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Background: When monotherapy with PD-1 inhibitors in metastatic melanoma fails, there are currently no standard second-line choices. In case of the unavailability of clinical trials, ipilimumab represents a possible alternative treatment., Methods: We collected data of 44 patients who received ipilimumab after the failure of PD-1 inhibitors from July 2017 to May 2023 at our Institute. Overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) based on BRAF or NRAS mutation status, sex, and the presence of brain metastases were estimated using the Kaplan-Meier method. Cox regression was used to evaluate independence in multivariate analysis. The objective response rate (ORR) was estimated based on RECIST 1.1., Results: Among the 44 patients enrolled in this study, 28 BRAF-wildtype, 9 BRAF-mutated, and 7 NRAS-mutated patients were identified. OS analysis showed a significant difference between wildtype and BRAF- or NRAS-mutated patients: 23.2 months vs 5.3 and 4.59, respectively, p = 0.017. The presence of brain metastases and BRAF or NRAS mutation were independent factors for mortality in multivariate analysis., Conclusions: In case of failure to enroll patients in innovative clinical trials, second-line ipilimumab still represents an effective therapy in patients with metastatic wildtype melanoma and in the absence of brain metastases.

Immunotherapy with anti-PD-1 antibodies significantly improved the prognosis in advanced melanoma patients, but most of them develop primary or secondary resistance to the treatment. In this study, we evaluated efficacy and safety of a chemotherapy regimen with weekly carboplatin plus paclitaxel (wCP) in patients previously treated with anti-PD-1 antibodies. We retrospectively identified 30 patients with advanced melanoma treated at our Institute over the last eight years with wCP. The co-primary endpoints of the study were overall survival (OS) and progression-free survival (PFS). In addition, we evaluated treatment tolerability. For this patient cohort, median PFS and OS were 3.25 and 7.69 months, respectively. All included patients had previously received anti-PD-1 immunotherapy, most of them had ECOG PS 0-1, and only 5 patients had a BRAF V600 mutation. In univariable analysis, we observed shorter OS in patients with > 2 involved metastatic sites, superficial spreading histology, and serum lactate dehydrogenase (LDH) values above the median. Liver metastases were associated with worse outcomes, while radiotherapy treatment of brain metastases was associated with improved OS. However, in a multivariable Cox regression model, only LDH above the median, superficial spreading histology, and female sex were significantly associated with worse OS. We reported grade 3 and 4 treatment-related toxicities in 4 and 0 patients, respectively. In conclusion, chemotherapy with wCP is a valid palliative treatment in advanced melanoma who progressed with anti-PD-1 antibodies., (© 2024. The Author(s).)

Background: Stage III surgically resected melanoma is a disease at high risk of recurrence. Immune checkpoint inhibitors (ICIs) and the target therapy with BRAF and MEK inhibitors significantly changed the outcome of patients with metastatic melanoma and several studies have also shown their benefit in the adjuvant setting for the delay of recurrence in stage III melanoma patients. Hyperprogression disease was observed as a possible adverse response to immunotherapy in the metastatic setting, suggesting that some patients could face additional risk of progression with ICIs, although no consensus was found for the correct definition of this event., Case Presentation: We describe here two cases of rapid multiorgan metastatization during adjuvant immunotherapy in patients with stage III resected melanoma. Even though it would be not accurate to define this syndrome as hyperprogression because of apparent absence of the initial disease in the adjuvant setting, we observed in these two cases the same very rapid progression after first administration of adjuvant ICIs that resulted in death of patients within two months from the starting of treatment. Both patients had NRAS mutated melanoma., Conclusion: There is an urgent need for a better understanding of the causes of these fatal outcomes and for the identification of biomarkers that would allow to select the patients before offering them an adjuvant treatment, reducing the risk of hyperprogression. From these cases, we suggest that it could be useful a particular attention in proposing ICI adjuvant treatment based on the molecular profile., Competing Interests: FG has been a speaker at BMS, and Novartis conference. PM had a consultant/advisory role for BMS, ROCHE Genentech, MSD, Novartis, AMGEN, Merck Serono, Pierre Fabre, INCYTE. The remaining authors declare that this research was conducted in the absence of any commercial or financial relationships that could be considered as a potential conflict of interest., (Copyright © 2024 Di Pietro, Verkhovskaia, Falcone, Poti, Carbone, Morelli, Zappalà, Morese, Di Rocco, Piesco, Chesi, Failla, Marchetti and De Galitiis.)

(1) Background: Mucosal melanoma (MM) is a rare tumor, accounting for about 1% of all diagnosed melanomas. The etiology and pathogenesis of this tumor are unknown. It is characterized by an aggressive phenotype with poor prognosis and a low response rate to approved treatments. (2) Methods: We retrospectively analyzed the clinical features, treatments and outcomes of patients diagnosed with MM from different sub-sites (head and neck, gynecological and gastro-intestinal region) between 2013 and 2023 at our Institute. Survival times were estimated with the Kaplan-Meier method. Multivariate Cox regression was used to test the independence of significant factors in univariate analysis. (3) Results: Twenty-five patients were included in this study; the disease was equally distributed among females and males. The median age at diagnosis was 74 years old. The majority had MM originating from the head and neck (56%), particularly from the nasal cavity. BRAF V600 mutations were detected in 16% of the study population, limited to gastro-intestinal and gynecological MM. At diagnosis, at least half the patients (52%) had the disease located also at distant sites. The median overall survival (OS) in the whole study population was 22 months, with a longer OS for patients diagnosed at an early stage (38 months, p < 0.001). Longer OSs were reported for head and neck MM compared to other anatomic regions (0.06). Surgery of the primary tumor and radiotherapy were performed in 64% and 36% of the study population, respectively. Radiotherapy was performed only in head and neck MM. At multivariate analysis, the single factor that showed a reduced hazard ratio for death was radiotherapy. (4) Conclusions: The overall survival of MM from different sub-sites treated at our Italian Institution was 22 months, with better outcomes for early-stage disease and head and neck MM. Performing radiotherapy may have a protective effect on OS for head and neck MM. New treatment strategies are urgently needed to improve the outcome in this disease.

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide.

Plasma tumour DNA (ptDNA) is a potential early noninvasive biomarker of treatment outcome in metastatic castration-resistant prostate cancer (mCRPC). Herein, we investigated whether pretreatment ptDNA levels reflect metabolic tumour burden in mCRPC and better predict treatment outcome in combination with functional imaging. Targeted next-generation sequencing was performed to estimate the ptDNA fraction from 102 mCRPC patients receiving abiraterone or enzalutamide. The maximum standardized uptake value (SUVmax), total lesion activity (TLA) and metabolic tumour volume (MTV) were evaluated on 18 F-fluorocholine positron emission tomography/computed tomography. We assessed a Weibull multiple regression model to determine the combined impact of clinical, molecular and imaging characteristics on overall survival (OS) and progression-free survival (PFS), and to obtain prognostic scores. A significant association was seen between ptDNA and SUVmax, MTV and TLA. For survival analysis, patients were randomly allocated into a training (n = 68) and a validation (n = 34) set. In the training set, multivariable analyses showed that ptDNA, MTV and serum lactate dehydrogenase together with visceral metastasis were independent predictors of both OS and PFS. Prognostic scores were generated, with the identification of three groups of patients with significantly different median OS (29.2, 15.9 and 8.7 months) and PFS (13.3, 7.7 and 3.2 months) probabilities. The differences in median survival between risk groups were confirmed in the validation cohort for both OS and PFS. In our study, we showed that integrating plasma DNA analysis with functional imaging may improve prognostic risk stratification and treatment selection in mCRPC., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)

Over the years, an increasing proportion of metastatic prostate cancer patients has been found to experience an initial bone flare phenomenon under both standard therapies (androgen deprivation therapy, chemotherapy, radiotherapy, abiraterone, enzalutamide) and novel agents (immunotherapy, bone-targeting radioisotopes). The underlying biological mechanisms of the flare phenomenon are still elusive and need further clarification, particularly in relation to different types of treatment and their treatment response assessment. Flare phenomenon is often underestimated and, in some cases, can negatively affect clinical outcome. In cases with suspected bone flare, the treatment should be continued for a minimum of 12 more weeks before further decisions about efficacy can be taken. Physicians and patients should be aware of this effect to avoid unwarranted anxiety and inadequate early discontinuation of treatment. This review aims at highlighting new evidence on flare phenomenon arising after the introduction of new drugs extending across the biochemical, radiographic and clinical spectrum of the disease., Competing Interests: Conflict of interest statement: VC has received speaker honoraria or travel support from Astellas, Janssen-Cilag and Sanofi-Aventis, and has received consulting fee from Bayer and Janssen-Cilag. PM has/had a consultant/advisory role for BMS, Roche, Genentech, MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte. UDG has served as consultant/advisory board member for Astellas, Bayer, BMS, Ipsen, Janssen, Merck, Pfizer and Sanofi; has received travel support from BMS, Ipsen, Janssen and Pfizer; and has received research funding from AstraZeneca, Roche and Sanofi (Inst). No potential conflicts of interest were disclosed by the other authors., (© The Author(s), 2021.)

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

Inhibiting androgen receptor (AR) signaling with androgen deprivation therapy (ADT) represents the mainstay of therapy for advanced and metastatic prostate cancer. However, about 20-60% of patients receiving first-line treatment for prostate cancer will relapse, evolving in a more aggressive and lethal form of the disease, the castration-resistant prostate cancer (CRPC), despite the use of ADT. Multiple approved systemic therapies able to prolong survival of patients with metastatic CRPC (mCRPC) exist, but almost invariably, patients treated with these drugs develop primary or acquired resistance. Multiple factors are involved in CRPC treatment resistance and elucidating the mechanisms of action of these factors is a key question and an active area of research. Due to such a complex scenario, treatment personalization is necessary to improve treatment effectiveness and reduce relapse rates in CRPC. In this review, current evidence about the major mechanisms of resistance to the available prostate cancer treatments were examined by introducing insights on new and future therapeutic approaches., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Aims: Evaluation of ambulatory blood pressure monitoring (ABPM), two-dimensional (2D) echo and clinical variables in predicting cardiac death and acute decompensated heart failure in patients with ischaemic cardiomyopathy and receiving a cardioverter-defibrillator implantation., Methods and Results: We studied 180 consecutive patients (169 men) on an out-patient basis, with systolic dysfunction (ejection fraction ≤35%) and previous myocardial infarction. All received a cardioverter defibrillator (ICD) (116 dual chamber, 36 monocameral and 28 biventricular), for primary prevention of sudden death and standard medical therapy for heart failure. Mean follow-up was 11.7 months. Two-dimensional echo was performed just before ICD implantation, ABPM and haematological samples 2 weeks later. Age, ejection fraction, creatinine, haemoglobin concentration, mean 24-h systolic blood pressure, mean 24-h diastolic blood pressure, mean 24-h heart rate, brain natriuretic peptide, QRS duration, % paced beats, ventricular scar, biventricular pacing, sex and diabetes were considered. Cox proportional hazards regression analysis was used to explore the relationship between events. ROC curves were built for each independent variable. Events occurred in 47 patients (26%); 7 deaths for refractory heart failure and 40 hospitalizations for acute decompensated heart failure. Low mean 24-h systolic blood pressure [hazard ratio 0.96, 95% confidence interval (CI) 0.93-0.99, P = 0.02], high creatinine (hazard ratio 1.61, 95% CI 1.06-2.47, P = 0.01), low haemoglobin concentration (hazard ratio 0.81, 95% CI 0.65-0.99, P = 0.04) and older age (hazard ratio 1.04, 95% CI 1.01-1.08, P = 0.02) were independent predictors of events., Conclusions: Ambulatory systolic blood pressure, haemoglobin, creatinine and age can stratify risk of death and acute decompensated heart failure in patients with ischaemic cardiomyopathy and ICD in whom 2D-echo ejection fraction is not predictive.

In this study we analysed serum IL-2 levels in 61 patients with multiple myeloma (MM). Patients serum IL-2 levels were significantly higher than normal controls. Moreover, higher serum IL-2 levels were associated with a prolonged actuarial survival. In particular, 87% of the MM patients with IL-2 greater the or equal to 10 U/ml are still alive at 5 years while only 13% of the remaining patients with IL-2 less than 10 U/ml are alive. The multivariate analysis confirmed these data indicating that high serum IL-2 levels are the most useful predictor index of longer survival in MM patients. Furthermore, among the 50 patients in whom serum beta-2-microglobulin (SB2M) determination was available we observed that all patients with serum IL-2 levels greater than or equal to 10 U/ml had SB2M less than 6 micrograms/ml, whereas in patients with serum IL-2 less than 10 U/ml SB2M ranged from 1.3 to 15 micrograms/ml. Using these two parameters we were able to identify three groups of patients with different survival duration. Group A (9 patients) defined by serum IL-2 greater than or equal to 10 U/ml and SB2M less than 6 micrograms/ml in which all patients are alive: group B (26 patients) characterized by serum IL-2 less than 10 U/ml and SB2M less than 6 micrograms/ml in which 24% of patients are alive and group C (15 patients) characterized by serum IL-2 levels less than 10 U/ml and SB2M greater than or equal to 6 micrograms/ml in which the actuarial survival curve drops to 0 at 2.5 years. A statistically significant difference was observed between groups A and B (P less than 0.05), groups A and C (P less than 0.01) and groups B and C (P less than 0.01). These data could reflect the existence of an active T cell control on B cell neoplasia and may suggest the opportunity of a more extensive use of recombinant biological modifiers such as IL-2 in the therapeutic strategy of MM.