Citations

We have identified 25 lesions involving alveolar lung parenchyma characterized by nodular proliferation of bland bilayered bronchiolar-type epithelium containing a continuous layer of basal cells. These lesions shared some histologic features with the recently described entity of ciliated muconodular papillary tumor (CMPT); however, the majority did not fit all diagnostic criteria in that they exhibited only focal or absent papillary architecture, and they had variable number of ciliated and mucinous cells, with some lesions entirely lacking 1 or both of these components. The morphologic and immunohistochemical features ranged from those resembling proximal bronchioles (proximal-type: moderate to abundant mucinous and ciliated cells; negative or weak TTF1 in luminal cells; n=8) to those resembling respiratory bronchioles (distal-type: scant or absent mucinous and ciliated cells; positive TTF1 in luminal cells; n=17). The hallmark of all lesions was a continuous layer of basal cells (p40 and CK5/6-positive). We provisionally designated these lesions as bronchiolar adenomas (BAs) and analyzed their clinicopathologic and molecular features. All BAs were discrete, sharply circumscribed lesions with a median size of 0.5 cm (range, 0.2 to 2.0 cm). Most lesions were either entirely flat (n=14) or contained focal papillary architecture (n=7); only 4 lesions, all proximal-type, were predominantly papillary, fitting the classic description of CMPT. Notably, of 9 lesions submitted for frozen section evaluation, 7 were diagnosed as adenocarcinoma. No postsurgical recurrences were observed for any lesions (median follow-up, 11 mo). Twenty-one BAs underwent next-generation sequencing and/or immunohistochemistry for BRAF V600E, revealing mutation profiles similar to those previously described for CMPTs, including BRAF V600E mutations (n=8, 38%), unusual EGFR exon 19 deletions (n=2, 10%), EGFR exon 20 insertions (n=2, 10%), KRAS mutations (n=5, 24%), and HRAS mutations (n=1, 5%). The mutation profiles were similar in proximal-type and distal-type lesions. In conclusion, we describe a family of putatively benign clonal proliferations with a spectrum of morphology recapitulating various levels of the bronchiolar tree, of which only a minor subset fits the classic description of CMPT. Comparable mutation profiles and partially overlapping morphologic features across the spectrum of these lesions support their nosological relationship. We propose designating this entire family of lesions as BAs, and that lesions currently designated CMPTs represent a subgroup of this family.

Background. Shared decision making (SDM) is recommended prior to initiation of statin therapy for primary prevention but is underutilized. We designed an informatics decision-support tool to facilitate use of the Mayo Clinic Statin Choice decision aid at the point-of-care and evaluated its impact. Methods. Using an iterative approach, we designed and implemented a single-click decision-support tool embedded within the electronic health records (EHRs) to automate the calculation of 10-year atherosclerotic cardiovascular disease (ASCVD) risk and populate the Statin Choice decision aid. We surveyed primary care providers at two clinics regarding their attitudes about SDM before and after deployment of intervention, as well as their usage of and perceived competence regarding SDM for primary prevention statin therapy. Three-month web traffic to the Statin Choice website was calculated before and after deployment of the intervention. Results. Pre–post surveys were completed by 60 primary care providers (24 [40%] attending physicians and 36 [60%] housestaff physicians). After deployment of the EHR tool, respondents were more aware of the Statin Choice decision aid ( P < 0.001), reported being more competent regarding SDM ( P = 0.047), and reported using decision aids more often when considering statin initiation ( P = 0.043). There was no significant change in attitudes about SDM as measured through the Patient Provider Orientation Scale (pre 4.23 ± 0.40 v. post 4.16 ± 0.38, P = 0.11) and the SDM belief scale (pre 21.4 ± 2.1 v. post 21.1 ± 2.0, P = 0.35). Web-based usage rates for the Statin Choice decision aid increased from 3.4 to 5.2 per 1,000 outpatient clinic visits ( P = 0.002). Conclusions. Implementation of a point-of-care decision-support tool increased the usage of decision aids for primary prevention statin therapy. This effect does not appear to be mediated by any concomitant changes in physician attitude toward SDM.

Abstract Background We quantified loss of response (LOR) to vedolizumab (VDZ) in clinical practice and assessed the effectiveness of VDZ dose intensification for managing LOR. Methods Retrospective review (May 2014–December 2016) of a prospectively maintained inflammatory bowel disease (IBD) registry. Kaplan-Meier estimates were used to determine rates of LOR to VDZ . Independent predictors of LOR were identified using univariate and multivariable Cox proportional hazard regression. Success of recapturing response (>50% reduction in symptoms from baseline) and remission (complete resolution of symptoms) after dose intensification was quantified. Results Cumulative rates for VDZ LOR were 20% at 6 months and 35% at 12 months, with slightly lower rates in Crohn’s disease than in ulcerative colitis (6 months 15% vs 18% and 12 months 30% vs 39%, P = 0.03). On multivariable analysis, LOR to a tumor necrosis factor (TNF) antagonist before VDZ use was associated with an increased risk for LOR to VDZ [hazard ratio (HR) 1.93; 95% confidence interval (CI) 1.25–2.97] in all patients. For Crohn’s disease patients specifically, higher baseline C-reactive protein concentration was associated with increased risk for LOR to VDZ (HR 1.01 per mg/dL increase, 95% CI 1.01–1.02). Shortening of VDZ infusion interval from 8 to every 4 or 6 weeks recaptured response in 49% and remission in 18% of patients. Conclusions LOR to a TNF antagonist before VDZ use and higher baseline C-reactive protein are important predictors of VDZ LOR. Treatment response can be recaptured in almost half of these patients with VDZ infusion interval shortening.

Background Lower extremity salvage following significant soft tissue loss can be complicated by lack of recipient vessel for free tissue transfer. We describe our experience in lower limb salvage for patients with no recipient vessels with the use of pedicle, free and cable bridge flaps. Methods A retrospective review from 1985 to 2017 of patients undergoing lower limb salvage using a contralateral pedicle cross leg (PCL) flaps, free cross leg (FCL) flaps, or free cable bridge (FCB) flaps was conducted. Demographics, etiology of the reconstruction, type of flap used, donor-site vessels, defect size, operating time, time of pedicle division, length of hospital stay, time to ambulation, and complications were analyzed. Results A total of 53 patients (48 males and 5 females) with an average age of 35 years (range, 29–38 years) were identified. The etiology for the reconstruction was trauma in 52 patients and oncological resection in 1 patient. There were 18 PCL, 25 FCL, and 10 FCB completed. The recipient vessels for all flaps were the posterior tibial artery and vein. The average operating room times for PCL, FCL, and FCB flaps were 4, 9, and 10 hours, respectively. The average length of hospital stay was 5 weeks and average time to ambulation was 4 weeks. The average follow-up time was 7.5 years (range, 3–12 years). Complications encountered were hematoma (six), prolonged pain (six), total flap loss (two), reoperation (five), and infection (four). Limb salvage rates were 96.2%. Conclusion When ipsilateral limb vessels are not available, and other reconstructive options have been exhausted, cross leg flaps can be a viable option for limb salvage in the setting of extensive defects.

Abstract Purpose: Currently, no genomic signature exists to distinguish men most likely to progress on adjuvant androgen deprivation therapy (ADT) after radical prostatectomy for high-risk prostate cancer. Here we develop and validate a gene expression signature to predict response to postoperative ADT. Experimental Design: A training set consisting of 284 radical prostatectomy patients was established after 1:1 propensity score matching metastasis between adjuvant-ADT (a-ADT)-treated and no ADT–treated groups. An ADT Response Signature (ADT-RS) was identified from neuroendocrine and AR signaling–related genes. Two independent cohorts were used to form three separate data sets for validation (set I, n = 232; set II, n = 435; set III, n = 612). The primary endpoint of the analysis was postoperative metastasis. Results: Increases in ADT-RS score were associated with a reduction in risk of metastasis only in a-ADT patients. On multivariable analysis, ADT-RS by ADT treatment interaction term remained associated with metastasis in both validation sets (set I: HR = 0.18, Pinteraction = 0.009; set II: HR = 0.25, Pinteraction = 0.019). In a matched validation set III, patients with Low ADT-RS scores had similar 10-year metastasis rates in the a-ADT and no-ADT groups (30.1% vs. 31.0%, P = 0.989). Among High ADT-RS patients, 10-year metastasis rates were significantly lower for a-ADT versus no-ADT patients (9.4% vs. 29.2%, P = 0.021). The marginal ADT-RS by ADT interaction remained significant in the matched dataset (Pinteraction = 0.035). Conclusions: Patients with High ADT-RS benefited from a-ADT. In combination with prognostic risk factors, use of ADT-RS may thus allow for identification of ADT-responsive tumors that may benefit most from early androgen blockade after radical prostatectomy. We discovered a gene signature that when present in primary prostate tumors may be useful to predict patients who may respond to early ADT after surgery. Clin Cancer Res; 24(16); 3908–16. ©2018 AACR.

Abstract Background Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10−8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk. Methods We conducted a GWAS in European descent CRC cases and control subjects using a discovery–replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10−8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided. Results The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10−8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0. Conclusions This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.

AbstractBackgroundIrritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, diagnosed on symptom‐based criteria. Many have reported discrepancies between formal Rome criteria and diagnoses made in clinical practice. The aim of the study was to explore whether a quantitative version of the Rome criteria would better represent a clinical diagnosis of IBS than the current dichotomous criteria for symptom measure.MethodsAs part of a large, case‐control study, participants completed a validated bowel disease questionnaire. Rome criteria were analyzed based on 15 individual symptoms. Penalized logistic regression model with stepwise selection was used to identify significant symptoms of IBS which were independently associated with case‐control status.Key ResultsIn cases with a clinical diagnosis of IBS, 347 (70%) met Rome criteria for IBS. Increasing number of Rome symptoms were found related to the odds of being diagnosed with IBS. Nearly half of the Rome‐negative case group experienced infrequent symptoms suggesting milder disease. Five of 15 Rome symptoms were associated with predicting case‐control status in the final model, with 96% correctly classified among Rome‐positive cases, 76% for Rome‐negative cases, and 91% for controls.Conclusions and InferencesIrritable bowel syndrome appears to be a spectrum disorder. Quantifying individual symptoms of Rome criteria has greater utility than the current application in representing the degree of IBS affectedness and appears to better reflect a clinical diagnosis of IBS applied by physicians. The use of a quantitative diagnostic Rome “score” may be helpful in clinical practice and research studies to better reflect the degree an individual is affected with IBS.

Background: Massive irreparable rotator cuff tears in both the primary and the revision setting are challenging problems. There remains controversy over the ideal treatment methods for these patients. In the case of an irreparable posterosuperior rotator cuff tear, tendon transfers 1–12 have emerged as a reliable option, with a durable outcome. The most commonly used tendon transfer options are the latissimus dorsi (LD) 1–6 and the lower trapezius (LT) 12 . Description: The LD transfer is performed by first harvesting the LT tendon from the humeral shaft. It is critical to release the many adhesions to the muscle belly as well as to separate it from the teres major muscle. The tendon is then transferred intra-articularly, in an interval between the deltoid and the teres minor. The tendon is anchored arthroscopically after preparation of the anterolateral aspect of the tuberosity. The LT transfer is performed by harvesting the LT muscle and tendon off its insertion on the medial aspect of the scapular spine. It should be mobilized to maximize excursion by releasing adhesions. An Achilles tendon allograft is anchored into the anterior aspect of the greater tuberosity arthroscopically. The Achilles tendon is then secured to the LT tendon. Alternatives: In addition to tendon transfer, options include: Partial or complete attempted repair 13–17 . Augmentation or bridging with allografts 18–23 . Superior capsular reconstruction 24 . Subacromial balloon 25 . Rationale: There remains a paucity of literature comparing tendon transfers with alternatives. However, when considering a tendon transfer, certain principles are critical in order to achieve an optimal outcome: The recipient and transferred tendons must have similar musculotendinous excursion. The recipient and transferred tendons should have similar lines of pull. One tendon (the transferred) should be designed to replace 1 function (of the recipient). The function of the transferred tendon and muscle should be expendable without substantial donor site morbidity. The strength of the transferred muscle must be at least grade 4. When deciding between the LT and LD transfer, certain considerations should be taken into account. The LD transfer has a proven history of successfully treating massive irreparable posterosuperior rotator cuff tears in studies with long-term follow-up 1–6 . Alternatively, although the LT transfer has only recently gained popularity, it has the advantage of “in-phase” muscle function, since the trapezius naturally contracts during shoulder external rotation. Furthermore, its line of pull almost completely mimics the infraspinatus.