Microsatellite Instability, Epstein–Barr Virus, and Programmed Cell Death Ligand 1 as Predictive Markers for Immunotherapy in Gastric Cancer

Immunotherapy benefits selected cases of gastric cancer (GC), but the correlation between biomarkers and prognosis is still unclear. Fifty-two patients with GC who underwent immunotherapy were enrolled from June 2016 to December 2020. Their clinical features and biomarkers—microsatellite instability-high (MSI-H), programmed cell death ligand 1 (PD-L1) combined positive score (CPS), and Epstein–Barr encoding region (EBER)—were analyzed. Eight patients had MSI-H, five patients had EBER, 29 patients had CPS ≥ 1, and 20 patients had no biomarker. The overall response rates (ORRs) of the MSI-H, EBER, PD-L1 CPS ≥ 1, and all-negative group were 75%, 60%, 44.8%, and 15%, respectively. Compared with that of the all-negative group, progression-free survival (PFS) was better in the MSI-H (p = 0.018), CPS ≥ 5 (p = 0.012), and CPS ≥ 10 (p = 0.006) groups, but not in the EBER (p = 0.2) and CPS ≥ 1 groups (p = 0.35). Ten patients had combined biomarkers, CPS ≥ 1 with either MSI-H or EBER. The ORRs were 66.7% for CPS ≥ 1 and MSI-H and 75% for CPS ≥ 1 and EBER. PFS was better in patients with combined biomarkers (p = 0.01). MSI-H, EBER, and CPS are useful biomarkers for predicting the efficacy of immunotherapy.

Programmed Death Ligand-1 Expression Is Associated With Poorer Survival in Anal Squamous Cell Carcinoma

Context.— Upregulation of programmed death ligand-1 (PD-L1), an immunoregulatory protein, is associated with an adverse outcome in several malignancies. Very few studies have evaluated PD-L1 expression in invasive anal squamous cell carcinoma (ASCC). Objective.— To assess PD-L1 expression in patients with ASCC and correlate it with clinicopathologic factors and clinical outcomes. Design.— Fifty-one cases of ASCC were immunostained for PD-L1. PD-L1 expression by combined positive score and tumor proportion score was correlated with age, gender, HIV status, HIV viral load, CD4 count, stage, and outcomes. Kaplan-Meier curves for overall survival were plotted and compared using the log-rank test. Cox regression analysis was performed to identify significant prognostic factors (2-tailed P < .05 was considered statistically significant). Results.— PD-L1 was positive in 24 of 51 cases (47%) by combined positive score and in 18 of 51 (35%) by tumor proportion score. The median cancer-specific survival and 5-year overall survival were significantly lower in PD-L1+ patients. Age, gender, HIV status, HIV viral load, stage, and cancer progression were not significantly different between the two groups. CD4 count of more than 200/μL was significantly higher in PD-L1+ patients. PD-L1+ status remained statistically significant for worse overall survival on multivariate analysis. Conclusions.— PD-L1+ status is an independent adverse prognostic factor for overall survival in ASCC. This study highlights the potential of PD-L1 targeted therapy in better management of ASCC.

Awareness and Use of Current Sports Injury Prevention Programs among Physiotherapists Worldwide

Purpose. Physiotherapists are trained to prevent, assess, and rehabilitate all kinds of injuries including sports injury. The goal of the physical therapist should be making sure that the athlete is in optimal shape to perform, with a minimal risk for developing an injury. This study aims to assess the physiotherapists’ awareness, implementation, and views of sports injury prevention programs (IPPs) from an international perspective. Materials and methods. A self-administered questionnaire was developed and distributed to physiotherapists worldwide through World Physiotherapy member organizations. The study targeted physiotherapists at an international level. The study included 484 participants, of whom 44.4% were male and 55.6% were female physiotherapists. Results. A total of 287 (59.3%) of the participants were aware of the current sports IPPs, 177 (36.6%) were implementing sports IPPs in their current practice. Participants who implemented the sports IPPs reported a positive opinion about the program efficacy, with a score of 7.3 ± 2.11 out of 10. Conclusions. Globally, physiotherapists have average awareness and low implementation levels of IPPs. Physiotherapists showed a positive score regarding the effectiveness of IPPS, especially the KIPP and the iSPRINT.

Case Report: Response With Immunotherapy in a Patient With Mixed Neuroendocrine Non-Neuroendocrine Neoplasms of the Gallbladder

BackgroundPrimary neuroendocrine tumors of the gallbladder (GB-NETs) are rare, accounting for 2% of all gallbladder cancers. Among GB-NETs, mixed neuroendocrine non-neuroendocrine neoplasms of the gallbladder (GB-MiNENs) are sporadic.Case PresentationA 56-year-old woman admitted to our hospital due to right upper abdominal pain of 3 days duration. She underwent positron emission tomography/computed tomography, which showed multiple metastatic tumors and was unsuitable for operation. Initially, the patient was diagnosed with gallbladder adenocarcinoma. She underwent PD-1 inhibitor or combined with chemotherapy considering the PD-L1 high positive score. In the latter, the patient has the opportunity of surgery, and the new diagnosis was MiNENs. She achieved long-term disease control and has been alive from the first diagnosis.ConclusionThis case might support the strategy that PD-1 inhibitor could provide a feasible treatment option for MiNENs of gallbladder patients with the positive expression of PD-L1 in the future.

Probing the Therapeutic Potential of Marine Phyla by SPE Extraction

The marine environment is potentially a prolific source of small molecules with significant biological activities. In recent years, the development of new chromatographic phases and the progress in cell and molecular techniques have facilitated the search for marine natural products (MNPs) as novel pharmacophores and enhanced the success rate in the selection of new potential drug candidates. However, most of this exploration has so far been driven by anticancer research and has been limited to a reduced number of taxonomic groups. In this article, we report a test study on the screening potential of an in-house library of natural small molecules composed of 285 samples derived from 57 marine organisms that were chosen from among the major eukaryotic phyla so far represented in studies on bioactive MNPs. Both the extracts and SPE fractions of these organisms were simultaneously submitted to three different bioassays—two phenotypic and one enzymatic—for cytotoxic, antidiabetic, and antibacterial activity. On the whole, the screening of the MNP library selected 11 potential hits, but the distribution of the biological results showed that SPE fractionation increased the positive score regardless of the taxonomic group. In many cases, activity could be detected only in the enriched fractions after the elimination of the bulky effect due to salts. On a statistical basis, sponges and molluscs were confirmed to be the most significant source of cytotoxic and antimicrobial products, but other phyla were found to be effective with the other therapeutic targets.

Food Myths or Food Facts? Study about Perceptions and Knowledge in a Portuguese Sample

Food myths are nutritional concepts poorly justified or even contradict existing scientific evidence that individuals take as the truth. Knowledge in nutrition is an important tool in tackling misinformation and in the promotion of adequate food choices. This study aimed to investigate the beliefs and perceptions of a sample of the Portuguese population regarding a series of food myths and facts, evaluating, consequently, the level of knowledge and the main sources of information. The research was conducted on a sample of 503 participants, using a questionnaire disclosed online, by email, and social networks, between May and June of 2021. Thirty statements, some true and others false, were analyzed to assess people’s perceptions. Based on the respondents’ answers, a score was calculated for each statement, allowing to differentiate the correct (positive score) from incorrect (negative score) perceptions. The results showed that most statements obtained positive scores, corresponding to correct perceptions. Moreover, the level of knowledge was measured, being very high for 21.7% of the participants and high for 42.1%. The main sources where the participants acquire nutritional information are scientific journals (43.3%), website of the Portuguese General Health Office (DGS) (31.4%), and technical books (31.0%), which is concordant with the level of trust in these sources. Hence, it was concluded that, despite the levels of nutritional knowledge, there are still several food myths that need to be debunked, through the proper channels, in order to promote healthy, balanced, and adequate eating behaviors.

Comparison of programmed death ligand 1 immunostaining for pancreatic ductal adenocarcinoma between paired cytological and surgical samples

Objectives: Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with surgery or chemotherapy. Programmed death ligand 1 expression (PD-L1) immunotherapy has been successful for treating lung and other cancers with PD-L1 expression. However, in many unresectable PDAC cases, cytological samples are the only available tissues for PD-L1 testing. The aim of this study is to retrospectively compare the expression of PD-L1 using cytological and surgical samples. Material and Methods: Paired formalin-fixed cell blocks and surgical samples from the same patients with confirmed diagnoses of PDAC (n = 28) were sectioned for PD-L1 immunohistochemistry. Using tumor proportion score (TPS) and combined positive score (CPS) to evaluate paired cell blocks and surgical samples, we counted and analyzed the data. Results: With TPS, the PD-L1 was expressed in 9/28 (32%) of PDAC surgical samples and in 9/28 (32%) of paired cytological samples. Overall, the PD-L1 expression had a correlation of 26/28 (93%). With CPS, the PD-L1 was expressed in 20/28 (71%) of PDAC surgical samples and in 16/28 (57%) of paired cytological samples. The PD-L1 expression had a correlation of 20/28 (71%) and a discrepancy of 8/28 (29%). The PD-L1 expression was significantly higher in moderately-differentiated PDAC than in well-differentiated with TPS. Conclusion: Cytological samples are useful for evaluating PD-L1 expression with TPS because the concordant rate was 93%. With CPS, cytological samples are limited due to the scant inflammatory cells with the concordant rate of 71%. Extensive sampling of the pancreatic tumor may improve the detection of immune cells expressing PD-L1 in cytological samples. With TPS, PD-L1 expression was significantly higher in moderate-differentiation of PDAC than in poor- and well-differentiation.

60 Use of the Combined Positive Score (CPS) with the companion diagnostic PD-L1 IHC 22C3 pharmDx provides precise evaluation of PD-L1 expression across multiple tumor indications and cutoffs

BackgroundThe Combined Positive Score (CPS)1 algorithm includes tumor and immune cells for determination of Programed Death-Ligand 1 (PD-L1) protein expression in tumor tissues and has been analytically and clinically validated for use with PD-L1 IHC 22C3 pharmDx across multiple indications and cutoffs.2 PD-L1 22C3 IHC pharmDx is a qualitative immunohistochemical assay using anti-PD-L1, Clone 22C3 to detect PD-L1 in formalin-fixed, paraffin-embedded (FFPE) tumor tissues using Autostainer Link 48. PD-L1 IHC 22C3 pharmDx is FDA-approved as an aid in identifying patients for treatment with KEYTRUDA® for six tumor indications at clinically validated CPS diagnostic cutoffs2: gastric or gastroesophageal junction (GC/GEJ) adenocarcinoma (CPS ≥ 1), cervical cancer (CPS ≥ 1), urothelial carcinoma (CPS ≥ 10), head and neck squamous cell carcinoma (HNSCC) (CPS ≥ 1), esophageal squamous cell carcinoma (ESCC) (CPS ≥ 10)3, and triple-negative breast cancer (TNBC) (CPS ≥ 10).MethodsPrecision of PD-L1 IHC 22C3 pharmDx using CPS was assessed for all six indications at the corresponding clinically validated diagnostic cutoffs and at additional exploratory cutoffs under normal, day-to-day testing conditions. Precision testing included Combined Precision (inter-instrument/operator/run (day)), Intra-Run Repeatability, and Observer (inter-/intra-) Scoring Reproducibility studies. FFPE specimens were stained with PD-L1 IHC 22C3 pharmDx and scored using CPS as described in the package insert.2 Four CPS cutoffs were evaluated: CPS ≥ 1 (GC/GEJ, urothelial carcinoma, ESCC, cervical cancer, HNSCC, TNBC), CPS ≥ 10 (GC/GEJ, urothelial carcinoma, ESCC, TNBC), CPS ≥ 20 (HNSCC), and CPS ≥ 50 (HNSCC). Data were analyzed using negative percent agreement (NPA), positive percent agreement (PPA), and overall agreement (OA) with two-sided 95% percentile bootstrap confidence intervals (CIs) based on PD-L1 binary status at the applicable cutoff(s). For each study, data from each CPS cutoff-indication pair were individually analyzed. Meta-analyses were also performed by pooling data from all indications per (i) study and cutoff, and (ii) per study for all tested cutoffs.ResultsNearly all agreement analyses (142/144) for each CPS cutoff-indication pair showed NPA/PPA/OA point estimates (PE) ≥ 90% and CI lower bounds (CILB) ≥ 85%. Meta-analyses showed PE ≥ 90% for NPA/PPA/OA and CILB ≥ 85% per study and cutoff, and per study for all tested cutoffs. Discordant comparisons accounted for <5% of total comparisons performed for each study type.ConclusionsCPS used with PD-L1 IHC 22C3 pharmDx provides precise evaluation of PD-L1 expression across multiple tumor indications and cutoffs under normal, day-to-day testing conditions.AcknowledgementsWe thank the IUSCC Cancer Center at Indiana University School of Medicine, for the use of the Tissue Procurement and Distribution Core, which provided Dako North America, Inc. service.The data and biospecimens used in this project were provided by US Biolab (Gaithersburg, MD, USA), Sofia Bio LLC (New York, NY, USA), Contract Research Ltd (Charlestown, Nevis), and Centre Hospitalier Universitaire (CHU) de Nice (Nice, France) with appropriate ethics approval and through Trans-Hit Biomarkers Inc. Tissue samples were provided by the Cooperative Human Tissue Network which is funded by the National Cancer Institute. Other investigators may have received specimens from the same subjects. Tissue samples supplied by BioIVT (Hicksville, NY, USA).Trial RegistrationN/AReferencesCPS = (# PD-L1 staining cells (tumor cells, lymphotcytes, macrophages))/(Total # viable tumor cells )×100PD-L1 IHC 22C3 pharmDx [Instructions for Use]. Available at: www.agilent.com/library/eifu. Code SK006. Accessed July 2, 2021ESCC was analytically validated as a subtype of esophageal cancer [2].Ethics ApprovalN/AConsentN/A

Diagnostik und Therapie des Magenkarzinoms

Was ist neu? Molekulare Subtypen Die molekularen Alterationen beim Magenkarzinom wurden umfassend charakterisiert. Darauf basiert eine Einteilung in 4 Subtypen, die sich hinsichtlich ihrer Frequenz in unterschiedlichen Lokalisationen des Magens sowie im biologischen Verhalten und der Prognose unterscheiden. Vorsorge und erbliche Formen Chronische Entzündungen der Schleimhaut (unter dem Einfluss von Helicobacter pylori) spielen bei den Nicht-Kardia-Karzinomen eine zentrale pathogenetische Rolle. Patienten mit ausgedehnter Atrophie oder intestinaler Metaplasie sollten endoskopisch überwacht werden. Bei Risikopersonen sollte Helicobacter pylori eradiziert werden. Ein frühes Erkrankungsalter kann auf eine erbliche Disposition hinweisen (Keimbahnmutationen im E-Cadherin-Gen). Patienten mit hereditärem nicht polypösem kolorektalem Karzinom haben ebenfalls ein erhöhtes Risiko, an Magenkarzinomen zu erkranken. Eine humangenetische Beratung ist in beiden Fällen obligat. Therapie des Magenkarzinoms und des Adenokarzinoms des gastroösophagealen Übergangs Frühkarzinome können unter klar definierten Voraussetzungen mittels endoskopischer Resektion behandelt werden. Lokal fortgeschrittene Magenkarzinome werden mit einer perioperativen Systemtherapie behandelt. Das FLOT-Regime, bestehend aus Folinsäure/5-Fluorouracil, Oxaliplatin und Docetaxel, wurde kürzlich als neuer Standard etabliert. Patienten mit metastasierter Erkrankung profitieren von einer Systemtherapie. Diese führt sowohl zu einer Verlängerung des Überlebens als auch über die Kontrolle der Tumorerkrankung zu einer Verbesserung der Symptomkontrolle und Lebensqualität. Platin-Fluoropyrimidin-Doubletten sind in der ersten Behandlungslinie Standard, im Falle von HER2-Positivität in Kombination mit Trastuzumab. Aktuell wurde Pembrolizumab, ein gegen PD-1 gerichteter Antikörper in Kombination mit einer Platin- und Fluoropyrimidin-basierten Chemotherapie bei Her-2 negativen, metastasierten Adenokarzinomen des gastroösophagealen Übergangs mit einer PD-L1 Expression (Combined Positive Score, CPS ≥ 10) zugelassen. Paclitaxel und der antiangiogene Antikörper Ramucirumab sind zugelassen für die zweite Therapielinie. Die orale Wirkstoffkombination Trifluridin/Tipiracil (TAS-102) steht basierend auf einer Phase-III-Studie seit Kurzem für die Drittlinientherapie zur Verfügung. Epstein-Barr-Virus-positive und Mikrosatelliten-instabile Magenkarzinome sind in besonderem Maße immunogen. Immuncheckpoint-Inhibitoren sind hier hoch wirksam, aber in Europa nicht zugelassen.