BRAF/MEK Inhibition as a Bridge to Immunotherapy for Symptomatic BRAF V600 Melanoma Brain Metastases: A Case Series.

Targeted and immune therapies have changed the paradigm of treatment for patients with metastatic melanoma. Treatment of patients with symptomatic melanoma brain metastases, however, is complicated by the frequent use of immune suppression for the management of vasogenic edema and the urgency in addressing disease burden. Use of BRAF/MEK inhibitors in patients with a corresponding BRAF V600 mutation often results in rapid response but is hindered by high rates of disease relapse and progression. Immunotherapy has higher durability of response, but the rate of response is slower and responses can be significantly diminished for patients on concurrent steroid therapy. Considering this gap in evidence-based guidance for optimal adjuvant therapy sequence in immunosuppressed patients with BRAF V600-mutant melanoma brain metastases, we report on 4 cases utilizing BRAF/MEK inhibitors as a bridging therapy for brain metastases management before initiation of immune checkpoint inhibitor therapy. Future prospective studies will be required to determine the optimal treatment sequencing for patients in this population with high unmet medical need.

Determining PARP Inhibition as a Treatment Strategy in Melanoma Based on Homologous Recombination Deficiency-Related Loss of Heterozygosity.

There is a lack of effective treatments for immunotherapy-refectory melanoma. Although PARP inhibitors (PARPi) are an effective treatment strategy in cancers with homologous recombination deficiency (HRD), determining HRD status is challenging in melanoma. Here, we chart the longitudinal relationship between PARPi response and HRD scores derived from genome-wide loss of heterozygosity (LOH) in 4 patients with metastatic melanoma. When next examining 933 melanoma cases, using an updated threshold, we observed HRD-related LOH (HRD-LOH) in nearly one-third of all cases compared with <10% using traditional gene panels. Taken together, HRD-LOH in refractory melanoma is both a common occurrence and a potential biomarker for response to PARPi.

Clinical outcomes and longitudinal circulating tumor DNA changes after treatment with nivolumab and olaparib in immunotherapy relapsed melanoma with detected homologous recombination deficiency.

The treatment of immunotherapy relapsed cutaneous melanoma constitutes a challenge in both research and clinical practice fields given the lack of effective therapeutic options. Homologous recombination deficiency (HRD) has been identified in several solid cancers including cutaneous melanoma. However, the utility of medications targeting HRD cancer cells is an uncharted territory in melanoma. Moreover, preclinical evidence suggests a synergistic role of combining immune checkpoint blockade (ICB) with drugs targeting HRD cancer cells such as PARP inhibitors. Here, we present a case study of a patient with immunotherapy relapsed melanoma who was found to have detected HRD and was treated with nivolumab (ICB) and olaparib (PARP inhibitors).

Normalization of electroretinogram and symptom resolution of melanoma-associated retinopathy with negative autoantibodies after treatment with programmed death-1 (PD-1) inhibitors for metastatic melanoma.

Melanoma-associated retinopathy (MAR) is a paraneoplastic syndrome that involves the production of autoantibodies which can cross-react with retinal epitopes leading to visual symptoms. Autoantibodies can target intracellular proteins, and only a few are directed against membrane proteins. This discrepancy in autoantibody-protein target can translate into different immune responses (T-cell mediated vs B-cell mediated). Historically, treatment of MAR has focused on surgical reduction or immunosuppressive medication, mainly glucocorticoids. However, tumor resection is not relevant in metastatic melanoma in which MAR is mostly encountered. Moreover, the use of glucocorticoids can reduce the efficacy of immunotherapy. We report the first case to our knowledge with subjective resolution of visual symptoms and objective evidence of normalization of electroretinogram of MAR with undetectable autoantibodies after administration of programmed death-1 (PD-1) inhibitor (pembrolizumab) without the use of surgical reduction or systemic immunosuppression. This case highlights the potential improvement and resolution of negative autoantibody MAR with the use of PD-1 inhibitors and emphasizes the importance of multidisciplinary approach and team discussion to avoid interventions that can decrease immunotherapy-mediated anti-tumor effect.

Metachronous cutaneous squamous cell carcinoma in a young patient as the only presenting symptom to uncover Lynch syndrome with MLH1 Germline mutation.

BACKGROUND: Cutaneous malignancies are rare complications of Lynch syndrome and can include Muir-Torre and Turcot syndromes that are associated with sebaceous gland tumors and keratoacanthomas. The incidence and clinical course of cutaneous squamous cell carcinoma have not been well documented in Lynch syndrome due to its rarity. CASE PRESENTATION: A 49-year male presented with an enlarging groin skin lesion that was biopsed and demonstrated cutaneous squamous cell carcinoma for which he underwent a surgical resection. The patient experienced later a recurrence of cutaneous squamous cell carcinoma around the resected margins. Next generation sequencing of tumor tissue revealed mutations in MSH6 and MLH1, in addition to high microsatellite instability. The patient underwent pembrolizumab treatment with complete resolution of the cutaneous lesion in the groin, but subsequently developed a new mass in the right antecubital fossa shortly after discontinuation of pembrolizumab. Repeat biopsy of the antecubital fossa lesion revealed a recurrence of cutaneous squamous cell carcinoma. Germline mutation testing revealed MLH1 mutation, compatible with Lynch syndrome, and the patient restarted pembrolizumab which was associated with a complete response. The patient was referred for genetic counseling and cancer screening. CONCLUSIONS: Cutaneous squamous cell carcinoma, although rare, can be the initial presenting symptom in patients with Lynch syndrome. This association has been described in patients with germline mutations in MLH1. Lynch syndrome should be considered when evaluating young patients presenting with recurrent cutaneous squamous cell carcinoma with positive family history of malignancy and/ or without any identifiable risk factors for skin cancers, including those with a durable and rapid response to immunotherapy.

Internal medicine resident training and provision of diabetes quality of care indicators.

OBJECTIVE: Existing research is inconsistent on whether clinical experience is associated with improved management of type 2 diabetes mellitus. We sought to determine whether meeting diabetes quality indicators improves as general internal medicine physicians progress from first to last year of residency. METHODS: We performed a chart abstraction of electronic health records data covering the period from September 2008 to August 2011. In all, 352 patient records were abstracted and linked to year of resident provider. Type 2 diabetes quality indicators included glycated hemoglobin (A1C), low-density lipoprotein, diastolic and systolic blood pressure control, obtaining urine microalbumin or prescription for angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and documented foot and eye examinations. Chi-square tests and logistic regression analysis were used to determine whether year of residency was associated with quality of care indices before and after adjusting for patient age, gender, race, body mass index and cigarette smoking. RESULTS: Urine microalbumin was the most often met indicator (76.9%), and the least often met indicator was documented eye examination (37.4%). Results of adjusted analysis indicated that the odds of A1C, low-density lipoprotein control, obtaining urine microalbumin and documented eye and foot examinations were greater among patients of second- and third-year residents compared with those of first-year residents (odds ratios range, 1.26-5.12). Urine microalbumin was the indicator most often in optimal control and least often met indicators were eye and foot examinations. CONCLUSIONS: We observed improvement in quality of diabetes care throughout residency. However, the low prevalence of several quality indicators indicates a need for additional training and quality improvement.

Randomized, controlled trial of standard-definition white-light, high-definition white-light, and narrow-band imaging colonoscopy for the detection of colon polyps and prediction of polyp histology.

BACKGROUND: Missing adenomas and the inability to accurately differentiate between polyp histology remain the main limitations of standard-definition white-light (SD-WL) colonoscopy. OBJECTIVE: To compare the adenoma detection rates of SD-WL with those of high-definition white-light (HD-WL) and narrow-band imaging (NBI) as well as the accuracy of predicting polyp histology. DESIGN: Multicenter, prospective, randomized, controlled trial. SETTING: Two academic medical centers in the United States. PATIENTS: Subjects undergoing screening or surveillance colonoscopy. INTERVENTION: Subjects were randomized to undergo colonoscopy with one of the following: SD-WL, HD-WL, or NBI. MAIN OUTCOME MEASUREMENTS: The proportion of subjects detected with adenomas, adenomas detected per subject, and the accuracy of predicting polyp histology real time. RESULTS: A total of 630 subjects were included. The proportion of subjects with adenomas was 38.6% with SD-WL compared with 45.7% with HD-WL and 46.2% with NBI (P = .17 and P = .14, respectively). Adenomas detected per subject were 0.69 with SD-WL compared with 1.12 with HD-WL and 1.13 with NBI (P = .016 and P = .014, respectively). HD-WL and NBI detected more subjects with flat and right-sided adenomas compared with SD-WL (all P values <.005). NBI had a superior sensitivity (90%) and accuracy (82%) to predict adenomas compared with SD-WL and HD-WL (all P values <.005). LIMITATIONS: Academic medical centers with experienced endoscopists. CONCLUSIONS: There was no difference in the proportion of subjects with adenomas detected with SD-WL, HD-WL, and NBI. However, HD-WL and NBI detected significantly more adenomas per subject (>60%) compared with SD-WL. NBI had the highest accuracy in predicting adenomas in real time during colonoscopy. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT 00614770.).

Risk of post-ERCP pancreatitis with placement of self-expandable metallic stents.

BACKGROUND: There are conflicting data on the risk of post-ERCP pancreatitis (PEP) related to self-expandable metallic stents (SEMSs). OBJECTIVE: To compare rates of PEP in patients who undergo biliary drainage with SEMSs or polyethylene stents (PSs). DESIGN: Retrospective, cohort study. SETTING: Tertiary-care medical center. PATIENTS: This study involved patients undergoing ERCP for malignant biliary obstruction between January 2005 and October 2008. INTERVENTION: First-time placement of a SEMS or PS for biliary decompression. MAIN OUTCOME MEASUREMENTS: Early post-ERCP complications, particularly PEP. RESULTS: We identified 544 eligible patients, 248 SEMSs (102 covered), and 296 PSs. The etiology of malignant biliary obstruction was similar between groups, with 55% from pancreatic cancer. The frequency of PEP was significantly higher in the SEMS group (7.3%) versus the PS group (1.3%) (OR 5.7 [95% CI, 1.9-17.1]). On univariate analysis, patient age of <40 years, a history of PEP, and at least 1 pancreatic duct injection were also significant predictors of PEP, whereas female sex and having pancreatic cancer were not. When significant variables were added to a multiple-predictor regression model, the odds of PEP from SEMS placement increased to 6.8 (95% CI, 2.2, 21.4). However, the frequency of PEP was similar between covered (6.9%) and uncovered (7.5%) SEMSs (OR 0.9 [CI, 0.3-2.4]). Purported SEMS-specific risk factors, including the use of cSEMSs, overlapping SEMSs, or having a biliary sphincterotomy were not found to be significant contributors to the higher risk. LIMITATIONS: Retrospective design. CONCLUSION: After we controlled for confounding variables, the frequency of PEP was significantly higher with placement of a SEMS compared with a PS. Rates of PEP were comparable with use of covered and uncovered SEMSs.

Findings at endoscopic retrograde cholangiopancreatography after endoscopic treatment of postcholecystectomy bile leaks.

BACKGROUND: Although the endoscopic management of bile leaks after cholecystectomy (CCY) is well established, the yield of a routine endoscopic retrograde cholangiogram (ERC) with a bile duct sweep at the time of stent removal is unclear. This study aimed to describe the prevalence of abnormal findings at follow-up ERC to determine whether upper endoscopy with stent removal and without cholangiography would suffice. METHODS: A retrospective cohort analysis of all patients referred for initial and follow-up ERC with post-CCY bile leak was performed. The rate of abnormal findings was measured including choledocholithiasis, biliary strictures, and persistent bile leaks at follow-up ERC. Secondarily, the study sought to define the clinical characteristics of patients who demonstrated stones or sludge at follow-up assessment. RESULTS: Between January, 2003 and April, 2008, 105 patients underwent initial and follow-up ERC. After a mean interval of 6.9 +/- 2.7 weeks between endoscopies, 29 (27.6%) of the 105 patients demonstrated one or more abnormalities including persistent bile leak (n = 8), common bile duct (CBD) stones (n = 12), and CBD sludge alone (n = 9). In the subgroup analysis of the patients who underwent a balloon sweep at initial and follow-up ERC, the prevalence of CBD stones or sludge at the follow-up ERC was 17.6%. Besides stones during the initial ERC, no significant clinical predictors of CBD stones were found at follow-up ERC including surgical approach, interval between endoscopies, and location of bile leak. CONCLUSION: After endoscopic treatment of a bile leak, the prevalence of abnormalities at follow-up ERC is significant. A repeat cholangiogram with a balloon sweep is preferred at the time of stent removal.

Incidence of sedation-related complications with propofol use during advanced endoscopic procedures.

BACKGROUND & AIMS: Propofol is an effective sedative in advanced endoscopy. However, the incidence of sedation-related complications is unclear. We sought to define the frequency of sedation-related adverse events, particularly the rate of airway modifications (AMs), with propofol use during advanced endoscopy. We also evaluated independent predictors of AMs. METHODS: Patients undergoing sedation with propofol for advanced endoscopic procedures, including endoscopic retrograde cholangiopancreatography, endoscopic ultrasound, and small-bowel enteroscopy, were studied prospectively. Sedative dosing was determined by a certified registered nurse anesthetist with the goal of achieving deep sedation. Sedation-related complications included AMs, hypoxemia (pulse oximetry [SpO(2)] < 90%), hypotension requiring vasopressors, and early procedure termination. AMs were defined as chin lift, modified face mask ventilation, and nasal airway. We performed a regression analysis to compare characteristics of patients requiring AMs (AM+) with those who did not (AM-). RESULTS: A total of 799 patients were enrolled over 7 months. Procedures included endoscopic ultrasound (423), endoscopic retrograde cholangiopancreatography (336), and small-bowel enteroscopy (40). A total of 87.2% of patients showed no response to endoscopic intubation. Hypoxemia occurred in 12.8%, hypotension in 0.5%, and premature termination in 0.6% of the patients. No patients required bag-mask ventilation or endotracheal intubation. There were 154 AMs performed in 115 (14.4%) patients, including chin lift (12.1%), modified face mask ventilation (3.6%), and nasal airway (3.5%). Body mass index, male sex, and American Society of Anesthesiologists class of 3 or higher were independent predictors of AMs. CONCLUSIONS: Propofol can be used safely for advanced endoscopic procedures when administered by a trained professional. Independent predictors of AMs included male sex, American Society of Anesthesiologists class of 3 or higher, and increased body mass index.

Difficult biliary cannulation: use of physician-controlled wire-guided cannulation over a pancreatic duct stent to reduce the rate of precut sphincterotomy (with video).

BACKGROUND: Successful cannulation of the common bile duct (CBD) remains the benchmark for ERCP. Use of a pancreatic duct (PD) stent to facilitate biliary cannulation has been described, although the majority of patients require precut sphincterotomy to achieve CBD cannulation. OBJECTIVE: To report the performance characteristics of using a PD stent in conjunction with physician-controlled wire-guided cannulation (WGC) to facilitate bile duct cannulation. DESIGN: Retrospective cohort. SETTING: Two tertiary care, academic medical centers. PATIENTS: All undergoing ERCP with native papillae. INTERVENTION: In cases of difficult biliary access in which the PD is cannulated, a pancreatic stent is placed. After this, physician-controlled WGC is attempted by using the PD stent to direct the sphincterotome into the biliary orifice. If cannulation is unsuccessful after several minutes, a precut sphincterotomy is performed over the PD stent or the procedure is terminated. MAIN OUTCOME MEASUREMENTS: Frequency of successful bile duct cannulation and precut sphincterotomy. RESULTS: A total of 2345 ERCPs were identified, 1544 with native papillae. Among these, CBD and PD cannulation failed in 16 (1.0%) patients, whereas 76 (4.9%) patients received a PD stent to facilitate biliary cannulation. Successful cannulation was achieved in 71 (93.4%) of 76 patients, 60 (78.9%) of whom did not require precut sphincterotomy. Complications included mild post-ERCP pancreatitis in 4 (5.3%) and aspiration in 1 (1.3%). Precut sphincterotomy was complicated by hemorrhage, controlled during the procedure in 2 (13.3%) of 15. CONCLUSIONS: Physician-controlled WGC over a PD stent facilitates biliary cannulation while maintaining a low rate of precut sphincterotomy.