Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.

BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).

Oncologic outcomes with and without amniotic membranes in robotic-assisted radical prostatectomy: A propensity score matched analysis.

Objective: Placement of human placenta derived grafts during robotic-assisted radical prostatectomy (RARP) hastens the return of continence and potency. The long-term impact on the oncologic outcomes remains to be investigated. Our objective was to determine the oncologic outcomes of patients with dehydrated human amnion chorion membrane (dHACM) at RARP compared to a matched cohort. Methods: In a referral centre, from August 2013 to October 2019, 599 patients used dHACM in bilateral nerve-sparing RARP. We excluded patients with less than 12 months follow-up, simple prostatectomy, and unilateral nerve-sparing. Patients with dHACM (amnio group) were 529, and were propensity score matched 1:1 to 2465 patients without dHACM (non-amnio group) and a minimum follow-up of 36 months. At the time of RARP, dHACM was placed around the neurovascular bundle in the amnio group. Continuous and categorical variables in matched groups was tested by two-sample Kolmogorov-Smirnov test and Fisher's exact test respectively. Outcomes measured were biochemical recurrence (BCR), adjuvant and salvage therapy rates. Results: Propensity score matching resulted in two groups of 444 patients. Cumulative incidence functions for BCR did not show a difference between the groups (p=0.3). Patients in the non-amnio group required salvage therapy more frequently than the amnio group, particularly after partial nerve-sparing RARP (6.3% vs. 2.3%, p=0.001). Limitations are the absence of prospective randomization. Conclusion: The data suggest that using dHACM does not have a negative impact on BCR in patients. Outcomes of cancer specific and overall survival will require follow-up study to increase our understanding of these grafts' impact on prostate cancer biology.

THE IMPACT OF ROUTINE CARDIAC TROPONIN I-BASED CARDIOTOXICITY SCREENING ON CLINICAL OUTCOMES IN PATIENTS ON CANCER IMMUNOTHERAPY.

Purpose: Immune checkpoint inhibitors (ICI) used as cancer therapy have been associated with a range of cardiac immune-related adverse events (irAEs), including fulminant myocarditis with a high case fatality rate. Early detection through cardiotoxicity screening by biomarker monitoring can lead to prompt intervention and improved patient outcomes. In this study, we investigate the association between cardiotoxicity screening with routine serial troponin I monitoring in asymptomatic patients receiving ICI, cardiovascular adverse event (CV AE) detection, and overall survival (OS). Methods: We instituted a standardized troponin I screening protocol at baseline and with each ICI dose (every 2-4 weeks) in all patients receiving ICI at our center starting Jan 2019. We subsequently collected data in 825 patients receiving ICI at our institution from January 2018 to October 2021. Of these patients, 428 underwent cardiotoxicity screening with serial troponin I monitoring during ICI administration (Jan 2019-Oct 2021) and 397 patients were unmonitored (Jan 2018-Dec 2018). We followed patients for nine months following their first dose of ICI and compared outcomes of CV AEs and OS between monitored and unmonitored patients. Additionally, we investigated rates of CV AEs, all-cause mortality, and oncologic time-to-treatment failure (TTF) between patients with an elevated troponin I value during the monitoring period versus patients without elevated troponin I. Results: We found a lower rate of severe (grades 4-5) CV AEs, resulting in critical illness or death, in patients who underwent troponin monitoring (0.5%) compared to patients who did not undergo monitoring (1.8%), (HR 0.17, 95% CI 0.02-0.79, p = 0.04). There was no difference in overall CV AEs (grades 3-5) or OS between monitored and unmonitored patients. In the entire cohort, patients with at least one elevated troponin I during the follow up period, during routine monitoring or unmonitored, had a higher risk of overall CV AEs (HR 10.96, 95% CI 4.65-25.85, p<0.001) as well as overall mortality (HR 2.67, 95% CI 1.69 - 4.10, p<0.001) compared to those without elevated troponin. Oncologic time-to-treatment failure (TTF) was not significantly different in a sub-cohort of monitored vs. unmonitored patients. Conclusions: Patients undergoing cardiotoxicity screening with troponin I monitoring during ICI therapy had a lower rate of severe (grade 4-5) CV AEs compared patients who were not screened. Troponin I elevation in screened and unscreened patients was significantly associated with increased CV AEs as well as increased mortality. Troponin I monitoring did not impact oncologic time-to-treatment-failure in a sub-cohort analysis of patients treated with ICI. These results provide preliminary evidence for clinical utility of cardiotoxicity screening with troponin I monitoring in patients receiving ICI therapy.

Circulating Tumor DNA Assay Detects Merkel Cell Carcinoma Recurrence, Disease Progression, and Minimal Residual Disease: Surveillance and Prognostic Implications.

PURPOSE: Merkel cell carcinoma (MCC) is an aggressive skin cancer with a 40% recurrence rate, lacking effective prognostic biomarkers and surveillance methods. This prospective, multicenter, observational study aimed to evaluate circulating tumor DNA (ctDNA) as a biomarker for detecting MCC recurrence. METHODS: Plasma samples, clinical data, and imaging results were collected from 319 patients. A tumor-informed ctDNA assay was used for analysis. Patients were divided into discovery (167 patients) and validation (152 patients) cohorts. Diagnostic performance, including sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), was assessed. RESULTS: ctDNA showed high sensitivity, 95% (discovery; 95% CI, 87 to 99) and 94% (validation; 95% CI, 85 to 98), for detecting disease at enrollment, with corresponding specificities of 90% (95% CI, 82 to 95) and 86% (95% CI, 77 to 93). A positive ctDNA during surveillance indicated increased recurrence risk, with hazard ratios (HRs) of 6.8 (discovery; 95% CI, 2.9 to 16) and 20 (validation; 95% CI, 8.3 to 50). The PPV for clinical recurrence at 1 year after a positive ctDNA test was 69% (discovery; 95% CI, 32 to 91) and 94% (validation; 95% CI, 71 to 100), respectively. The NPV at 135 days after a negative ctDNA test was 94% (discovery; 95% CI, 90 to 97) and 93% (validation; 95% CI, 89 to 97), respectively. Patients positive for ctDNA within 4 months after treatment had higher rates of recurrence, with 1-year rates of 74% versus 21% (adjusted HR, 7.4 [95% CI, 2.7 to 20]). CONCLUSION: ctDNA testing exhibited high prognostic accuracy in detecting MCC recurrence, suggesting its potential to reduce frequent surveillance imaging. ctDNA also identifies high-risk patients who need more frequent imaging and may be best suited for adjuvant therapy trials.

Minimally invasive lymphocele drainage using the Da Vinci® single port platform: step-by- step technique

ABSTRACT Background: Reports in the literature describe lymphocele formation in up to half of patients following pelvic lymph node dissection (PLND) (1) in robotic-assisted radical prostatectomy (RARP), with 1-2% requiring intervention (2). The advantage of surgical approach is permanent excision of the lymphocele capsule and fewer days with pelvic drains compared to percutaneous drainage. This study aims to describe the step-by-step surgical management of symptomatic lymphoceles using a less invasive robotic platform, the Da Vinci® Single Port (SP). Material and Methods: We describe the technique of lymphocelectomy and marsupialization with the Da Vinci® SP for symptomatic lymphocele. For this study, several treatment modalities for symptomatic lymphoceles were available, including percutaneous drainage, sclerosing agents, and surgical marsupialization. All the data for this study were obtained through the procedure via Da Vinci® SP. Results: Operative time for the case was 84 minutes. Blood loss was 25ml. No intra- or post- operative complications were reported. The patient had his drain removed in under 24 hours after surgery. The mean follow-up period was 7.7 months. There were no complications or lymphocele recurrence. Conclusion: Da Vinci® SP lymphocelectomy is safe and feasible with satisfactory outcomes. The SP enables definitive treatment of the lymphocele sac (3), reducing the number of days with abdominal drains and allows further decrease in surgical invasiveness with fewer incisions and better cosmesis.

A validated RP-HPLC method for the determination of Irinotecan hydrochloride residues for cleaning validation in production area / Método RP- HPLC validado para la determinación de residuos de Irinotecan Hidrocloruro para la validación de la limpieza en el área de producción

Introduction: cleaning validation is an integral part of current good manufacturing practices in pharmaceutical industry. The main purpose of cleaning validation is to prove the effectiveness and consistency of cleaning in a given pharmaceutical production equipment to prevent cross contamination and adulteration of drug product with other active ingredient. Objective: a rapid, sensitive and specific reverse phase HPLC method was developed and validated for the quantitative determination of irinotecan hydrochloride in cleaning validation swab samples. Method: the method was validated using waters symmetry shield RP-18 (250mm x 4.6mm) 5 µm column with isocratic mobile phase containing a mixture of 0.02 M potassium di-hydrogen ortho-phosphate, pH adjusted to 3.5 with ortho-phosphoric acid, methanol and acetonitrile (60:20:20 v/v/v). The flow rate of mobile phase was 1.0 mL/min with column temperature of 25°C and detection wavelength at 220nm. The sample injection volume was 100 µl. Results: the calibration curve was linear over a concentration range from 0.024 to 0.143 µg/mL with a correlation coefficient of 0.997. The intra-day and inter-day precision expressed as relative standard deviation were below 3.2%. The recoveries obtained from stainless steel, PCGI, epoxy, glass and decron cloth surfaces were more than 85% and there was no interference from the cotton swab. The detection limit (DL) and quantitation limit (QL) were 0.008 and 0.023 µg ml-1, respectively. Conclusion: the developed method was validated with respect to specificity, linearity, limit of detection and quantification, accuracy, precision and solution stability. The overall procedure can be used as part of a cleaning validation program in pharmaceutical manufacture of irinotecan hydrochloride.