Citations

Purpose To evaluate (1) activity level and knee function, (2) reoperation and failure rates, and (3) risk factors for reoperation and failure of osteochondral autograft transfer (OAT) at minimum long‐term follow‐up. Methods A comprehensive review was performed for long‐term outcomes after OAT. Studies reported on activity‐based outcomes (Tegner Activity Scale) and clinical outcomes (Lysholm score and International Knee Documentation Committee score). Reoperation and failure rates, as defined by the publishing authors, were recorded for each study. Modified Coleman Methodology Scores were calculated to assess study methodological quality. Results Ten studies with a total of 610 patients with an average age of 27.0 years at the time of surgery and a mean follow‐up of 10.2 years were included. The mean defect size was 2.6 cm 2 (range, 0.9 to 20.0 cm 2 ). The mean duration of symptoms before surgery was 4.8 years. From preoperative to final follow‐up, International Knee Documentation Committee scores and Lysholm scores improved significantly by 42.4 (95% confidence interval [CI], 31.8 to 53.1, P < .001) and 21.1 (95% CI, 12.2 to 30.0, P < .01), respectively. Tegner score did not improve significantly (0.76, 95% CI, −0.83 to 2.36, P = .35). Overall failure rate was 28% and reoperation rate was 19%. Increased age, previous surgery, and defect size positively correlated with increased risk of failure. Concomitant surgical procedures negatively correlated with failure rate. Conclusions Overall, OAT showed successful outcomes in 72% of patients at long‐term follow‐up. Increased age, previous surgery, and defect size correlated positively with failure rate, whereas success improved with concomitant surgical procedures. Nonetheless, this systematic review is limited by heterogeneity in a surgical technique, lesion and patient characteristics, and reporting of nonstandardized outcome measures. Level of Evidence Level IV, systematic review of Level I‐IV studies.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE‐PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of “precision medicine.” The February 2015 eMERGE‐PGx data release includes sequence‐derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation‐Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Abstract Purpose: We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC). Experimental Design: We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response. Results: Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusions: In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445–52. ©2016 AACR. See related commentary by Voss and Hsieh, p. 2320

BACKGROUNDLeukoreduced (LR) or cytomegalovirus (CMV)‐seronegative cellular blood components are commonly used to reduce the risk of transfusion‐transmitted CMV infection in high‐risk patients.STUDY DESIGN AND METHODSWe performed a systematic review and meta‐analysis to evaluate the evidence for the use of LR cellular blood components with or without concurrent CMV testing of donor units in patients undergoing chemotherapy or solid organ and hematopoietic stem cell transplantation, in pregnant women, in very‐low‐birthweight infants, and in patients with primary immunodeficiency. We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from 1980 through February 2015. Studies were included if they had a comparison group. Two independent reviewers selected and appraised studies. Meta‐analysis was performed when appropriate.RESULTSOf 457 studies screened, 11 were eligible. One study was excluded from the meta‐analysis because the comparison performed differed significantly from the others. Meta‐analysis of five studies that compared leukoreduction to transfusing CMV‐untested blood components showed no significant difference in clinical CMV infection (relative risk [RR], 0.26; 95% confidence interval [CI], 0.04‐1.57) or laboratory CMV infection (RR, 0.33; 95% CI, 0.08‐1.37). Meta‐analysis of three studies that compared leukoreduction to transfusing CMV‐seronegative cellular components showed no significant difference in laboratory CMV infection (RR, 2.18; 95% CI, 0.96‐4.98). Meta‐analysis of two studies that compared adding CMV testing to leukoreduction (vs. leukoreduction alone) showed no significant difference in clinical or laboratory CMV infection. The certainty in estimates was low for all comparisons.CONCLUSIONAt present, the scientific evidence does not favor a single strategy for reducing the risk of transfusion‐related CMV infection in high‐risk patients.

Key Points HERC4 is the first identified ubiquitin ligase that mediates c-Maf ubiquitination and degradation. HERC4 suppresses MM cell proliferation and delays MM tumor growth.

Background: The adductor magnus (AM) has historically been a potential source of confusion in patients with suspected proximal hamstring avulsion injuries. Purpose: To investigate the anatomic characteristics of the AM, including its osseous origin, anatomic dimensions, and relationship to the proximal hamstring tendons. Study Design: Descriptive laboratory study. Methods: Dissection of the AM origin was performed in 11 (8 cadavers) fresh-frozen hip-to-foot cadaveric hemipelvis specimens. The gross anatomy and architecture of the proximal hamstring and AM tendons were studied. After dissecting the hamstring tendons away from their origin, the dimension, shape, and orientation of the tendon footprints on the ischial tuberosity were determined. Results: The AM was identified in all cadaveric specimens. The mean tendon thickness (anterior to posterior [AP]) was 5.7 ± 2.9 mm. The mean tendon width (medial to lateral [ML]) was 7.1 ± 2.2 mm. The mean tendon length was 13.1 ± 8.7 cm. The mean footprint height (AP dimension) was 12.1 ± 2.9 mm, and mean footprint width (ML dimension) was 17.3 ± 7.1 mm. The mean distance between the AM footprint and the most medial aspect of the conjoint tendon footprint was 8.5 ± 4.2 mm. Tendon measurements demonstrated a considerable degree of both intra- and interspecimen variability. Conclusion: The AM tendon is consistently present just medial to the conjoint tendon at the ischial tuberosity, representing the lateral-most portion of the AM muscle. This study found wide variation in the dimensional characteristics of the AM tendon between specimens. Its shape and location can mimic the appearance of an intact hamstring (conjoint or semimembranosus) tendon intraoperatively or on diagnostic imaging, potentially misleading surgeons and radiologists. Therefore, detailed knowledge of the AM tendon anatomy, footprint anatomy, and its relationship to the hamstring muscle complex is paramount when planning surgical approach and technique. Clinical Relevance: The reported data may aid surgeons in more accurate recognition, diagnosis, and repair of proximal hamstring avulsion injuries.

Purpose Several bioabsorbable and metal options are available for internal fixation of an unstable osteochondritis dissecans (OCD) lesion, but currently there are little data on outcomes with metal headless compression screws in the adult knee. The purpose of this study was to determine (1) the radiographic healing rates, (2) midterm clinical outcomes, and (3) comparison between healed and unhealed OCD fragments after use of headless metal compression screws for the treatment of unstable OCD lesions in the knees of skeletally mature patients. Methods Retrospective chart review for all skeletally mature patients who presented with unstable femoral condyle OCD lesions of the knee was conducted. All patients underwent open or arthroscopic reduction and internal fixation using headless metal compression screws. Preoperative and postoperative radiographs were reviewed with healing defined as radiographic evidence of union of the OCD progeny fragment with the condyle. Clinical outcome data were collected retrospectively using 3 validated outcome scores: International Knee Documentation Committee (IKDC), Knee Injury and Osteoarthritis Outcome Score (KOOS), and Marx. Results Twenty-two knees in 22 patients with a mean age of 21 years (range= 14-37 years) were followed for an average of 8.7 years (range = 2-22 years). Metal, headless, cannulated compression screws were used in all 22 cases. At a mean of 31 months postoperatively (range = 2-262), fragment union was observed in 18 knees (82%). The remaining 4 knees (18%) required loose fragment excision and hardware removal at a mean of 9 months (range = 2-16 months) postoperatively. Mean postoperative Marx score was 7 (range = 0-16), the mean postoperative IKDC score was 85 (range = 62-100), and mean KOOS scores included KOOS Pain (93; range = 69-100), KOOS Symptoms (86; range = 71-100), KOOS ADL (98; range = 90-100), KOOS Sports (82; range = 50-100), and KOOS QOL (76; range = 50-100). Conclusion Headless metal compression screws provide a satisfactory union rate for treatment of unstable OCD lesions of the femoral condyles in skeletally mature patients. Patients achieving union have good knee function, maintain satisfactory activity levels, and have superior knee outcomes compared with those that failed to heal after fixation at mid to long-term follow-up.

Abstract Purpose: The expression of programmed cell death ligand 1 (PD-L1) provides limited predictive value in identifying patients most likely to respond to immunotherapy. As the heterogeneity of PD-L1 expression may lead to sampling error and the misclassification of PD-L1 status, we assessed the distribution of PD-L1 expression in paired, resected multifocal lung cancers. Experimental Design: PD-L1 was assessed by IHC. Paired lesions were defined as independent primaries or related lesions using mate pair next-generation sequencing. Agreement statistics were used for analysis. Results: Sixty-seven multifocal lung cancers from 32 patients were sequenced and stained for PD-L1. There was agreement of PD-L1 expression by the tumor cells in paired lesions of 20 patients and disagreement of PD-L1 expression by the tumor cells in paired lesions of 12 patients (κ = 0.01). Sequencing identified that 23 patients had independent primary lung cancers and that 9 patients had related cancers. In paired lesions of patients with independent cancers, there was agreement of PD-L1 expression by the tumor cells in 12 patients and disagreement in 11 patients (κ = 0.31). In paired lesions of patients with related lung cancers, there was agreement of PD-L1 expression by the tumor cells in 8 patients and disagreement in 1 patient (κ = 0.73). Conclusions: The expression of PD-L1 is heterogeneous among paired independent lung cancers, but there are high levels of agreement in intrapulmonary metastasis. Clin Cancer Res; 22(9); 2177–82. ©2015 AACR.