Trial of Cinpanemab in Early Parkinson's Disease.

BACKGROUND: Aggregated α-synuclein plays an important role in Parkinson's disease pathogenesis. Cinpanemab, a human-derived monoclonal antibody that binds to α-synuclein, is being evaluated as a disease-modifying treatment for Parkinson's disease. METHODS: In a 52-week, multicenter, double-blind, phase 2 trial, we randomly assigned, in a 2:1:2:2 ratio, participants with early Parkinson's disease to receive intravenous infusions of placebo (control) or cinpanemab at a dose of 250 mg, 1250 mg, or 3500 mg every 4 weeks, followed by an active-treatment dose-blinded extension period for up to 112 weeks. The primary end points were the changes from baseline in the Movement Disorder Society-sponsored revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) total score (range, 0 to 236, with higher scores indicating worse performance) at weeks 52 and 72. Secondary end points included MDS-UPDRS subscale scores and striatal binding as assessed on dopamine transporter single-photon-emission computed tomography (DaT-SPECT). RESULTS: Of the 357 enrolled participants, 100 were assigned to the control group, 55 to the 250-mg cinpanemab group, 102 to the 1250-mg group, and 100 to the 3500-mg group. The trial was stopped after the week 72 interim analysis owing to lack of efficacy. The change to week 52 in the MDS-UPDRS score was 10.8 points in the control group, 10.5 points in the 250-mg group, 11.3 points in the 1250-mg group, and 10.9 points in the 3500-mg group (adjusted mean difference vs. control, -0.3 points [95% confidence interval {CI}, -4.9 to 4.3], P = 0.90; 0.5 points [95% CI, -3.3 to 4.3], P = 0.80; and 0.1 point [95% CI, -3.8 to 4.0], P = 0.97, respectively). The adjusted mean difference at 72 weeks between participants who received cinpanemab through 72 weeks and the pooled group of those who started cinpanemab at 52 weeks was -0.9 points (95% CI, -5.6 to 3.8) for the 250-mg dose, 0.6 points (95% CI, -3.3 to 4.4) for the 1250-mg dose, and -0.8 points (95% CI, -4.6 to 3.0) for the 3500-mg dose. Results for secondary end points were similar to those for the primary end points. DaT-SPECT imaging at week 52 showed no differences between the control group and any cinpanemab group. The most common adverse events with cinpanemab were headache, nasopharyngitis, and falls. CONCLUSIONS: In participants with early Parkinson's disease, the effects of cinpanemab on clinical measures of disease progression and changes in DaT-SPECT imaging did not differ from those of placebo over a 52-week period. (Funded by Biogen; SPARK ClinicalTrials.gov number, NCT03318523.).

Characterizing germline APC and MUTYH variants in Ashkenazi Jews compared to other individuals.

Germline variants in the APC and MUTYH genes contribute to colorectal cancer (CRC) and adenoma risk, though may occur with varying frequencies in individuals of different ancestries. The aim of this study was to evaluate the prevalence of APC, monoallelic MUTYH and biallelic MUTYH germline variants in Ashkenazi Jewish (AJ) and Other Ancestry (OA) individuals with colorectal adenomas. We studied 7225 individuals with colorectal adenomas who had germline APC and MUTYH testing at a commercial laboratory. Cross-sectional medical history data were extracted from provider-completed test requisition forms. We performed bivariate analysis to compare the frequency of APC and MUTYH variants between AJ and OA, and examined APC p.I1307K and monoallelic MUTYH carrier phenotypes using logistic regression. Pathogenic APC variants occurred in 38/285 AJ (13%) and 1342/6940 OA (19%; P = 0.09); biallelic MUTYH variants in 2/285 (1%) AJ and 399/6940 (6%) OA (P < 0.0001); APC p.I1307K in 35/285 (12%) AJ and 29/6940 (1%) OA (P < 0.0001); and monoallelic MUTYH in 2/285 (1%) AJ and 133/6940 (2%) OA (P = 0.06). Monoallelic MUTYH variants were significantly associated with having a personal history of CRC, regardless of ancestry (OR 1.78; 95% CI 1.21-2.49; P < 0.01), but no significant association was found between APC p.I1307K variants and personal history of CRC (OR 1.38; 95% CI 0.79-2.44; P = 0.26). Ashkenazim with colorectal adenomas rarely have monoallelic or biallelic MUTYH variants, suggesting different genetic etiologies for polyposis in AJ compared to OA individuals. AJ ancestry assessment may be important in clinical evaluation for polyposis.

An active learning curriculum improves fellows' knowledge and faculty teaching skills.

OBJECTIVES: Traditional didactic lectures are the mainstay of teaching for graduate medical education, although this method may not be the most effective way to transmit information. We created an active learning curriculum for Brigham and Women's Hospital (BWH) gastroenterology fellows to maximize learning. We evaluated whether this new curriculum improved perceived knowledge acquisition and knowledge base. In addition, our study assessed whether coaching faculty members in specific methods to enhance active learning improved their perceived teaching and presentation skills. METHODS: We compared the Gastroenterology Training Exam (GTE) scores before and after the implementation of this curriculum to assess whether an improved knowledge base was documented. In addition, fellows and faculty members were asked to complete anonymous evaluations regarding their learning and teaching experiences. RESULTS: Fifteen fellows were invited to 12 lectures over a 2-year period. GTE scores improved in the areas of stomach (p<0.001), general gastroenterology (p=0.005), esophagus (p<0.001), and small bowel (p=0.001), and the total score (p=0.001) between pre- and postimplementation of the active learning curriculum. Scores in hepatology, as well as biliary and pancreatic study, showed a trend toward improvement (p>0.05). All fellows believed the lectures were helpful, felt more prepared to take the GTE, and preferred the interactive format to traditional didactic lectures. All lecturers agreed that they acquired new teaching skills, improved teaching and presentation skills, and learned new tools that could help them teach better in the future. CONCLUSION: An active learning curriculum is preferred by GI fellows and may be helpful for improving transmission of information in any specialty in medical education. Individualized faculty coaching sessions demonstrating new ways to transmit information may be important for an individual faculty member's teaching excellence.

Comparison of Colonoscopy Quality Measures Across Various Practice Settings and the Impact of Performance Scorecards.

BACKGROUND: Quality performance measures for screening colonoscopy vary among endoscopists. The impact of practice setting is unknown. AIMS: We aimed to (1) compare screening colonoscopy performance measures among three different US practice settings; (2) evaluate factors associated with adenoma detection; and (3) assess a scorecard intervention on performance metrics. METHODS: This multi-center prospective study compared patient, endoscopist, and colonoscopy characteristics performed at a tertiary care hospital (TCH), community-based hospital (CBH), and private practice group (PPG). Withdrawal times (WT), cecal intubation, and adenoma detection rates (ADR) were compared by site at baseline and 12 weeks following scorecard distribution. Generalized linear mixed models identified factors associated with adenoma detection. RESULTS: Twenty-eight endoscopists performed colonoscopies on 1987 asymptomatic, average-risk individuals ≥50 years. Endoscopist and patient characteristics were similar across sites. The PPG screened more men (TCH: 42.8%, CBH: 45.0%, PPG: 54.2%; p < 0.0001). Preparation quality varied with good/excellent results in 70.6, 88.3, and 92% of TCH, CBH, and PPG cases, respectively (p < 0.0001). Male ADRs, cecal intubation, and WT exceeded recommended benchmarks despite variable results at each site; female ADRs were <15% at the PPG which screened the fewest females. Performance remained unchanged following scorecard distribution. Adenoma detection was associated with increasing patient age, male gender, WT, adequate preparation, but not practice setting. CONCLUSIONS: Each practice performed high-quality screening colonoscopy. Scorecards did not improve performance metrics. Preparation quality varies among practice settings and can be modified to improve adenoma detection.

Racial variation in frequency and phenotypes of APC and MUTYH mutations in 6,169 individuals undergoing genetic testing.

PURPOSE: The aim of this study was to assess whether differences in frequency and phenotype of APC and MUTYH mutations exist among racially/ethnically diverse populations. METHODS: We studied 6,169 individuals with a personal and/or family history of colorectal cancer (CRC) and polyps. APC testing involved full sequencing/large rearrangement analysis (FS/LRA); MUTYH involved "panel testing" (for Y165C, G382D mutations) or FS/LRA performed by Myriad Genetics, a commercial laboratory. Subjects were identified as Caucasian, Asian, African American (AA), or other. Statistical tests included χ(2), Fisher's exact test, analysis of variance, and z approximation. RESULTS: Among participants, 17.5% had pathogenic APC mutations and 4.8% were biallelic MUTYH carriers. With regard to race/ethnicity, 18% were non-Caucasian, with >100 adenomas and younger ages at adenoma or CRC diagnosis (P < 0.0001) than Caucasians. The overall APC mutation rate was higher in Asians, AAs, and others as compared with Caucasians (25.2, 30.9, 24, and 15.5%, respectively; P < 0.0001) but was similar in all groups when adjusted for polyp burden. More MUTYH biallelic carriers were Caucasian or other than Asian or AA (5, 7, 2.7, and 0.3%, respectively; P < 0.0001). Among Caucasians, 5% were biallelic carriers identified by panel testing versus 2% identified by sequencing/large rearrangement analysis (LRA) (P = 0.002). Among non-Caucasians, 3% undergoing panel testing were biallelic carriers versus 10% identified by sequencing/LRA (P < 0.0002). CONCLUSION: Non-Caucasians undergo genetic testing at more advanced stages of polyposis and/or are younger at CRC/polyp diagnosis. Restricted MUTYH analysis may miss significant numbers of biallelic carriers, particularly in non-Caucasians.

Colorectal cancer in young adults.

The incidence and mortality rates of colorectal cancer (CRC) have been decreasing in adults over 50 years of age, however, these rates have been increasing in adults under 50. The majority of CRC in young adults is sporadic, and is likely due to behavioral and environmental causes, however the exact etiology still remains unclear. The minority of CRC in this population is due to inherited CRC syndromes. Young adults with CRC are often symptomatic (abdominal pain, rectal bleeding), and diagnosis is often delayed due to reasons such as under-utilized health care services, and physicians attributing symptoms to diagnoses other than CRC. Young adults with CRC often have more aggressive tumor characteristics, but they tend to have better survival rates when compared with older adults when matched for stage. Treatment is the same for young patients with CRC, however there are issues that arise in this population that do not necessarily affect older adults, such as the negative effect of chemotherapy/radiation on fertility. It is not clear that screening individuals for CRC at ages under 50 is beneficial or cost-effective. Further studies are needed regarding this topic.

High expression of the Met receptor in prostate cancer metastasis to bone.

OBJECTIVES: Expression of the active Met receptor tyrosine kinase causes tumor metastasis in animal models. To begin to analyze whether Met expression might be related to the spread of prostate cancer cells, we investigated whether its expression correlates with prostate-specific antigen recurrence and whether its expression depends on the site of metastasis. METHODS: Ninety radical prostatectomy specimens with a Gleason sum of 6 or 7 and 86 specimens of bone, lymph node, and soft-tissue metastasis were immunohistochemically stained for Met, and a semiquantitative scoring system for Met in heterogeneously positive prostate cancers was applied. Met protein in prostate cancer cell lines was measured by Western blotting. RESULTS: With the exception of two lymph node metastases, all metastases and 51% of the primary prostate cancers expressed Met. Moreover, the bone metastases expressed significantly more Met than did the lymph node metastases. However, in prostate cancer with a Gleason sum of 6 or 7, Met was not a prognostic marker for prostate-specific antigen recurrence. In prostate cancer cell lines, Met expression correlated inversely with expression of the androgen receptor. CONCLUSIONS: The high expression of the Met receptor tyrosine kinase in bone metastasis renders Met a promising target for nuclear imaging and treatment of metastatic prostate cancer.