Citations

Purpose To (1) evaluate long‐term outcomes of osteochondral allograft (OCA) with regard to clinical outcome scores, reoperation and failure rates, and (2) examine if certain factors predispose patients to worse outcomes. Methods A comprehensive review was performed with specific inclusion criteria for studies with long‐term outcomes after OCA. Studies reported on patient clinical scores such as Hospital for Special Surgery score, Knee Society Score (knee and function score), and Lysholm score. Reoperation and failure rates were recorded for each study. Modified Coleman Methodology Scores assessed study methodological quality. Results Five studies with a total of 291 patients (55% male, 45% female) and average age of 34.8 years (range, 15 to 69 years) were included. Of all lesions, 67% were on the femoral condyles, 29% on the tibial plateau, and 4% were patellofemoral. All scores (Knee Society Function Score, Knee Society Knee Score, and Lysholm score) have significant mean improvement from preoperative to final follow‐up. The mean postoperative Hospital for Special Surgery score was 84.1. The mean failure rate was 25% at 12.3 years with a reoperation rate of 36%. A total of 72% of the failures were conversion to total (68%) or unicompartmental (4%) knee arthroplasty and 28% involved graft removal, graft fixation, and graft revision. Patellofemoral lesions (83%) had a significantly higher reoperation rate than lesions involving the tibial plateau or the femoral condyles (34%, P = .01). Conclusions Overall, OCA demonstrated significant improvements in clinical outcome scores and good durability with successful outcomes in 75% of the patients at 12.3 years after surgery. Patellofemoral lesions are associated with decreased clinical improvement and more frequent reoperations. The orthopaedic literature is limited by heterogeneity in surgical technique, lesion and patient characteristics, and reporting of nonstandardized outcome measures. Level of Evidence Level IV, systematic review of Level II and IV studies.

Background: Female soccer players have a well-known risk for anterior cruciate ligament (ACL) injury, but few studies have reported on second ACL injuries in this population. Purpose: To (1) report the rates of subsequent ACL injury (ipsilateral graft rupture or contralateral tear) in competitive female soccer players, (2) compare these rates with those of other female athletes of similar competitive level, (3) determine risk factors for second ACL injury, and (4) report clinical outcome scores in this population. Study Design: Cohort study; Level of evidence, 3. Methods: The medical records at a single institution were reviewed for female patients who were injured during a competitive athletic event and treated with primary ACL reconstruction (ACLR) between 1998 and 2013. Patients were followed for a mean of 68.8 months postoperatively (range, 24-115.2 months). Clinical outcome was obtained via Lysholm and International Knee Documentation Committee (IKDC) scores. Soccer players were matched 1:1 to non-soccer athletes for age, activity level, and graft type. Results: A total of 180 female ACLR patients with a mean ± SD age of 19.6 ± 6.9 years met the study inclusion and exclusion criteria (90 soccer players and 90 non-soccer players). Soccer players sustained more second ACL injuries, including both graft failures (11% vs 1%; P < .01) and contralateral ACL tears (17% vs 4%; P < .01), compared with non-soccer players. Of the 67 patients who returned to soccer after ACLR (mean age, 17.5 years; range, 13-27 years), significantly more had graft tears compared with those who did not return to soccer (15% vs 0%, respectively; P = .04); however, the difference in contralateral ACL tears (19% for returning players vs 9% for those who did not return; P = .34) was not significant. Relatively older age (odds ratio, 1.5 per year; P = .03) was a significant risk factor for ACL graft tear but not for contralateral ACL injury. Both groups had similar mean Lysholm (96 vs 95) and IKDC scores (95 vs 96) at final follow-up. Conclusion: Twenty-eight percent of all female soccer players and 34% of those players who returned to soccer had a second ACL tear. Soccer players had an increased rate of both graft tear and contralateral ACL injury compared with similar non-soccer athletes. Older age and return to soccer were significant risk factors for graft rupture.

Purpose (1) To determine the radiographic correction/healing rate, patient‐reported outcomes, reoperation rate, and complication rate after distal femoral osteotomy (DFO) for the valgus knee with lateral compartment pathology. (2) To summarize the reported results of medial closing wedge and lateral opening wedge DFO. Methods We conducted a systematic review of PubMed, MEDLINE, and CINAHL to identify studies reporting outcomes of DFOs for the valgus knee. Keywords included “distal femoral osteotomy,” “chondral,” “cartilage,” “valgus,” “joint restoration,” “joint preservation,” “arthritis,” and “gonarthrosis.” Two authors first reviewed the articles; our study exclusion criteria were then applied, and the articles were included on the basis relevance defined by the aforementioned criteria. The Methodological Index for Nonrandomized Studies scale judged the quality of the literature. Sixteen studies were relevant to the research questions out of 191 studies identified by the original search. Results Sixteen studies were identified reporting on 372 osteotomies with mean follow‐up of 45 to 180 months. All studies reported mean radiographic correction to a near neutral mechanical axis, with 3.2% nonunion and 3.8% delayed union rates. There was a 9% complication rate and a 34% reoperation rate, of which 15% were converted to arthroplasty. There were similar results reported for medial closing wedge and lateral opening wedge techniques, with a higher conversion to arthroplasty in the medial closing wedge that was confounded by longer mean follow‐up in this group (mean follow‐up 100 v 58 months). Conclusions DFOs for the valgus knee with lateral compartment disease provide improvements in patient‐reported knee health–related quality of life at midterm follow‐up but have high rates of reoperation. No evidence exists proving better results of either the lateral opening wedge or medial closing wedge techniques. Level of Evidence Level IV, systematic review of Level IV studies.

Abstract Background Protein phosphatase (PP2A) is a multifunctional protein involved in regulation of cell cycle, DNA-damage response, and apoptosis. LB-100, a novel small molecule inhibitor of PP2A, inhibits the growth of a broad spectrum of leukemic and solid tumor cell lines. In addition, LB100 potentiates the effectiveness of cytotoxic drugs (cisplatin, docetaxel, doxorubicin, temozolomide) and radiation without significant increases in toxicity. The predominant mechanisms responsible for potentiation are inhibition of mitotic exit and homologous recombination repair. Methods This is an open label, first-time-in-human, multicenter, phase 1 study of LB-100 in patients with advanced cancer refractory to standard therapies. The first part of the study determines the maximum tolerated dose (MTD) of LB-100 as a single agent when given intravenously days 1-3 every 21 days. Utilizing a standard 3+3 design, patients (pts) are evaluated for dose limiting toxicities (DLT) through 2 cycles. Once the single agent MTD is determined, the dose will be reduced by 2 dose levels (DL) and combined with docetaxel given on day 2. Escalation will continue until the MTD of the combination is determined. Plasma sampling for pharmacokinetics of LB-100 will be collected on days 1 and 3 of cycle 1 in the MTD confirmation cohort. Results The starting dose of LB-100 was 0.25 mg/m2 and 21 pts have enrolled in part 1 of the study through six dose levels. At DL6, pts received 2.33 mg/m2 and no DLTs have been observed. One pt with metastatic colon cancer at DL6 had a grade 2 creatinine after 2 doses that resolved with hydration. This was related to LB-100 and the study was amended to increase the volume and infusion time. One pt on DL3 with stage 4 pancreas cancer had stable disease through 15 cycles of treatment and another pt on DL5 with metastatic thymoma remains on treatment through 8 cycles. Stable disease for 4-6 cycles was also observed in breast, ovarian, carcinoid and testicular cancer patients. Conclusions Rb and p53 mutations are common in malignancies leading to chromosomal instability and overexpression of the mitotic checkpoint gene Mad2. PP2A inhibition results in synthetic lethality of cancer cells overexpressing Mad2 which may be a biomarker for LB100 responsiveness. Through 6 DLs, LB-100 has been well tolerated without any DLTs and early activity has been observed with stabilization of disease in a wide variety of cancers. Correlative studies for biomarkers of response are planned. Clinical trial identifier: NCTO1837667 Citation Format: Vincent Chung, Donald Richards, Fadi Braiteh, John S. Kovach, Aaron Scott Mansfield. A phase 1 study of a novel inhibitor of protein phosphatase 2A alone or in combination with docetaxel. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A175.

Abstract Gene expression profiling has identified molecular subtypes that classify invasive breast cancers into distinct categories that vary in their clinical behavior and response to treatment. These subtypes highlight the many possible biologically and clinically distinct types of breast cancer. Immunohistochemical (IHC) staining of tumor sections using antibody panels has been used as a surrogate for the molecular subtypes identified through gene expression profiling, resulting in a set of intrinsic molecular subtypes. Given the heterogeneity within breast cancer, one might expect that different risk factors influence specific subtypes of breast cancer through various etiologic pathways. We evaluated whether percent mammographic density (MD), the proportion of fibroglandular or white tissue on a mammogram and one of the strongest and most consistent risk factors for breast cancer, is associated equally with all intrinsic molecular subtypes. Data were pooled from six cohort or case-control studies including 3389 women with invasive breast cancer and 9860 without, who underwent screening mammography. Percent MD was assessed from digitized film-screen mammograms (for cases, at a median 4 years prior to diagnosis) using a computer-assisted threshold technique, and categorized as 0-10%, 11-25%, 26-50% and 51%+. Receptor status was abstracted from clinical pathology records and supplemented by IHC staining of tumor sections or microarrays. With estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor (HER2) information, we classified tumors into the intrinsic molecular subtypes: Luminal A ( ER+ and/or PR+ and HER2- and grade 1 or 2), Luminal B (ER+ and/or PR+ and HER2+ or Luminal A and grade 3), HER2 expressing (HER2+/ER-/PR-) and triple negative (ER-/PR-/HER2-). For cancers found to be triple negative (TN), we also stained for epidermal growth factor receptor (EGFR) and cytokeratins (CK) 5/6 to differentiate basal-like tumors (positive for EGFR and/or CK 5/6) from the unclassifieds (negative on both EGFR and CK 5/6). We used polytomous logistic regression to calculate the odds (OR) of each of the intrinsic subtypes of breast cancer by categories of percent MD, adjusting for age, BMI and study. Contrasts were constructed and tested within the polytomous model framework to investigate differences in the strength of association of percent MD across subtypes. On average, cases were slightly older (56.4 years [SD=11.3]) than controls (55.8 [10.9]). Of the 3389 invasive breast cancer cases, 2146 (63%) were classified as Luminal A, 709 (21%) as Luminal B, 169 (5%) as HER-2 expressing, and 365(11%) as triple negative (TN). Of the TN tumors, 203 had tumor tissue available and were evaluated for CK 5/6 and EGFR, with 167 (82%) classified as basal-like and 36 (18%) as unclassified. Percent (%) MD was associated with breast cancer risk across all intrinsic subtypes. For Luminal A, compared to women with 11-25% MD (reference), women with 0-10% MD had a reduced risk of breast cancer (OR=0.64 [95% confidence interval (CI): 0.55, 0.74]) while women with 26-50% MD had an OR=1.5 (1.3,1.7) and women with 51%+ MD had the highest risk, OR=2.4 (2.0, 2.8). Similar associations were seen for Luminal B, HER2 expressing, and TN across percent MD categories. The small differences among the percent MD-breast cancer associations observed for the different subtypes were not statistically significant, either when comparing the four (Luminal A, Luminal B, HER-2 expressing and TN; p=0.61) or five categories of subtypes (Luminal A, Luminal B, HER-2 expressing, basal-like, unclassified; p=0.66). Our results suggest percent MD is a risk factor for all intrinsic molecular subtypes. Additional study is needed to examine whether these results hold for younger and older aged women. Understanding the importance of mammographic density measures for subtypes of breast cancer has significance for development of subtype-specific risk models. Citation Format: Celine Vachon, Rulla Tamimi, Yunn-Yi Chen, Christopher Scott, Kimberly Bertrand, Matthew Jensen, Daniel Visscher, Aaron Norman, Fergus Couch, John Shepherd, Bo Fan, Fang-Fang Wu, Lin Ma, Andrew Beck, Steve Cummings, V. Shane Pankratz, Karla Kerlikowske. Mammographic density: A risk factor for all breast cancers or only specific subtypes? [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr IA22.

Abstract Purpose: The NCI Cancer Therapy Evaluation Program sponsors hepatic dysfunction phase I clinical trials (HDCT) and phase 1 clinical trials (P1CT) to determine safe doses and schedules of antineoplastic therapeutics. We sought to compare clinical outcomes between these trial types while stratifying by hepatotoxic agents. Experimental Design: Individual subject data were extracted from the records of 51 NCI-sponsored HDCT and P1CT. The NCI's Organ Dysfunction Working Group's hepatic impairment categorization and two drug-induced liver injury (DILI) scales (FDA R ratio and Hy's law) were used to classify subjects. The number of cycles administered and treatment discontinuation reason were also evaluated and compared between groups. Results: There were 513 and 1,328 subjects treated on HDCT (n = 9) and P1CT (n = 42), respectively. There were differing patterns of DILI with significant worsening of total bilirubin in subjects on HDCT, and worsening of alanine aminotransferase (ALT) in subjects on P1CT. Cholestatic peak patterns of liver impairment (predominant increases in alkaline phosphatase rather than transaminases) were more frequent in HDCT. Criteria for Hy's law were met by 11 subjects on P1CT, but not by any subjects on HDCT. Disease progression was the most common reason for treatment discontinuation, followed by adverse events at similar frequencies in both HDCT and P1CT. Conclusions: The differential effects on hepatotoxicity suggest that underlying hepatic function may affect susceptibility to and patterns of DILI. The incorporation of additional measures of hepatic function may help identify those at highest risk of hepatotoxicity in future trials because baseline liver tests did not. Clin Cancer Res; 22(22); 5472–9. ©2016 AACR.

OBJECTIVE Improvement in treatment outcome for patients with glioblastoma multiforme (GBM) requires a multifaceted approach due to dysregulation of numerous signaling pathways. The murine double minute 2 (MDM2) protein may fulfill this requirement because it is involved in the regulation of growth, survival, and invasion. The objective of this study was to investigate the impact of modulating MDM2 function in combination with front-line temozolomide (TMZ) therapy in GBM. METHODS The combination of TMZ with the MDM2 protein–protein interaction inhibitor nutlin3a was evaluated for effects on cell growth, p53 pathway activation, expression of DNA repair proteins, and invasive properties. In vivo efficacy was assessed in xenograft models of human GBM. RESULTS In combination, TMZ/nutlin3a was additive to synergistic in decreasing growth of wild-type p53 GBM cells. Pharmacodynamic studies demonstrated that inhibition of cell growth following exposure to TMZ/nutlin3a correlated with: 1) activation of the p53 pathway, 2) downregulation of DNA repair proteins, 3) persistence of DNA damage, and 4) decreased invasion. Pharmacokinetic studies indicated that nutlin3a was detected in human intracranial tumor xenografts. To assess therapeutic potential, efficacy studies were conducted in a xenograft model of intracranial GBM by using GBM cells derived from a recurrent wild-type p53 GBM that is highly TMZ resistant (GBM10). Three 5-day cycles of TMZ/nutlin3a resulted in a significant increase in the survival of mice with GBM10 intracranial tumors compared with single-agent therapy. CONCLUSIONS Modulation of MDM2/p53-associated signaling pathways is a novel approach for decreasing TMZ resistance in GBM. To the authors' knowledge, this is the first study in a humanized intracranial patient-derived xenograft model to demonstrate the efficacy of combining front-line TMZ therapy and an inhibitor of MDM2 protein–protein interactions.

Immune checkpoint therapy with PD-1 blockade has emerged as an effective therapy for many advanced cancers; however, only a small fraction of patients achieve durable responses. To date, there is no validated blood-based means of predicting the response to PD-1 blockade. We report that Bim is a downstream signaling molecule of the PD-1 pathway, and its detection in T cells is significantly associated with expression of PD-1 and effector T cell markers. High levels of Bim in circulating tumor-reactive (PD-1 + CD11a hi CD8 + ) T cells were prognostic of poor survival in patients with metastatic melanoma who did not receive anti–PD-1 therapy and were also predictive of clinical benefit in patients with metastatic melanoma who were treated with anti–PD-1 therapy. Moreover, this circulating tumor-reactive T cell population significantly decreased after successful anti–PD-1 therapy. Our study supports a crucial role of Bim in both T cell activation and apoptosis as regulated by PD-1 and PD-L1 interactions in effector CD8 + T cells. Measurement of Bim levels in circulating T cells of patients with cancer may provide a less invasive strategy to predict and monitor responses to anti–PD-1 therapy, although future prospective analyses are needed to validate its utility.

Purpose To determine whether the amount of pain relief after preoperative intra‐articular (IA) anesthetic injection predicts clinical and functional outcomes after hip arthroscopy, especially when controlling for the presence of chondral degeneration. Methods We identified patients who underwent IA injection and subsequent hip arthroscopy for labral pathology between 2007 and 2013 performed by a single surgeon. Inclusion criteria were ultrasound‐ or fluoroscopic‐guided IA anesthetic injection performed at our institution, prospectively documented pre‐ and postinjection numerical rating scale pain scores, and minimum 1‐year follow‐up postoperatively. Patients were divided into 2 groups, those who received >50% pain relief from preoperative IA anesthetic injection and those who received ≤50% relief. Preoperative radiographs were reviewed, and degree of osteoarthritis was determined using the Tonnis classification system. Outcomes were assessed with Modified Harris Hip Score and Hip Outcome Score (HOS). Univariate and multivariate models were performed to assess whether percent pain relief correlated with outcome. Results Of the 319 arthroscopic hip surgeries performed between 2007 and 2013, 115 (37%) patients were lost to follow‐up, 16 (5%) patients did not receive an IA injection, 16 (5%) patients had an injection containing gadolinium, and 40 (13%) patients completed injections at an outside institution. Five (2%) patients were excluded for a history of ipsilateral hip surgery, and 3 (1%) for a history of contralateral hip surgery, leaving 96 hips in 96 patients. There were 71 females (74%) and 25 males (26%) with a mean age of 37.6 ± 14.0 years. Tonnis was grade 0, 1, and 2 for 26 (27%), 55 (56%), and 16 (17%) patients, respectively. Fifty‐one (53%) of the injections contained a corticosteroid. The mean pain relief after IA injection was 73% ± 36% (range, 0% to 100%). Twenty‐six hips (26%) had ≤50% pain relief, whereas 70 (73%) had >50% pain relief, and the median time interval from injection to surgery was 3 (range, <1 to 20) months. Outcome scores were obtained at a mean 14.8 (range, 11 to 30) months after arthroscopic surgery. Postoperative mean Modified Harris Hip Score, HOS activities of daily living, and HOS‐Sport scores were 79.2 ± 17.3, 82.6 ± 17.3, and 67.4 ± 28.2, respectively. There was no statistical correlation between percent pain relief and outcome. There was no significant difference in outcome scores between those with ≤50% and >50% pain relief. Multivariate regression analysis showed no significant predictors of outcome, including age, gender, Tonnis grade, percent relief with IA injection, or type of surgery. Conclusions In this study of patients undergoing hip arthroscopy for labral pathology, our data indicate that the amount of pain relief from IA injection may be a poor predictor of short‐term outcome, even when adjusting for chondral degeneration. Although anesthetic injections can be an important diagnostic tool in select patients, a combination of the clinical history, physical examination, and imaging findings is fundamental. Level of Evidence Level IV, therapeutic case series.

Purpose To (1) report outcomes for patients who underwent revision meniscal repair and (2) define both clinical and surgical risk factors for recurrent failure. Methods The records of all patients who underwent revision meniscal repair between 1997 and 2012 were retrospectively reviewed. Surgical technique of primary and revision meniscus repair was detailed, and tears were characterized by type and location. Clinical examination and International Knee Documentation Committee (IKDC) and Tegner scores were used to determine outcomes after revision meniscus repair. Radiographs were reviewed and graded for degenerative changes. Risk factors for failure were analyzed. Results Thirty‐four patients (24 male/10 female) with an average age of 22 ± 6 years (range, 14 to 38) were included in this study. Twelve lateral menisci and 22 medial meniscal repairs were revised at mean 25 ± 20 months (range, 2 to 76) after primary repair for 11 simple, 9 bucket‐handle, and 14 complex tear patterns. Twenty‐one tears occurred in the red‐red zone and 13 in the red‐white zone. At 72 ± 56–month follow‐up (range, 2 to 17 years), 7 (21%) cases had documented failure of revision repairs and underwent subsequent partial meniscectomy. Mean Tegner score for all patients was 6.2 ± 1.5 (range, 3 to 9) and IKDC score was 84.8 ± 13.1 (range, 51.7 to 100) at final follow‐up. Affected side joint space on radiographs remained stable from a baseline of 4.26 ± 0.88 mm to a final of 4.01 ± 0.84 mm. Multivariable regression identified younger patient age as an independent risk factor for failed revision meniscal repair ( P = .01). Conclusions In this study of select revision meniscus repairs, 79% of patients were pain free, without any mechanical symptoms or additional surgeries at a mean of 6 years after revision repair. Younger patients may be at higher risk of failure of the revision meniscus repair. Level of Evidence Level IV, therapeutic case series.