Opioid Misuse Harm Reduction.

BACKGROUND/AIMS: The misuse of opioids by the public is a major health issue. Prescription opioids and nonprescription opioids, such as heroin and opium, are misused in epidemic proportions. When opioids are used incorrectly or illegally, they can lead to drug dependence, addiction, morbidity, and mortality. This program is in collaboration with the Jolt Foundation that provides resources to prevent opioid overdose deaths. DESIGN/METHODS: This program involves community education on the dangers of opioid use and training on the use of naloxone rescue procedures to prevent overdose deaths. A pretest-posttest design was employed to determine if participants gained knowledge regarding the naloxone administration procedures. PARTICIPANTS: The researcher presented 10 community naloxone trainings that included staff from 20 different social service agencies, two schools, and three local churches. Each agency received at least one naloxone kit. FINDINGS: The outcomes were met and included educating 137 participants on the risk factors and signs and symptoms of opioid overdose and the proper procedure to administer naloxone. One hundred twenty-eight posttests were returned and showed that the objectives for the project were met. The overall mean score for the pretests was 65.00 ( n = 126) with a standard deviation of 19.01, and the overall mean for the posttests was 86.64 ( n = 128) with a standard deviation of 14.60. CONCLUSIONS: Community social service agency staff were successfully educated to respond appropriately to overdose situations in a group training setting as evidenced by significant posttest scores.

Characterization of genetics in patients with mucosal melanoma treated with immune checkpoint blockade.

Mucosal melanoma is a rare form of melanoma which arises from melanocytes in the mucosal membranes and can be effectively treated with immune checkpoint blockade (ICB). However, response rates in mucosal melanoma are lower than those observed for cutaneous melanomas. Targeted sequencing of up to 447 genes (OncoPanel) was performed on tumors from all mucosal melanoma patients seen at the Dana-Farber Cancer Institute from 2011 until March 2019. We identified a total of 46 patients who received ICB with both tumor-genotype and ICB response data available. Within this cohort of patients, 16 (35%) had durable clinical benefit (DCB) to their first line of ICB. The average mutational burden/megabase was 6.23 and did not correlate with tumor response to ICB. Patients with KIT aberrations had a higher DCB rate compared with patients with wildtype KIT (71 vs. 28%), but this was not found to be statistically significant. For comparison, we analyzed tumor genotypes from an additional 50 mucosal melanoma tumors and 189 cutaneous melanoma tumors. The most frequent mutations in mucosal melanoma were in SF3B1 (27%), KIT (18%), and NF1 (17%), a pattern that is distinct from cutaneous melanomas. In addition, there were genetic differences observed based upon the site of origin of the mucosal melanoma. Our findings explore clinical features of response in patients with mucosal melanoma treated with ICB and demonstrate a low mutational burden that does not correlate with response. In addition, the lack of significant association between the genetic aberrations tested and response to ICB indicates the need for further exploration in this patient population.

Immune-Related Tumor Response Dynamics in Melanoma Patients Treated with Pembrolizumab: Identifying Markers for Clinical Outcome and Treatment Decisions.

Purpose: Characterize tumor burden dynamics during PD-1 inhibitor therapy and investigate the association with overall survival (OS) in advanced melanoma.Experimental Design: The study included 107 advanced melanoma patients treated with pembrolizumab. Tumor burden dynamics were assessed on serial CT scans using irRECIST and were studied for the association with OS.Results: Among 107 patients, 96 patients had measurable tumor burden and 11 had nontarget lesions alone at baseline. In the 96 patients, maximal tumor shrinkage ranged from -100% to 567% (median, -18.5%). Overall response rate was 44% (42/96; 5 immune-related complete responses, 37 immune-related partial responses). Tumor burden remained <20% increase from baseline throughout therapy in 57 patients (55%). Using a 3-month landmark analysis, patients with <20% tumor burden increase from baseline had longer OS than patients with ≥20% increase (12-month OS rate: 82% vs. 53%). In extended Cox models, patients with <20% tumor burden increase during therapy had significantly reduced hazards of death [HR = 0.19; 95% confidence interval (CI), 0.08-0.43; P < 0.0001 univariate; HR = 0.18; 95% CI, 0.08-0.41; P < 0.0001, multivariable]. Four patients (4%) experienced pseudoprogression; 3 patients had target lesion increase with subsequent response, which was noted after confirmed immune-related progressive disease (irPD). One patient without measurable disease progressed with new lesion that subsequently regressed.Conclusions: Tumor burden increase of <20% from the baseline during pembrolizumab therapy was associated with longer OS, proposing a practical marker for treatment decision guides that needs to be prospectively validated. Pseudoprogressors may experience response after confirmed irPD, indicating a limitation of the current strategy for immune-related response evaluations. Evaluations of patients without measurable disease may require further attention. Clin Cancer Res; 23(16); 4671-9. ©2017 AACR.

Diagnostic Comparison of CT Scans and Colonoscopy for Immune-Related Colitis in Ipilimumab-Treated Advanced Melanoma Patients.

Colitis can be a life-threatening toxicity for patients treated with immune checkpoint blockade antibodies. With the anticipated widespread use of these reagents, the timely and accurate diagnosis of immune-related colitis becomes increasingly important. To better understand the clinical presentation of colitis from ipilimumab and to assess the use of CT scans of the abdomen/pelvis as a diagnostic tool, we retrospectively analyzed patients with advanced melanoma who received ipilimumab at our institution. Ninety nine (33%) of 303 patients developed diarrhea during therapy, and 46 patients (15%) received corticosteroids for colitis. Of the patients with diarrhea, 48 (48%) underwent colonoscopy and 46 (46%) underwent both CT and colonoscopy. In the 34 patients (34%) with a CT and biopsy, CT was highly predictive of colitis on biopsy (positive predictive value 96%), and the absence of CT findings was predictive of a negative biopsy (negative likelihood ratio 0.2). In patients who had symptoms and CT evaluation, CT was highly predictive of the need for steroids to reach resolution of symptoms (positive predictive value 92%, positive likelihood ratio 7.3). We conclude that CT is a fast, reliable, and noninvasive mode of diagnosing colitis, whereas colonoscopy and biopsy may not be needed to establish that diagnosis. Cancer Immunol Res; 5(4); 286-91. ©2017 AACR.

Targeted next-generation sequencing reveals high frequency of mutations in epigenetic regulators across treatment-naïve patient melanomas.

BACKGROUND: Recent developments in genomic sequencing have advanced our understanding of the mutations underlying human malignancy. Melanoma is a prototype of an aggressive, genetically heterogeneous cancer notorious for its biologic plasticity and predilection towards developing resistance to targeted therapies. Evidence is rapidly accumulating that dysregulated epigenetic mechanisms (DNA methylation/demethylation, histone modification, non-coding RNAs) may play a central role in the pathogenesis of melanoma. Therefore, we sought to characterize the frequency and nature of mutations in epigenetic regulators in clinical, treatment-naïve, patient melanoma specimens obtained from one academic institution. RESULTS: Targeted next-generation sequencing for 275 known and investigative cancer genes (of which 41 genes, or 14.9 %, encoded an epigenetic regulator) of 38 treatment-naïve patient melanoma samples revealed that 22.3 % (165 of 740) of all non-silent mutations affected an epigenetic regulator. The most frequently mutated genes were BRAF, MECOM, NRAS, TP53, MLL2, and CDKN2A. Of the 40 most commonly mutated genes, 12 (30.0 %) encoded epigenetic regulators, including genes encoding enzymes involved in histone modification (MECOM, MLL2, SETD2), chromatin remodeling (ARID1B, ARID2), and DNA methylation and demethylation (TET2, IDH1). Among the 38 patient melanoma samples, 35 (92.1 %) harbored at least one mutation in an epigenetic regulator. The genes with the highest number of total UVB-signature mutations encoded epigenetic regulators, including MLL2 (100 %, 16 of 16) and MECOM (82.6 %, 19 of 23). Moreover, on average, epigenetic genes harbored a significantly greater number of UVB-signature mutations per gene than non-epigenetic genes (3.7 versus 2.4, respectively; p = 0.01). Bioinformatics analysis of The Cancer Genome Atlas (TCGA) melanoma mutation dataset also revealed a frequency of mutations in the 41 epigenetic genes comparable to that found within our cohort of patient melanoma samples. CONCLUSIONS: Our study identified a high prevalence of somatic mutations in genes encoding epigenetic regulators, including those involved in DNA demethylation, histone modification, chromatin remodeling, and microRNA processing. Moreover, UVB-signature mutations were found more commonly among epigenetic genes than in non-epigenetic genes. Taken together, these findings further implicate epigenetic mechanisms, particularly those involving the chromatin-remodeling enzyme MECOM/EVI1 and histone-modifying enzyme MLL2, in the pathobiology of melanoma.

Radiographic Profiling of Immune-Related Adverse Events in Advanced Melanoma Patients Treated with Ipilimumab.

Ipilimumab is a promising novel immunotherapy agent and is associated with a variety of immune-related adverse events (irAE). The purpose of this study was to investigate the manifestations of irAEs on body imaging in patients with advanced melanoma treated with ipilimumab. One-hundred forty-seven patients with advanced melanoma (59 women, 88 men; median age, 64.5 years) treated with ipilimumab were studied. All patients had the baseline and at least one follow-up chest/abdomen/pelvis CT or PET/CT during therapy, which were reviewed by a consensus of two radiologists blinded to the clinical data. Findings indicative of individual types of irAEs were assessed, including thyroiditis, sarcoid-like lymphadenopathy, pneumonitis, hepatitis, pancreatitis, and colitis. Among the 147 patients, 46 (31%) had radiologically identified irAEs. The time interval from the initiation of therapy to the development of irAEs was less than 3 months in 76% (35 of 46) of the patients (range, 0.2-9.1 months). Clinical characteristics did not differ between patients with and without irAEs (P > 0.18). Among the individual types of irAEs, colitis was most common (n = 28; 19%), followed by sarcoid-like lymphadenopathy (n = 8; 5%) and pneumonitis (n = 8; 5%). Hepatitis (n = 3), thyroiditis (n = 2), and pancreatitis (n = 1) were less common. The resolution of irAEs was noted in 32 of 36 patients (89%) with further follow-up scans, with a median time of 2.3 months after the detection of irAE. In conclusion, irAEs were noted on body imaging in 31% of patients with melanoma treated with ipilimumab. Colitis was the most common, followed by sarcoid-like lymphadenopathy and pneumonitis. The results call for an increased awareness of irAEs, given the expanding role of cancer immunotherapy.

Single Institution Experience of Ipilimumab 3 mg/kg with Sargramostim (GM-CSF) in Metastatic Melanoma.

Ipilimumab, 10 mg/kg with sargramostim (GM-CSF; GM), improved overall survival (OS) and safety of patients with advanced melanoma over ipilimumab in a randomized phase II trial. The FDA-approved dose of ipilimumab of 3 mg/kg has not been assessed with GM (IPI-GM). Consecutive patients treated with IPI-GM at a single institution were reviewed. Treatment included ipilimumab every 3 weeks × 4 and GM, 250-µg s.c. injection days 1 to 14 of each ipilimumab cycle. Efficacy, clinical characteristics, toxicities, and blinded radiology review of tumor burden were evaluated. Thirty-two patients were identified with 25 (78%) having immune-related response criteria (irRC) measurable disease and 41% with central nervous system metastases. A total of 88.6% of GM doses were administered. Response rate by irRC and disease control rate at 12 weeks were 20% and 44%, respectively (median follow-up 37 weeks). Immune-related adverse events (irAE) were observed in 10 (31.3%) patients, with 3 (9.4%) grade 3 events. Patients with grade 3 irAEs had prior autoimmunity, advanced age, and poor performance status. The median OS from first dose of ipilimumab was 41 weeks. Ipi-GM treatment is feasible and in this poor-risk advanced melanoma population, efficacy appeared similar but safety appeared improved relative to historical ipilimumab alone.

A nonradiographic system for assessing pressure for the Codman-Hakim Programmable Valve.

BACKGROUND: The Codman-Hakim Programmable Valve is widely used in shunting hydrocephalus and other conditions. OBJECT: To establish an accurate valve verification system for the Codman-Hakim programmable valve that does not require radiographic exposure. METHODS: Prospective clinical trial tested a new valve verification system at 9 research sites. RESULTS: The Valve Programming and Verification System allowed us to establish the valve setting in 62% of subjects with a programmable valve. CONCLUSION: The Valve Programming and Verification System avoids radiation exposure, is cost-effective, and time efficient for the patient and provider. In approximately one third of subjects, those in whom "adjustment complete" is not achieved, cranial radiographs are still needed.

Scale to predict survival after surgery for recurrent glioblastoma multiforme.

PURPOSE: Despite initial treatment with surgical resection, radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) virtually always recurs. Surgery is sometimes recommended to treat recurrence. In this study, we sought to devise a preoperative scale that predicts survival after surgery for recurrent glioblastoma multiforme. PATIENTS AND METHODS: The preoperative clinical and radiographic data of 34 patients who underwent re-operation of recurrent GBM tumors were analyzed using Kaplan-Meier survival analysis and Cox proportional hazards regression modeling. The factors associated with decreased postoperative survival (P < .05) were used to devise a prognostic scale which was validated with a separate cohort of 109 patients. RESULTS: The factors associated with poor postoperative survival were: tumor involvement of prespecified eloquent/critical brain regions (P = .021), Karnofsky performance status (KPS) < or = 80 (P = .030), and tumor volume > or = 50 cm(3) (P = .048). An additive scale (range, 0 to 3 points) comprised of these three variables distinguishes patients with good (0 points), intermediate (1 to 2 points), and poor (3 points) postoperative survival (median survival, 10.8, 4.5, and 1.0 months, respectively; P < .001). The scale identified three statistically distinct groups within the validation cohort as well (median survival, 9.2, 6.3, and 1.9 months, respectively; P < .001). CONCLUSION: We devised and validated a preoperative scale that identifies patients likely to have poor, intermediate, and good relative outcomes after surgical resection of a recurrent GBM tumor. Application of this simple scale may be useful in counseling patients regarding their treatment options and in designing clinical trials.

Decreases in ventricular volume correlate with decreases in ventricular pressure in idiopathic normal pressure hydrocephalus patients who experienced clinical improvement after implantation with adjustable valve shunts.

OBJECTIVE: This retrospective study examined whether changes in ventricular volume correspond with changes in adjustable valve pressure settings in a cohort of patients who received shunts to treat idiopathic normal pressure hydrocephalus. We also examined whether these pressure-volume curves and other patient variables would co-occur with a positive clinical response to shunting. METHODS: We selected 51 patients diagnosed with idiopathic normal pressure hydrocephalus who had undergone implantation of a Codman Hakim programmable valve (Medos S.A., Le Locle, Switzerland). Clinical data were gathered from the patients' records and clinical notes by an investigator blinded to patients' ventricular volumes. Ventricular volume was measured using 3D Slicer, an image analysis and interactive visualization software package developed and maintained at the Surgical Planning Laboratory at Brigham and Women's Hospital. RESULTS: Eighty-six percent of patients with gait disturbance at presentation showed improvement of this symptom, 70% experienced improvement in incontinence, and 69% experienced improvement in dementia. For the group showing 100% clinical improvement, the correlation coefficient of average changes in valve pressure over time (delta P/delta T) and average changes in ventricular volume over time (delta V/delta T) were high at 0.843 (P < 0.05). For the group experiencing no or only partial improvement, the correlation coefficient was 0.257 (P = 0.32), indicating no correlation between average delta V/delta T and average delta P/delta T for each patient. CONCLUSION: This was a carefully analyzed modeling study of idiopathic normal pressure hydrocephalus treatment made possible only by adjustable valve technology. With careful volumetric analysis, we found that changes in ventricular volume correlated with adjustments in valve pressure settings for those patients who improved clinically after shunting. This suggests that positive clinical responders retained parenchymal elasticity, emphasizing the importance of dynamic changes in this cohort.

Enhancing quality of care for acute myocardial infarction: shifting the focus of improvement from key indicators to process of care and tool use: the American College of Cardiology Acute Myocardial Infarction Guidelines Applied in Practice Project in Michigan: Flint and Saginaw Expansion.

OBJECTIVES: This project evaluated if by focusing on process changes and tool use rather than key indicator rates, the use of evidence-based therapies in patients with acute myocardial infarction (AMI) would increase. BACKGROUND: The use of tools designed to improve quality of care in the American College of Cardiology AMI Guidelines Applied in Practice Pilot Project resulted in improved adherence to evidence-based therapies for patients, but overall, tool use was modest. METHODS: The current project, implemented in five hospitals, was modeled after the previous project, but with greater emphasis on tool use. This allowed early identification of barriers to tool use and strategies to overcome barriers. Main outcome measures were AMI quality indicators in pre-measurement (January 1, 2001 to June 30, 2001) and post-measurement (December 15, 2001 to March 31, 2002) samples. RESULTS: One or more tools were used in 93% of patients (standard orders = 82%, and discharge document = 47%). Tool use was associated with significantly higher adherence to most discharge quality indicator rates with increases in aspirin, angiotensin-converting enzyme inhibitors, and smoking cessation and dietary counseling. Patients undergoing coronary artery bypass grafting (CABG) had low rates of discharge indicators. Patients undergoing percutaneous coronary revascularization were more likely to receive evidence-based therapies. CONCLUSIONS: These data validate the results of the pilot project that quality of AMI care can be improved through the use of guideline-based tools. Identifying and overcoming barriers to tool use led to substantially higher rates of tool use. The low rates of adherence to quality indicators in patients undergoing CABG suggest that these patients should be particularly targeted for quality improvement efforts.