scholarly journals Apoptotic Gastritis in Melanoma Patients Treated With PD-1-Based Immune Checkpoint Inhibition – Clinical and Histopathological Findings Including the Diagnostic Value of Anti-Caspase-3 Immunohistochemistry

2021 ◽  
Vol 11 ◽  
Author(s):  
Jan-Malte Placke ◽  
Josefine Rawitzer ◽  
Henning Reis ◽  
Jassin Rashidi-Alavijeh ◽  
Elisabeth Livingstone ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Clinical Symptoms ◽  
Checkpoint Inhibitors ◽  
Epigastric Pain ◽  
Type A ◽  
Diagnostic Value ◽  
Statistical Testing ◽  
Histopathological Features ◽  
Gastric Biopsies ◽  
Melanoma Patients

BackgroundGastritis induced by checkpoint inhibitors (CPI) is a rare but severe drug-related side effect. The reference standard for confirming CPI-associated gastritis (CPI-assGastritis) is histopathological assessment; however, the histopathological features of CPI-assGastritis are not yet adequately defined.Materials and MethodsGastric biopsies of melanoma patients with histopathologically suspected CPI-assGastritis were compared with gastric biopsies of patients with inflammation free gastric mucosa (IFGM), type A, B, and C gastritis with respect to apoptosis count and predominant histopathological features. Immunohistochemical anti-caspase-3 staining was performed to identify apoptosis. Quantification was performed by manually counting the number of apoptotic events per 10 high-power fields (HPF). Clinical symptoms, treatment, and follow-up data of patients with CPI-assGastritis were examined. The nonparametric Mann–Whitney U test was used for statistical testing.ResultsFive melanoma patients (three women, two men; median age: 45 years) were treated with PD-1-based CPI. The patients reported epigastric pain, weight loss, nausea, and vomiting. Histologically, the patients with CPI-assGastritis showed a partly lymphocytic, partly granulocytic inflammatory infiltrate. Manual counting of apoptotic cells in biopsy tissue slides stained against caspase 3 revealed a median of 6 apoptotic events/10 HPF (95% CI, 2.75-17.30) in the patients with CPI-assGastritis. Results for the comparison cohort (patients n = 21) were a median of 1 apoptotic event/10 HPF (95% CI, 0.5–4.5) for type-A gastritis (six patients), a median of 2 apoptotic events/10 HPF (95% CI, 0–4.5) for type-B gastritis (five patients), and no apoptosis for IFGM and type-C gastritis (five patients). Patients with CPI-assGastritis had a significantly higher apoptosis count than patients with IFGM (p<0.01), type A (p<0.05), B (p<0.05), and C gastritis (p<0.01). None of the CPI-assGastritis biopsies showed evidence of Helicobacter pylori. All CPI-assGastritis patients responded to systemic treatment with corticosteroids.ConclusionCPI-assGastritis manifests with nonspecific symptoms but histologically shows a high number of apoptotic events, which can best be visualized by anti-caspase-3 immunohistochemistry. This histopathological feature may help to histologically differentiate CPI-assGastritis from other forms of gastritis and inform decision-making regarding its optimal management.

scholarly journals Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

2021 ◽  
Author(s):  
Maaike Biewenga ◽  
Monique K. van der Kooij ◽  
Michel W. J. M. Wouters ◽  
Maureen J. B. Aarts ◽  
Franchette W. P. J. van den Berkmortel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Metastasis ◽  
Combination Therapy ◽  
Real World ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Negative Effect ◽  
Melanoma Patients

Abstract Background Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort. Methods Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome. Results 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44). Conclusion Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

scholarly journals Evaluation of the modified immune prognostic index to prognosticate outcomes in metastatic uveal melanoma patients treated with immune checkpoint inhibitors

2021 ◽  
Vol 10 (8) ◽  
pp. 2618-2626
Author(s):  
Michael S. Sander ◽  
Igor Stukalin ◽  
Isabelle A. Vallerand ◽  
Siddhartha Goutam ◽  
Benjamin W. Ewanchuk ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Prognostic Index ◽  
Melanoma Patients

381 Role of CT scans of abdomen and pelvis in management of patients with immunotherapy-induced colitis

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A406-A406
Author(s):  
Juan Ibarra Rovira ◽  
Raghunandan Vikram ◽  
Selvi Thirumurthi ◽  
Bulent Yilmaz ◽  
Heather Lin ◽  
...  
Keyword(s):  
Negative Predictive Value ◽  
Clinical Diagnosis ◽  
Predictive Value ◽  
Clinical Symptoms ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Ct Scans ◽  
Wall Thickening ◽  
Low Sensitivity ◽  
Sensitivity Specificity

BackgroundColitis is one of the most common immune-related adverse event in patients who receive immune checkpoint inhibitors targeting cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death-1 (PD-1). Although radiographic changes are reported on computed tomography such as mild diffuse bowel thickening or segmental colitis, the utility of CT in diagnosis of patients with suspected immune-related colitis is not well studied.MethodsCT scans of the abdomen and pelvis of 34 patients on immunotherapy with a clinical diagnosis of immunotherapy induced colitis and 19 patients receiving immunotherapy without clinical symptoms of colitis (control) were enrolled in this retrospective study. Segments of the colon (rectum, sigmoid, descending, transverse, ascending and cecum) were assessed independently by two fellowship trained abdominal imaging specialists with 7 and 13 years‘ experience who were blinded to the clinical diagnosis. Each segment was assessed for mucosal enhancement, wall thickening, distension, peri-serosal fat stranding. Any disagreements were resolved in consensus. The degree of distension and the spurious assignment of wall thickening were the most common causes for disagreement. The presence of any of the signs was considered as radiographic evidence of colitis.ResultsCT evidence of colitis was seen in 16 of 34 patients with symptoms of colitis. 7 of 19 patients who did not have symptoms of colitis showed signs of colitis on CT. The sensitivity, specificity, Positive Predictive Value and Negative Predictive Value for colitis on CT is 47%, 63.2%, 69.5% and 40%, respectively.ConclusionsCT has a low sensitivity, specificity and negative predictive value for the diagnosis of immunotherapy-induced colitis. CT has no role in the diagnosis of patients suspected of having uncomplicated immune-related colitis and should not be used routinely for management.Trial RegistrationThis protocol is not registered on clinicaltrials.gov.Ethics ApprovalThis protocol was IRB approved on: 11/16/2015 - IRB 4 Chair Designee FWA #: 00000363 OHRP IRB Registration Number: IRB 4 IRB00005015ConsentThis protocol utilizes an IRB approved waiver of consent.

scholarly journals The Efficacy of Anti-PD-L1 Treatment in Melanoma Is Associated with the Expression of the ECM Molecule EMILIN2

2021 ◽  
Vol 22 (14) ◽  
pp. 7511
Author(s):  
Albina Fejza ◽  
Maurizio Polano ◽  
Lucrezia Camicia ◽  
Evelina Poletto ◽  
Greta Carobolante ◽  
...  
Keyword(s):  
Gene Expression ◽  
Effective Treatment ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumor Hypoxia ◽  
Melanoma Cells ◽  
Vessel Normalization ◽  
Melanoma Patients

The use of immune checkpoint inhibitors has revolutionized the treatment of melanoma patients, leading to remarkable improvements in the cure. However, to ensure a safe and effective treatment, there is the need to develop markers to identify the patients that would most likely respond to the therapies. The microenvironment is gaining attention in this context, since it can regulate both the immunotherapy efficacyand angiogenesis, which is known to be affected by treatment. Here, we investigated the putative role of the ECM molecule EMILIN-2, a tumor suppressive and pro-angiogenic molecule. We verified that the EMILIN2 expression is variable among melanoma patients and is associated with the response to PD-L1 inhibitors. Consistently, in preclinical settings,the absence of EMILIN-2 is associated with higher PD-L1 expression and increased immunotherapy efficacy. We verified that EMILIN-2 modulates PD-L1 expression in melanoma cells through indirect immune-dependent mechanisms. Notably, upon PD-L1 blockage, Emilin2−/− mice displayed improved intra-tumoral vessel normalization and decreased tumor hypoxia. Finally, we provide evidence indicating that the inclusion of EMILIN2 in a number of gene expression signatures improves their predictive potential, a further indication that the analysis of this molecule may be key for the development of new markers to predict immunotherapy efficacy.

778 Preclinical study using a glutamatergic signaling and immune-checkpoint inhibitors in a spontaneous melanoma prone mouse model

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A828-A828
Author(s):  
Kevinn Eddy ◽  
Christina Marinaro ◽  
Maryam Rasheed ◽  
Joseph Campagnolo ◽  
Xiaoxuan Zhong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Immune Checkpoint ◽  
Metabotropic Glutamate Receptor ◽  
Checkpoint Inhibitors ◽  
Ectopic Expression ◽  
Tumor Burden ◽  
In Vivo Studies ◽  
Combination Group ◽  
Glutamatergic Signaling ◽  
Melanoma Patients

BackgroundMuch progress has been made in understanding melanoma pathogenesis within the last few years through targeted therapies and immunotherapies. However, resistance to small molecule inhibitors remains an obstacle. Immunotherapies such as checkpoint inhibitors against PD-1/PD-L1 lead to durable responses but only in a subset of melanoma patients. Mouse models reflecting human cancers provide invaluable tools towards the translation of basic science discoveries to clinical therapies, but many of these in vivo studies are short-term and do not accurately mimic patient circumstances. Our lab has a melanoma-prone transgenic mouse model which is driven by ectopic expression of a normal neuronal receptor, metabotropic glutamate receptor 1 (GRM1). This mouse model recapitulates melanoma development and progression frequently associated with melanoma patients, where aberrant GRM1 expression is detected. We have shown that in >90% of late-stage melanoma patients, there is atypical GRM1 mediated signaling and expression.MethodsIn this study, we are using these mice, TGS, to determine the long-term, 18-week, therapeutic consequences of troriluzole, a prodrug for riluzole, which is an inhibitor of glutamatergic signaling plus anti-PD-1, an immune-checkpoint inhibitor. Tumor burden is monitored every 6 weeks for 18 weeks using a small imaging system, IVIS and tumor burden is quantified using ImageJ software. Blood, lymphoid, and tumor samples were collected at several time points during the study for molecular, and immune analyses.ResultsPreliminary results suggest a gender-biased treatment response and that the combination of troriluzole and anti-PD-1 is more efficacious than either agent alone. In males, a 43.9% reduction in tumor burden was observed while in females there was a 29.6% increase in tumor burden in the combination group compared to vehicle. In concordance, after the removal of the treatment modality, the male mice in the combinatorial group survived 42 days longer compared to vehicle controls with sustained tumor reduction by 68.3%. In female mice no significant advantage in survival or reduction in tumor burden was noted.ConclusionsN/A

Frequency of rdx A Deletion Mutation Conferring Metronidazole Resistance in Helicobacter pylori

2020 ◽  
Vol 29 (3) ◽  
pp. 59-64
Author(s):  
Hanaa M. El Maghraby ◽  
Samar Mohaseb
Keyword(s):  
Helicobacter Pylori ◽  
Epigastric Pain ◽  
Deletion Mutation ◽  
Rapid Urease Test ◽  
Rrna Gene ◽  
University Hospitals ◽  
Metronidazole Resistance ◽  
Urease Test ◽  
Gastric Biopsies ◽  
H Pylori

Background: Metronidazole is one of the antimicrobial drugs that can be used in combination with other drugs for eradication of Helicobacter pylori (H. pylori).Unfortunately, metronidazole resistance in H. plori is an increasing health problem which may be attributed to inactivation of many genes as rdx A gene. Objective: To determine the frequency of rdx A deletion mutation in H. pylori detected in infected patients attending at the Gastroenterology Unit, Zagazig University Hospitals. Methodology: Two gastric biopsies were taken from each enrolled patient by endoscopy. H.pylori detection was done by rapid urease test and polymerase chain reaction (PCR) amplification of 16S rRNA gene. Deletion mutation in rdx A gene was detected by conventional PCR. Results: Out of 134 doubled gastric biopsies obtained from 134 patients, 52.2% were positive for H. pylori. Epigastric pain, vomiting and gastritis were significantly associated with detection of H. pylori infection (p˂ 0.05). Deletion mutation of rdx A gene was detected in 28.6% of H. pylori positive specimens obtained from infected patients. Conclusion: Deletion mutation of rdx A gene is a frequent determinant of rdx A inactivation conferring metronidazole resistance among H. pylori.

18 F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography imaging for the diagnosis of immune checkpoint inhibitors associated myocarditis

2021 ◽  
Author(s):  
Stéphane Ederhy ◽  
Perrine Devos ◽  
Bruno Pinna ◽  
Elisa Funck-Brentano ◽  
Baptiste Abbar ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Fdg Pet ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Diagnostic Value ◽  
Predictive Values ◽  
Fdg Uptake ◽  
Positron Emission ◽  
Medicine Physician ◽  
Oncology Unit

Abstract Immune-checkpoint inhibitors (ICI) have profoundly improved the prognosis of cancer patients but are associated with life-threatening myocarditis (incidence≤1%).The diagnosis of ICI-myocarditis remains challenging necessitating the need for novel diagnostic strategies.This single center cohort included 61 consecutive patients referred to our cardio-oncology unit for a suspicion of ICI-myocarditis with a positive troponin, between March 2019 and March 2021. In the 31 patients with suspected ICI-myocarditis with available FDG-PET, the median delay between admission and the first available FDG-PET performed was 12 days [interquartile-range:9-30]. Patients received ICI (ICI-monotherapy: 24/31, 77% and ICI-combination therapy: 7/31, 23%), mainly for lung cancer (n=10), melanoma (n=5), and kidney cancer (n=3). FDG-PET was performed using a standardized protocol involving dietary measures prior to PET, including fasting of at least 6h and a fat enriched diet without carbohydrates for 24h. FDG-PET platforms included Biograph-mCT-Flow Siemens (n=9/34, 26%) or Discovery-MI-5-Ring General Electric (n=25/34, 74%) devices and analysed using Singo.via Workstation (Siemens) by a nuclear medicine physician blinded to patients’ medical records. Interpretation of FDG-PET was based on the following classification: 1/No FDG uptake, 2/Diffuse FDG uptake, 3/Focal FDG uptake, 4/Focal on diffuse FDG uptake.An abnormal cardiac fixation on FDG-PET suggestive of myocarditis was observed in only 2/21 (9.5%) patients with otherwise definite ICI-myocarditis (1 diffuse, 1 focal), not different in proportion versus 1/7 (14.3%, 1 focal) patient without ICI-myocarditis (p>0.99). The sensitivity, specificity, positive predictive and negative predictive values (with their 95% confidence-interval) of FDG-PET for ICI-myocarditis was 9.5% (1.2-30.4%), 85.7% (42.1-99.6%), 66% (17.5-95%), 24% (18.5-30.6%), respectively. Only 2/14(14.2%) FDG-PET were positive despite being performed at a time in which ICI-myocarditis was fully active with troponin levels over ten-times the normal values versus 0/6(0%,p>0.99) for FDG-PET performed when troponin levels were abnormal but below ten-times the upper limit. Similarly, there was no difference in FDG-PET positivity rate for exams performed within 14 days (1/7, 14.3%; plus 3 inconclusive exams) versus those performed after 14 days (1/14, 7.2%; no inconclusive exams; p>0.99) of hospital admission.Altogether, our study suggests that FDG-PET has a limited diagnostic value for the diagnosis of ICI-Myocarditis.

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