Citations

Abstract The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (P < 0.0001). However, all TML-high anal cancers (8.3%) were microsatellite stable (MSS). Higher PD-L1 expression was more likely to be seen in MSI compared with MSS tumors (20.6% vs. 7.8%, P < 0.0001). Implications: TML-high rate varied widely among gastrointestinal cancers. Although MSI is conceivably the main driver for TML-high, other factors may be involved. Future clinical trials are needed to evaluate whether the integration of TML, MSI, and PD-L1 could better identify potential responders to immunotherapy. Mol Cancer Res; 16(5); 805–12. ©2018 AACR.

Background: Medial meniscus root tears are a common knee injury and can lead to accelerated osteoarthritis, which might ultimately result in a total knee replacement. Purpose: To compare meniscus repair, meniscectomy, and nonoperative treatment approaches among middle-aged patients in terms of osteoarthritis development, total knee replacement rates (clinical effectiveness), and cost-effectiveness. Study Design: Meta-analysis and cost-effectiveness analysis. Methods: A systematic literature search was conducted. Progression to osteoarthritis was pooled and meta-analyzed. A Markov model projected strategy-specific costs and disutilities in a cohort of 55-year-old patients presenting with a meniscus root tear without osteoarthritis at baseline. Failure rates of repair and meniscectomy procedures and disutilities associated with osteoarthritis, total knee replacement, and revision total knee replacement were accounted for. Utilities, costs, and event rates were based on literature and public databases. Analyses considered a time frame between 5 years and lifetime and explored the effects of parameter uncertainty. Results: Over 10 years, meniscus repair, meniscectomy, and nonoperative treatment led to 53.0%, 99.3%, and 95.1% rates of osteoarthritis and 33.5%, 51.5%, and 45.5% rates of total knee replacement, respectively. Meta-analysis confirmed lower osteoarthritis and total knee replacement rates for meniscus repair versus meniscectomy and nonoperative treatment. Discounted 10-year costs were $22,590 for meniscus repair, as opposed to $31,528 and $25,006 for meniscectomy and nonoperative treatment, respectively; projected quality-adjusted life years were 6.892, 6.533, and 6.693, respectively, yielding meniscus repair to be an economically dominant strategy. Repair was either cost-effective or dominant when compared with meniscectomy and nonoperative treatment across a broad range of assumptions starting from 5 years after surgery. Conclusion: Repair of medial meniscus root tears, as compared with total meniscectomy and nonsurgical treatment, leads to less osteoarthritis and is a cost-saving intervention. While small confirmatory randomized clinical head-to-head trials are warranted, the presented evidence seems to point relatively clearly toward adopting meniscus repair as the preferred initial intervention for medial meniscus root tears.

Background Non–vitamin K antagonist oral anticoagulants (NOACs) are indicated for stroke prevention in atrial fibrillation (AF) but require lower doses in certain patients. We sought to describe the frequency, appropriateness (according to Food and Drug Administration labeling), and outcomes of patients prescribed reduced doses of NOACs in community practice. Methods and Results We analyzed data from the ORBIT‐AF II (The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II) registry, a prospective, national, observational registry of AF patients. Among 7925 AF patients receiving NOACs, we assessed patterns of use of reduced NOAC doses and associated cardiovascular and bleeding outcomes at median follow‐up of 1 year. Overall, 6636 patients (84%) received a NOAC at standard dose, which was consistent with US Food and Drug Administration labeling in 6376 (96%). Reduced NOAC dose was prescribed to 1289 (16% overall), which was consistent with Food and Drug Administration labeling in only 555 patients (43%). Compared with those whose NOAC dose was appropriately reduced, patients receiving inappropriate dose reductions were younger (median age 79 versus 84, P <0.0001) and had lower ORBIT bleeding risk scores (26% ≥4 versus 45%, P <0.0001). Compared with those appropriately receiving standard dosing, patients receiving inappropriately reduced‐dose NOACs had higher unadjusted rates of thromboembolic events (2.11 versus 1.35 events per 100 patient years, hazard ratio 1.56, 95% confidence interval 0.92‐2.67) and death (6.77 versus 2.60, hazard ratio 2.61, 95% confidence interval 1.86‐3.67). After adjustment, outcomes were not significantly different but tended to favor patients dosed appropriately. Conclusions The majority of dose reductions of NOACs in AF are inconsistent with US Food and Drug Administration recommendations. There appear to be opportunities to improve current NOAC dosing in community practice. Clinical Trial Registration URL: http://www.clinicaltrials.gov . Unique identifier: NCT01701817.

Abstract BACKGROUND The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown. OBJECTIVE To examine these uncertainties. METHODS NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan–Meier method. RESULTS A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings ( P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire ( P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test–Revised Delayed Recognition [ P = .048], Trail Making Test Part A [ P = .035], and Controlled Oral Word Association [ P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures. CONCLUSION STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients.

Purpose To evaluate clinical outcomes, demographics, and radiographic findings for patients whose hip arthroscopies involved amorphous calcification (AC) excision and to compare them with a control group with no AC and with the general population regarding diabetes mellitus and hypothyroidism. Methods Patients who underwent primary hip arthroscopy involving surgical excision of AC deposit in the anterosuperior labralcapsular recess between October 2008 and July 2014 were reviewed. Demographics, radiographic findings, intraoperative findings, and procedures were reviewed. Minimum follow‐up was 2 years and included visual analog scale for pain, patient satisfaction, and the following patient‐reported outcome scores: modified Harris hip score, hip outcomes score sport‐specific subscale, and nonarthritic hip score. These patients were matched (1:2 ratio) to patients who underwent hip arthroscopy with no AC using the following matching criteria: age at surgery ± 5 years, body mass index ± 5, gender, type of labral treatment, and type of capsular treatment. Results We reviewed 12 cases in 11 female patients. Mean latest follow‐up scores improved from 64.0 to 83.4 ( P = .003) for modified Harris hip score, from 57.6 to 80.6 ( P < .001) for nonarthritic hip score, from 35.4 to 62.7 ( P = .021) for hip outcomes score sport‐specific subscale, and from 6.4 to 2.8 ( P = .016) for visual analog scale. The survivorship rate was 91.7%, with one hip converting to total hip arthroplasty. Mean patient satisfaction was 8.4 ± 2.3. Six hips of the 12 (50%) had clock face localization of the AC. They were all between 11 and 12 with a mean of 12:30. Postoperative radiographic findings showed no subsequent AC in all 12 hips. No complications or revisions were reported. There were no significant differences between the AC group and the control group. Conclusions The treatment of AC as part of hip arthroscopy for labral tear and femoro‐acetabular impingement is safe and has favorable and similar outcomes compared with a control group at minimum 2‐year follow‐up. Female gender may be a risk factor for the development of AC. There is no strong evidence that AC should be debrided. Level of Evidence Level III, case control study.

Abstract BACKGROUND Several hypotheses have been proposed for the pathophysiology of suprascapular nerve (SSN) palsy, including compression, traction, and nerve inflammation. OBJECTIVE To provide insight into the pathophysiology of isolated nontraumatic SSN palsy by performing critical reinterpretations of electrodiagnostic (EDX) studies and magnetic resonance (MR) images of patients with such diagnosis. METHODS We retrospectively reviewed all patients referred to our institution for the past 20 yr with a diagnosis of nontraumatic isolated suprascapular neuropathy who had an upper extremity EDX study and a shoulder or brachial plexus MR scan. Patient charts were reviewed to analyze their initial clinical examination, and their original EDX study and MR images were reinterpreted by an experienced neurologist and a musculoskeletal radiologist, respectively, both blinded from the authors’ hypothesis and from each other's findings. RESULTS Fifty-nine patients were included. Fifty of them (85%) presented with at least 1 finding that was inconsistent with an isolated SSN palsy. Forty patients (68%) had signs on physical examination beyond the SSN distribution. Thirty-one patients (53%) had abnormalities on their EDX studies not related to the SSN. Twenty-two patients (37%) had denervation atrophy in other muscles than the spinati, or neural hyperintensity in other nerves than the SSN on their MR scans, without any evidence of SSN extrinsic compression. CONCLUSION The great majority of patients with presumed isolated SSN palsy had clinical, electrophysiological, and/or imaging evidence of a more diffuse pattern of neuromuscular involvement. These data strongly support an inflammatory pathophysiology in many cases of “isolated” SSN palsy.