Pembrolizumab in patients with advanced upper tract urothelial carcinoma: a real-world study from ARON-2 project.

Upper tract urothelial carcinoma (UTUC) accounts for the 5-10% of all urothelial carcinomas (UCs). In this analysis, we reported the real-world data from the ARON-2 study (NCT05290038) on the efficacy of pembrolizumab in patients with UTUC who recurred or progressed after platinum-based chemotherapy. Medical records of patients with metastatic UTUC treated with pembrolizumab as second-line therapy were reviewed from 34 institutions in 14 countries. Patients were assessed for overall survival (OS), progression-free survival (PFS), and overall response rate (ORR). Univariate and multivariate analyses were used to explore the association of variables of interest with OS and PFS. 235 patients were included in our analysis. Median OS was 8.6 months (95% CI 6.6-12.1), the 1 year OS rate was 43% while the 2 years OS rate 29%. The median PFS was 5.1 months (95% CI 3.9-6.9); 46% of patients were alive at 6 months, 34% at 12 months and 25% at 24 months. According to RECIST 1.1, 18 patients (8%) experienced complete response (CR), 57 (24%) partial response (PR), 44 (19%) stable disease (SD), and 116 (49%) progressive disease (PD), with an ORR of 32%. Our study confirms the effectiveness of pembrolizumab in patients pretreated with a platinum-based combination, irrespective of their sensitivity to the first-line treatment and of their histology. In addition, we emphasized the limited benefit of the treatment with pembrolizumab in patients with hepatic metastases and poor ECOG performance status.

Cemiplimab in an Elderly Frail Population of Patients With Locally Advanced or Metastatic Cutaneous Squamous Cell Carcinoma: A Single-Center Real-Life Experience From Italy.

BACKGROUND: Cutaneous squamous cell carcinoma (CSCC) is the second most common skin cancer whose incidence is growing parallel to the lengthening of the average lifespan. Cemiplimab, an antiPD-1 monoclonal antibody, is the first approved immunotherapy for patients with locally advanced CSCC (laCSCC) or metastatic CSCC (mCSCC) thanks to phase I and II studies showing high antitumor activity and good tolerability. Nevertheless, at present, very few data are available regarding cemiplimab in real-life experience and in frail, elderly, and immunosuppressed patients as well as regarding biomarkers able to predict response so as to guide therapeutic choices. PATIENTS AND METHODS: We built a retroprospective cohort study including 30 non-selected patients with laCSCC (25) and mCSCC (five) treated with cemiplimab from August 2019 to November 2020. Clinical outcomes, toxicity profile, and correlations with disease, patients, and peripheral blood parameters are explored. RESULTS: The median age was 81 years (range, 36-95), with 24 males and five patients having an immunosuppressive condition, while the frailty prevalence was 83% based on index derived from age, Eastern Cooperative Oncology Group performance status, and Charlson Comorbidity Index. We reported 23 responses (76.7%) with nine complete responses (30%). A statistically significant higher response rate was observed in head and neck primary tumors and in patients with hemoglobin level >12 g/dl. No difference was observed with respect to frailty, median age, sex, and body mass index. The baseline low neuthophil/lymphocyte ratio and low platelet/lymphocyte ratio resulted to be also correlated with a better response. Moreover, lymphocyte, neutrophil, and monocyte behaviors had an opposite trend in responders and non-responders. An overall response was reported in four of five immunosuppressed patients. Seventeen patients (57.6%) have an ongoing response and are still alive. Six responders had interrupted treatment (two for toxicity and four for personal choice) but maintained their response. The treatment was well tolerated by the majority of patients. The most common adverse events were fatigue in seven patients (23.3%) and skin toxicity in 10 patients (33.3%), including pruritus in six patients, rash in three patients, and bullous erythema in one patient. CONCLUSIONS: In our real-life experience, cemiplimab showed a high antitumor activity with acceptable safety profile similar to those in trials with selected patients. Moreover, its antitumor activity resulted to be not impaired in very elderly patients and in those with immunocompromised status.

Remote mentoring in laparotomic and laparoscopic cancer surgery during Covid-19 pandemic: an experimental setup based on mixed reality.

In this paper, Mixed Reality (MR) has been exploited in the operating rooms to perform laparoscopic and open surgery with the aim of providing remote mentoring to the medical doctors under training during the Covid-19 pandemic. The employed architecture, which has put together MR smartglasses, a Digital Imaging Player, and a Mixed Reality Toolkit, has been used for cancer surgery at the IRCCS Hospital 'Giovanni Paolo II' in southern Italy. The feasibility of using the conceived platform for real-time remote mentoring has been assessed on the basis of surveys distributed to the trainees after each surgery.

Electrochemotherapy as a Trigger to Overcome Primary Resistance to Anti-PD-1 Treatment: A Case Report of Melanoma of the Scalp.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors is one of the main therapies for advanced melanoma. Nevertheless, albeit remarkable, immunotherapy results are still unsatisfactory as more than half of patients progress, and resistance to treatment still has a dramatic impact on clinical outcomes. Local treatments such as radiotherapy or electrochemotherapy (ECT), in addition to local control with palliative intent, have been shown to release tumoral neoantigens that can stimulate a robust systemic antitumor immune response. CASE PRESENTATION: We report the case of a patient with multiple nodular melanoma lesions of the scalp initially treated with local ECT. Soon after the procedure, multiple new lesions appeared close to the treated ones, therefore the patient started a systemic treatment with the anti-PD-1 nivolumab. The lesions of the scalp did not respond to immunotherapy, presenting a loco-regional spreading. To control the bleeding and painful lesions, we performed a second ECT, while continuing systemic immunotherapy. The treated lesions responded to the second procedure, while the other lesions continued progressing in number and dimension. Unexpectedly, after 2 months from the second ECT, the patient presented a progressive shrinkage of both treated and untreated lesions until complete remission. Concomitantly, he developed immune-related adverse events including grade 4 thyroid toxicity, grade 2 vitiligo-like depigmentation and grade 2 pemphigoid. At present, after 18 months from the first ECT and 14 months from the starting of anti-PD-1 immunotherapy, the patient is in good clinical condition and complete remission of disease still persists. CONCLUSION: This case highlights the potential role of ECT in increasing tumor immunogenicity and consequently in inducing a powerful immune response overcoming primary resistance to checkpoint inhibitor immunotherapy.

The Interaction between Reactive Peritoneal Mesothelial Cells and Tumor Cells via Extracellular Vesicles Facilitates Colorectal Cancer Dissemination.

Advanced colorectal cancer (CRC) is highly metastatic and often results in peritoneal dissemination. The extracellular vesicles (EVs) released by cancer cells in the microenvironment are important mediators of tumor metastasis. We investigated the contribution of EV-mediated interaction between peritoneal mesothelial cells (MCs) and CRC cells in generating a pro-metastatic environment in the peritoneal cavity. Peritoneal MCs isolated from peritoneal lavage fluids displayed high CD44 expression, substantial mesothelial-to-mesenchymal transition (MMT) and released EVs that both directed tumor invasion and caused reprogramming of secretory profiles by increasing TGF-ß1 and uPA/uPAR expression and MMP-2/9 activation in tumor cells. Notably, the EVs released by tumor cells induced apoptosis by activating caspase-3, peritoneal MC senescence, and MMT, thereby augmenting the tumor-promoting potential of these cells in the peritoneal cavity. By using pantoprazole, we reduced the biogenesis of EVs and their pro-tumor functions. In conclusion, our findings provided evidence of underlying mechanisms of CRC dissemination driven by the interaction of peritoneal MCs and tumor cells via the EVs released in the peritoneal cavity, which may have important implications for the clinical management of patients.

Examining the Relationship between Circulating CD4- CD8- Double-Negative T Cells and Outcomes of Immuno-Checkpoint Inhibitor Therapy-Looking for Biomarkers and Therapeutic Targets in Metastatic Melanoma.

BACKGROUND: The role of circulating CD4-/CD8- double-negative T cells (DNTs) in the immune response to melanoma is poorly understood, as are the effects of checkpoint inhibitors on T cell subpopulations. METHODS: We performed a basal and longitudinal assessment of circulating immune cells, including DNTs, in metastatic melanoma patients treated with checkpoint blockade in a single-center cohort, and examined the correlations levels of immune cells with clinical features and therapy outcomes. RESULTS: Sixty-eight patients (48 ipilimumab, 20 PD1 inhibitors) were enrolled in the study. Our analysis indicated that better outcomes were associated with normal LDH, fewer than three metastatic sites, an ECOG performance status of 0, M1a stage, lower WBC and a higher lymphocyte count. The increase in lymphocyte count and decrease of DNTs were significantly associated with the achievement of an overall response. The median value of DNT decreased while the CD4+ and NK cells increased in patients that responded to treatment compare to those who did not respond to treatment. CONCLUSIONS: DNT cells change during treatment with checkpoint inhibitors and may be adept at sensing the immune response to melanoma. The complementary variation of DNT cells with respect to CD4+ and other immune actors may improve the reliability of lymphocyte assessment. Further investigation of DNT as a potential target in checkpoint inhibitor resistant melanoma is warranted.

Somatostatin Receptors in Merkel-Cell Carcinoma: A Therapeutic Opportunity Using Somatostatin Analog Alone or in Association With Checkpoint Inhibitors Immunotherapy. A Case Report.

Background: Merkel-cell carcinoma (MCC) is a rare, highly aggressive skin cancer typically involving elderly people. Surgery is usually the first treatment for primary tumor. In adjuvant setting, radiotherapy is effective in reducing local recurrence and in improving overall survival. Regarding advanced disease, systemic chemotherapy ended up disappointing results whereas antiPD1/antiPD-L1 immunotherapy recently gave relevant clinical benefits. Interestingly, about the half of MCC patients expresses high somatostatin receptors (SRs) to possibly represent a target for the therapeutic use of somatostatin analogs (SSAs). Nevertheless, SSAs have been little studied in MCC and cases treated with SSAs in association with checkpoint inhibitor immunotherapy have not been published yet. Case Report: We report the case of a 73-year-old man affected by metastatic MCC of right arm previously treated with surgery and adjuvant radio and chemotherapy. Three years later the patient presented loco-regional relapse involving lateral-cervical, mediastinal, and submandibular lymph nodes with high value of chromogranin A and neuron specific enolase. Due to the high expression of SRs at octreoscan and immunoistochemistry, patient started octreotide 30 mg i.m. every 28 days with a good control of disease for about 2 years. A widespread progression of disease was reported afterwards. The patient started the antiPD-L1 avelumab immunotherapy, only recently available in Italy, while still taking SSA. The patient showed an impressive regression of the disease after only four cycles of avelumab until complete remission. Conclusions: SSA could be a valid therapeutic option in patients with MCC with high SR expression. When combined with PD-1/PD-L1 immune-checkpoint inhibition, SSA is likely to enhance antiproliferative activity. Our case report provides the rationale to conduct a prospective trial and translational research to verify the efficacy and safety of combined SSA and checkpoint inhibitors for advanced MCC.

The search for a melanoma-tailored chemotherapy in the new era of personalized therapy: a phase II study of chemo-modulating temozolomide followed by fotemustine and a cooperative study of GOIM (Gruppo Oncologico Italia Meridionale).

BACKGROUND: It is frequently asked whether chemotherapy can still play a role in metastatic melanoma considering the effectiveness of the available drugs today, including antiCTLA4/antiPD1 immunotherapy and antiBRAF/antiMEK inhibitors. However, only approximately half of patients respond to these drugs, and the majority progress after 6-11 months. Therefore, a need for other therapeutic options is still very much apparent. We report the first large trial of a sequential full dose of fotemustine (FM) preceded by a low dose of temozolomide (TMZ) as a chemo-modulator in order to inactivate the DNA repair action of O(6)-methylguanine DNA-methyltransferase (MGMT). Primary endpoints were overall response and safety. We also evaluated specific biological parameters aiming to tailor these chemotherapies to selected patients. METHODS: A total of 69 consecutive patients were enrolled. The main features included a median age of 60 years (21-81) and M1c stage, observed in 74% of the patients, with brain metastases in 15% and high LDH levels in 42% of the patients. The following schedule was used: oral TMZ 100 mg/m2 on days 1 and 2 and FM iv 100 mg/m2 on day 2, 4 h after TMZ; A translational study aiming to analyse MGMT methylation status and base-excision repair (BER) gene expression was performed in a subset of 14 patients. RESULTS: We reported an overall response rate of 30.3% with 3 complete responses and a disease control rate of 50.5%. The related toxicity rate was low and mainly of haematological types. Although our population had a very poor prognosis, we observed a PFS of 6 months and an OS of 10 months. A non-significant correlation with response was found with the mean expression level of the three genes involved in the BER pathway (APE1, XRCC1 and PARP1), whereas no association was found with MGMT methylation status. CONCLUSION: This schedule could represent a good alternative for patients who are not eligible for immune or targeted therapy or whose previous therapies have failed. TRIAL REGISTRATION: EUDRACT 2009-016487-36l ; date of registration 23 June 2010.

Detrimental effects of melanocortin-1 receptor (MC1R) variants on the clinical outcomes of BRAF V600 metastatic melanoma patients treated with BRAF inhibitors.

Melanocortin-1 receptor (MC1R) plays a key role in skin pigmentation, and its variants are linked with a higher melanoma risk. The influence of MC1R variants on the outcomes of patients with metastatic melanoma (MM) treated with BRAF inhibitors (BRAFi) is unknown. We studied the MC1R status in a cohort of 53 consecutive BRAF-mutated patients with MM treated with BRAFi. We also evaluated the effect of vemurafenib in four V600 BRAF melanoma cell lines with/without MC1R variants. We found a significant correlation between the presence of MC1R variants and worse outcomes in terms of both overall response rate (ORR; 59% versus 95%, P = 0.011 univariate, P = 0.028 multivariate analysis) and progression-free survival (PFS) shorter than 6 months (72% versus 33%, P = 0.012 univariate, P = 0.027 multivariate analysis). No difference in overall survival (OS) was reported, probably due to subsequent treatments. Data in vitro showed a significant different phosphorylation of Erk1/2 and p38 MAPK during treatment, associated with a greater increase in vemurafenib IC50 in MC1R variant cell lines.

MicroRNA expression in BRAF-mutated and wild-type metastatic melanoma and its correlation with response duration to BRAF inhibitors.

Objective: Currently, the treatment of BRAF V600-mutated metastatic melanoma with BRAF inhibitors gives a response rate of ~ 50% with a progression-free survival of ~ 6 -- 7 months. In order to identify predictive biomarkers capable of stratifying BRAF-mutated patients at high risk of shorter response duration to anti-BRAF therapy, the authors analyzed the expression of 15 microRNAs (miRNAs) targeting crucial genes involved in melanoma biology and drug response.Research design and methods: A total of 15 miRNAs and target gene expression were investigated in 43 patients (30 BRAF-mutated, and 13 BRAF wild-type). Moreover, 20 BRAF-mutated patients treated with vemurafenib were analyzed for miRNA expression in respect to time-to-progression.Results: All miRNAs except miR-192 showed low expression in BRAF-mutated as compared with BRAF wild-type patients. In particular, miR-101, miR-221,miR-21, miR-338-3p and miR-191 resulted in significant downregulation inBRAF-mutated patients. Moreover, high expression of miR-192 and miR-193b* and low expression of miR-132 resulted in significant association with shorter progression.Conclusion: Three miRNAs were significantly associated with clinical outcome in metastatic melanoma patients. An increased understanding of the molecular assessment of BRAF-mutated melanomas could allow development of specific molecular tests able to predict response duration.

Herbal-drug interaction induced rhabdomyolysis in a liposarcoma patient receiving trabectedin.

BACKGROUND: Rhabdomyolysis is an uncommon side effect of trabectedin which is used for the second line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. This side effect may be due to pharmacokinetic interactions caused by shared mechanisms of metabolism involving the cytochrome P450 (CYP) system in the liver. Here, for the first time in literature, we describe the unexpected onset of heavy toxicity, including rhabdomyolysis, after the fourth course of trabectedin in a patient with retroperitoneal liposarcoma who at the same time was taking an alternative herbal medicine suspected of triggering this adverse event. CASE PRESENTATION: This is the case of a 56 year old Caucasian man affected by a relapsed de-differentiated liposarcoma who, after the fourth cycle of second-line chemotherapy with trabectedin, complained of sudden weakness, difficulty walking and diffuse muscle pain necessitating complete bed rest. Upon admission to our ward the patient showed grade (G) 4 pancytopenia and a marked increase in liver lytic enzymes, serum levels of myoglobin, creatine phosphokinase (CPK) and lactate dehydrogenase. No cardiac or kidney function injuries were present. Based on these clinical and laboratory features, our conclusive diagnosis was of rhabdomyolysis induced by trabectedin.The patient did not report any trauma or muscular overexertion and no co-morbidities were present. He had not received any drugs during treatment with trabectedin, but upon further questioning the patient informed us he had been taking a folk medicine preparation of chokeberry (Aronia melanocarpa) daily during the last course of trabectedin and in the 2 subsequent weeks.One week after hospitalization and cessation of intake of chokeberry extract, CPK and other markers of myolysis slowly returned to standard range, and the patient noted a progressive recovery of muscle strength.The patient was discharged on day 14 when a blood transfusion and parenteral hydration gradually lowered general toxicity. Progressive mobilization of the patient was obtained as well as a complete normalization of the laboratory findings. CONCLUSIONS: The level of evidence of drug interaction leading to the adverse event observed in our patient was 2 (probable). Thus our case underlines the importance of understanding rare treatment-related toxicities such as trabectedin-induced rhabdomyolysis and the possible role of the drug-drug interactions in the pathogenesis of this rare side effect. Furthermore, this report draws attention to a potential problem of particular concern, that of nutritional supplements and complementary and alternative drug interactions. These are not widely recognized and can cause treatment failure.