Citations

Background The rarity of mutations in PALB2, CHEK2 and ATM make it difficult to estimate precisely associated cancer risks. Population-based family studies have provided evidence that at least some of these mutations are associated with breast cancer risk as high as those associated with rare BRCA2 mutations. We aimed to estimate the relative risks associated with specific rare variants in PALB2, CHEK2 and ATM via a multicentre case-control study. Methods We genotyped 10 rare mutations using the custom iCOGS array: PALB2 c.1592delT, c.2816T>G and c.3113G>A, CHEK2 c.349A>G, c.538C>T, c.715G>A, c.1036C>T, c.1312G>T, and c.1343T>G and ATM c.7271T>G. We assessed associations with breast cancer risk (42 671 cases and 42 164 controls), as well as prostate (22 301 cases and 22 320 controls) and ovarian (14 542 cases and 23 491 controls) cancer risk, for each variant. Results For European women, strong evidence of association with breast cancer risk was observed for PALB2 c.1592delT OR 3.44 (95% CI 1.39 to 8.52, p=7.1×10−5), PALB2 c.3113G>A OR 4.21 (95% CI 1.84 to 9.60, p=6.9×10−8) and ATM c.7271T>G OR 11.0 (95% CI 1.42 to 85.7, p=0.0012). We also found evidence of association with breast cancer risk for three variants in CHEK2, c.349A>G OR 2.26 (95% CI 1.29 to 3.95), c.1036C>T OR 5.06 (95% CI 1.09 to 23.5) and c.538C>T OR 1.33 (95% CI 1.05 to 1.67) (p≤0.017). Evidence for prostate cancer risk was observed for CHEK2 c.1343T>G OR 3.03 (95% CI 1.53 to 6.03, p=0.0006) for African men and CHEK2 c.1312G>T OR 2.21 (95% CI 1.06 to 4.63, p=0.030) for European men. No evidence of association with ovarian cancer was found for any of these variants. Conclusions This report adds to accumulating evidence that at least some variants in these genes are associated with an increased risk of breast cancer that is clinically important.

AbstractA “look‐up line” (LUL) has been proposed for ice hockey, which is an orange 1 m (40′) warning line (WL) painted on the ice at the base of the boards. The LUL purports to provide an early warning to players to keep their head up prior to and as they are being checked. We determined if players looked up more on a rink with the LUL compared to a traditional Control rink. Elite offensive (O) and defensive (D) players competed 1 vs. 1, while wearing an eye tracker that recorded their quiet eye (QE) and fixation and tracking (F‐T) and an electrogoniometer that measured head angle. External cameras recorded skate duration during four skate phases: P1 preparation, P2 decision‐making, P3 cut to boards, P4 contact. The QE was the final fixation prior to contact between O and D as they skated towards and across the WL during P3 and P4. Skate phase durations (%) did not differ by rink or rink by position. More QE and F‐T occurred on the WL on the LUL rink than on the Control. The expected increase in head angle on the LUL rink did not occur during P3 or P4. Post‐hoc results also showed O and D skated further from the boards on the LUL rink, suggesting the players preferred to control the puck on white ice, rather than the orange colour of the LUL rink. More research is needed to determine if these results apply to the competitive setting.

BACKGROUNDThere is global variation in the onset of hepatocellular carcinoma (HCC). The objective of the current study was to investigate the impact of country of birth on age at the time of HCC diagnosis in the United States.METHODSIncident HCC cases diagnosed between 2000 and 2012 in the Surveillance, Epidemiology, and End Results program 18 registry were included. Factors associated with very early onset (age at diagnosis < 40 years) and early onset (age at diagnosis < 50 years) were identified by logistic regression.RESULTSA total of 59,907 patients were included. The median age at the time of diagnosis of HCC was 62 years and 76% of the patients were male. Of the 75% of patients for whom information regarding birth country was available, 29% were foreign born. In multivariate logistic regression, birth in West Africa (adjusted odds ratio [AOR], 16.3; 95% confidence interval [95% CI], 9.2‐27.9 [P<.01]), Central/South/other Africa (AOR, 11.0; 95% CI, 4.5‐23.7 [P<.01]), Oceania (AOR, 4.9; 95% CI, 2.9‐8.0 [P<.01]), and East Africa (AOR, 3.5; 95% CI, 1.5‐6.8 [P<.01]) was found to have the strongest association with very early‐onset HCC after adjusting for sex and race/ethnicity. Birth in West Africa, Central/South/other Africa, Oceania, or East Africa also was found to be strongly associated with early‐onset HCC.CONCLUSIONSBirth country was found to be independently associated with age at the time of HCC diagnosis in the United States. Birth in Africa (except for North Africa) and Oceania was strongly associated with very early‐onset HCC. These findings have implications for the design of comprehensive HCC surveillance programs in the United States. Cancer 2016. © 2016 American Cancer Society. Cancer 2017;81–89. © 2016 American Cancer Society.

Abstract Background: The strongest known risk factor for endometrial cancer is obesity. To determine whether SNPs associated with increased body mass index (BMI) or waist–hip ratio (WHR) are associated with endometrial cancer risk, independent of measured BMI, we investigated relationships between 77 BMI and 47 WHR SNPs and endometrial cancer in 6,609 cases and 37,926 country-matched controls. Methods: Logistic regression analysis and fixed effects meta-analysis were used to test for associations between endometrial cancer risk and (i) individual BMI or WHR SNPs, (ii) a combined weighted genetic risk score (wGRS) for BMI or WHR. Causality of BMI for endometrial cancer was assessed using Mendelian randomization, with BMIwGRS as instrumental variable. Results: The BMIwGRS was significantly associated with endometrial cancer risk (P = 3.4 × 10−17). Scaling the effect of the BMIwGRS on endometrial cancer risk by its effect on BMI, the endometrial cancer OR per 5 kg/m2 of genetically predicted BMI was 2.06 [95% confidence interval (CI), 1.89–2.21], larger than the observed effect of BMI on endometrial cancer risk (OR = 1.55; 95% CI, 1.44–1.68, per 5 kg/m2). The association attenuated but remained significant after adjusting for BMI (OR = 1.22; 95% CI, 1.10–1.39; P = 5.3 × 10−4). There was evidence of directional pleiotropy (P = 1.5 × 10−4). BMI SNP rs2075650 was associated with endometrial cancer at study-wide significance (P &lt; 4.0 × 10−4), independent of BMI. Endometrial cancer was not significantly associated with individual WHR SNPs or the WHRwGRS. Conclusions: BMI, but not WHR, is causally associated with endometrial cancer risk, with evidence that some BMI-associated SNPs alter endometrial cancer risk via mechanisms other than measurable BMI. Impact: The causal association between BMI SNPs and endometrial cancer has possible implications for endometrial cancer risk modeling. Cancer Epidemiol Biomarkers Prev; 25(11); 1503–10. ©2016 AACR.

Objective Assess the effects of linezolid on hematologic outcomes in newly diagnosed patients with acute myeloid leukemia ( AML ) following induction chemotherapy. Design Single‐center, retrospective, observational, cohort study. Setting Large, tertiary care academic medical center. Patients A total of 225 patients ≥ 18 years admitted between December 2010 and 2013 with newly diagnosed AML were assessed for inclusion. Patients were identified through the use of ICD ‐9 codes and chemotherapy ordered via the computerized physician order entry system. Sixty‐eight patients met inclusion criteria and were grouped into two arms based on antimicrobial treatment: LZD group (linezolid plus gram‐negative antimicrobial, n=21) or control group (vancomycin or daptomycin plus gram‐negative antimicrobial, n=47). Interventions The LZD group received linezolid ≥ 72 hours. The control group received vancomycin or daptomycin ≥ 72 hours. If patients switched extended gram‐positive therapy, they were included in the LZD group as long as they had received ≥ 72 hours of linezolid. Measurements/Results The primary end point of time to neutrophil recovery was not statistically different (28 days for LZD group vs 26 days for control group; p=0.675). The preplanned subgroup analysis of patients who received ≥ 14 days of linezolid demonstrated statistically similar median times to neutrophil recovery (29 days for LZD group vs 26 days for control group; p=0.487). Total duration of extended gram‐positive antimicrobial therapy was significantly longer in the LZD group (27 days vs 16 days; p<0.001). Secondary end points not found to be statistically significant included platelet count at time of neutrophil recovery, duration of neutropenia, and length of hospital stay. Conclusions There were no significant differences in hematologic outcomes in newly diagnosed AML patients who received linezolid for extended gram‐positive antimicrobial coverage following induction chemotherapy. This study provides new insight with a primary focus on the effects of hematologic outcomes when using linezolid in a well‐defined acute leukemia population. Further study is warranted with larger populations to assess the potential adverse effects linezolid may have in patients with acute leukemia.

ABSTRACTIntroduction: Voltage‐gated Kv1 potassium channel complex (VGKC) autoantibodies subtyped for leucine‐rich glioma‐inactivated 1 (LGI1), contactin‐associated‐proteinlike 2 (CASPR2), and Kv IgGs have a spectrum of neurological presentations. Painful polyneuropathy is seen in some patients, but nerve pathology descriptions are lacking. Methods: Clinicopathologic features were studied in subtyped VGKC‐autoantibody‐seropositive patients who had undergone nerve biopsies. Results: Five patients were identified, 1 LGI1 IgG positive and 1 CASPR2 IgG positive, but all negative for Kv1.1‐, 1.2‐, 1.6‐subtyped IgG autoantibodies. Median symptom duration was 17 months. Pain was the predominant symptom; 3 had mild sensory loss and/or weakness. Histopathological abnormalities were limited to axonal loss in 3. None had mononuclear cellular infiltrates. Electron micrographs revealed no interstitial abnormalities. Three patients reported marked improvement in pain with immunotherapy. Conclusions: The nerve biopsy histopathology of patients subtyped for LGI1 and CASPR2 IgGs within the VGKC‐complex spectrum disorders shows either normal density or axonal fiber loss without inflammatory infiltrates. A reversible neural hyperexcitable mechanism is considered to be the cause of this painful polyneuropathy. Muscle Nerve 55: 520–525, 2017

Abstract Although the majority of patients with endometrial cancer (EC) are diagnosed early when disease is confined in the uterus and prognosis is excellent, there is a subset of patients with advanced, metastatic, recurrent or persistent after surgery disease with dismal prognosis. Chemotherapy has a critical role for these patients. Carboplatin (carbo) and paclitaxel (taxol) is the standard first-line chemotherapy in EC with response rates as low as 50% and even lower for recurrent disease. Furthermore, many patients will eventually relapse with chemo-resistant disease and very poor prognosis. As the chemotherapeutic options for these patients are limited and of questionable efficacy, it is of paramount importance that novel agents are identified to increase or restore chemo-sensitization to platinum-based chemotherapy. Quinacrine (QC) is an inexpensive antimalarial drug with a predictable safety profile which recently surfaced as a promising anticancer agent thought to be associated with decreased risk of developing chemo-resistance through targeting multiple pathways simultaneously. While prior investigators have provided evidence that QC exerts strong anticancer activity against a wide range of solid tumors, there are no studies focused on QC in EC. In our study, QC exhibited strong synergism in vitro when combined with cisplatin, carbo or taxol with the highest level of synergism being observed in the most chemo-resistant EC cell line. Neither QC monotherapy (QC every other day for 3 weeks) nor standard chemotherapy (carbo+taxol for 3 cycles, on days 3, 7, 11) significantly delayed tumor growth in the mouse xenografts. Only combination (standard chemo + QC every other day during carbo+taxol treatment) and maintenance (combination regimen followed by QC every other day until end of study) significantly augmented carbo+taxol antiproliferative effect as evidenced by the significant decrease in tumor burden and delayed tumor growth in xenografts. Combination treatment was associated with a 14-day prolongation of median survival compared to carbo+taxol (68 vs. 54 days). Maintenance therapy with QC was proven superior to carbo+taxol as it resulted in long-term stabilization of disease and further prolongation of overall survival; in fact, median survival in the maintenance group was not reached as the mice were surviving at the end of study. QC alone, in combination with carbo+taxol or as maintenance was well-tolerated with no issues of weight loss compared to control mice. A yellow skin discoloration was noted during QC treatment which was entirely reversible within few days upon QC discontinuation. In conclusion, QC exhibited significant antitumor activity against EC cell lines in vitro and was successful in stabilizing disease and prolonging survival as maintenance therapy in chemo-resistant EC mouse xenografts. This data suggests that QC may be an important adjunct to standard chemotherapy for patients with recurrent EC. Citation Format: Eleftheria Kalogera, Debarshi Roy, Ashwani Khurana, Susmita Mondal, Xiaoping He, Sean C. Dowdy, Viji Shridhar. Quinacrine in endometrial cancer: repurposing an old antimalarial drug. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 261.

Abstract Resistance is one the main reason for overall decrease in survival of cancer patient treated with cisplatin in different types of cancer. Cisplatin kills cancer cells by various mechanisms, but mainly through formation of inter- and intra stand crosslinks of DNA. Different types of translesion polymerase including Polymerase kappa (POLK) are involved in repair of DNA lesions. We observed high expression levels of POLK in cisplatin resistant bladder and ovarian cancer cells compared to parental cells. Due to its low proof-reading activity POLK can incorporate 8-oxo-dGTP into DNA. The MTH1 protein (Nudix hydrolase- NUDT1) sanitizes oxidized dNTP pools to prevent incorporation of damaged bases during DNA replication. Recently we have generated MTH1 inhibitors that damage the DNA and induce cancer specific cell death through incorporation of more oxidized dNTPs. We found cisplatin resistant bladder cancer cells (NTUB1/P) were more sensitive to MTH1 inhibitors in comparison to parental NTUB1 cells. As POLK is involved in incorporation of 8-oxo-dGTP into DNA, we hypothesized that high expression levels of POLK in cisplatin resistant cells make them more sensitive to MTH1 inhibitors as more 8-oxo-dGTP would be incorporated into DNA, resulting in more DNA damage and cell death in comparison to parental cells. Indeed, we observes higher induction of cleaved-PARP, γH2AX, cleaved-Caspase 3 and more annexin v positive cells in cisplatin resistant NTUB1/P cells in comparison to parental NTUB1 cells upon treatment with MTH1 inhibitors. MTH1 inhibitor also significantly delays the NTUB1/P xenograft tumor growth in comparison to vehicle treatment in immunosuppressive mice. Knocking down POLK in cisplatin resistant NTUB1/P cells by siRNA resulted in decreased incorporation of 8-oxo-dGTP and sensitivity to MTH1 inhibitors compared to non target control cells. Overexpression of POLK in NTUB1 and NTUB1/P cells results in further sensitization to MTH1 inhibitors. In conclusion elevated levels of POLK in cisplatin resistance cells determines increased sensitivity towards MTH1 inhibitors. Thus MTH1 inhibitors can be a potential promising therapy for the treatment of cisplatin resistant tumors in patients. Citation Format: Kumar Sanjiv, Helge Gad, Sean Rudd, Rachel Hurley, Patric Herr, José Manuel Calderón Montaño, Oliver Mortusewicz, Tobias Koolmeister, Sylvain Jaques, Estefanía Burgos Morón, Andreas Hoglund, Te-Chang Lee, Martin Scobie, Scott Kaufmann, John Weroha, Ulrika Warpman Berglund, Andrea Wahner Hendrickson, Thomas Helleday. Polymerase kappa determines the sensitivity of MTH1 inhibitors to cisplatin-resistant cell. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1260.