bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of immunotherapy and sequencing of checkpoint inhibition for metastatic ocular melanoma.
Authors: Abhyankar Anuja , Maharaj Satish , Miller Donald M. 
Published: June 2022

e21526 Background: Ocular melanoma (OM) is the most common intraocular tumor in adults. However, it is still rare as compared to other subtypes of melanoma. Treatment of primary OM is certainly successful, but most therapies assessed in treatment of metastatic OM have not shown promise. Immunotherapy (IO), which has otherwise held prospect for durable remissions in other metastatic melanoma has shown no evidence in metastatic OM. Our study aims at narrowing the gap in knowledge in the treatment of OM with IO. Methods: We conducted a retrospective cohort study of patients with metastatic OM treated during the period 2017-2021 at the University of Louisville. Patients aged 18 years or more with treatment-naïve metastatic (Stage IV) OM were included. Data was censored according to date of last recorded clinical follow up or death. The primary outcome of interest was overall survival (OS). Subgroup analysis was done to examine survival based on initial treatment with dual versus single checkpoint inhibition. After progression on initial therapy, patients previously on dual inhibition went on to receive single inhibition, and vice versa. Kaplan-Meier survival analyses were generated using all-cause mortality as the competing outcome event and log-rank testing to evaluate differences between groups with alpha set at 0.05 for significance. Results: A total of 21 patients with Stage IV OM were identified with 4 excluded due to lack of data. The majority were male (10/17) and median age was 66 years, ranging from 30 to 89 years. More than half (10/17) received dual checkpoint inhibition as initial IO, with ipilimumab and nivolumab. The remainder received pembrolizumab or Nivolumab monotherapy (7/17). IO was well tolerated with no treatment related mortality and incidence of immune-related adverse effects similar to cutaneous melanoma. The median follow-up time overall was 56 months using the reverse Kaplan-Meier method with a median OS of 15 months. Estimated 2-year OS was 41%. No significant difference was found between single and dual checkpoint inhibition as the initial treatment regimen. Conclusions: While IO has markedly improved survival in advanced melanomas, OM continues to have inferior survival. Consistent with the literature by Zimmer et al, survival in this cohort is better than that reported with ipilimumab monotherapy. The median survival of 15 months is consistent with that reported by Heppt et al in the German multicenter study. IO for Stage IV OM was well tolerated, resulting in median survival of 15 months and 2-year OS of 41%. There was no survival advantage to initial treatment with single versus dual checkpoint inhibition, allowing for crossover at progression. Further research with novel agents and enrollment in clinical trials are needed in ocular melanoma.
Comparison of PET-based criteria of evaluation of response to immunotherapy in patients with advanced melanoma.
Authors: Comito Francesca , Pagani Rachele , Aprile Marta , Dragonetti Valentino , Bonazzi Norma , Battisti Giacomo , Malizia Claudio , Nanni Cristina 
Published: June 2022

e21536 Background: Immune checkpoint inhibitors (ICI), such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death-1 (PD-1), have evolved as a dominant strategy in the treatment of metastatic melanoma (MM) in the last decade. At least three PET-based criteria are available for the early assessment of response to immunotherapy: PET/CT Criteria for Early Prediction of Response to Immune Checkpoint Inhibitor Therapy (PECRIT), PET Response Evaluation Criteria for Immunotherapy (PERCIMT) and European Organization for Research and Treatment of Cancer (EORTC) criteria. The aim of this study was evaluation of the concordance of different PET-based criteria for the assessment of response to immunotherapy and to assess their capability of properly stratifying patients in terms of overall survival (OS) and progression free survival (PFS). Methods: We retrospectively enrolled patients with the following inclusion criteria: diagnosis of MM, treatment with ICI for MM and tumor assessment performed by at least two [18F]F-fluorodeoxyglucose (FDG) PET/CT scans (a baseline and ad interim scan). [18F]F-FDG PET/CT scans were analyzed according to PECRIT, PERCIMT and EORTC criteria. Agreement was assessed using Fleiss' kappa and Cohen’s kappa. Prognostic curves of PET/CT response according to different criteria were evaluated in terms of PFS and OS by Kaplan-Meier estimates and were compared by log-rank test. Results: From December 2021 to January 2022, 30 patients were enrolled. 18/30 patients received nivolumab, 8/30 pembrolizumab, 3/30 ipilimumab and 1/30 the combination of nivolumab and ipilimumab. According to PECRIT criteria, 6 patients achieved complete metabolic response (CMR), 7 partial metabolic response (PMR), 5 stable metabolic disease (SMD) and 12 (40%) progressive metabolic disease (PMD). By PERCIMT criteria, 6 patients had response classified as CMR, 9 PMR, 8 SMD and 7 (23.4%) PMD. Finally, by EORTC criteria there were 6 CMR, 10 PMR, 2 SMD and 12 (40%) PMD. In 9 cases out of 30, one criteria assessment differed from the other two and in one patient each criteria evaluation differed from the others (PMD by PECRIT, SMD by PERCIMT, PMR by EORTC). The percentage of patients concordantly evaluated by the three criteria was 68% (Fleiss’ kappa = 0.68). PECRIT and EORTC criteria showed the highest agreement (Cohen’s kappa 0.719), followed by PERCIMT and PERCRIT (Cohen’s kappa 0.69). PERCIMT and EORTC showed 64.4% of concordance. Furthermore, all three criteria were successful in stratifying patients in terms of OS and PFS (p-value < 0.05). Conclusions: We observed substantial agreement among different PET evaluation criteria, with PECRIT and EORTC criteria showing the highest concordance. Analysis of a larger population is needed to prove the utility of PET response evaluation in early prognostic stratification.
Toxicity and response to ipilimumab and nivolumab in elderly patients with metastatic melanoma: A multicenter retrospective analysis.
Authors: Pathmanathan Shivanshan , Babu Hari S , Dzienis Marcin Radoslaw , Azer Mary , Eastgate Melissa A. 
Published: June 2022

e21540 Background: Dual immunotherapy (nivolumab and ipilimumab) is an effective therapy in the treatment of metastatic melanoma, however, its benefit in older patients is unclear. This study aims to investigate the impact of age on the efficacy and toxicity of dual immunotherapy. Methods: A multicentre retrospective study involving centres in Australia [Royal Brisbane and Women’s Hospital, Gold Coast University Hospital and Sunshine Coast University Hospital] was performed to compare the efficacy and toxicity of dual immunotherapy in metastatic melanoma in patients ≥65 years versus patients < 65 years old treated between 2017 and 2021. Data collected included: baseline demographics, PFS, OS, Grade 3 or higher (Gr3+) adverse events as per CTCAEv5, discontinuation rate, duration and complications of steroids used to treat toxicity. Groups were compared using the Fisher exact test for categorical variables and Mann-Whitney test for continuous variables. Survival outcomes were compared using Kaplan Meier, Log rank test and multivariate Cox regression analysis. Results: A total of 139 patients were included with 52 patients ≥65 years and 87 patients < 65 years. There were more males in patients ≥65years [78.9 v 59.8% p = 0.025], and a trend towards fewer BRAF mutations as expected [32.7 v 50.6% p = 0.053]. Other baseline characteristics were similar. Fewer patients received prior BRAF/MEK inhibitor therapy in patients ≥65 years [19.2 v 41.4% p = 0.009]. Median dose of ipilimumab received was 3 cycles in both groups. Median OS was similar in patients ≥65 years v < 65 years [14.9 v 17.3mths p = 0.58]. Median progression free survival was also similar in patients ≥65 years v < 65 years [7.1 v 6.9mths p = 0.79]. Age was not associated with a difference in overall survival on multivariate analysis. There was similar rates of Gr3+ adverse events in patients ≥65 years v < 65 years [50 v 49% p = 1.0] and discontinuation rates secondary to toxicity [55.8 v 56% p = 1.0]. Arthritis lead to more discontinuation in the older patients [9.6% v 0% p = 0.006]. There was one death secondary to pancreatitis in a patient ≥65 years. Median duration of steroids used to treat adverse events was similar in patients ≥65 years v < 65 years [12.2 v 11.7mths p = 0.46]. Complications of steroids requiring inpatient admission was numerically higher in the elderly population [41.3 v 20.4% p = 0.07]. The most common complication related to immunosuppression was infection. There were 2 deaths in patients ≥65 years secondary to infection while on higher dose steroids. Conclusions: Patients ≥65years received similar benefit from dual immunotherapy in comparison to their younger counterparts with similar toxicity. There was a trend towards greater number of complications secondary to steroids. Optimisation of steroid dose and duration in the older patients may reduce the above risk, while maintaining clinical benefit.
New diagnostic index for prediction of severe irAEs in patients with metastatic melanoma taking checkpoint inhibitors.
Authors: Zhukova Natalia V. , Orlova Rashida , Malkova Anna , Kaledina Ekaterina , Demchenkova Alexandra , Naymushina Polina , Nazarov V , Mazing A , Lapin S , Beliak Natalia P. , Shoenfeld Y 
Published: June 2022

e21565 Background: Immune-related adverse events (irAEs) occur in up to 50% of patients treated with immune checkpoint inhibitors (ICI). Severe forms of toxicity are observed in 3% of patients and require systemic steroid therapy and constant monitoring. One of the considered predictor biomarkers of irAEs development is HLA-genotypes. This research aims to evaluate the diagnostic significance of HLA-DRB1 genotypes and other clinical, laboratory parameters to predict the development of irAEs. Methods: The study involved 28 patients (pts) with metastatic melanoma taking ICI (nivo 53.6%, ipi+nivo 32.1%, other 14.3%). The PD-L1 expression, HLA-DRB1 genotype were evaluated. After 2-3 months the development of irAES was assessed. The complications of 3-4 grade or multi-organ damage were termed as a severe irAEs. Statistical analysis was performed in GraphPad Prism 6 (Graph Pad Software, USA) using Fisher, Mann-Whitney, ROC statistical analysis. The project is supported by a grant (14. W03.31.0009). Results: Different IrAEs developed in 57.1% (16/28) of patients, while severe irAEs in 35.7% (10/28). Among all patients HLA-DRB1 genotypes associated with the risk of autoimmune diseases were found in 78.5% (22/28). The PD-L1 expression was detected in 60.7% (17/28) of individuals.Combination treatment increases the risk of toxicity, p = 0.003, with a diagnostic sensitivity (S) of 56% and a diagnostic specificity (Sp) of 100% (RR = 2.71, OR = 31.67). The analysis of specific complications revealed associations between HLA-DRB1*04 with diabetes mellitus, p = 0.026 (OR = 33.57, S = 100%, Sp = 88.5%), HLA-DRB1*04/15 with autoimmune hepatitis or increased transaminases, p = 0.037 (OR = 17.27, S = 100%, Sp = 72%). An index based on the parameters studied (HLA-DRB1, the absence of PD-L1 expression, type of treatment) was created. With index value ≥2 a sensitivity for predicting severe toxicity is 40.00% and a specificity is 83.33%, p = 0.0126. Conclusions: According to the results obtained it can be assumed that the development of severe forms of irAES has a multifactorial origin, in particular, combination therapy, the absence of PD-L1 expression, which can lead to the loss of ICI drug specificity, and the presence of HLA-DRB1 genotypes associated with the risk of developing autoimmune diseases. The new diagnostic index to predict severe complications based on these parameters was created and showed a sensitivity of 40.00% and a specificity of 83.33%. The authors consider the limitations of the study, such as the small sample, the short observational period.
Usage of immunotherapy in Merkel cell carcinoma from 2004 to 2016: A National Cancer Database (NCDB) analysis.
Authors: Luka Michael , Burright Isaac , Townley Liam , Silberstein Peter T. , Eaton Vincent 
Published: June 2022

e21576 Background: Merkel Cell Carcinoma (MCC) is a rare and aggressive skin malignancy with increasing incidence, likely due to an aging population. MCC has been shown to have an increased prevalence in immunosuppressed patients, and current clinical trials are investigating the potential for immunotherapy treatments. As the understanding of the underlying pathogenesis of MCC progresses, the ability to implement specific immunotherapy targets is being investigated and showing promise. Methods: Using the NCDB, we identified 6,918 patients diagnosed with Merkel Cell Carcinoma between 2004-2016 using ICD-O-3 histology code 8247. The cohort was analyzed to identify differences in survival outcomes among patients who received immunotherapy, chemotherapy, a combination of chemotherapy and immunotherapy, and neither chemotherapy nor immunotherapy. We performed univariate analysis to assess median length of survival for each of these specific treatment modality cohorts, in addition to descriptive statistics. Data were analyzed using SPSS and statistical significance was set at α = 0.05. Results: Between 2004 and 2016, 118 patients in the NCDB received immunotherapy. From 2004-14, 21 patients received immunotherapy (1.9 patients per year). The usage of immunotherapy increased drastically in 2015 and 2016 with 18 patients and 79 patients being treated with immunotherapy, respectively. Most immunotherapy patients (59%) received treatment at an academic research center while the remaining patients received immunotherapy at a comprehensive community cancer program (24.8%), an integrated cancer network (12%), or a community cancer program (4.3%). 41.7% of MCC immunotherapy patients were between 33 and 69 years of age, whereas 59.3% ranged from 70-90 years of age. Of the 118 MCC patients who received some form of immunotherapy, 39% had stage IV MCC, 38.1% had stage III MCC, 5.9% had stage II MCC, and 9.3% had stage I MCC. Conclusions: As the use of immunotherapy in MCC continues to rise, especially at academic research centers, future studies should investigate the trends of its usage, its effects on patient survival, and the stage of MCC in which immunotherapy is most often used. We found that patients that received both chemotherapy and immunotherapy had a significantly lower median survival than all other treatment combinations. We hypothesize that the poorer survival rates in the patients that received some form of immunotherapy is due to a later stage of treatment, but this will become clearer as the sample size of MCC patients receiving immunotherapy continues to grow.[Table: see text]
Immunotherapy versus targeted therapy in the adjuvant setting for resected stage III melanoma: A single institution study.
Authors: Dima Danai , Lopetegui-Lia Nerea , Ogbue Olisaemeka , Osantowski Bennett , Ahmed Ramsha , Basali Diana , Chamseddine Fatimah , Eicher Donald Matthew , Song Jung Min , Gastman Brian , Kennedy Lucy Boyce , Funchain Pauline 
Published: June 2022

e21578 Background: Both immunotherapy (IO) and targeted therapy (TT) are approved as adjuvant (Adj) treatment for stage III melanoma, as they have proven to significantly decrease disease recurrence. While there is evidence to suggest overall survival (OS) benefit with TT, data demonstrating OS advantage with Adj IO is lacking. There are no prospective head-to-head trials to date comparing these two treatment modalities. Our aim is to determine whether Adj IO equally improves outcomes compared to Adj TT. Methods: We retrospectively analyzed 104 patients (pts) with resected stage III melanoma who received Adj IO or TT from 1/2016 - 12/2021. Relapse free survival (RFS), distant metastasis free survival (DMFS) and OS rates were assessed between the 2 groups. Results: Of 104 pts, 78 received IO (91% nivolumab, 7% pembrolizumab, 2% other) and 26 pts TT (100% dabrafenib/trametinib). Median follow up was 21 months. At data cutoff, among the 26 pts who received TT, 50% completed 1 year of planned therapy, whereas 50% discontinued TT prematurely (42% due to adverse events [AEs], 8% due to disease relapse). Among the 78 pts who received IO, 70% completed 1 year of planned treatment or continued to receive IO at the end of the study, whereas 30% discontinued IO prematurely (18% due to disease relapse, 12% due to AEs). Relapsed disease was noted in 6/26 (23%) and 27/78 (34.6%) pts of the TT and IO groups, respectively. With regards to location of recurrence, in the TT group 2/6 pts relapsed locally and 4/6 distally, whereas in the IO group 14/27 pts relapsed locally and 13/27 distally. The estimated median RFS of the TT vs IO groups was not reached (NA) (95% Cl: 17 months, NA) vs. 30 months (95% CI: 17 months, NA) respectively, which was not statistically significant (p = 0.49). Comparison of DMFS rate was found not to be statistically significant between the 2 groups (p = 0.86). Finally, median OS was NA in either group. At the end of the study 91% and 90.5% of the pts in the TT and IO arms, respectively, were still alive. The most common AEs in the TT group were fatigue (23%), fever (23%), nausea/vomiting (19%), whereas in the IO group were fatigue (22%), hypothyroidism (14%), diarrhea/colitis (10%), pruritic rash (9%). Conclusions: Both TT and IO appear to equally decrease disease recurrence, locally or distally, when given as Adj therapy for stage III melanoma. Prospective, randomized control trials with longer follow up and larger sample size are warranted to determine any difference in potential OS benefit.[Table: see text]
Multicenter prospective clinical trial of molecular genetic markers for non-invasive differential diagnosis of benign and malignant melanocytic skin lesions.
Authors: Samoylenko Igor , Zaretsky Andrew R , Chudakova Lidia V , Drozd Oleg V , Garanina Oksana E , Shlivko Irena L , Zinovev Grigory , Baryshnikov Kirill A , Orlova Kristina V. , Maximova Tatiana , Sinelnikov Igor , Kim Anna , Mikhaylova Irina N. , Demidov Lev V. 
Published: June 2022

e21581 Background: Improving the accuracy of non-invasive diagnosis of skin tumors is becoming an urgent problem, given the clear increase in the incidence of melanoma in many countries. Dermoscopy and examination by an experienced dermatologist can reduce the NNE to 5–10 per melanoma (M) detected, however, achieving even this, clearly suboptimal, rate requires a long specialist training. Methods: We report results of prospective nonrandomized trial evaluating sensitivity and specificity of RNA profiling of cytological samples from adhesive transparent patches (ATP) applied to skin lesions. Routine pathology reports were obtained for all surgery samples. RNA extracted from ATP specimens (N = 126) was tested for mRNA expression of PRAME and LINC00518 genes. GAPDH was used as a reference gene. Sample was considered marker-positive if either PRAME or LINC00518 expression was detected. Results: Between June 2021 and November 2021, 126 pts undegoing excisional biopsy of skin lesions were included in the study at 5 centers. On pathology, invasive M was detected in 49 (38.9%) patients (mean Breslow thickness was 2.41 mm [95%CI 1,44 to 3.37]), M in situ in 6 (4.8%), non-melanoma skin cancer in 4 (3.2%) and dysplastic nevus in 56 (44.4%). In the day of preplanned excision ATP was applied to the target lesion for 5–6 min and sent to the central lab. Amplifiable mRNA was found in all 126 ATP samples. 82 samples of 126 (65,1%) tested marker-positive. Sensitivity of RNA profiling for detection of skin cancers reached 88.14% (95% CI 77.07% – 95.09%), while specificity was only 53.85% (41.03% – 66.30%), with PPV of 63.41% (56.74% – 69.61%), NPV of 83.33% (70.65% – 91.22%) and accuracy of 70.16% (61.29% – 78.04%). Among the seven false negative results there were 3 M in situ and 4 invasive M. Conclusions: RNA profiling of skin ATP specimens is feasible and has high sensitivity but rather low specificity. Randomized studies are needed to evaluate if this technique can add anything to dermoscopy or other noninvasive diagnostic modalities. Clinical trial information: NCT04353050. [Table: see text]
Oncolytic and protective effects of strain 100 of a new group of non-classified rotavirus of reoviridae family on B16/F10 melanoma growth in experiment.
Authors: Kolpakova Elena P. , Zlatnik Elena Yu , Shulgina Oksana G. , Zolotareva Ekaterina I. , Vashchenko Larisa N. , Ausheva Tatiana V. , Bakulina Svetlana M. , Dashkova Irina R. 
Published: June 2022

e21587 Background: The purpose of this study was to assess the effect of a strain 100 of a new group of rotavirus of Reoviridae family on the growth of transplantable B16/F10 melanoma in mice and the survival of the animals. Methods: We studied the strain 100 of a new group of rotavirus of Reoviridae family (RVK) ( http://jbks.ru/archive/issue-10/article-6 ). RVK 100 is a live attenuated non-pathogenic virus growing on pig embryo kidney cell culture with concentration 5·109 per 1 ml. The dynamics of melanoma growth and the survival of tumor-bearing animals receiving RVK were studied in 25 male mice divided into 5 equal groups, each n = 5. RVK was administered intramuscularly and orally once a week 0.3 mL and 25 µL, respectively: to groups 1-2 21 days prior to the tumor inoculation, a total of 4 injections (“vaccination” regimen); to groups 3-4 – 7 days after tumor inoculation with the onset of tumor nodes, a total of 3 injections (“treatment” regimen); group 5 included controls receiving 0.85% NaCl solution. Groups 1 and 3 received live RVK, groups 2 and 4 - RVK inactivated by UV radiation. Results: Survival of mice in groups 1-2 receiving both live and inactivated RVK in the “vaccination” regimen was increased statistically significantly: in group 1, Me = 25 days after melanoma transplantation (LQ 24; UQ 30), in group 2 Me = 26 days (LQ 25; UQ 30), in controls Me = 14 days (LQ 10; UQ 22); p = 0.032 and p = 0.0079, respectively. RVK administration in the “treatment” regimen did not cause such changes. While mice of group 3 receiving the live strain 100 showed a tendency to higher survival, compared to controls (Me = 23 days, LQ 22; UQ 24, p = 0.056), the administration of inactivated RVK (group 4) did not significantly improve the survival of animals, compared to controls (Me = 22 days (LQ 21; UQ 33, p = 0.151). Conclusions: Improved survival of animals with B16/F10 melanoma after the RVK administration indicates the virus ability to slow down tumor growth and confirms our previously published data on the RVK strain 228, although, in contrast to it, the strain 100 is able to increase the survival rate of tumor-bearing mice only when used in the “vaccination” regimen, which refers mainly to the inactivated virus. Since the inactivation of the RVK strain 100 eliminates its effect when used in the “treatment”, but not “vaccination” regimen, it seems to be associated with an immunostimulatory effect but not with an oncolytic one.