fatalistic perception of cancer were less likely to have a BCS., Conclusion: We found that it is feasible to conduct a large-scale study in Peru. The results of this pilot study highlight an urgent need of extensive education and awareness about BCS in Peru., Competing Interests: The authors declare that they have no conflicts of interest., (© the authors; licensee ecancermedicalscience.)

Purpose: To report the effectiveness of the surgical procedure of the tarsoconjunctival flap (FTC) in patients with severe ocular surface impairment refractory to previous conventional treatments., Methods: A retrospective, noncomparative, consecutive case series., Results: Pillar tarsoconjunctival flap (PTCF) was performed in eight eyes of eight patients. Three patients had neurotrophic corneal ulcer (NCU), three had exposure keratopathy and two had corneal melting. Seven of them had satisfactory postoperative results, showing total corneal re-epithelialization that lasted throughout the postoperative follow-up (mean 10.33 ± 2.65 months [SD], range 6 to 12 months). Mean time for the re-epithelization was 11.28 ± 8.97 days [SD] (range 4 to 30 days)., Conclusion: This study suggest PTCF is a valid alternative to tarsorrhaphy in cases of persistent epithelial defect (PED) or NCU resistant to conventional treatments. Notwithstanding, prospective comparative trials comparing PTFC with conventional and/or novel therapies in PED or NCU are needed to corroborate these findings.

Background: Multiple System Atrophy (MSA) is a rare neurodegenerative disease with pronounced autonomic failure (AF). Severe cardiovascular AF is associated with poor prognosis. Since sweating dysfunction is less well known, we investigated the interest of a quick and non-invasive assessment of sweating using electrochemical skin conductance (ESC) as a marker for AF in MSA., Methods: 138 MSA patients of the French Reference center for MSA with an annual follow-up including the Unified MSA Rating Scale (UMSARS), COMPASS (autonomic symptoms) and measurements of foot and hand ESC (Sudoscan®) participated to this study (age 65 ± 8 years, 66% probable MSA, 72% AMS-P). Statistical analysis included: (i) correlations between ESC and MSA type, age, disease duration, severity, blood pressure (BP), COMPASS, (ii) comparisons between groups with normal or abnormal ESC, and (iii) multivariate analysis by logistic regression. Relationships between severity progression during follow-up with ESC and other variables were modeled by Generalized Estimating Equation., Results: Hands and feet ESCs were abnormal in 81/138 (59%) and 93/138 (67%) cases, respectively. Abnormal ESCs were significantly correlated to disease severity and several features of AF. ESCs worsening over time was more pronounced than other autonomic features such as orthostatic hypotension. Abnormal ESCs at baseline were significantly associated with a higher progression of UMSARS's score during follow-up., Conclusion: Sweating dysfunction assessed by ESC is frequent in MSA and is significantly related to disease severity and AF. The gradual decrease in ESC with disease duration could be useful as a quantitative marker of autonomic dysfunction., Competing Interests: Declaration of competing interest None., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

On February 24, 2022, a war began within the Ukrainian borders. At least 3.0 million Ukrainian inhabitants have already fled the country. Critical infrastructure, including hospitals, has been damaged. Children with cancer were urgently transported to foreign countries, in an effort to minimize interruption of their life-saving treatments. Most adults did not have that option. War breeds cancer-delaying diagnosis, preventing treatment, and increasing risk. We project that a modest delay in care of only 4 months for five prevalent types of cancer will lead to an excess of over 3,600 cancer deaths in the subsequent years. It is critical that we establish plans to mitigate that risk as soon as possible., Competing Interests: Christian CaglevicConsulting or Advisory Role: MSD, RocheSpeakers' Bureau: MSD, RocheResearch Funding: Merck Sharp & Dohme, Medivation, AstraZeneca, Roche, Astellas Pharma, Bristol Myers Squibb, GlaxoSmithKline, Athenex Christian RolfoConsulting or Advisory Role: Archer, Inivata, Merck Serono, Bristol Myers Squibb, Novartis, Boston Pharmaceuticals, Eisai, Mirati TherapeuticsSpeakers' Bureau: MSD, AstraZeneca, Guardant Health, Roche Molecular DiagnosticsResearch Funding: Lung Cancer Research FoundationTravel, Accommodations, Expenses: AstraZenecaUncompensated Relationships: Guardant Health Ignacio Gil-BazoConsulting or Advisory Role: MSD Oncology, Lilly, AstraZeneca Spain, Bristol Myers Squibb/CelgeneSpeakers' Bureau: MSD Oncology, AstraZeneca, Bristol Myers Squibb/Celgene, Roche, AmgenTravel, Accommodations, Expenses: MSD Oncology, Lilly Andrés CardonaHonoraria: Bristol Myers Squibb, Roche, Boehringer Ingelheim, AbbVie, Merck Sharp & Dohme, CelldexConsulting or Advisory Role: Roche, Merck Sharp & Dohme, Novartis, AstraZeneca, Bristol Myers Squibb, Foundation Medicine, Boehringer Ingelheim, Foundation for Clinical and Applied Cancer Research (FICMAC)Speakers' Bureau: Merck Sharp & Dohme, Roche, Bristol Myers Squibb, Novartis, Foundation for Clinical and Applied Cancer Research (FICMAC), Foundation MedicineTravel, Accommodations, Expenses: Merck Sharp & Dohme, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Foundation Medicine Fred R. HirschConsulting or Advisory Role: AstraZeneca, Genentech, Merck, Bristol Myers Squibb, Novartis, Amgen, Oncocyte, Sanofi/Regeneron, Daiichi Sankyo/UCB Japan, Nectin Therapeutics, Novocure, Blueprint MedicinesPatents, Royalties, Other Intellectual Property: EGFR FISH and IHC for prediction of outcome in patients treated with EGFR inhibitors (Inst)Expert Testimony: Gerson Lehrman Group David R. GandaraHonoraria: Merck, AmgenConsulting or Advisory Role: AstraZeneca (Inst), Guardant Health (Inst), OncoCyte (Inst), IO Biotech (Inst), Roche/Genentech (Inst), Lilly, Novartis, Adagene (Inst), OncoHost (Inst), Ocean Genomics (Inst), Daiichi Sankyo Alliance, SanofiResearch Funding: Merck (Inst), Amgen (Inst), Genentech (Inst), AstraZeneca (Inst) Gilberto MorganConsulting or Advisory Role: Novartis Silvia NovelloConsulting or Advisory Role: SanofiSpeakers' Bureau: AstraZeneca, MSD, Bristol Myers Squibb, Roche, Pfizer, Lilly, Takeda, AbbVie, Boehringer Ingelheim, Bayer, Amgen, Beigene, Novartis, Janssen Marina-Chiara GarassinoHonoraria: MSD Oncology, AstraZeneca/MedImmune, GlaxoSmithKline, Takeda, Roche, Bristol Myers SquibbConsulting or Advisory Role: Bristol Myers Squibb, MSD, AstraZeneca, Novartis, Takeda, Roche, Tiziana Life Sciences, Sanofi, Celgene, Daiiki Sankyo, Inivata, Incyte, Pfizer, Seattle Genetics, Lilly, GlaxoSmithKline, Bayer, Blueprint Medicines, Janssen, RegeneronSpeakers' Bureau: AstraZeneca, Takeda, MSD Oncology, Celgene, Incyte, Roche, Bristol Myers Squibb, Otsuka, LillyResearch Funding: Bristol Myers Squibb (Inst), MSD (Inst), Roche/Genentech (Inst), AstraZeneca/MedImmune (Inst), Pfizer (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Merck (Inst), Incyte (Inst), Takeda (Inst), Spectrum Pharmaceuticals (Inst), Blueprint Medicines (Inst), Lilly (Inst), AstraZeneca (Inst), Ipsen (Inst), Janssen (Inst), Exelixis (Inst), MedImmune (Inst), Sanofi (Inst), Amgen (Inst)Travel, Accommodations, Expenses: Pfizer, Roche, AstraZeneca Giannis MountziosHonoraria: Roche, Boehringer Ingelheim, AstraZeneca, MSD, BMS GmbH & Co KG, Novartis, Amgen, TakedaConsulting or Advisory Role: Roche, Astra Zeneca Greece, MSD, Amgen, Novartis, BMS GmbH & Co KG, TakedaSpeakers' Bureau: AstraZenecaTravel, Accommodations, Expenses: AstraZeneca, Ipsen, MSD, Roche, Novartis, BMS GmbH & Co KG Natasha B. LeighlResearch Funding: Roche Canada (Inst), Guardant Health (Inst), MSD (Inst), EMD Serono (Inst), Lilly (Inst), AstraZeneca Canada (Inst), Takeda (Inst), Amgen (Inst), Bayer (Inst), MSD Oncology (Inst)Travel, Accommodations, Expenses: Merck Sharp & Dohme Oscar ArrietaHonoraria: Pfizer, AstraZeneca, Boehringer Ingelheim, RocheConsulting or Advisory Role: AstraZeneca, Roche, Lilly, Merck, Bristol Myers SquibbResearch Funding: Roche (Inst), BMS (Inst), Merck (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Lilly Alfredo AddeoConsulting or Advisory Role: Roche, AstraZeneca/MedImmune, Bristol Myers Squibb Foundation, MSD Oncology, Pfizer, Novartis, Astellas Pharma, Amgen, LillySpeakers' Bureau: Lilly, AstraZeneca/MedImmuneTravel, Accommodations, Expenses: Roche, Takeda Stephen V. LiuConsulting or Advisory Role: Genentech, Lilly, Bristol Myers Squibb, AstraZeneca, Takeda, Regeneron, Guardant Health, Janssen Oncology, MSD Oncology, Jazz Pharmaceuticals, Blueprint Medicines, Daiichi Sankyo/UCB Japan, BeiGene, Amgen, Turning Point Therapeutics, Elevation Oncology, Novartis, Eisai, Bayer, Gilead Sciences, SanofiResearch Funding: Genentech/Roche (Inst), Pfizer (Inst), Bayer (Inst), Merck (Inst), Blueprint Medicines (Inst), Lilly (Inst), Rain Therapeutics (Inst), Alkermes (Inst), Bristol Myers Squibb (Inst), Turning Point Therapeutics (Inst), RAPT Therapeutics (Inst), Merus (Inst), Elevation Oncology (Inst), Nuvalent, Inc (Inst), Gilead Sciences (Inst)Travel, Accommodations, Expenses: Caris Life Sciences Luis CorralesConsulting or Advisory Role: AstraZeneca, Roche, MSD Oncology, PfizerSpeakers' Bureau: Roche, AstraZeneca, MSD OncologyResearch Funding: RocheTravel, Accommodations, Expenses: Roche, AstraZeneca, MSD Oncology Vivek SubbiahConsulting or Advisory Role: MedImmune, Helsinn Therapeutics, Loxo, R-Pharm, QED TherapeuticsResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), NanoCarrier (Inst), Northwest Biotherapeutics (Inst), Genentech/Roche (Inst), Berg Pharma (Inst), Bayer (Inst), Incyte (Inst), Fujifilm (Inst), PharmaMar (Inst), D3 Oncology Solutions (Inst), Pfizer (Inst), Amgen (Inst), AbbVie (Inst), Multivir (Inst), Blueprint Medicines (Inst), LOXO (Inst), Vegenics (Inst), Takeda (Inst), Alfasigma (Inst), Agensys (Inst), Idera (Inst), Boston Biomedical (Inst), Inhibrx (Inst), Exelixis (Inst), Turning Point Therapeutics (Inst)Travel, Accommodations, Expenses: PharmaMar, Bayer, Novartis, Helsinn TherapeuticsOther Relationship: Medscape Franz Villarroel-EspindolaConsulting or Advisory Role: Ilico GeneticsResearch Funding: Gebrax-Chile Laboratory & Gebrax Cia Ltda Ricardo MoralesConsulting or Advisory Role: Pfizer Luis RaezResearch Funding: Genentech/Roche (Inst), Merck Serono (Inst), Boehringer Ingelheim (Inst), Novartis (Inst), Pfizer (Inst), Syndax (Inst), Loxo (Inst), Merck (Inst), Bristol Myers Squibb (Inst), Guardant Health (Inst), Heat Biologics (Inst), Amgen (Inst), Calithera Biosciences (Inst), Daiichi Sankyo/UCB Japan (Inst), NantHealth (Inst) Jorge AlatorreHonoraria: Bristol Myers Squibb (Mexico), AstraZeneca, Roche/GenentechConsulting or Advisory Role: MSD Oncology, AstraZeneca, Roche/Genentech, Bristol Myers Squibb, NovartisSpeakers' Bureau: Roche/Genentech, AstraZeneca, MSDTravel, Accommodations, Expenses: AstraZeneca, Roche Edgardo SantosSpeakers' Bureau: Genentech/Roche, Pfizer, Amgen, Boehringer Ingelheim, Merck, Novartis, AstraZeneca, Takeda, Genzyme, Lilly, Astellas Pharma, G1 Therapeutics, Regeneron Luis UbillosHonoraria: Tecnofarma, Fármaco UruguayoConsulting or Advisory Role: Tecnofarma, Roche, Fármaco Uruguayo, PfizerSpeakers' Bureau: Tecnofarma, RocheTravel, Accommodations, Expenses: GlaxoSmithKline, Roche, Pfizer, AstraZeneca, Tecnofarma Daniel S.W. TanHonoraria: Bristol Myers Squibb, Takeda, Novartis, Roche, PfizerConsulting or Advisory Role: Novartis, Merck, Loxo, AstraZeneca, Roche, Pfizer, C4 TherapeuticsResearch Funding: Novartis (Inst), GlaxoSmithKline (Inst), AstraZeneca (Inst)Travel, Accommodations, Expenses: Pfizer, Boehringer Ingelheim, Roche Christoph ZielinskiHonoraria: Athenex, MSD, Roche, AstraZeneca, ImugeneConsulting or Advisory Role: Roche (Inst), Merck Sharp & Dohme (Inst), Imugene, Fibrogen (Inst), AstraZeneca (Inst), Servier (Inst), Athenex, Lilly (Inst), Amgen (Inst), Bristol Myers Squibb (Inst)Research Funding: Pfizer (Inst), Bristol Myers Squibb (Inst), AstraZeneca (Inst), Merck Sharp & Dohme (Inst)Patents, Royalties, Other Intellectual Property: Patent Property, ImugeneNo other potential conflicts of interest were reported.

Background: The expression of SYK in cancer cells has been associated with both tumor promoting and tumor suppressive effects. Despite being proposed as anticancer therapeutic target, the possible role of SYK in modulating local adaptive antitumor immune responses remains uncertain. Using detailed analysis of primary human tumors and in vitro models, we reveal the immunomodulatory effect of SYK protein in human solid cancer., Methods: We spatially mapped SYK kinase in tumor cells, stromal cells and tumor-infiltrating leukocytes (TILs) in 808 primary non-small cell lung carcinomas (NSCLCs) from two cohorts and in 374 breast carcinomas (BCs) from two independent cohorts. We established the associations of localized SYK with clinicopathologic variables and outcomes. The immunomodulatory role of SYK on tumor cells was assessed using in vitro cytokine stimulation, transcriptomic analysis and selective SYK blockade using a small molecule inhibitor. Functional responses were assessed using cocultures of tumor cells with peripheral blood lymphocytes. T cell responses in baseline and post-treatment biopsies from patients with BC treated with a SYK inhibitor in a phase I clinical trial were also studied., Results: Elevated tumor cell or leukocyte SYK expression was associated with high CD4 + and CD8 + TILs and better outcome in both NSCLC and BC. Tumor cell SYK was associated with oncogenic driver mutations in EGFR or KRAS in lung adenocarcinomas and with triple negative phenotype in BC. In cultured tumor cells, SYK was upregulated by TNFα and required for the TNFα-induced proinflammatory responses and T cell activation. SYK blockade after nivolumab in a phase I clinical trial including three patients with advanced triple negative BC reduced TILs and T cell proliferation. Our work establishes the proinflammatory function of tumor cell SYK in lung and breast cancer. SYK signaling in cultured tumor cells is required for T cell activation and SYK blockade limits adaptive antitumor immune responses and tumor rejection in patients with cancer., Conclusions: Together, our results establish the immunomodulatory role of SYK expression in human solid tumors. This information could be used to develop novel biomarkers and/or therapeutic strategies., Competing Interests: Competing interests: KAS reports research funding from Navigate Biopharma, Tesaro/GlaxoSmithKline, Moderna Inc, Takeda, Surface Oncology, Pierre-Fabre Research Institute, Merck-Sharp & Dohme, Bristol-Myers Squibb, AstraZeneca, Ribon Therapeutics, Akoya Biosciences, Eli Lilly and Boehringer-Ingelheim. KAS has received honoraria for consultant/advisory/speaker roles from Moderna Inc, Shattuck Labs, Pierre-Fabre, AstraZeneca, EMD Serono, Ono Pharmaceuticals, Clinica Alemana de Santiago, Dynamo Therapeutics, PeerView, Abbvie, Fluidigm, Takeda/Millenium Pharmaceuticals, Merck-Sharp & Dohme, Bristol Myers-Squibb, Agenus, Parthenon Therapeutics, Molecular Templates, and Torque Therapeutics., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Penile, vulvar and anal neoplasms show an incidence lower than 0.5% of the population per year and therefore can be considered as rare cancers but with a dramatic impact on quality of life and survival. This work describes the experience of a Chilean cancer center using multiplexed immunofluorescence to study a case series of four penile cancers, two anal cancers and one vulvar cancer and simultaneous detection of CD8, CD68, PD-L1, Cytokeratin and Ki-67 in FFPE samples. Fluorescent image analyses were performed using open sources for automated tissue segmentation and cell phenotyping. Our results showed an objective and reliable counting of objects with a single or combined labeling or within a specific tissue compartment. The variability was below 10%, and the correlation between analytical events was 0.92-0.97. Critical cell phenotypes, such as TILs, PD-L1+ or proliferative tumor cells were detected in a supervised and unsupervised manner with a limit of detection of less than 1% of relative abundance. Finally, the observed diversity and abundance of the different cell phenotypes within the tumor microenvironment for the three studied tumor types confirmed that our methodology is useful and robust to be applicable for many other solid tumors.

The current paper describes the work carried out in the Horizon 2020 AFTERLIFE project -  "Advanced Filtration TEchnologies for the Recovery and Later conversIon of relevant Fractions from wastEwater" - (Grant Agreement no. 745737) which focuses on bioprocess modelling and optimisation using computational tools. The project addresses the development of a flexible, cost- and resource-efficient process framed in the zero-waste and circular economy approach for the recovery and valorisation of the relevant fractions from wastewater. The first step of such a process is an initial step consisting of a cascade of membrane filtration units to separate the total solids in sewage. Then, the concentrates recovered in each unit will be treated to obtain high-pure extracts and metabolites or to be converted into value-added biopolymers (polyhydroxyalkanoates). Moreover, the outflow of the process is an ultra-pure water stream that can be directly reused. Following a holistic approach, the design and optimisation of the AFTERLIFE process will improve performance and reduce the costs associated with wastewater treatment by maximising the value recovery. The paper focuses on the work done developing and implementing computational tools to model and optimise the design of the process. A framework for modelling-based optimisation has been developed. The applied optimisation approach is not computationally demanding and can be systematically applied to different processes. Finally, a use case establishing a scenario for testing the developed framework is described. The defined process model and optimisation methodology were applied to simulate the treatment of wastewater from the fish processing industry. The performance of the optimisation tool is analysed considering the simulation results., Competing Interests: No competing interests were disclosed., (Copyright: © 2022 Rodriguez-Perez S et al.)

Many studies have focused on the metabolic capacity of human gut microbiota to produce short-chain fatty acids and subsequent effects on host physiology. Given scarce data on how SCFAs produced by gut bacteria participate in cross-feeding to influence community structure and function, we evaluated the potential of SCFAs to modulate human gut microbiota in vitro. We employed anaerobic fecal cultivation in chemically defined medium supplemented with one of nine SCFAs to determine effects on both gut microbial community structure via 16S rRNA sequencing and function via genome reconstruction analysis. Each SCFA displayed significant and unique modulatory potential with respect to the relative abundance of bacterial taxa. Analysis of SCFA-supplemented communities revealed that alterations of individual closely related phylotypes displayed coherent changes, although exceptions were also observed which suggest strain-dependent differences in SCFA-induced changes. We used genome reconstruction to evaluate the functional implications of SCFA-mediated restructuring of fecal communities. We note that some SCFA-supplemented cultures displayed a reduction in the predicted abundance of SCFA producers, which suggests a possible undefined negative feedback mechanism. We conclude that SCFAs are not simply end-products of metabolism but also serve to modulate the gut microbiota through cross-feeding that alters the fitness of specified taxa. These results are important in the identification of prebiotics that elevate specific SCFAs for therapeutic benefit and highlight SCFA consumers as a salient part of the overall metabolic flux pertaining to bacterial fermentative processes., (© 2022. The Author(s).)

Purpose: The aim of this study was to explore what methods should be used to determine the minimal important difference (MID) and minimal important change (MIC) in scores for the European Organisation for Research and Treatment of Cancer Head and Neck Cancer Module, the EORTC QLQ-HN43., Methods: In an international multi-centre study, patients with head and neck cancer completed the EORTC QLQ-HN43 before the onset of treatment (t1), three months after baseline (t2), and six months after baseline (t3). The methods explored for determining the MID were: (1) group comparisons based on performance status; (2) 0.5 and 0.3 standard deviation and standard error of the mean. The methods examined for the MIC were patients' subjective change ratings and receiver-operating characteristics (ROC) curves, predictive modelling, standard deviation, and standard error of the mean. The EORTC QLQ-HN43 Swallowing scale was used to investigate these methods., Results: From 28 hospitals in 18 countries, 503 patients participated. Correlations with the performance status were |r|< 0.4 in 17 out of 19 scales; hence, performance status was regarded as an unsuitable anchor. The ROC approach yielded an implausible MIC and was also discarded. The remaining approaches worked well and delivered MID values ranging from 10 to 14; the MIC for deterioration ranged from 8 to 16 and the MIC for improvement from - 3 to - 14., Conclusions: For determining MIDs of the remaining scales of the EORTC QLQ-HN43, we will omit comparisons of groups based on the Karnofsky Performance Score. Other external anchors are needed instead. Distribution-based methods worked well and will be applied as a starting strategy for analyses. For the calculation of MICs, subjective change ratings, predictive modelling, and standard-deviation based approaches are suitable methods whereas ROC analyses seem to be inappropriate., (© 2021. The Author(s).)

Introduction: In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up., Methods: Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs)., Results: After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65-0.90) and PD-L1 less than 1% (0.64; 0.51-0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population., Conclusions: At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Major advances in sequencing technologies and targeted therapies have accelerated the incorporation of oncology into the era of precision medicine and "biomarker-driven" treatments. However, the impact of this approach on the everyday clinic has yet to be determined. Most precision oncology reports are based on developed countries and usually involve metastatic, hard-to-treat or incurable cancer patients. Moreover, in many cases race and ethnicity in these studies is commonly unreported and real-world evidence in this topic is scarce. Herein, we report data from a total of 202 Chilean advanced stage refractory cancer patients. Retrospectively, we collected patient data from NGS tests and IHC in order to determine the proportion of patients that would benefit from targeted treatments. Overall >20 tumor types were included in our cohort and 37% of patients ( n = 74) displayed potentially actionable alterations, including on-label, off-label and immune checkpoint inhibitor recommendations. Our findings were in-line with previous reports such as the cancer genome atlas (TCGA). To our knowledge, this is the first report of its kind in Latin America delivering real-world evidence to estimate the percentage of refractory tumor patients that might benefit from precision oncology. Although this approach is still in its infancy in Chile, we strongly encourage the implementation of mutational tumor boards in our country in order to provide more therapeutic options for advanced stage refractory patients., Competing Interests: The authors declare no conflicts of interest.

Background: Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation., Methods: In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review., Results: The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group., Conclusions: The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.)., (Copyright © 2022 Massachusetts Medical Society.)

Abstract: Perivascular epithelioid cell tumors (PEComas) are infrequent mesenchymal neoplasms that have particular histological and immunohistochemical features. Only a few cases have been described in the eye and orbit. This report presents a 28-year-old man who consulted for a painless left orbital mass. With the presumptive diagnosis of cavernous hemangioma, a surgical excisional biopsy was performed. Histopathological examination showed a well-delimited tumor composed of epithelioid cells with an eosinophilic cytoplasm and oval nucleus. The tumor cells stained diffusely for HMB-45 and transcription factor E3 (TFE3) and were focally positive for actin. There was no reactivity to S100 or desmin. Genetic testing revealed a TFE3 rearrangement. Based on these results, an extremely rare orbital TFE3-rearranged PEComa was diagnosed. Although no recurrence was seen at last follow-up, a review of the literature shows experience is limited regarding orbital PEComas and their malignant potential. Further research is needed to establish management guidelines, their association with the tuberous sclerosis complex, and the role of genetic mutations such as TFE3 rearrangement., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: In the phase III KEYNOTE-061 trial (NCT02370498), pembrolizumab did not significantly improve overall survival versus paclitaxel as second-line therapy for gastric/gastroesophageal junction (GEJ) adenocarcinoma with programmed death-ligand 1 (PD-L1) combined positive score (CPS) ≥1 tumors. The association of tissue tumor mutational burden (tTMB) status and clinical outcomes was determined, including the relationship with CPS and microsatellite instability-high (MSI-H) status., Patients and Methods: In patients with whole exome sequencing (WES) data [420/592 (71%); pembrolizumab, 218; paclitaxel, 202], the association of tTMB with objective response rate (ORR; logistic regression), progression-free survival (PFS; Cox proportional hazards regression), and overall survival (OS; Cox proportional hazards regression) were measured using one-sided (pembrolizumab) and two-sided [paclitaxel] P values. tTMB was also evaluated using FoundationOne®CDx [205/592 (35%)]. Prespecified equivalent cut-offs of 175 mut/exome for WES and 10 mut/Mb for FoundationOne®CDx were used., Results: WES-tTMB was significantly associated with ORR, PFS, and OS in pembrolizumab-treated (all P < 0.001) but not paclitaxel-treated patients (all P > 0.6) in univariate analysis. The area under the receiver operating characteristics curve for WES-tTMB and response was 0.68 [95% confidence interval (CI) 0.56-0.81] for pembrolizumab and 0.51 (95% CI 0.39-0.63) for paclitaxel in univariate analysis. There was low correlation between WES-tTMB and CPS in both treatment groups (r ≤ 0.16). WES-tTMB remained significantly associated with all clinical endpoints with pembrolizumab after adjusting for CPS and with PFS and OS after excluding known MSI-H tumors (n = 26). FoundationOne®CDx-tTMB demonstrated a positive association with ORR, PFS, and OS in pembrolizumab-treated patients (all P ≤ 0.003) but not PFS or OS in paclitaxel-treated patients (P > 0.1)., Conclusion: This exploratory analysis from KEYNOTE-061 is the first to demonstrate a strong association between tTMB and efficacy with pembrolizumab but not paclitaxel in patients with gastric/GEJ adenocarcinoma in a randomized setting. Data further suggest tTMB is a significant and independent predictor beyond PD-L1 status., Competing Interests: Disclosure KS reports honoraria for AbbVie, Novartis, and Yakult; consulting or advisory role for AbbVie, Astellas Pharma, Bristol Myers Squibb, Eli Lilly, Glaxo Smith Kline, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, Pfizer, Taiho, and Takeda; researching funding for Astellas Pharma, Chugai Pharmaceutical, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Medi Science, Ono Pharmaceutical, and Taiho Pharmaceutical. MÖ reports honoraria for Astellas Pharma, Janssen, and Roche; consulting or advisory role for Janssen; and travel, accommodations, expenses for AstraZeneca. Y-JB reports consulting/advisory for Astellas, AstraZeneca, Bayer, BeiGene, BMS, Daiichi Sankyo, Eli Lilly, Genentech/Roche, Genexine, Green Cross, Hammi, Merck Serono, MSD, Novartis, Samyang Biopharm, and Taiho; grants (to the institution for clinical trials) from Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bostin Biomedical, BMS, CKD Pharma, Curis, Daiichi-Sankyo, Eli Lilly, Five Prime, Genentech/Roche, Genexine Green Cross, GSK, MacroGenics, Merck Serono, MSD, Novartis, Ono, Pfizer, Taiho, and Takeda. MDB reports honoraria for Eli Lilly, Merck Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Servier; consulting or advisory role for Eli Lilly; speakers’ bureau for Eli Lilly and Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; researching funding for Eli Lilly; and travel, accommodations, expenses for Roche. MM reports honoraria for Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, and Pierre Fabre; consulting or advisory role for Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, and Pierre Fabre; speakers’ bureau for Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, and Pierre Fabre; and research funding for Novartis and Roche. M-HR reports honoraria for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho; and consulting or advisory role for Bristol Myers Squibb, Daehwa Pharmaceutical, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Novartis, Ono Pharmaceutical, and Taiho. CC reports honoraria for Andes Biotechnologies; consulting or advisory role for Boehringer Ingelheim Bristol Myers Squibb, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; speakers’ bureau for Bristol Myers Squibb, Eli Lilly, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Roche; research funding for AstraZeneca, Astella Pharma, Bristol Myers Squibb, Medivation, and Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA; and travel, accommodations, expenses for Bristol Myers Squibb and Roche. HCC reports honoraria for Eli Lilly and Merck Serono; consulting or advisory role for Amgen, BeiGene, Bristol Myers Squibb, Celltrion, Eli Lilly, Gloria, Merck Serono, Quintiles, Taiho, and Zymeworks; and research funding for Amgen, BeiGene, Bristol Myers Squibb/Ono Pharmaceutical, Eli Lilly, Glaxo Smith Kline, Merch Serono, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and Taiho. KM reports research funding (to his institution) from Daiichi Sankyo, MEDISCIENCE PLANNING, MSD, Parexel International, Pfizer, Sanofi, Solasia Pharma, and Sumitomo Dainippon Pharma; honoraria for speaking from Bristol Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Ono Pharmaceutical Co., Ltd., Taiho Pharmaceutical, Takeda Pharmaceutical, and Sanofi; and advisory/consultancy for Amgen, AstraZeneca, and Ono Pharmaceutical Co., Ltd. EVC reports consulting or advisory role for Array BioPharma, AstraZeneca, Bayer, Bristol Myers Squibb, Celgene, Eli Lilly, Halozyme, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier; and research funding (to his institution) for Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck Sharp and Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Merck KGaA, Novartis, Roche, and Servier. JK is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. RC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. DA-G is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA and received travel, accommodations, or expenses from Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. JL is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. C-SS is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc, and received researching funding and travel, accommodations, or expenses for Exelixis. DA is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and stockholder of Merck & Co., Inc., Kenilworth, NJ, USA. ZAC is an employee of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, and has stock ownership interests in Merck & Co., Inc., Kenilworth, NJ, USA, and in Bristol Myers Squibb. CSF served in an advisory/consultancy role for Agios, Amylin Pharmaceuticals, AstraZeneca, Bain Capital, CytomX Therapeutics, Daiichi Sankyo, Eli Lilly, Entrinsic Health, EvolveImmune Therapeutics, Genentech, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA, Taiho, and Unum Therapeutics. He also serves as a director for CytomX Therapeutics and owns unexercised stock options for CytomX and Entrinsic Health; is a cofounder of EvolveImmune Therapeutics and has equity in this private company; and has provided expert testimony for Amylin Pharmaceuticals and Eli Lilly., (Copyright © 2021 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Purpose: International guideline recommendations may not always be extrapolated to developing countries where access to resources is limited. In metastatic castration-sensitive prostate cancer (mCSPC), there have been successful drug and imaging advancements that were addressed in the Prostate Cancer Consensus Conference for Developing Countries for best-practice and limited-resource scenarios., Methods: A total of 24 out of 300 questions addressed staging, treatment, and follow-up for patients with mCSPC both in best-practice settings and resource-limited settings. Responses were compiled and presented in percentage of clinicians supporting each response. Questions had 4-8 options for response., Results: Recommendations for staging in mCSPC were split but there was consensus that chest x-ray, abdominal and pelvic computed tomography, and bone scan should be used where resources are limited. In both de novo and relapsed low-volume mCSPC, orchiectomy alone in limited resources was favored and in relapsed high-volume disease, androgen deprivation therapy plus docetaxel in limited resources and androgen deprivation therapy plus abiraterone in high-resource settings were consensus. A 3-weekly regimen of docetaxel was consensus among voters. When using abiraterone, a regimen of 1,000 mg plus prednisone 5 mg/d is optimal, but in limited-resource settings, half the panel agreed that abiraterone 250 mg with fatty foods plus prednisone 5 mg/d is acceptable. The panel recommended against the use of osteoclast-targeted therapy to prevent osseous complications. There was consensus that monitoring of patients undergoing systemic treatment should only be conducted in case of prostate-specific antigen elevation or progression-suggestive symptoms., Conclusion: The treatment recommendations for most topics addressed differed between the best-practice setting and resource-limited setting, accentuating the need for high-quality evidence that contemplates the effect of limited resources on the management of mCSPC., Competing Interests: Fernando Cotait MalufHonoraria: Janssen Oncology, Astellas Pharma, Bayer Schering Pharma, Merck Sharp and Dohme,Roche/Genentech, BMS Brazil, Ipsen, Sanofi/Aventis, Merck Serono, AstraZenecaConsulting or Advisory Role: Janssen Oncology, Astellas Pharma, Bayer Schering Pharma, Merck Sharp and Dohme, Roche/Genentech, BMS Brazil, Ipsen, Merck Serono, AstraZenecaResearch Funding: Janssen-Cilag, Merck Sharp and DohmeTravel, Accommodations, Expenses: Merck Sharp and Dohme, Bayer Schering Pharma Felipe Moraes Toledo PereiraHonoraria: Janssen, Zodiac Pharma, MSD, Libbs, Bayer, AmgenConsulting or Advisory Role: Janssen Diogo Assed BastosHonoraria: MSD, Roche, Bristol-Myers Squibb, Janssen-Cilag, Astellas Pharma, AstraZeneca, BayerConsulting or Advisory Role: Roche, Bayer, Janssen-CilagResearch Funding: Janssen-Cilag, Pfizer, Astellas PharmaTravel, Accommodations, Expenses: Janssen-Cilag, Bayer Diogo Augusto Rodrigues da RosaHonoraria: RocheConsulting or Advisory Role: Janssen-Cilag, Bristol-Myers Squibb, AstraZeneca, Astellas PharmaSpeakers' Bureau: AstraZeneca, Dr. Reddy's Laboratories, Roche, MSD Oncology, BMS BrazilTravel, Accommodations, Expenses: Janssen-Cilag, Roche, BMS Brazil, Ipsen Evanius Garcia WiermannConsulting or Advisory Role: Janssen OncologySpeakers' Bureau: BayerTravel, Accommodations, Expenses: Bayer Schering Pharma Fábio A. SchutzEmployment: IpsenConsulting or Advisory Role: Bayer, Janssen Oncology, Roche, Merck Sharp and Dohme, Bristol-Myers Squibb, Pfizer, Astellas Pharma, AstraZenecaSpeakers' Bureau: Janssen Oncology, Astellas Pharma, Bayer, Pfizer, Bristol-Myers Squibb, AstraZeneca, Merck Sharp and Dohme, RocheResearch Funding: Janssen OncologyTravel, Accommodations, Expenses: Merck Sharp and Dohme, Roche, Bristol-Myers Squibb, Astellas Pharma, Janssen-Cilag Fábio Roberto KaterConsulting or Advisory Role: Janssen-Cilag, PfizerTravel, Accommodations, Expenses: Janssen-Cilag Fernando Nunes Galvão de OliveiraConsulting or Advisory Role: Janssen OncologySpeakers' Bureau: Janssen Oncology, Astellas Pharma, MSD OncologyTravel, Accommodations, Expenses: Astellas Pharma, MSD Oncology Fernando Sabino Marques MonteiroConsulting or Advisory Role: Bristol-Myers Squibb, Roche, MSD Oncology, JanssenSpeakers' Bureau: Janssen, MSD Oncology, IpsenResearch Funding: JanssenTravel, Accommodations, Expenses: Janssen, Roche, Bristol-Myers Squibb Francisco Javier OrlandiHonoraria: Roche/GenentechConsulting or Advisory Role: AstraZeneca, Roche/Genentech, Bristol-Myers Squibb, MSD Oncology, Lilly, Pfizer, Novartis, SanofiSpeakers' Bureau: AstraZeneca/MedImmune, RocheResearch Funding: AstraZeneca/MedImmune, Amgen, Genentech/Roche, Boehringer Ingelheim, Astellas Medivation, MSD Oncology, Bristol-Myers Squibb, Celltrion, Pfizer, mAbxience, Nektar, Sanofi, Genentech/Roche, AstraZeneca/MedImmune Pamela Salman BoghikianConsulting or Advisory Role: Roche/Genentech, Novartis, Lilly, Merck SeronoSpeakers' Bureau: Roche/Genentech, Novartis, Lilly Ray Manneh KoppHonoraria: Astellas Scientific and Medical Affairs,Inc., Janssen-Cilag, Bayer, Merck Sharp and Dohme, Roche, Bristol-Myers Squibb, Sanofi, AstraZeneca, PfizerConsulting or Advisory Role: Astellas Pharma, Janssen-Cilag, Roche, Merck Serono, Merck Sharp and Dohme, AstraZeneca, Sanofi, PfizerSpeakers' Bureau: San Jorge Foundation, ACHOResearch Funding: Pfizer, Merck Sharp and Dohme, NovartisTravel, Accommodations, Expenses: Merck Sharp and Dohme Rodrigo Nogueira de FogaceTravel, Accommodations, Expenses: Bayer Schering Pharma Sandro Roberto de Araújo CavalleroHonoraria: Astellas Pharma, Janssen Oncology, AstraZenecaConsulting or Advisory Role: Janssen Oncology, Astellas PharmaSpeakers' Bureau: Pfizer, Janssen-Cilag, Astellas PharmaTravel, Accommodations, Expenses: Pfizer, Roche/Genentech, Janssen-Cilag, Astellas Pharma Vinicius Carreira SouzaConsulting or Advisory Role: Janssen, Astellas Pharma, Bayer, BMS BrazilResearch Funding: JanssenTravel, Accommodations, Expenses: Janssen Silke Gillessen SommerConsulting or Advisory Role: Astellas Pharma, Advanced Accelerator Applications, Roche, Janssen, Bayer, Orion Pharma GmbH, Menarini Silicon Biosystems, Tolero Pharmaceuticals, MSD Oncology, Amgen, PfizerSpeakers' Bureau: Janssen-CilagPatents, Royalties, Other Intellectual Property: Method for biomarker (WO 3752009138392 A1)Travel, Accommodations, Expenses: ProteoMedixOther Relationship: ProteoMediX, Aranda PharmaNo other potential conflicts of interest were reported.

Historically, the health benefits and immunomodulatory potential of medicinal herbs have been considered an intrinsic quality of the herb itself. We have hypothesized that the health benefits of medicinal herbs may be partially due to their prebiotic potential that alter gut microbiota leading to changes in short chain fatty acids and vitamin production or biotransformation of herb encoded molecules and secondary metabolites. Accumulating studies emphasize the relationship between the gut microbiota and host immune function. While largely unknown, these interactions are mediated by secreted microbial products that activate or repress a variety of immune cell types. Here we evaluated the effect of immunomodulatory, medicinal Ayurvedic herbs on gut microbiota in vitro using 16S rRNA sequencing to assess changes in community composition and functional potential. All immunomodulatory herbs displayed substantial prebiotic potential, targeting unique taxonomic groups. Application of genome reconstruction and analysis of biosynthetic capacity of herb selected communities suggests that many of the 11 herbs tested altered the community metabolism as the result of differential glycan harvest and sugar utilization and secreted products including multiple vitamins, butyrate, and propionate that may impact host physiology and immune function. Taken together, these results provide a useful framework for the further evaluation of these immunomodulatory herbs in vivo to maintain immune homeostasis or achieve desired regulation of immune components in the context of disease., Competing Interests: DC is a founder of the Chopra Foundation and Chopra Center and a co-owner of the Chopra Center. DR is a co-founder of PhenoBiome Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Peterson, Iablokov, Uchitel, Chopra, Perez-Santiago, Rodionov and Peterson.)

Background: First-line nivolumab plus ipilimumab has shown improved overall survival in patients with advanced non-small-cell lung cancer (NSCLC). We aimed to investigate whether the addition of a limited course (two cycles) of chemotherapy to this combination would further enhance the clinical benefit., Methods: This randomised, open-label, phase 3 trial was done at 103 hospitals in 19 countries. Eligible patients were aged 18 years or older with treatment-naive, histologically confirmed stage IV or recurrent NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) by an interactive web response system via permuted blocks (block size of four) to nivolumab (360 mg intravenously every 3 weeks) plus ipilimumab (1 mg/kg intravenously every 6 weeks) combined with histology-based, platinum doublet chemotherapy (intravenously every 3 weeks for two cycles; experimental group), or chemotherapy alone (every 3 weeks for four cycles; control group). Randomisation was stratified by tumour histology, sex, and PD-L1 expression. The primary endpoint was overall survival in all randomly assigned patients. Safety was analysed in all treated patients. Results reported here are from a pre-planned interim analysis (when the study met its primary endpoint) and an exploratory longer-term follow-up analysis. This study is active but no longer recruiting patients, and is registered with ClinicalTrials.gov, number NCT03215706., Findings: Between Aug 24, 2017, and Jan 30, 2019, 1150 patients were enrolled and 719 (62·5%) randomly assigned to nivolumab plus ipilimumab with two cycles of chemotherapy (n=361 [50%]) or four cycles of chemotherapy alone (n=358 [50%]). At the pre-planned interim analysis (median follow-up 9·7 months [IQR 6·4-12·8]), overall survival in all randomly assigned patients was significantly longer in the experimental group than in the control group (median 14·1 months [95% CI 13·2-16·2] vs 10·7 months [9·5-12·4]; hazard ratio [HR] 0·69 [96·71% CI 0·55-0·87]; p=0·00065). With 3·5 months longer median follow-up (median 13·2 months [IQR 6·4-17·0]), median overall survival was 15·6 months (95% CI 13·9-20·0) in the experimental group versus 10·9 months (9·5-12·6) in the control group (HR 0·66 [95% CI 0·55-0·80]). The most common grade 3-4 treatment-related adverse events were neutropenia (in 24 [7%] patients in the experimental group vs 32 [9%] in the control group), anaemia (21 [6%] vs 50 [14%]), diarrhoea (14 [4%] vs two [1%]), increased lipase (22 [6%] vs three [1%]), and asthenia (tjree [1%] vs eight [2%]). Serious treatment-related adverse events of any grade occurred in 106 (30%) patients in the experimental group and 62 (18%) in the control group. Seven (2%) deaths in the experimental group (acute kidney failure, diarrhoea, hepatotoxicity, hepatitis, pneumonitis, sepsis with acute renal insufficiency, and thrombocytopenia; one patient each) and six (2%) deaths in the control group (anaemia, febrile neutropenia, pancytopenia, pulmonary sepsis, respiratory failure, and sepsis; one patient each) were treatment related., Interpretation: Nivolumab plus ipilimumab with two cycles of chemotherapy provided a significant improvement in overall survival versus chemotherapy alone and had a favourable risk-benefit profile. These data support this regimen as a new first-line treatment option for patients with advanced NSCLC., Funding: Bristol Myers Squibb., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Prostate-specific membrane antigen (PSMA)-ligand PET/CT is performed on patients with prostate cancer to stage the disease initially or to identify sites of recurrence after definitive therapy. On the basis of clinical results, 18 F-PSMA-1007 is a promising PSMA PET tracer, but detailed histologic confirmation has been lacking. Methods: Ninety-six patients with prostate cancer underwent 18 F-PSMA-1007 PET/CT followed by either radical prostatectomy with lymphadenectomy or salvage lymphadenectomy. The histologic findings of PSMA PET-positive nodes were analyzed retrospectively. A lesion-based and patient-based analysis was performed comparing all positive lesions and only lesions larger than 3 mm on histopathology. Results: Of the patients, 90.6% received 18 F-PSMA-1007 PET/CT for staging before the primary treatment, whereas 9.4% underwent imaging for biochemical recurrence. In 34.4% of the cohort, positive lymph nodes were present on imaging. In total, 1,746 lymph nodes were dissected in 96 patients. 18 F-PSMA-1007 PET had a lesion-based sensitivity of 81.7%, a specificity of 99.6%, a positive predictive value of 92.4%, and a negative predictive value of 98.9% for detecting positive lymph nodes larger than 3 mm. In the analysis of all malignant nodes regardless of size, the overall sensitivity, specificity, positive predictive value, and negative predictive value on lesion-based analysis were 71.2%, 99.5%, 91.3%, and 97.9%, respectively. The patient-based analysis showed a sensitivity of 85.9% and a specificity of 99.5% for lymph nodes larger than 3 mm. Conclusion: 18 F-PSMA-1007 PET/CT reliably detects malignant lymph nodes and has an exceptional specificity of more than 99% for nodal metastases., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

During the last several years, multiple gene rearrangements with oncogenic potential have been described in NSCLC, identifying specific clinic-pathological subgroups of patients that benefit from a targeted therapeutic approach, including anaplastic lymphoma kinase ( ALK ), c-ros protooncogene 1 ( ROS1 ) and, more recently, REarranged during Transfection ( RET ) and neurotrophic tyrosine receptor kinases ( NTRK ) genes. Despite initial impressive antitumor activity, the use of targeted therapies in oncogene-addicted NSCLC subgroups is invariably associated with the development of acquired resistance through multiple mechanisms that can include both on-target and off-target mechanisms. However, the process of acquired resistance is a rapidly evolving clinical scenario that constantly evolves under the selective pressure of tyrosine kinase inhibitors. The development of increasingly higher selective and potent inhibitors, traditionally used to overcome resistance to first generation inhibitors, is associated with the development of novel mechanisms of resistance that encompass complex resistance mutations, highly recalcitrant to available TKIs, and bypass track mechanisms. Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including ALK , ROS1 , RET , and NTRK rearrangements., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tlcr-2019-cnsclc-06). The series “Looking for Chimeras in NSCLC: Widen Therapeutic Options Targeting Oncogenic Fusions” was commissioned by the editorial office without any funding or sponsorship. OA serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2019 to Sep 2021. CR serves as an unpaid editorial board member of Translational Lung Cancer Research from Sep 2018 to Sep 2020. Dr. Russo reports advisory board role for Astra Zeneca, MSD and Roche, outside the submitted work. Dr. Cardona reports personal fees from Abbvie, Celldex, Roche, MSD, Novartis, Astra Zeneca, Bristol Myers Squibb, Foundation Medicine, Boehringer Ingelheim, Foundation for Clinical and Applied Cancer Research, and other from MSD, Bristol Myers Squibb, Roche, Boehringer Ingelheim, Foundation Medicine, outside the submitted work. Dr. Caglevic reports honoraria from Andes Biotechnologies; consulting or advisory role for Bristol-Myers Squibb, MSD, Roche, and Boehringer-Ingelheim; speakers' bureau for Bristol-Myers Squibb, MSD, Lilly and Roche, research funding from Merck Sharp & Dohme, Medivation, AstraZeneca, Roche, Astellas Pharma, Bristol-Myers Squibb; Travel, Accommodations, Expenses from Bristol-Myers Squibb, outside the submitted work. Dr. Arrieta reports personal fees from MSD, Roche, Astra Zeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, and Pfizer, and grants from AstraZeneca, Roche and MSD, outside the submitted work, outside the submitted work. Dr. Rolfo reports advisor board role for Inivata, ARCHER, MD Serono, Oncompass (non-financial), and Mylan; speakers’ bureau for Astra Zeneca and MSD; honoraria from Elsevier; grants/research support from LCRF (Lung Cancer Research Foundation), ACS (American Cancer Society), GuardantHealth (non-financial), and Biomarkers (non-financial), outside the submitted work. The authors have no other conflicts of interest to declare., (2020 Translational Lung Cancer Research. All rights reserved.)

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. Id1 (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of Id1 inhibition and pharmacological PD-L1 blockade in three different syngeneic murine KRAS -mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and Id1 expression levels. This observation was confirmed in vitro in human and murine KRAS -driven lung cancer cell lines. In vivo experiments in KRAS -mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting Id1 and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3 + /CD4 + /CD8 + T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8 + T cells, whilst in vivo CD8 + T cell depletion led to tumor growth restoration. Co-culture assays using CD8 + cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack Id1 expression. These findings highlight that Id1 blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8 + T lymphocytes.

Importance: Safe and effective therapies for untreated, advanced gastric/gastroesophageal junction (G/GEJ) cancer remain an unmet need., Objective: To evaluate the antitumor activity of pembrolizumab, pembrolizumab plus chemotherapy, or chemotherapy alone in patients with untreated, advanced G/GEJ cancer with programmed cell death ligand 1 (PD-L1) combined positive score (CPS) of 1 or greater., Design, Setting, and Participants: The phase 3 KEYNOTE-062 randomized, controlled, partially blinded interventional trial enrolled 763 patients with untreated, locally advanced/unresectable or metastatic G/GEJ cancer with PD-L1 CPS of 1 or greater from 200 centers in 29 countries between September 18, 2015, and May 26, 2017., Interventions: Patients were randomized 1:1:1 to pembrolizumab 200 mg, pembrolizumab plus chemotherapy (cisplatin 80 mg/m2/d on day 1 plus fluorouracil 800 mg/m2/d on days 1 to 5 or capecitabine 1000 mg/m2 twice daily), or chemotherapy plus placebo, every 3 weeks., Main Outcomes and Measures: Primary end points were overall survival (OS) and progression-free survival (PFS) in patients with PD-L1 CPS of 1 or greater or 10 or greater., Results: A total of 763 patients were randomized to pembrolizumab (n = 256), pembrolizumab plus chemotherapy (n = 257), or chemotherapy (n = 250). The median (range) age of all patients in the study cohort was 62 (20-87) years; 554 of 763 (72.6%) were men. At final analysis, after a median (range) follow-up of 29.4 (22.0-41.3) months, pembrolizumab was noninferior to chemotherapy for OS in patients with CPS of 1 or greater (median, 10.6 vs 11.1 months; hazard ratio [HR], 0.91; 99.2% CI, 0.69-1.18). Pembrolizumab monotherapy was not superior to chemotherapy in patients with CPS of 1 or greater. Pembrolizumab prolonged OS vs chemotherapy in patients with CPS of 10 or greater (median, 17.4 vs 10.8 months; HR, 0.69; 95% CI, 0.49-0.97), but this difference was not statistically tested. Pembrolizumab plus chemotherapy was not superior to chemotherapy for OS in patients with CPS of 1 or greater (12.5 vs 11.1 months; HR, 0.85; 95% CI, 0.70-1.03; P = .05) or CPS of 10 or greater (12.3 vs 10.8 months; HR, 0.85; 95% CI, 0.62-1.17; P = .16) or for PFS in patients with CPS of 1 or greater (6.9 vs 6.4 months; HR, 0.84; 95% CI, 0.70-1.02; P = .04). Grade 3 to 5 treatment-related adverse event rates for pembrolizumab, pembrolizumab plus chemotherapy, and chemotherapy were 17%, 73%, and 69%, respectively., Conclusions and Relevance: This phase 3 randomized clinical trial found that among patients with untreated, advanced G/GEJ cancer, pembrolizumab was noninferior to chemotherapy, with fewer adverse events observed. Pembrolizumab or pembrolizumab plus chemotherapy was not superior to chemotherapy for the OS and PFS end points tested., Trial Registration: ClinicalTrials.gov Identifier: NCT02494583.

Claspin is a multifunctional protein that participates in physiological processes essential for cell homeostasis that are often defective in cancer, namely due to genetic changes. It is conceivable that Claspin gene ( CLSPN ) alterations may contribute to cancer development. Therefore, CLSPN germline alterations were characterized in sporadic and familial breast cancer and glioma samples, as well as in six cancer cell lines. Their association to cancer susceptibility and functional impact were investigated. Eight variants were identified (c.-68C>T, c.17G>A, c.1574A>G, c.2230T>C, c.2028+16G>A, c.3595-3597del, and c.3839C>T). CLSPN c.1574A>G (p.Asn525Ser) was significantly associated with breast cancer and was shown to cause partial exon skipping and decreased Claspin expression and Chk1 activation in a minigene splicing assay and in signalling experiments, respectively. CLSPN c.2028+16G>A was significantly associated with familial breast cancer and glioma, whereas c.2230T>C (p.Ser744Pro), was exclusively detected in breast cancer and glioma patients, but not in healthy controls. The remaining variants lacked a significant association with cancer. Nevertheless, the c.-68C>T promoter variant increased transcriptional activity in a luciferase assay. In conclusion, some of the CLSPN variants identified in the present study appear to modulate Claspin's function by altering CLSPN transcription and RNA processing, as well as Chk1 activation.

Objective: Over the years, Meckel's cave pathologies have been judged off-limits because of high rates of morbidity. Even though several studies have defined various surgical routes with tolerable morbidity and mortality rates, controversies related to the optimal avenue to treat different categories of Meckel's cave and cavernous sinus neoplasms persist. With unceasing energy to cultivate minimally invasive neurosurgical approaches, the endoscopic endonasal route has been tested, and the approach effectively performed, to provide a valid surgical window to these areas. In this dynamic and challenging scenario, another ventral endoscopic minimally invasive route-that is, the superior eyelid endoscopic transorbital approach-has been very recently proposed, and used in selected cases, to access the cavernous sinus and Meckel's cave regions., Methods: The authors report the technical nuances of a combined and simultaneous endoscopic endonasal and transorbital surgical treatment of a patient with a Meckel's cave schwannoma. The operation involved collaboration among neurosurgery, otorhinolaryngology, and ophthalmology (oculoplastic surgery). The patient recovered well, had no neurological deficits, and was discharged to home 3 days after surgery., Results: The multiportal combined route was proposed for the following reasons. The endonasal approach, considered to be more familiar to our skull base team, could allow control of possible damage of the internal carotid artery. From the endonasal perspective, the most inferior and medial portion of the tumor could be properly managed. Finally, the transorbital route, by means of opening the lateral wall of the cavernous sinus via the meningoorbital band, could allow control of the superolateral part of the tumor and, most importantly, could permit removal of the portion entering the posterior cranial fossa via the trigeminal pore. Simultaneous surgery with two surgical teams working together was planned in order to reduce operative time, hospital stay, and patient stress and discomfort, and to ensure "one-shot" complete tumor removal, with minimal or no complications., Conclusions: This study represents the translation into the real surgical setting of recent anatomical contributions related to the novel endoscopic transorbital approach and its simultaneous integration with the endoscopic endonasal pathway. Accordingly, it may pave the way for future applications related to minimally invasive, multiportal endoscopic surgery for skull base tumors.

The purpose of this study was to assess the predictive and prognostic value of interim FDG PET (iPET) in evaluating early response to immunochemotherapy after 2 cycles (PET-2) in diffuse large B-cell lymphoma (DLBCL) by applying 2 different methods of interpretation: the Deauville visual 5-point scale (5-PS) and a change in SUV (ΔSUV) by semiquantitative evaluation. Methods: In total, 145 patients with newly diagnosed DLBCL underwent pretreatment PET and PET-2 assessment. PET-2 was classified according to both 5-PS and percentage ΔSUV. Receiver-operating-characteristic analysis was performed to compare the accuracy of the 2 methods for predicting progression-free survival. Survival estimates, based on each method separately and combined, were calculated for iPET-positive (iPET+) and iPET-negative (iPET-) groups and compared. Results: Both with 5-PS and with ΔSUV-based evaluations, significant differences were found between the progression-free survival of iPET- and iPET+ patient groups ( P < 0.001). Visually, the best negative predictive value (NPV) and positive predictive value (PPV) occurred when iPET was defined as positive if the Deauville score was 4-5 (89% and 59%, respectively). Using the 66% ΔSUV cutoff reported previously, NPV and PPV were 80% and 76%, respectively. ΔSUV at the 48.9% cutoff, reported for the first time here, produced 100% specificity along with the highest sensitivity (24%). The 5-PS and a semiquantitative ΔSUV of less than 48.9% for each PET-2 gave the same PET-2 classification (positive or negative) in 70% (102/145) of all patients. This combined classification delivered NPV and PPV of 89% and 100%, respectively, and all iPET+ patients failed to achieve or remain in remission. Conclusion: In this large consistently treated and assessed series of DLBCL patients, iPET had good prognostic value interpreted either visually or semiquantitatively. We determined that the most effective ΔSUV cutoff was 48.9% and that when combined with 5-PS assessment, a positive PET-2 result was highly predictive of treatment failure., (© 2020 by the Society of Nuclear Medicine and Molecular Imaging.)

Purpose: To assess the impact of implementing the recommendations included in the 2014 American Urological Association (AUA) white paper on complications of transrectal prostate needle biopsy (PNB)., Methods: In the outpatient setting of a single tertiary-care institution, prophylactic antibiotic use and rate of infectious complications were compared before and after implementation by nursing of a standardized algorithm to select antibiotic prophylaxis (derived from the recommendations of the AUA white paper). The 584 patients in cohort A (January 2011-January 2012) received antimicrobial prophylaxis at the discretion of the treating physician; 654 patients in cohort B (January 2014-January 2015) received standardized risk-adapted antibiotic prophylaxis. Data on antibiotics administered and infectious complications were analyzed., Results: Fluoroquinolone was the most common prophylactic regimen in both cohorts. In cohort A, 73% of men received a single-drug regimen, although 19 different regimens were utilized with duration of 72 h. In cohort B, 97% received 1 of 4 standardized single-drug antibiotic regimens for duration of 24 h. Infectious complications occurred in 19 men (3.3%) in cohort A, and in 18 men (2.8%) in cohort B (difference - 0.5%; one-sided 95% CI 1.1%). No clinically relevant increase in infectious complication rates was found after implementing this quality improvement initiative., Conclusions: Use of a standardized risk-adapted approach to select antibiotic prophylaxis for PNB by nursing staff reduced the duration of antimicrobial prophylaxis and number of antibiotic regimens used, without increasing the rate of infectious complications. Our findings validate the current AUA recommendations for antibiotic prophylaxis.

Importance: Neuroprotective and remyelinating therapies are required for multiple sclerosis (MS), and acute optic neuritis (AON) is a potential condition to evaluate such treatments., Objective: To comprehensively assess key biological and methodological aspects of AON trials for testing neuroprotection and remyelination in MS., Design, Setting, and Participants: The AON-VisualPath prospective cohort study was conducted from February 2011 to November 2018 at the Hospital Clinic of University of Barcelona, Barcelona, Spain. Consecutive patients with AON were prospectively enrolled in the cohort and followed up for 18 months. Data analyses occurred from November 2018 to February 2019., Exposures: Participants were followed up for 18 months using optical coherence tomography, visual acuity tests, and in a subset of 25 participants, multifocal visual evoked potentials., Main Outcomes and Measures: Dynamic models of retinal changes and nerve conduction and their associations with visual end points; and eligibility criteria, stratification, and sample-size estimation for future trials., Results: A total of 60 patients (50 women [83%]; median age, 34 years) with AON were included. The patients studied displayed early and intense inner retinal thinning, with a thinning rate of approximately 2.38 μm per week in the ganglion cell plus inner plexiform layer (GCIPL) during the first 4 weeks. Eyes with AON displayed a 6-month change in latency of about 20 milliseconds, while the expected change in the eyes of healthy participants by random variability was 0.13 (95% CI, -0.80 to 1.06) milliseconds. The strongest associations with visual end points were for the 6-month intereye difference in 2.5% low-contrast letter acuity, which was correlated with the peripapillary retinal nerve fiber layer thinning (adjusted R2, 0.57), GCIPL thinning (adjusted R2, 0.50), and changes in mfVEP latency (adjusted R2, 0.26). A 5-letter increment in high-contrast visual acuity at presentation (but not sex or age) was associated with 6-month retinal thinning (1.41 [95% CI, 0.60-2.23] μm less peripapillary retinal nerve fiber layer thinning thinning; P = .001; adjusted R2, 0.20; 0.86 [95% CI, 0.35-1.37] μm less GCIPL thinning; P = .001; adjusted R2, 0.19) but not any change in multifocal visual evoked potential latency. To demonstrate 50% efficacy in GCIPL thinning or change in multifocal visual evoked potential latency, a 6-month, 2-arm, parallel-group trial would need 37 or 50 participants per group to test a neuroprotective or remyelinating drug, respectively (power, 80%; α, .05)., Conclusions and Relevance: Acute optic neuritis is a suitable condition to test neuroprotective and remyelinating therapies after acute inflammation, providing sensitive markers to assess the effects on both processes and prospective visual recovery within a manageable timeframe and with a relatively small sample size.

Purpose: To compare IL-6, sIL-6R, and IL-17 secretion in peripheral blood mononuclear cells (PBMCs) cultured with tocilizumab (a humanized monoclonal antibody against the interleukin-6 receptor), dexamethasone, and placebo, obtained from patients with thyroid eye disease (TED) and healthy controls., Methods: The study was a prospective proof of concept test. We cultured peripheral blood mononuclear cells from TED patients and healthy controls with tocilizumab, dexamethasone, and placebo. IL-6, sIL-6R, and IL-17 levels in supernatants obtained from PBMCs cultures were analyzed by ELISA., Results: We included seventeen patients with thyroid eye disease (12 females and five males). The mean age was 49 years. Both dexamethasone and tocilizumab influenced IL-6 and IL-6Rs levels in patients' group. Supernatants obtained from PBMCs treated with dexamethasone showed 77.2% and 82.8% lower IL-6 levels compared with those cultured with placebo and tocilizumab, respectively. Furthermore, overnight culture of PBMCs with dexamethasone showed significantly lower sIL-6R secretion compared with untreated (33.71%, p = 0.04) and tocilizumab treated (58.21%, p = 0.01) PBMCs. Neither dexamethasone nor tocilizumab affected IL-17 concentrations in PBMCs cultures., Conclusions: Both dexamethasone and tocilizumab affect the IL-6/sIL-6R system. Specifically, dexamethasone reduces and tocilizumab increases the levels of these cytokines in PBMCs cultures. These results strengthen the molecular rationale for interrogating the efficacy of tocilizumab in steroid-resistant TED, as IL-6 seems to be a common target for both anti-IL-6R antibody and steroids.