Weekly carboplatin plus paclitaxel chemotherapy in advanced melanoma patients resistant to anti-PD-1 inhibitors: a retrospective, monocentric experience.

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.

A multicenter study of skin toxicity management in patients with left-sided, RAS/BRAF wild-type metastatic colorectal cancer treated with first-line anti-EGFR-based doublet regimen: is there room for improvement?

BACKGROUND: Skin toxicity in patients affected by metastatic colorectal cancer (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors is well known. However, ad hoc ESMO guidelines have only recently been published. AIM AND METHODS: To describe the management (pre-emptive or reactive) of anti-EGFR-related cutaneous adverse events (AEs), in a real-life clinical context, in a selected population of patients with left-sided, metastatic RAS/BRAF wild-type mCRC treated with doublet chemotherapy plus anti-EGFR monoclonal antibody (i.e., panitumumab or cetuximab) as first-line regimen at 22 Institutions. The measured clinical outcomes were treatment-related adverse events, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). RESULTS: Of 515 patients included in the analysis, 173 (33.6%) received a pre-emptive and 342 (66.4%) a reactive treatment. The median follow-up period for the overall population was 30.0 months. A significantly lower incidence of any grade acneiform rash was found in the pre-emptive compared to the reactive cohort both in the overall population (78.6% vs 94.4%, p < 0.001) and in patients treated with panitumumab (76.1% vs 93.7%, p < 0.001) or cetuximab (83.3% vs 95.4%, p = 0.004), respectively. A lower incidence of any grade (41.6% vs 50.9%, p = 0.047) but a higher incidence of G3-G4 (9.2% vs 4.7%, p = 0.042) paronychia/nail disorders were found in the pre-emptive compared to the reactive cohort. Nevertheless, a lower rate of patients within the reactive compared to the pre-emptive cohort was referred to dermatological counseling (21.4% vs 15.3%, respectively, p = 0.001). A higher rate of anti-EGFR therapy modification was needed in the pre-emptive compared to the reactive cohort (35.9% vs 41.6%, respectively, p < 0.001). The pre-emptive approach did not reduce the efficacy of antineoplastic therapy compared to the reactive in terms of ORR (69.2% vs 72.8%), median PFS (12.3 vs 13.0 months), and median OS (28.8 vs 33.5 months). CONCLUSION: Although recommended by international guidelines, the pre-emptive approach of anti-EGFR-related skin toxicity in mCRC patients still appears less adopted in daily clinical practice, compared to the reactive one. A wider reception and application of this indication is desirable to improve patients' quality of life without compromising the continuity and efficacy of antineoplastic therapy.

The role of opioids in cancer response to immunotherapy.

BACKGROUND: The response to immunotherapy can be impaired by several factors including external intervention such as drug interactions with immune system. We aimed to examine the immunomodulatory action of opioids, since immune cells express opioid receptors able to negatively influence their activities. METHODS: This observational, multicenter, retrospective study, recruited patients with different metastatic solid tumors, who have received immunotherapy between September 2014 and September 2019. Immunotherapy was administered according to the standard schedule approved for each primary tumor and line of treatment. The concomitant intake of antibiotics, antifungals, corticosteroids and opioids were evaluated in all included patients. The relationship between tumor response to immunotherapy and the oncological outcomes were evaluated. A multivariate Cox-proportional hazard model was used to identify independent prognostic factors for survival. RESULTS: One hundred ninety-three patients were recruited. Overall, progression-free survival (PFS) and overall survival (OS) were significantly shorter in those patients taking opioids than in those who didn't (median PFS, 3 months vs. 19 months, HR 1.70, 95% CI 1.37-2.09, p < 0.0001; median OS, 4 months vs. 35 months, HR 1.60, 95% CI 1.26-2.02, p < 0.0001). In addition, PFS and OS were significantly impaired in those patients taking corticosteroids, antibiotics or antifungals, in those patients with an ECOG PS ≥ 1 and in patients with a high tumor burden. Using the multivariate analyses, opioids and ECOG PS were independent prognostic factors for PFS, whereas only ECOG PS resulted to be an independent prognostic factor for OS, with trend toward significance for opioids as well as tumor burden. DISCUSSION: Our study suggests that the concomitant administration of drugs as well as some clinical features could negatively predict the outcomes of cancer patients receiving immunotherapy. In particular, opioids use during immunotherapy is associated with early progression, potentially representing a predictive factor for PFS and negatively influencing OS as well. CONCLUSIONS: A possible negative drug interaction able to impair the immune response to anti-PD-1/PD-L1 agents has been highlighted. Our findings suggest the need to further explore the impact of opioids on immune system modulation and their role in restoring the response to immunotherapy treatment, thereby improving patients' outcomes.

Gut metabolomics profiling of non-small cell lung cancer (NSCLC) patients under immunotherapy treatment.

BACKGROUND: Despite the efficacy of immune checkpoint inhibitors (ICIs) only the 20-30% of treated patients present long term benefits. The metabolic changes occurring in the gut microbiota metabolome are herein proposed as a factor potentially influencing the response to immunotherapy. METHODS: The metabolomic profiling of gut microbiota was characterized in 11 patients affected by non-small cell lung cancer (NSCLC) treated with nivolumab in second-line treatment with anti-PD-1 nivolumab. The metabolomics analyses were performed by GC-MS/SPME and 1H-NMR in order to detect volatile and non-volatile metabolites. Metabolomic data were processed by statistical profiling and chemometric analyses. RESULTS: Four out of 11 patients (36%) presented early progression, while the remaining 7 out of 11 (64%) presented disease progression after 12 months. 2-Pentanone (ketone) and tridecane (alkane) were significantly associated with early progression, and on the contrary short chain fatty acids (SCFAs) (i.e., propionate, butyrate), lysine and nicotinic acid were significantly associated with long-term beneficial effects. CONCLUSIONS: Our preliminary data suggest a significant role of gut microbiota metabolic pathways in affecting response to immunotherapy. The metabolic approach could be a promising strategy to contribute to the personalized management of cancer patients by the identification of microbiota-linked "indicators" of early progressor and long responder patients.

The treatment paradigm of right-sided metastatic colon cancer: harboring BRAF mutation makes the difference.

PURPOSE: BRAF mutations represent the main negative prognostic factor for metastatic colorectal cancer and a supposed negative predictive factor of response to standard chemotherapy. We have explored survival difference in right-sided colon cancer (RCC) patients according to BRAF mutations, with the aim to identify any predictive factors of response to targeted-based therapy. METHODS: A retrospective study of RCC patients, with BRAF known mutation status, treated with chemotherapy (CT) from October 2008 to June 2019 in 5 Italian centers, was conducted. RESULTS: We identified 207 advanced RCC patients: 20.3% BRAF mutant and 79.7% BRAF wild type (wt). BRAF-mutant cancers were more likely to be pT4 (50.0% v 25.7%, p = 0.016), undifferentiated (71.4% v 44.0%, p = 0.004), KRAS wt (90.5% v 38.2%, p < 0.001), and MSI-H (41.7% v 16.2%, p = 0.019) tumors, with synchronous (52.4% v 31.5%, p = 0.018) and peritoneal metastases (38.1% v 22.4%, p = 0.003). Median overall survival (OS) was 16 v 27 months in BRAF mutant and BRAF wt (P = 0.020). In first-line setting, BRAF-mutant showed a 2ys OS of 80% in clinical trials, 32% in anti-VEGF, 14% in epidermial growth factor receptor (EGFR), and 0% in chemotherapy alone regimens (P = 0.009). BRAF-mutant patients demonstrated worse survival, regardless of targeted therapy administered. However, survival difference was statistically significant in the anti-EGFR-treated subgroup (16 v 28 months, P = 0.005 in BRAF mutant v BRAF wt, respectively). CONCLUSIONS: Our study demonstrated that BRAF status makes the difference in treatment's outcome. Therefore, the anti-EGFR should not be excluded in all advanced RCC but considered on a case-by-case basis.

A nomogram to predict survival in non-small cell lung cancer patients treated with nivolumab.

BACKGROUND: The advent of immune checkpoint inhibitors (ICIs) has considerably expanded the armamentarium against non-small cell lung cancer (NSCLC) contributing to reshaping treatment paradigms in the advanced disease setting. While promising tissue- and plasma-based biomarkers are under investigation, no reliable predictive factor is currently available to aid in treatment selection. METHODS: Patients with stage IIIB-IV NSCLC receiving nivolumab at Sant'Andrea Hospital and Regina Elena National Cancer Institute from June 2016 to July 2017 were enrolled onto this study. Major clinicopathological parameters were retrieved and correlated with patients' survival outcomes in order to assess their prognostic value and build a useful tool to assist in the decision making process. RESULTS: A total of 102 patients were included in this study. The median age was 69 years (range 44-85 years), 69 (68%) were male and 52% had ECOG PS 0. Loco-regional/distant lymph nodes were the most commonly involved site of metastasis (71%), followed by lung parenchyma (67%) and bone (26%). Overall survival (OS) in the whole patients' population was 83.6%, 63.2% and 46.9% at 3, 6 and 12 months, respectively; while progression-free survival (PFS) was 66.5%, 44.4% and 26.4% at 3, 6 and 12 months, respectively. At univariate analysis, age ≥ 69 years (P = 0.057), ECOG PS (P < 0.001), the presence of liver (P < 0.001), lung (P = 0.017) metastases, lymph nodes only involvement (P = 0.0145) were significantly associated with OS and ECOG PS (P < 0.001) and liver metastases (P < 0.001), retained statistical significance at multivariate analysis. A prognostic nomogram based on three variables (liver and lung metastases and ECOG PS) was built to assign survival probability at 3, 6, and 12 months after nivolumab treatment commencement. CONCLUSION: We developed a nomogram based on easily available and inexpensive clinical factors showing a good performance in predicting individual OS probability among NSCLC patients treated with nivolumab. This prognostic device could be valuable to clinicians in more accurately driving treatment decision in daily practice as well as enrollment onto clinical trials.

Early fatigue in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: an insight from clinical practice.

BACKGROUND: Fatigue was reported as the most common any-grade adverse event (18.3%), and the most common grade 3 or higher immune-related adverse event (irAE) (0.89%) in patients receiving PD-1/PD-L1 checkpoint inhibitors in clinical trial. METHODS: The aim of this retrospective multicenter study was to evaluate the correlations between "early ir-fatigue", "delayed ir-fatigue", and clinical outcomes in cancer patients receiving PD-1/PD-L1 inhibitors in clinical practice. RESULTS: 517 patients were evaluated. After the 12-weeks landmark selection, 386 (74.7%) patients were eligible for the clinical outcomes analysis. 40.4% were NSCLC, 42.2% were melanoma, 15.3% renal cell carcinoma and 2.1% other malignancies. 76 patients (19.7%) experienced early ir-fatigue (within 1 month from treatment commencement), while 150 patients (38.9%) experienced delayed ir-fatigue. Early ir-fatigue was significantly related to shortened PFS (HR = 2.29 [95% CI 1.62-3.22], p < 0.0001) and OS (HR = 2.32 [95% CI 1.59-3.38], p < 0.0001) at the multivariate analysis. On the other hand, we found a significant association between the occurrence of early ir-fatigue, ECOG-PS ≥ 2 (p < 0.0001), and disease burden (p = 0.0003). Delayed ir-fatigue was not significantly related to PFS nor OS. CONCLUSIONS: Early ir-fatigue seems to be negative prognostic parameter, but to proper weight its role we must to consider the predominant role of performance status, which was related to early ir-fatigue in the study population.

The Incidence of Alcoholism in Patients with Advanced Cancer Receiving Active Treatment in Two Tertiary Care Centers in Italy.

INTRODUCTION: Substance abuse is frequently under-diagnosed among cancer patients. Alcoholism is a problem afflicting about 18% of the general population. This percentage is higher in hospitalized patients. Previous studies conducted on advanced cancer patients admitted in palliative care units have highlighted this problem only for a small percentage of cases. The objective of the study was to evaluate the incidence of alcoholism in patients with advanced cancer admitted to two Italian Oncology Units for active cancer treatment, using a recognized and validated assessment tool. SHORT SUMMARY: To evaluate the incidence of alcoholism in cancer patients and its impact on symptoms, the CAGE questionnaire was completed by 117 patients in active anticancer treatment. The percentage of CAGE-positive patients was higher than previously detected in palliative settings and was associated to male sex and lower ESAS score. METHODS: All eligible patients were enrolled consecutively during a 12-month recruitment period. Clinical and demographic data were collected. Each enrolled patient completed the Cut down, Annoyed, Guilty, Eye-opener (CAGE) questionnaire. RESULTS: Hundred and seventeen consecutive patients were surveyed in the 12-month period. The mean age was 63.3 (SD 12.0) years and 66 were males. The mean Karnofsky level was 68.3 (SD 16.0). Twelve patients were CAGE positive (10.3%). Males (P = 0.05) and patients with low Edmonton Symptom Assessment System score (P = 0.03) proved to be CAGE positive. CONCLUSIONS: Alcoholism is widespread and under-diagnosed among patients undergoing active cancer treatment. Compared with other experience in palliative settings among European population, percentage of CAGE-positive patients was double. CAGE-positive patients were more likely to be male, with lower ESAS score. It is possible to hypothesize an effect of alcohol consumption on patients' perception of symptoms. This data has never been reported in the literature and will certainly need confirmation studies.

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27-87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3-4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.

Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.

BACKGROUND: On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers. METHODS: Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis. RESULTS: One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1-4 and G3-4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor (<0.86 ng/mL/106 cells/min) and ultra-rapid (>2.1 ng/mL/106 cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values <0.86 or >2.10 ng/mL/106 cells/min) was associated with grade 3-4 adverse events (OR = 2.09, 95% CI: 1.14-3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand-foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04-3.96, P = 0.03). CONCLUSIONS: 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.

Compressed SENSitivity Encoding (SENSE): Qualitative and Quantitative Analysis.

BACKGROUND: This study aimed to qualitatively and quantitatively evaluate T1-TSE, T2-TSE and 3D FLAIR sequences obtained with and without Compressed-SENSE technique by assessing the contrast (C), the contrast-to-noise ratio (CNR) and the signal-to-noise ratio (SNR). METHODS: A total of 142 MRI images were acquired: 69 with Compressed-SENSE and 73 without Compressed-SENSE. All the MRI images were contoured, spatially aligned and co-registered using 3D Slicer Software. Two radiologists manually drew 12 regions of interests on three different structures of CNS: white matter (WM), grey matter (GM) and cerebrospinal fluid (CSF). RESULTS: C values were significantly higher in Compressed-SENSE T1-TSE compared to No Compressed-SENSE T1-TSE for three different structures of the CNS. C values were also significantly lower for Compressed-SENSE 3D FLAIR and Compressed-SENSE T2-TSE compared to the corresponding No Compressed-SENSE scans. While CNR values did not significantly differ in GM-WM between Compressed-SENSE and No Compressed-SENSE for the 3D FLAIR and T1-TSE sequences, the differences in GM-CSF and WM-CSF were always statistically significant. CONCLUSION: Compressed-SENSE for 3D T2 FLAIR, T1w and T2w sequences enables faster MRI acquisition, reducing scan time and maintaining equivalent image quality. Compressed-SENSE is very useful in specific medical conditions where lower SAR levels are required without sacrificing the acquisition of helpful diagnostic sequences.

Case report: Fast disease progression during adjuvant therapy with anti-PD-1 in stage III melanoma patients.

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.

Primary Mucosal Melanoma: Clinical Experience from a Single Italian Center.

(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.

Survival of Patients with Metastatic Melanoma Treated with Ipilimumab after PD-1 Inhibitors: A Single-Center Real-World Study.

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.

Transperineal laser ablation (TPLA) with ultrasound/MRI fusion guidance in the treatment of localized radiotherapy-resistant prostate cancer.

Objective: The objective of this study was to assess the technical feasibility, safety, and efficacy of transperineal laser ablation (TPLA) guided by ultrasound/magnetic resonance (MR) fusion as a salvage treatment for refractory focal prostate cancer. Methods: A total of five patients who had undergone radiation therapy (RT) for prostate carcinoma and biochemical recurrence, confirmed by both prostate-specific antigen (PSA) levels and MRI (3T mpMRI), were enrolled in this study. Focal ablation was performed using a 1064 nm diode laser. Post-ablation follow-up was conducted for a duration of 18 months, which included regular PSA sampling, 3T mpMRI, and ultrasound/MR fusion-guided biopsies systematic and targeted at the site of the focal treatment. Results: The focal ablation procedure was carried out in an outpatient setting regimen with optimal clinical and biochemical outcomes. No recurrence was detected throughout the follow-up period. Conclusion: TPLA focal treatment effectively manages local recurrences of RT refractory prostate cancer without side-effects or complications. Preservation of quality of life and functional outcomes, along with a >70% reduction in PSA, were achieved. Advances in knowledge: Our study investigated TPLA as a salvage treatment for low-risk recurrent prostate cancer after RT, demonstrating its tolerability, feasibility, and effectiveness.

The Impact of Drug-Drug Interactions on the Toxicity Profile of Combined Treatment with BRAF and MEK Inhibitors in Patients with BRAF-Mutated Metastatic Melanoma.

BACKGROUND: BRAF and MEK inhibition is a successful strategy in managing BRAF-mutant melanoma, even if the treatment-related toxicity is substantial. We analyzed the role of drug-drug interactions (DDI) on the toxicity profile of anti-BRAF/anti-MEK therapy. METHODS: In this multicenter, observational, and retrospective study, DDIs were assessed using Drug-PIN software (V 2/23). The association between the Drug-PIN continuous score or the Drug-PIN traffic light and the occurrence of treatment-related toxicities and oncological outcomes was evaluated. RESULTS: In total, 177 patients with advanced BRAF-mutated melanoma undergoing BRAF/MEK targeted therapy were included. All grade toxicity was registered in 79% of patients. Cardiovascular toxicities occurred in 31 patients (17.5%). Further, 94 (55.9%) patients had comorbidities requiring specific pharmacological treatments. The median Drug-PIN score significantly increased when the target combination was added to the patient's home therapy (p-value < 0.0001). Cardiovascular toxicity was significantly associated with the Drug-PIN score (p-value = 0.048). The Drug-PIN traffic light (p = 0.00821) and the Drug-PIN score (p = 0.0291) were seen to be significant predictors of cardiotoxicity. Patients with low-grade vs. high-grade interactions showed a better prognosis regarding overall survival (OS) (p = 0.0045) and progression-free survival (PFS) (p = 0.012). The survival analysis of the subgroup of patients with cardiological toxicity demonstrated that patients with low-grade vs. high-grade DDIs had better outcomes in terms of OS (p = 0.0012) and a trend toward significance in PFS (p = 0.068). CONCLUSIONS: DDIs emerged as a critical issue for the risk of treatment-related cardiovascular toxicity. Our findings support the utility of DDI assessment in melanoma patients treated with BRAF/MEK inhibitors.

Vacuum-assisted Evacuation (VAEv) of Symptomatic and/or Voluminous Breast Haematomas Following Surgeries and Percutaneous Procedures.

BACKGROUND/AIM: Among postoperative complications in breast surgery, postoperative hematoma is the most common occurrence. While mostly self-limited, in some cases surgical revision is mandatory. Among percutaneous procedures, preliminary studies demonstrated the efficacy of vacuum-assisted breast biopsy (VAB) in evacuating postprocedural breast hematomas. However, no data are available regarding VAB evacuating postoperative breast hematomas. Therefore, the present study aimed to investigate the efficacy of the VAB system in evacuating postoperative and postprocedural hematoma, symptom resolution, and avoidance of surgery. PATIENTS AND METHODS: From January 2016 to January 2020, patients with ≥25 mm symptomatic breast hematomas developed after breast-conserving surgery (BCS) and percutaneous procedures were retrospectively enrolled from a perspective-maintained database. Hematoma maximum diameter, estimated hematoma volume, total procedure time, and visual analog scale (VAS) score before ultrasound (US) vacuum-assisted evacuation (VAEv) were recorded. At one-week VAS score, residual hematoma volume, and complications were recorded. RESULTS: Among 932 BCSs and 618 VAB procedures, a total of 15 late postoperative hematomas were recorded (9 after BCS and 6 after VAB). Preoperative median diameter was 43.00 (35.50-52.50) mm and median volume 12.60 (7.35-18.30) mm3 Regarding VAEv, median time recorded was 25.92 (21.89-36.81) min. At one week, the median hematoma reduction was 83.00% (78.00%-87.5%) with a statistically significant VAS reduction (5.00 vs. 2.00; p>0.001). No surgical treatment was needed and only one case of seroma occurred. CONCLUSION: VAEv represents a promising safe, time and resource-sparing treatment modality for the evacuation of breast hematomas, potentially decreasing the rate of reoperation after surgery.

Percutaneous transhepatic stent for chronic intestinal bleeding from jejunal varices in primary idiophatic superior mesenteric vein stenosis: A case report.

Jejunal varices are a rare cause of gastrointestinal bleeding. In most cases, they are due to portal hypertension related to liver cirrhosis, less frequently to superior mesenteric vein stenosis (SMV). In this article we describe an unusual case of a 61 year-old male patient who arrived at our emergency department with intermittent variceal bleeding due to jejunal varices causing melena and subsequent chronic anaemia. Patient was indeed discovered to have primary idiopathic superior mesenteric vein stenosis. We managed to treat this patient via SMV stenting through percutaneous transhepatic approach. In cases of upper-GI bleed with negative endoscopy for active bleeding, a contrast-enhanced CT scan should be performed to diagnose jejunal varices and their underlying cause, such as SMV stenosis which is best treated with percutaneous phlebography.

Vitiligo-like leukoderma as an indicator of clinical response to immune checkpoint inhibitors in late-stage melanoma patients.

PURPOSE: Although development of immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma, more than a half of treated patients experience disease progression during therapy. Cases of spontaneous vitiligo-like leukoderma have been described in melanoma patients and have been associated with a favorable outcome. This vitiligo-like leukoderma can also appear in melanoma patients undergoing immune therapies such as immune checkpoint inhibitors. However, no consensus exists about the relationship between vitiligo-like leukoderma onset and improved overall survival. Our study investigates the possible association between the onset of vitiligo-like leukoderma during immune checkpoint inhibitor treatment and a better prognosis. METHODS: A non-concurrent cohort study was conducted by identifying retrospectively 280 patients who had inoperable or metastatic melanoma and had undergone immune therapy with checkpoint inhibitors in any line of treatment. Toxicities developed during therapy were evaluated. RESULTS: Among the 280 study participants, 50% developed at least one type of toxicity, and vitiligo-like leukoderma was observed in 43 patients (15.4%). In the multivariate Cox model, a protective effect for mortality was observed for patients with vitiligo-like leukoderma development (HR : 0.23; 95% CI 0.11-0.44, p < 0.0001). In a sub-group analysis comprising only cutaneous melanoma in first line of treatment (N = 153), occurrence of vitiligo-like leukoderma was also an independent predictor factor for duration of clinical benefits measured by time to the next treatment (HR: 0.17; 95% CI 0.06-0.44). CONCLUSION: Our findings indicate that onset of vitiligo-like leukoderma during melanoma treatment could be a marker of favorable outcome in patients treated with immune checkpoint inhibitors.

The role of immune profile in predicting outcomes in cancer patients treated with immunotherapy.

Background: Despite the efficacy of immunotherapy, only a small percentage of patients achieves a long-term benefit in terms of overall survival. The aim of this study was to define an immune profile predicting the response to immune checkpoint inhibitors (ICIs). Methods: Patients with advanced solid tumors, who underwent ICI treatment were enrolled in this prospective study. Blood samples were collected at the baseline. Thirteen soluble immune checkpoints, 3 soluble adhesion molecules, 5 chemokines and 11 cytokines were analyzed. The results were associated with oncological outcomes. Results: Regardless of tumor type, patients with values of sTIM3, IFNα, IFNγ, IL1ß, IL1α, IL12p70, MIP1ß, IL13, sCD28, sGITR, sPDL1, IL10 and TNFα below the median had longer overall survival (p<0.05). By using cluster analysis and grouping the patients according to the trend of the molecules, two clusters were found. Cluster A had a significantly higher mean progression free survival (Cluster A=11.9 months vs Cluster B=3.5 months, p<0.01), a higher percentage of disease stability (Cluster A=34.5% vs. Cluster B=0%, p<0.05) and a lower percentage of disease progression (Cluster A=55.2% vs. Cluster B = 94.4%, p=0.04). Conclusion: The combined evaluation of soluble molecules, rather than a single circulating factor, may be more suitable to represent the fitness of the immune system status in each patient and could allow to identify two different prognostic and predictive outcome profiles.