Citations

Abstract Primary and acquired chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that heritable polymorphisms might be associated with clinical outcome. Through the Ovarian Cancer Association Consortium, we have collected detailed clinical data from a large number of ovarian cancer patients. We have conducted association analyses of progression-free survival (PFS) and overall survival (OS) for 2,901 European women with ovarian carcinoma for ∼8 million imputed SNPs with minor allele frequency ≥ 0.02 and good imputation quality (imputation r2 ≥ 0.3) from the iCOGS experiment (Pharoah et al Nat Genet. 2013). Cox regression models adjusted for known prognostic factors were used to assess the log-additive effects of SNPs on PFS and OS in 2,825 patients who underwent cytoreductive surgery and received any chemotherapy (‘all chemo’) and in the subset of 1,098 patients who underwent cytoreductive surgery followed by ≥ 4 cycles of carboplatin AUC 5 or 6 and paclitaxel 175 or 135 mg/m2 intravenously (‘standard chemo’). We identified five SNPs at four loci that were significantly associated with outcome (p ≤ 10-7) in at least one of four analyses (Table). Analysis of expression data for genes within a 1Mb region flanking each lead SNP indicates significant associations between nearby genes and ovarian cancer survival. Of particular interest is the heat shock protein crystalline αB (CRYAB) at 11q23.1. We have also identified significant associations with KIAA1598 and RAVER2. Further analysis of these loci in a larger genotyped sample is necessary to definitively identify SNP(s) associated with outcome. Our study adds to the growing evidence that genetic variants are associated with ovarian cancer prognosis. Table: SNPs associated with ovarian cancer outcome and gene expression Overall Survival (P)*Progression-Free Survival (P)*Lead SNPChromosome LocusImputation R²Expression AnalysisAll chemoStandard chemoAll chemoStandard chemors1429768671p31.30.742.14E-0512.69E-044.68E-055.11E-073.64E-09rs559375217q32.30.600.198.58E-082.32E-052.80E-031.85E-03rs7885346210q26.110.602.23E-0724.57E-036.57E-081.65E-016.85E-03rs1089121911q23.10.841.53E-0531.51E-059.50E-081.50E-042.32E-04rs3579103211q23.10.811.53E-0531.66E-055.88E-086.46E-051.87E-04*P-values are adjusted for known confounders of ovarian cancer outcomes; FIGO stage, grade, histology, residual disease, and additionally for age at diagnosis for OS.1 RAVER2; 2 KIAA1598; 3 CRYAB Citation Format: Sharon E. Johnatty, Jonathan Tyrer, Jonathan Beesley, Bo Gao, Yi Lu, Stuart MacGregor, Anna deFazio, Paul Pharoah, Ellen Goode, Georgia Chenevix-Trench. Identification of genetic loci associated with ovarian cancer prognosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3286. doi:10.1158/1538-7445.AM2014-3286

Background: Multiligament knee injuries (MLKIs) can also involve the medial patellofemoral ligament (MPFL), but there is a paucity of information regarding prevalence and relevance of MPFL involvement in this setting. Purpose: (1) To identify the prevalence of MPFL injury in MLKIs, (2) to determine whether an MPFL tear results in symptomatic patellar instability, and (3) to report clinical and functional outcomes of patients with and without MPFL tears after MLKI surgical reconstruction. Study Design: Cohort study; Level of evidence, 3. Methods: The records of all patients who underwent surgical reconstruction of MLKI (defined as a grade 3 injury of ≥2 ligaments) at a single institution from 2007 to 2010 were reviewed. Age, sex, knee dislocation classification (according to Schenck), and MRI findings were documented. All preoperative MRI scans were reviewed by an experienced musculoskeletal radiologist to determine the presence or absence of MPFL involvement. If an MPFL tear was present, its anatomic location and severity as well as the presence of patellar or lateral femoral condyle bone bruises were documented. Inclusion criteria included (1) MLKI treated at a single institution, (2) presence of MPFL tear on preoperative MRI, and (3) minimum 2-year clinical follow-up. Patellar instability symptoms were assessed with the Kujala Knee Questionnaire. Functional outcomes were measured using the International Knee Documentation Committee (IKDC) score. IKDC scores were compared between patients who sustained MLKIs with and without MPFL tears. There were 21 patients in each group. Results: Over the 4-year study period, 30 of 51 patients (59%) treated surgically for a MLKI had MRI evidence of an MPFL tear. Nine were lost to follow-up, leaving 21 patients for review. There were 13 complete (62%), 5 high-grade partial (24%), and 3 partial (14%) MPFL tears. Sixteen of 21 tears (76%) occurred at the proximal third, with the remainder exhibiting diffuse signal abnormality consistent with tearing throughout the length of the MPFL. The superficial medial collateral ligament was involved in all patients. In no case was the MPFL repaired or reconstructed. At mean follow-up of 3.6 years (range, 2.0-5.7 years), only 1 of 21 patients (5%) complained of patellofemoral instability symptoms whereas 20 of 21 patients (95%) did not experience patellar subluxation or dislocation. No significant difference was found when IKDC scores were compared between patients with and without an MPFL tear (mean ± SD, 65.5 ± 22.9 vs 79.4 ± 16.1; P = .07). Conclusion: MPFL tears occur frequently in patients with MLKI but rarely cause instability. In the majority of cases, MPFL tears do not need to be addressed at the time of surgery.

Abstract Purpose: Wee1 regulates key DNA damage checkpoints, and in this study, the efficacy of the Wee1 inhibitor MK-1775 was evaluated in glioblastoma multiforme (GBM) xenograft models alone and in combination with radiation and/or temozolomide. Experimental Design: In vitro MK-1775 efficacy alone and in combination with temozolomide, and the impact on DNA damage, was analyzed by Western blotting and γH2AX foci formation. In vivo efficacy was evaluated in orthotopic and heterotopic xenografts. Drug distribution was assessed by conventional mass spectrometry (MS) and matrix-assisted laser desorption/ionization (MALDI)-MS imaging. Results: GBM22 (IC50 = 68 nmol/L) was significantly more sensitive to MK-1775 compared with five other GBM xenograft lines, including GBM6 (IC50 >300 nmol/L), and this was associated with a significant difference in pan-nuclear γH2AX staining between treated GBM22 (81% cells positive) and GBM6 (20% cells positive) cells. However, there was no sensitizing effect of MK-1775 when combined with temozolomide in vitro. In an orthotopic GBM22 model, MK-1775 was ineffective when combined with temozolomide, whereas in a flank model of GBM22, MK-1775 exhibited both single-agent and combinatorial activity with temozolomide. Consistent with limited drug delivery into orthotopic tumors, the normal brain to whole blood ratio following a single MK-1775 dose was 5%, and MALDI-MS imaging demonstrated heterogeneous and markedly lower MK-1775 distribution in orthotopic as compared with heterotopic GBM22 tumors. Conclusions: Limited distribution to brain tumors may limit the efficacy of MK-1775 in GBM. Clin Cancer Res; 21(8); 1916–24. ©2015 AACR.

AbstractRecent studies reporting hundreds, to thousands, of circulating tumor cells (CTCs) in the blood of cancer patients have raised questions regarding the prevalence of CTCs, as enumerated by the CellSearch® CTC Test. Although CellSearch has been shown to consistently detect clinically relevant CTCs; the ability to only capture EpCAM positive cells has led to speculation that it captures limited subsets of CTCs. In contrast, alternative approaches to CTC isolation are often cited as capturing large numbers of CTCs from patient blood. Not surprisingly the number of cells isolated by alternative approaches show poor correlations when compared to CellSearch, even when accounting for EpCAM presence or absence. In an effort to address this discrepancy, we ran an exploratory method comparison study to characterize and compare the CTC subgroups captured from duplicate blood samples from 30 breast and prostate cancer patients using a microfiltration system (CellSieve™) and CellSearch. We then categorized the CellSieve Cytokeratin(CK)+/CD45−/DAPI+ cells into five morphologically distinct subpopulations for correlative analysis. Like other filtration techniques, CellSieve isolated greater numbers of CK+/CD45− cells than CellSearch. Furthermore, analysis showed low correlation between the total CK+/CD45− cells captured by these two assays, regardless of EpCAM presence. However, subgrouping of CK+/CD45−/DAPI+ cells based on distinct cytokeratin staining patterns and nuclear morphologies elucidated a subpopulation correlative to CellSearch. Using method comparison analyses, we identified a specific CTC morphology which is highly correlative between two distinct capture methods. These data suggests that although various morphologic CTCs with similar phenotypic expressions are present in the blood of cancer patients, the clinically relevant cells isolated by CellSearch can potentially be identified using non‐EpCAM dependent isolation. © 2014 The Authors. Published by Wiley Periodicals, Inc.

Background: Femoral nerve block (FNB) has become a popular method of postoperative analgesia for anterior cruciate ligament (ACL) reconstruction in pediatric and adolescent patients. Successful rehabilitation after surgery involves return of quadriceps and hamstring strength. Purpose: To compare knee strength and function 6 months after ACL reconstruction in pediatric and adolescent patients who received FNB versus patients with no nerve block. Study Design: Cohort study; Level of evidence, 3. Methods: Patients 18 years or younger who underwent primary ACL reconstruction between 2000 and 2010 at a single institution were identified. If the patient was skeletally immature, a transphyseal ACL reconstruction was performed. Of these patients, 68% underwent reconstruction with a patellar tendon autograft, and in 32% of patients a hamstring autograft was utilized. There were 124 patients who met the study inclusion criteria, including 62 in the FNB group (31 males, 31 females) and 62 patients in the control group (25 males, 37 females). All study patients participated in a comprehensive rehabilitation program that included isokinetic strength and functional testing at 6 months postoperatively. Results: Univariate analysis showed a significantly higher deficit at 6 months in the FNB group with respect to fast isokinetic extension strength (17.6% vs 11.2%; P = .01) as well as fast (9.9% vs 5.7%; P = .04) and slow (13.0% vs 8.5%; P = .03) isokinetic flexion strength. There was no difference in slow isokinetic extension strength deficit between the 2 groups (FNB, 22.3% vs control, 18.7%; P = .20). With respect to function, there were no differences in deficit for vertical jump (FNB, 9.4% vs control, 11.3%; P = .30), single hop (7.6% vs 7.5%; P = .96), or triple hop (8.0% vs 6.6%; P = .34) between the 2 groups. A significantly higher percentage of patients in the control group met functional and isokinetic criteria for return to sports at 6 months (90.2% vs 67.7%; odds ratio, 4.37; P = .002). Conclusion: Pediatric and adolescent patients treated with FNB for postoperative analgesia after ACL reconstruction had significant isokinetic deficits in knee extension and flexion strength at 6 months when compared with patients who did not receive a nerve block. Patients without a block were 4 times more likely to meet criteria for clearance to return to sports at 6 months.

Nitrate and nitrite are precursors in the endogenous formation of N‐nitroso compounds (NOC), potential human carcinogens. We evaluated the association of nitrate and nitrite ingestion with postmenopausal ovarian cancer risk in the Iowa Women's Health Study. Among 28,555 postmenopausal women, we identified 315 incident epithelial ovarian cancers from 1986 to 2010. Dietary nitrate and nitrite intakes were assessed at baseline using food frequency questionnaire data. Drinking water source at home was obtained in a 1989 follow‐up survey. Nitrate‐nitrogen (NO3‐N) and total trihalomethane (TTHM) levels for Iowa public water utilities were linked to residences and average levels were computed based on each woman's duration at the residence. We computed multivariable‐adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards regression. We tested interactions of nitrate with TTHMs and dietary factors known to influence NOC formation. Ovarian cancer risk was 2.03 times higher (CI = 1.22–3.38, ptrend = 0.003) in the highest quartile (≥2.98 mg/L) compared with the lowest quartile (≤0.47 mg/L; reference) of NO3‐N in public water, regardless of TTHM levels. Risk among private well users was also elevated (HR = 1.53, CI = 0.93–2.54) compared with the same reference group. Associations were stronger when vitamin C intake was <median (pinteraction = 0.01 and 0.33 for private well and public supplies, respectively). Dietary nitrate was inversely associated with ovarian cancer risk (ptrend = 0.02); whereas, dietary nitrite from processed meats was positively associated with the risk (ptrend = 0.04). Our findings indicate that high nitrate levels in public drinking water and private well use may increase ovarian cancer risk among postmenopausal women.

Abstract Meniscal root injuries can compromise knee function and lead to early degenerative changes if not appropriately treated. Numerous techniques have been described; however, the technical difficulties in performing these repairs are well known. Furthermore, the relative strengths of various repair techniques have been examined. This article describes a single–working portal meniscal root repair technique using a double‐locking loop suture configuration with a novel suture‐passing device that offers a strong, reproducible repair construct. Technique Video video See video under supplementary data.