Profile of ipilimumab and its role in the treatment of metastatic melanoma

Melanoma is an immunogenic cancer. However, the ability of the immune system to eradicate melanoma tumors is affected by intrinsic negative regulatory mechanisms. Multiple immune-modulatory therapies are currently being developed to optimize the immune response to melanoma tumors. Two recent Phase III studies using the monoclonal antibody ipilimumab, which targets the cytotoxic T-lymphocyte antigen (CTLA-4), a negative regulator of T-cell activation, have demonstrated improvement in overall survival of metastatic melanoma patients. This review highlights the clinical trial data that supports the efficacy of ipilimumab, the immune-related response criteria used to evaluate clinical response, and side-effect profile associated with ipilimumab treatment

Analysis of adverse drug reactions in a tertiary care emergency medicine department: prevalence, preventability and reporting

Background: Adverse drug reactions (ADRs) are negative consequences of drug therapy. ADR results in diminished quality of life, increased physician visits, hospitalizations, and even death. Hence a study was planned to detect and analyze ADR encountered in emergency medicine department.Methods: Data was collected over a period of 1 year after taking approval from IRB (Institutional Review Board) and written informed consent from patients. ADRs presenting as a cause of hospital admission or developed during hospitalization were analyzed.Results: A total of 229 ADRs were analyzed. Majority of ADRs were found in the age group of 40-60 Years. The M: F Ratio was 1.10:1. According to Wills and Brown Classification, majority of the ADRs belonged to Type A. According to Hartwig and Siegel classification of severity of ADRs, 18.78% of the ADRs were severe in nature. According to Schumock and Thornton preventability score, majority (64.19%) of the ADRs were not preventable, whereas 17.03% were definitely preventable. 120 (52.40%) of the ADRs were serious in nature Anti-infective were the most common drug class (30.13%) followed by CVS (24.03%) group of drugs. About (57.64%) ADRs fall in the category of probable/likely. Regarding their Outcome, 44.10% of the ADRs were recovered and 43.23% were recovering.Conclusions: Anti-infective were the most reported drug class to cause ADRs in a tertiary care emergency medicine department. Causality assessment according to WHO-UMC and Naranjo’s causality assessment criteria reported to be Probable. Whereas modified Schumock and Thornton scale preventability scale showed that majority were not preventable

Suspected immune mediated response to COVID-19 vaccine: two individual case reports

SARS-CoV-2, the virus that causes coronavirus disease 19 (COVID-19), has spread rapidly around the world. Researchers have been working round the clock to develop effective vaccines, which people started receiving in December 2020. Therefore, careful follow-up and surveillance studies for continued vaccine safety monitoring will be needed to ascertain the potential risks of such adverse events or disease. Here, we present two individual cases of pancreatitis and typhilitis following COVID 19 vaccination. In the first case of a 38 years old male patient developed pancreatitis after 4 days of COVID 19 vaccination and in second case, of a 60 years old female patient developing typhilitis after just one day after vaccination. All possible causes of this occurrence were ruled out. Two main factors suggest a possible link to the vaccine, the chronology of the events and the incongruent immune response to the vaccine component. It is not possible to establish a direct causal relation between vaccination and adverse event following immunization; however, this report can be used to alert practitioners to this possibility of adverse event following immunization after COVID-19 vaccine

Presence of Circulating Tumor Cells Predates Imaging Detection of Relapse in Patients with Stage III Melanoma

Stage III melanoma includes nodal metastasis or in-transit disease. Five-year survival rates vary between 32% and 93%. The identification of high-risk patients is important for clinical decision making. We demonstrated previously that ≥1 circulating tumor cells (CTCs) at baseline was associated with recurrence. In this study, we investigated how frequently CTCs were identified prior to radiologically detected recurrence. Stage III patients (n = 325) had imaging at baseline and q 3 months. Baseline and q 6-12 months blood draws (7.5 mL) were performed to identify CTCs up to 3.5 years from diagnosis. CTC assessment was performed using the immunomagnetic capture of CD146-positive cells and anti-MEL-PE. The presence of one or more CTCs was considered positive. We analyzed the cohort of patients with relapse confirmed by radiologic imaging. CTC collection dates were assessed to determine the lead time for CTC detection. CTC-negative patients were significantly less likely to relapse compared to patients positive for CTCs (p-value \u3c 0.001). Within the 325-patient cohort, 143 patients (44%) had recurrence, with a median follow-up of 52 months from diagnosis. The cohort (n = 143) with positive imaging and CTC results revealed 76% of patients (108/143) had CTC+ results before the radiological identification of relapse. The median time between positive CTC and positive imaging was 9 months. CTCs were positive in \u3e75% of patients prior to relapse at a median of 9 months before radiologic detection

Therapy with high-dose Interleukin-2 (HD IL-2) in metastatic melanoma and renal cell carcinoma following PD1 or PDL1 inhibition

Abstract Background Metastatic melanoma (mM) and renal cell carcinoma (mRCC) are often treated with anti-PD-1 based therapy, however not all patients respond and further therapies are needed. High dose interleukin-2 (HD IL-2) can lead to durable responses in a subset of mM and mRCC patients. The efficacy and toxicity of HD IL-2 therapy following anti-PD-1 or anti-PD-L1 therapy have not yet been explored. Methods Reports on mM and mRCC patients who had received HD IL-2 after PD-1 or PD-L1 inhibition were queried from the PROCLAIMSM database. Patient characteristics, toxicity and efficacy were analyzed. Results A total of 57 patients (40 mM, 17 mRCC) were treated with high dose IL-2 after PD-1 or PD-L1 inhibition and had data recorded in the PROCLAIM database. The best overall response rate to HD IL-2 was 22.5% for mM (4 complete response (CR), 5 partial responses (PRs)) and 24% for mRCC (2 CRs, 2 PRs). The toxicity related to HD IL-2 observed in these patients was similar to that observed in patients treated with HD IL-2 without prior checkpoint blockade. One patient who had received prior PD-L1 blockade developed drug induced pneumonitis with HD IL-2 requiring steroid therapy. Conclusion In this retrospective analysis, HD IL-2 therapy displayed durable antitumor activity in mM and mRCC patients who progressed following treatment with PD-1 and PD-L1 inhibition. The toxicities were generally manageable and consistent with expectations from HD IL-2 but physicians should watch for immune related toxicities such as pneumonitis. This analysis supports the development of randomized prospective trials to assess the proper sequencing and combination of immune checkpoint blockade and cytokine therapy.https://deepblue.lib.umich.edu/bitstream/2027.42/148134/1/40425_2019_Article_522.pd

Helicobacter pylori vacA transcription is genetically-determined and stratifies the level of human gastric inflammation and atrophy

Aims Helicobacter pylori infection is the major cause of peptic ulceration and gastric cancer, and an important virulence determinant is its vacuolating cytotoxin, vacA. Previously, we have described allelic variation in vacA which determines toxin activity and disease risk. We now aimed to quantify vacA mRNA expression in the human stomach, define its genetic determinants and assess how well itpredicted gastric pathology. Methods Gastric biopsies were donated by 39 H. pylori-infected patients attending for endoscopy at Queen’s Medical Centre, Nottingham, UK. Total RNA was extracted, and vacA mRNA quantified by reverse transcriptase quantitative polymerase chain reaction. Separate biopsies were histologically scored for inflammation and atrophy using the updated Sydney system. H. pylori strains were isolated from further biopsies, and the nucleotide sequence upstream of vacA determined. Results vacA mRNA levels in human stomachs varied by two orders of magnitude independently of vacA allelic type. Among vacA i1-type (toxic) strains, increased vacA expression was strongly associated with higher grade gastric inflammation (

T-Cell Receptor Beta Variable Gene Polymorphism Predicts Immune-Related adverse Events During Checkpoint Blockade Immunotherapy

BACKGROUND: Immune checkpoint inhibitors have revolutionized cancer treatment. However, they are associated with a unique spectrum of side effects, called immune-related adverse events (irAEs), which can cause significant morbidity and quickly progress to severe or life-threatening events if not treated promptly. Identifying predictive biomarkers for irAEs before immunotherapy initiation is therefore a critical area of research. Polymorphisms within the T-cell receptor beta (TCRB) variable (TRBV) gene have been implicated in autoimmune disease and may be mechanistically linked to irAEs. However, the repetitive nature of the TCRB locus and incomplete genome assembly has hampered the evaluation of TRBV polymorphisms in the past. PATIENTS AND METHODS: We used a novel method for long-amplicon next generation sequencing of rearranged TCRB chains from peripheral blood total RNA to evaluate the link between TRBV polymorphisms and irAEs in patients treated with immunotherapy for cancer. We employed multiplex PCR to create amplicons spanning the three beta chain complementarity-determining regions (CDR) regions to enable detection of polymorphism within the germline-encoded framework and CDR1 and CDR2 regions in addition to CDR3 profiling. Resultant amplicons were sequenced via the Ion torrent and TRBV allele profiles constructed for each individual was correlated with irAE annotations to identify haplotypes associated with severe irAEs (≥ grade 3). RESULTS: Our study included 81 patients who had irAEs when treated with immunotherapy for cancer. By using principal component analysis of the 81 TRBV allele profiles followed by k-means clustering, we identified six major TRBV haplotypes. Strikingly, we found that one-third of this cohort possessed a TRBV allele haplotype that appeared to be protective against severe irAEs. CONCLUSION: The data suggest that long-amplicon TCRB repertoire sequencing can potentially identify TRBV haplotype groups that correlate with the risk of severe irAEs. Germline-encoded TRBV polymorphisms may serve as a predictive biomarker of severe irAEs

Beyond BRAFV600: Clinical Mutation Panel Testing by Next-Generation Sequencing in Advanced Melanoma

The management of melanoma has evolved owing to improved understanding of its molecular drivers. To augment the current understanding of the prevalence, patterns, and associations of mutations in this disease, the results of clinical testing of 699 advanced melanoma patients using a pan-cancer next-generation sequencing (NGS) panel of hotspot regions in 46 genes were reviewed. Mutations were identified in 43 of the 46 genes on the panel. The most common mutations were BRAFV600 (36%), NRAS (21%), TP53 (16%), BRAFNon-V600 (6%), and KIT (4%). Approximately one-third of melanomas had >1 mutation detected, and the number of mutations per tumor was associated with melanoma subtype. Concurrent TP53 mutations were the most frequent events in tumors with BRAFV600and NRAS mutations. Melanomas with BRAFNon-V600mutations frequently harbored concurrent NRAS mutations (18%), which were rare in tumors with BRAFV600 mutations (1.6%). The prevalence of BRAFV600 and KIT mutations were significantly associated with melanoma subtypes, and BRAFV600 and TP53 mutations were significantly associated with cutaneous primary tumor location. Multiple potential therapeutic targets were identified in metastatic unknown primary and cutaneous melanomas that lacked BRAFV600and NRAS mutations. These results enrich our understanding of the patterns and clinical associations of oncogenic mutations in melanoma

Neoadjuvant Checkpoint Inhibitor Immunotherapy for Resectable Mucosal Melanoma

BACKGROUND: Neoadjuvant checkpoint inhibition (CPI) has recently demonstrated impressive outcomes in patients with stage 3 cutaneous melanoma. However, the safety, efficacy, and outcome of neoadjuvant CPI in patients with mucosal melanoma (MM) are not well studied as MM is a rare melanoma subtype. CPI such as combination nivolumab and ipilimumab achieves response rates of 37-43% in unresectable or metastatic MM but there is limited data regarding the efficacy of these agents in the preoperative setting. We hypothesize that neoadjuvant CPI is a safe and feasible approach for patients with resectable MM. METHOD: Under an institutionally approved protocol, we identified adult MM patients with resectable disease who received neoadjuvant anti-PD1 +/- anti-CTLA4 between 2015 to 2019 at our institution. Clinical information include age, gender, presence of nodal involvement or satellitosis, functional status, pre-treatment LDH, tumor mutation status, and treatment data was collected. Outcomes include event free survival (EFS), overall survival (OS), objective response rate (ORR), pathologic response rate (PRR), and grade ≥3 toxicities. RESULTS: We identified 36 patients. Median age was 62; 58% were female. Seventy-eight percent of patients received anti-PD1 + anti-CTLA4. Node positive disease or satellite lesions was present at the time of treatment initiation in 47% of patients. Primary sites of disease were anorectal (53%), urogenital (25%), head and neck (17%), and esophageal (6%). A minority of patients did not undergo surgery due to complete response (n=3, 8%) and disease progression (n=6, 17%), respectively. With a median follow up of 37.9 months, the median EFS was 9.2 months with 3-year EFS rate of 29%. Median OS had not been reached and 3-year OS rate was 55%. ORR was 47% and PRR was 35%. EFS was significantly higher for patients with objective response and for patients with pathologic response. OS was significantly higher for patients with pathologic response. Grade 3 toxicities were reported in 39% of patients. CONCLUSION: Neoadjuvant CPI for resectable MM is a feasible approach with signs of efficacy and an acceptable safety profile. As there is currently no standard approach for resectable MM, this study supports further investigations using neoadjuvant therapy for these patients

Daily angina documentation versus subsequent recall: development of a symptom smartphone app

Aims: The traditional approach to documenting angina outcomes in clinical trials is to ask the patient to recall their symptoms at the end of a month. With the ubiquitous availability of smartphones and tablets, daily contemporaneous documentation might be possible. Methods and results: The ORBITA-2 symptom smartphone app was developed with a user-centred iterative design and testing cycle involving a focus group of previous ORBITA participants. The feasibility and acceptability were assessed in an internal pilot of participants in the ongoing ORBITA-2 trial. Seven days of app entries by ORBITA-2 participants were compared with subsequent participant recall at the end of the 7-day period. The design focus group tested a prototype app. They reported that the final version captured their symptoms and was easy to use. In the completion assessment group, 141 of 142 (99%) completed the app in full and 47 of 141 (33%) without reminders. In the recall assessment group, 29 of 29 (100%) participants said they could recall the previous day’s symptoms, and 82% of them recalled correctly. For 2 days previously, 88% said they could recall and of those, 87% recalled correctly. The proportion saying they could recall their symptoms fell progressively thereafter: 89, 67, 61, 50%, and at 7 days, 55% (P < 0.001 for trend). The proportion of recalling correctly also fell progressively to 55% at 7 days (P = 0.04 for trend). Conclusion: Episode counts of angina are difficult to recall after a few days. For trials such as ORBITA-2 focusing on angina, daily symptom collection via a smartphone app will increase the validity of the results