TGF-ß mRNA levels in circulating extracellular vesicles are associated with response to anti-PD1 treatment in metastatic melanoma.

Introduction: Immune checkpoint inhibitors (ICIs) represent the standard therapy for metastatic melanoma. However, a few patients do not respond to ICIs and reliable predictive biomarkers are needed. Methods: This pilot study investigates the association between mRNA levels of programmed cell death-1 (PD-1) ligand 1 (PD-L1), interferon-gamma (IFN-γ), and transforming growth factor-ß (TGF-ß) in circulating extracellular vesicles (EVs) and survival in 30 patients with metastatic melanoma treated with first line anti-PD-1 antibodies. Blood samples were collected at baseline and RNA extracted from EVs; the RNA levels of PD-L1, IFN-γ, and TGF-ß were analysed by digital droplet PCR (ddPCR). A biomarker-radiomic correlation analysis was performed in a subset of patients. Results: Patients with high TGF-ß expression (cut-off fractional abundance [FA] >0.19) at baseline had longer median progression-free survival (8.4 vs. 1.8 months; p = 0.006) and overall survival (17.9 vs. 2.63 months; p = 0.0009). Moreover, radiomic analysis demonstrated that patients with high TGF-ß expression at baseline had smaller lesions (2.41 ± 3.27 mL vs. 42.79 ± 101.08 mL, p < 0.001) and higher dissimilarity (12.01 ± 28.23 vs. 5.65 ± 8.4; p = 0.018). Discussion: These results provide evidence that high TGF-ß expression in EVs is associated with a better response to immunotherapy. Further investigation on a larger patient population is needed to validate the predictive power of this potential biomarker of response to ICIs.

Immune Checkpoint Inhibitor Rechallenge in Renal Cell Carcinoma: Current Evidence and Future Directions.

Immune checkpoint inhibitor-based therapies represent the current standard of care in the first-line treatment of advanced renal cell carcinoma. Despite a clear benefit in survival outcomes, a considerable proportion of patients experience disease progression; prospective data about second-line therapy after first-line treatment with immune checkpoint inhibitors are limited to small phase II studies. As with other solid tumors (such as melanoma and non-small cell lung cancer), preliminary data about the clinical efficacy of rechallenge of immunotherapy (alone or in combination with other drugs) in renal cell carcinoma are beginning to emerge. Nevertheless, the role of rechallenge in immunotherapy in this setting of disease remains unclear and cannot be considered a standard of care; currently some randomized trials are exploring this approach in patients with metastatic renal cell carcinoma. The aim of our review is to summarize main evidence available in the literature concerning immunotherapy rechallenge in renal carcinoma, especially focusing on biological rationale of resistance to immune checkpoint inhibitors, on the published data of clinical efficacy and on future perspectives.

Comparison Between First Line Target Therapy and Immunotherapy in Different Prognostic Categories of BRAF Mutant Metastatic Melanoma Patients: An Italian Melanoma Intergroup Study.

Background: BRAF and MEK inhibitors target therapies (TT) and AntiPD1 immunotherapies (IT) are available first-line treatments for BRAF v600 mutant metastatic melanoma patients. ECOG PS (E), baseline LDH (L), and baseline number of metastatic sites (N) are well-known clinical prognostic markers that identify different prognostic categories of patients. Direct comparison between first-line TT and IT in different prognostic categories could help in first line treatment decision. Methods: This is a retrospective analysis conducted in 14 Italian centers on about 454 metastatic melanoma patients, divided in 3 groups: group A-patients with E = 0, L within normal range, and N less than 3; group B-patients not included in group A or C; group C-patients with E > 0, L over the normal range, and N more than 3. For each prognostic group, we compared TT and IT in terms of progression free survival (PFS), overall survival (OS), and disease control rate (DCR). Results: In group A, results in 140 TT and 36 IT-treated patients were, respectively, median PFS 35.5 vs 11.6 months (HR (95% CI) 1.949 (1.180-3.217) p value 0.009); median OS not reached vs 55 months (HR (95% CI) 1.195 (0.602-2.373) p value 0.610); DCR 99% vs 75% p value <0.001). In group B, results in 196 TT and 38 IT-treated patients were, respectively, median PFS 11.5 vs 5 months (HR 1.535 (1.036-2.275) p value 0.033); median OS 19 vs 20 months (HR 0.886 (0.546-1.437) p value 0.623); DCR 85% vs 47% p value <0.001). In group C, results in 41 TT and 3 IT-treated patients were, respectively, median PFS 6.4 vs 1.8 months (HR 4.860 (1.399-16) p value 0.013); median OS 9 vs 5 months (HR 3.443 (0.991-11.9) p value 0.052); DCR 66% vs 33% p value 0.612). Conclusions: In good prognosis, group A-TT showed statistically significant better PFS than IT, also in a long-term period, suggesting that TT can be a good first line option for this patient category. It is only in group B that we observed a crossing of the survival curves after the 3rd year of observation in favor of IT. Few patients were enrolled in group C, so few conclusions can be made on it.

Safety and Tolerability of COVID-19 Vaccines in Patients with Cancer: A Single Center Retrospective Analysis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 disease (COVID-19) has caused a worldwide challenging and threatening pandemic. Multinational, placebo-controlled, observer-blinded trials were conducted since the beginning of pandemic because safe and effective vaccines were needed urgently. In most trials of COVID-19 vaccines patients affected by malignancies or on treatment with immunosuppressive drugs were excluded. PATIENTS AND METHODS: A retrospective monocentric study was conducted at Medical Oncological Unit of Santa Chiara Hospital (Pisa, Italy) in this subset of population to investigate safety and tolerability of COVID-19 vaccines; 377 patients with solid tumor on treatment were enrolled. Vaccine-related adverse events were recorded using a face-to-face questionnaire including a toxicity grading scale. Most of the patients (94%) received mRNA vaccine as indicated by Italian health ministry guidelines. Mean age was 66 years (range 27-87), 62% of the patients were older than 65 years and 68% had at least one additional comorbidity. The majority (86%) of patients were in a metastatic setting and 29% received immunotherapy-based treatment. For statistical analysis, multivariate binary logistic regression models were performed and linear regression models were applied. RESULTS: Adverse events were mild and transient and ended in a few days without any sequelae. No severe or uncommon adverse events were recorded. In multivariate analysis, we found that the female sex was associated with a greater risk of more severe and longer lasting adverse events, and a higher risk of adverse events was found for patients treated with immunotherapy. CONCLUSIONS: Our results demonstrate that COVID-19 vaccines were safe and well-tolerated in this population of patients being treated for solid tumors.

Dedifferentiated liposarcoma: when eribulin can make the difference.

We describe the case of a male subject affected by retroperitoneal advanced, anthracycline-pretreated liposarcoma, who experienced a long, beneficial clinical effect from eribulin treatment. In March 2013, a left, paraortic, retroperitoneal mass was surgically removed and diagnosed as Mdm2-positive dedifferentiated liposarcoma. In June 2015, a CT scan revealed disease progression and first-line epirubicin/ifosfamide treatment was started, followed by epirubicin in monotherapy. In January 2017, following a new disease progression, the patient started a second-line eribulin treatment that went on for about 1 year with no major adverse events. The CT scans performed every 3-4 months showed stable disease. After 13 months of treatment, a CT scan revealed disease progression and 10 days later, the patient died of bowel perforation and peritonitis.

Detection of Uterine Leiomyosarcoma Peritoneal Lesions by SPECT/CT and ROLL Technique.

We reported the preoperative radio-guided localization of 4 peritoneal metastatic nodules in the case of a 45-year-old woman with uterine leiomyosarcoma. Three lines of chemotherapy were tried, but cardiotoxicity occurred. Within the context of so-called GOSTT (guided intraoperative scintigraphic tumor targeting), preoperative radio-guided localization of peritoneal metastases enabled their subsequent radio-guided excisional biopsy. SPECT/CT allowed for anatomical localization of the hot lesions and generated a 3-dimensional volume-rendering roadmap, facilitating a surgical approach.