Effect of N-acetylcysteine on liver recovery after resection: A randomized clinical trial

Background and Objectives

Liver failure following hepatic resection is a multifactorial complication. In experimental studies, infusion of N-acetylcysteine (NAC) can minimize hepatic parenchymal injury.

Methods

Patients undergoing liver resection were randomized to postoperative care with or without NAC. No blinding was performed. Overall complication rate was the primary outcome; liver failure, length of stay, and mortality were secondary outcomes. Due to safety concerns, a premature multivariate analysis was performed and included within the model randomization to NAC, preoperative ASA, extent of resection, and intraoperative vascular occlusion as factors.

Results

Two hundred and six patients were randomized (110 to conventional therapy; 96 to NAC). No significant differences were noted in overall complications (32.7% and 45.7%, P = 0.06) or hepatic failure (3.6% and 5.4%, P = 0.537) between treatment groups. There was significantly more delirium within the NAC group (2.7% and 9.8%, P < 0.05) that caused early trial termination. In multivariate analysis, only randomization to NAC (OR = 2.21, 95%CI = 1.16–4.19) and extensive resections (OR = 2.28, 95%CI = 1.22–4.29) were predictive of postoperative complications.

Conclusions

Patients randomized to postoperative NAC received no benefit. There was a trend toward a higher rate of overall complications and a significantly higher rate of delirium in the NAC group. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Forty-eight cases of leiomyosarcoma of bone in Japan: A multicenter study from the Japanese musculoskeletal oncology group

Background

Leiomyosarcoma of bone (LMSoB) is a rare malignant bone tumor. This multicenter retrospective study was conducted to investigate the diagnosis and the clinical outcome of primary LMSoB in Japan.

Methods

Forty-eight patients (average age: 52 years [range 14–88 years]) with primary LMSoB who were treated at registered institutes in Japan between 1991 and 2014 were recruited. The median follow-up period was 44 months (range: 2–273).

Results

The 5-year overall survival rates and disease-free survival rates were 78.3% and 44.9%, respectively. Surgical treatment was performed in 42 patients, and R0 resection was achieved in 31 patients. Neoadjuvant chemotherapy was administered in 18 patients. The most common regimen (cisplatin-based chemotherapy) was administered in 15 patients, however, no patient achieved a good response in both radiological and histological evaluations. The presence of metastasis at the first visit and a lack of definitive surgery were significantly correlated with poor overall survival, and the surgical margin was a significant prognostic factor for disease-free survival.

Conclusions

This study is the largest LMSoB case series ever reported. Surgical treatment with wide margins was the only treatment that proved to be effective, whereas adjuvant chemotherapy in the present setting did not improve the overall survival. J. Surg. Oncol. © 2016 Wiley Periodicals, Inc.

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Erratum to: Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP3Rs) in cancer: will they become a new battlefield for oncotherapy?

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Association of Genetic Risk for Schizophrenia With Nonparticipation Over Time in a Population-Based Cohort Study

Progress has recently been made in understanding the genetic basis of schizophrenia and other psychiatric disorders. Longitudinal studies are complicated by participant dropout, which could be related to the presence of psychiatric problems and associated genetic risk. We tested whether common genetic variants implicated in schizophrenia were associated with study nonparticipation among 7,867 children and 7,850 mothers from the Avon Longitudinal Study of Parents and Children (ALSPAC; 1991–2007), a longitudinal population cohort study. Higher polygenic risk scores for schizophrenia were consistently associated with noncompletion of questionnaires by study mothers and children and nonattendance at data collection throughout childhood and adolescence (ages 1–15 years). These associations persisted after adjustment for other potential correlates of nonparticipation. Results suggest that persons at higher genetic risk for schizophrenia are likely to be underrepresented in cohort studies, which will underestimate risk of this and related psychiatric, cognitive, and behavioral phenotypes in the population. Statistical power to detect associations with these phenotypes will be reduced, while analyses of schizophrenia-related phenotypes as outcomes may be biased by the nonrandom missingness of these phenotypes, even if multiple imputation is used. Similarly, in complete-case analyses, collider bias may affect associations between genetic risk and other factors associated with missingness.

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Exposure to Ambient Air Pollution and Premature Rupture of Membranes

Premature rupture of membranes (PROM) is a major factor that predisposes women to preterm delivery. Results from previous studies have suggested that there are associations between exposure to air pollution and preterm birth, but evidence of a relationship with PROM is sparse. Modified Community Multiscale Air Quality models were used to estimate mean exposures to particulate matter less than 10 µm or less than 2.5 µm in aerodynamic diameter, nitrogen oxides, carbon monoxide, sulfur dioxide, and ozone among 223,375 singleton deliveries in the Air Quality and Reproductive Health Study (2002–2008). We used log-linear models with generalized estimating equations to estimate adjusted relative risks and 95% confidence intervals for PROM per each interquartile-range increase in pollutants across the whole pregnancy, on the day of delivery, and 5 hours before delivery. Whole-pregnancy exposures to carbon monoxide and sulfur dioxide were associated with an increased risk of PROM (for carbon monoxide, relative risk (RR) = 1.09, 95% confidence interval (CI): 1.04, 1.14; for sulfur dioxide, RR = 1.15, 95% CI: 1.06, 1.25) but not preterm PROM. Ozone exposure increased the risk of PROM on the day of delivery (RR = 1.06, 95% CI: 1.02, 1.09) and 1 day prior (RR = 1.04, 95% CI: 1.01, 1.07). In the 5 hours preceding delivery, there were 3%–7% increases in risk associated with exposure to ozone and particulate matter less than 2.5 µm in aerodynamic diameter and inverse associations with exposure to carbon monoxide and nitrogen oxides. Acute and long-term air pollutant exposures merit further study in relation to PROM.

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Editorial Board

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Re: "The Natural History of Human Polyomaviruses and Herpesviruses in Early Life--The Rhea Birth Cohort in Greece"

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Subscription Page

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Beyond Access: Characteristics of the Food Environment and Risk of Diabetes

Characteristics of the built environment, including access to unhealthy food outlets, are hypothesized to contribute to type 2 diabetes mellitus (T2D). Swedish nationwide registry data on 4,718,583 adults aged 35–80 years living in 9,353 neighborhoods, each with at least 1 food outlet, were geocoded and linked to commercial registers (e.g., restaurants and grocery stores). Multilevel logistic regression was used to examine the prospective relationship between characteristics of the food environment and T2D from 2005 to 2010. Relative access to health-harming food outlets was associated with greater likelihood of both prevalent and incident T2D in a curvilinear manner, with the highest risk being observed for environments in which one-third of outlets were health-harming. Relative to individuals whose food environment did not change, those who moved into areas with more health-harming food outlets had higher odds of developing T2D (odds ratio = 3.67, 95% confidence interval: 2.14, 6.30). Among those who did not move, living in an area that gained relative access to health-harming food outlets was also associated with higher odds of T2D (odds ratio = 1.72, 95% confidence interval: 1.27, 2.33). These results suggest that local food environment, including changes that result in greater access to unhealthy food outlets, is associated with T2D.

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Contents Page

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Re: "Job Strain and the Cortisol Diurnal Cycle in MESA: Accounting for Between- and Within-Day Variability"

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Context-Specific Associations of Physical Activity and Sedentary Behavior With Cognition in Children

In the present study, we investigated how overall and specific domains of physical activity and sedentary behavior at the age of 7 years were associated with cognition at the age of 11 years in 8,462 children from the Millennium Cohort Study. Data were collected from 2001 to 2013. Participation in domains of physical activity and sedentary behavior at 7 years of age were reported. Activity levels were also measured objectively. Cognition was assessed using the British Ability Scales. General linear models were used to assess longitudinal associations of physical activity and sedentary behavior, measured both objectively and via self-report, with cognition. Analyses were adjusted for prespecified covariates. Sports/physical activity club attendance (B = 0.6, 95% confidence interval (CI): 0.2, 1.1), doing homework (B = 0.5, 95% CI: 0.0, 0.9), and objectively measured sedentary time (B = 0.8, 95% CI: 0.1, 1.4) at age 7 years were positively associated with cognition at age 11 years in final the models. Television viewing was negatively associated with cognition (B = –1.7, 95% CI: –2.4, –1.0), although the association was attenuated to the null after adjustments for baseline cognition. Objectively measured light physical activity was inversely associated with cognition (B = –0.7, 95% CI: –1.3, –0.1). Moderate-to-vigorous physical activity was also inversely associated with cognition in girls only (B = –1.1, 95% CI: –2.0, –0.3). Associations of physical activity and sedentary behavior with cognition appear to be context-specific in young people.

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Cover Page

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Invited Commentary: Lessons for Research on Cognitive Aging From a Study of Children

As the population ages, the burden of disease from cognitive decline and dementing illness is rising. In the absence of treatments to reverse cognitive decline, prevention is a public health priority. Physical fitness and physical activity have emerged as prevention targets based on evidence of "neuroprotective" benefits in observational studies. However, observational studies linking active lifestyle with successful cognitive aging might be subject to bias from "neuroselection," in which adults with better cognitive functioning are more likely to engage in healthy behaviors and avoid unhealthy ones. In their analysis of longitudinal data on several thousand children from the United Kingdom's Millennium Cohort Study, Aggio et al. (Am J Epidemiol. 2016;183(12):1075–1082) revealed that this pattern of neuroselection is already apparent in childhood. However, they also report data that suggest there are cognitive benefits to engaging in certain types of active behaviors over and above this selection. Their findings argue for greater attention to confounding by neuroselection in research on cognitive aging, and they suggest the possibility that early interventions to promote certain health behaviors may instill a virtuous cycle with benefits that accumulate across the lifespan.

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Placental Weight and Male Genital Anomalies: A Nationwide Danish Cohort Study

The most consistently reported risk indicators for the male genital anomalies cryptorchidism and hypospadias are prematurity and low birth weight. Placental dysfunction has been hypothesized as a possible underlying cause, and an association between placental weight at birth and hypospadias has been indicated. In a population-based cohort of 388,422 Danish singleton boys born alive (1997–2008), we studied the association between placental weight and cryptorchidism and hypospadias. Missing data were handled with multiple imputation, and we estimated hazard ratios by means of Cox regression models. During follow-up, 1,713 boys were diagnosed with hypospadias and 6,878 with cryptorchidism (3,624 underwent corrective surgery). We observed an association between low placental weight and risk of both genital anomalies. Boys with a placental weight in the lowest decile (<10%) had higher risks of both cryptorchidism (hazard ratio = 1.52, 95% confidence interval: 1.31, 1.76) and hypospadias (hazard ratio = 1.97, 95% confidence interval: 1.59, 2.45) than boys in the reference decile (50.0–59.9%). In conclusion, we found higher risks of both genital malformations in boys born with a low placental weight. The relationship seemed stronger for hypospadias than for cryptorchidism. Taken together, our data support a role for placental dysfunction in the etiology of these anomalies.

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Aggio et al. Respond to "Lessons for Research on Cognitive Aging"

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Scenario Analysis for Programmatic Tuberculosis Control in Western Province, Papua New Guinea

Tuberculosis (TB) and multidrug-resistant TB (MDR-TB) are major health problems in Western Province, Papua New Guinea. While comprehensive expansion of TB control programs is desirable, logistical challenges are considerable, and there is substantial uncertainty regarding the true disease burden. We parameterized our previously described mathematical model of Mycobacterium tuberculosis dynamics in Western Province, following an epidemiologic assessment. Five hypothetical scenarios representing alternative programmatic approaches during the period from 2013 to 2023 were developed with local staff. Bayesian uncertainty analyses were undertaken to explicitly acknowledge the uncertainty around key epidemiologic parameters, and an economic evaluation was performed. With continuation of existing programmatic strategies, overall TB incidence remained stable at 555 cases per 100,000 population per year (95% simulation interval (SI): 420, 807), but the proportion of incident cases attributable to MDR-TB increased from 16% to 35%. Comprehensive, provincewide strengthening of existing programs reduced incidence to 353 cases per 100,000 population per year (95% SI: 246, 558), with 46% being cases of MDR-TB, while incorporating programmatic management of MDR-TB into these programs reduced incidence to 233 cases per 100,000 population per year (95% SI: 198, 269) with 14% MDR-TB. Most economic costs were due to hospitalization during the intensive treatment phase. Broad scale-up of TB control activities in Western Province with incorporation of programmatic management of MDR-TB is vital if control is to be achieved. Community-based treatment approaches are important to reduce the associated economic costs.

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Neighborhood Socioeconomic Status and Cognitive Function in Late Life

Neighborhood socioeconomic status (NSES) is associated with cognitive function, independently of individual demographic, health, and socioeconomic characteristics. However, research has been largely cross-sectional, and mechanisms of the association are unknown. In 1992–1993, Cardiovascular Health Study participants (n = 3,595; mean age = 74.8 years; 15.7% black) underwent cognitive testing and magnetic resonance imaging of white matter hyperintensities (WMH), and their addresses were geocoded. NSES was calculated using 1990 US Census data (block groups; 6 measures of wealth, education, and occupation). The Modified Mini-Mental State Examination (3MS) was used to assess general cognition, and the Digit Symbol Substitution Test (DSST) was used to assess speed of processing annually for 6 years. Associations of race-specific NSES tertiles with 3MS, DSST, and WMH were estimated using linear mixed-effects models accounting for geographic clustering, stratified by race, and adjusted for demographic, health, and individual socioeconomic status (education, income, lifetime occupational status) variables. In fully adjusted models, higher NSES was associated with higher 3MS scores in blacks (mean difference between highest and lowest NSES = 2.4 points; P = 0.004) and whites (mean difference = 0.7 points; P = 0.02) at baseline but not with changes in 3MS over time. NSES was marginally associated with DSST and was not associated with WMH. Adjustment for WMH did not attenuate NSES-3MS associations. Associations of NSES with cognition in late adulthood differ by race, are not explained by WMH, and are evident only at baseline.

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Cost-Effectiveness of Pertussis Vaccination During Pregnancy in the United States

Vaccination against pertussis has reduced the disease burden dramatically, but the most severe cases and almost all fatalities occur in infants too young to be vaccinated. Recent epidemiologic evidence suggests that targeted vaccination of mothers during pregnancy can reduce pertussis incidence in their infants. To evaluate the cost-effectiveness of antepartum maternal vaccination in the United States, we created an age-stratified transmission model, incorporating empirical data on US contact patterns and explicitly modeling parent-infant exposure. Antepartum maternal vaccination incurs costs of $114,000 (95% prediction interval: 82,000, 183,000) per quality-adjusted life-year, in comparison with the strategy of no adult vaccination, and is cost-effective in the United States according to World Health Organization criteria. By contrast, vaccinating a second parent is not cost-effective, and vaccination of either parent postpartum is strongly dominated by antepartum maternal vaccination. Nonetheless, postpartum vaccination of mothers who were not vaccinated antepartum improves upon the current recommendation of untargeted adult vaccination. Additionally, the temporary direct protection of the infant due to maternal antibody transfer has efficacy for infants comparable to that conferred to toddlers by the full primary vaccination series. Efficient protection against pertussis for infants begins before birth. We highly recommend antepartum vaccination for as many US mothers as possible.

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Time-Dependent Risk of Cancer After a Diabetes Diagnosis in a Cohort of 2.3 Million Adults

Using a time-dependent approach, we investigated all-site and site-specific cancer incidence in a large population stratified by diabetes status. The study analyzed a closed cohort comprised of Israelis aged 21–89 years, enrolled in a health fund, and followed from 2002 to 2012. Adjusting for age, ethnicity, and socioeconomic status, we calculated hazard ratios for cancer incidence using Cox regression separately for participants with prevalent and incident diabetes; the latter was further divided by time since diabetes diagnosis. Of the 2,186,196 individuals included in the analysis, 159,104 were classified as having prevalent diabetes, 408,243 as having incident diabetes, and 1,618,849 as free of diabetes. In both men and women, diabetes posed an increased risk of cancers of the liver, pancreas, gallbladder, endometrium, stomach, kidney, brain (benign), brain (malignant), colon/rectum, lung (all, adenocarcinoma, and squamous cell carcinoma), ovary, and bladder, as well as leukemia, multiple myeloma, non-Hodgkin lymphoma, and breast cancer in postmenopausal women. No excess risk was observed for breast cancer in premenopausal women or for thyroid cancer. Diabetes was associated with a reduced risk of prostate cancer. Hazard ratios for all-site and site-specific cancers were particularly elevated during the first year following diabetes diagnosis. The findings of this large study with a time-dependent approach are consistent with those of previous studies that have observed associations between diabetes and cancer incidence.

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PEGylated Hyaluronidase Augments Pancreatic Cancer Treatment

Purpose: This phase Ib study evaluated the safety and tolerability of PEGylated human recombinant hyaluronidase (PEGPH20) in combination with gemcitabine (Gem), and established a phase II dose for patients with untreated stage IV metastatic pancreatic ductal adenocarcinoma (PDA). Objective response rate and treatment efficacy using biomarker and imaging measurements were also evaluated.

Experimental Design: Patients received escalating intravenous doses of PEGPH20 in combination with Gem using a standard 3+3 dose-escalation design. In cycle 1 (8 weeks), PEGPH20 was administrated twice weekly for 4 weeks, then once weekly for 3 weeks; Gem was administrated once weekly for 7 weeks, followed by 1 week off treatment. In each subsequent 4-week cycle, PEGPH20 and Gem were administered once weekly for 3 weeks, followed by 1 week off. Dexamethasone (8 mg) was given pre- and post-PEGPH20 administration. Several safety parameters were evaluated.

Results: Twenty-eight patients were enrolled and received PEGPH20 at 1.0 (n = 4), 1.6 (n = 4), or 3.0 μg/kg (n = 20), respectively. The most common PEGPH20-related adverse events were musculoskeletal and extremity pain, peripheral edema, and fatigue. The incidence of thromboembolic events was 29%. Median progression-free survival (PFS) and overall survival (OS) rates were 5.0 and 6.6 months, respectively. In 17 patients evaluated for pretreatment tissue hyaluronan (HA) levels, median PFS and OS rates were 7.2 and 13.0 months for "high"-HA patients (n = 6), and 3.5 and 5.7 months for "low"-HA patients (n = 11), respectively.

Conclusions: PEGPH20 in combination with Gem was well tolerated and may have therapeutic benefit in patients with advanced PDA, especially in those with high HA tumors. Clin Cancer Res; 22(12); 2848–54. ©2016 AACR.

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MET DNA Alterations in NSCLC

Purpose: Activation of MET oncogene as the result of amplification or activation mutation represents an emerging molecular target for cancer treatment. We comprehensively studied MET alterations and the clinicopathologic correlations in a large cohort of treatment-naïve non–small cell lung carcinoma (NSCLC).

Experimental Design: Six hundred eighty-seven NSCLCs were tested for MET exon 14 splicing site mutation (MET14), DNA copy number alterations, and protein expression by Sanger sequencing, FISH, and IHC, respectively.

Results: MET14 mutation was detected in 2.62% (18/687) of NSCLC. The mutation rates were 2.6% in adenocarcinoma, 4.8% in adenosquamous carcinoma, and 31.8% in sarcomatoid carcinoma. MET14 mutation was not detected in squamous cell carcinoma, large cell carcinoma, and lymphoepithelioma-like carcinoma but significantly enriched in sarcomatoid carcinoma (P < 0.001). MET14 occurred mutually exclusively with known driver mutations but tended to coexist with MET amplification or copy number gain (P < 0.001). Low-level MET amplification and polysomy might occur in the background of EGFR or KRAS mutation whereas high-level amplification (MET/CEP7 ratio ≥5) was mutually exclusive to the major driver genes except MET14. Oncogenic MET14 mutation and/or high-level amplification occurred in a total of 3.3% (23/687) of NSCLC and associated with higher MET protein expression. MET14 occurred more frequently in older patients whereas amplification was more common in ever-smokers. Both MET14 and high-level amplification were independent prognostic factors that predicted poorer survival by multivariable analysis.

Conclusions: The high incidence of MET14 mutation in sarcomatoid carcinoma suggested that MET inhibition might benefit this specific subgroup of patients. Clin Cancer Res; 22(12); 3048–56. ©2016 AACR.

See related commentary by Drilon, p. 2832

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Cisplatin/Veliparib in TNBC and BRCA Mutation-Positive BC

Purpose: Cisplatin is synergistic with vinorelbine and the PARP inhibitor veliparib, and has antineoplastic activity in triple-negative breast cancer (TNBC) and BRCA mutation–associated breast cancer. This phase I study assessed veliparib with cisplatin and vinorelbine.

Experimental Design: A 3+3 dose-escalation design evaluated veliparib administered twice daily for 14 days with cisplatin (75 mg/m² day 1) and vinorelbine (25 mg/m² days 1, 8) every 21 days, for 6 to 10 cycles, followed by veliparib monotherapy. Pharmacokinetics, measurement of poly(ADP-ribose) in peripheral blood mononuclear cells, and preliminary efficacy were assessed. IHC and gene-expression profiling were evaluated as potential predictors of response.

Results: Forty-five patients enrolled in nine dose cohorts plus five in an expansion cohort at the highest dose level and recommended phase II dose, 300 mg twice daily. The MTD of veliparib was not reached. Neutropenia (36%), anemia (30%), and thrombocytopenia (12%) were the most common grade 3/4 adverse events. Best overall response for 48 patients was radiologic response with 9-week confirmation for 17 (35%; 2 complete, 15 partial), and stable disease for 21 (44%). Germline BRCA mutation presence versus absence was associated with 6-month progression-free survival [PFS; 10 of 14 (71%) vs. 8 of 27 (30%), mid-P = 0.01]. Median PFS for all 50 patients was 5.5 months (95% confidence interval, 4.1–6.7).

Conclusions: Veliparib at 300 mg twice daily combined with cisplatin and vinorelbine is well tolerated with encouraging response rates. A phase II randomized trial is planned to assess veliparib's contribution to cisplatin chemotherapy in metastatic TNBC and BRCA mutation–associated breast cancer. Clin Cancer Res; 22(12); 2855–64. ©2016 AACR.

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HMGB1 Isoforms in Asbestos Exposure and Mesothelioma

Purpose: To determine whether serum levels of high mobility group box protein 1 (HMGB1) could differentiate malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls.

Experimental Design: Hyperacetylated and nonacetylated HMGB1 (together referred to as total HMGB1) were blindly measured in blood collected from malignant mesothelioma patients (n = 22), individuals with verified chronic asbestos exposure (n = 20), patients with benign pleural effusions (n = 13) or malignant pleural effusions not due to malignant mesothelioma (n = 25), and healthy controls (n = 20). Blood levels of previously proposed malignant mesothelioma biomarkers fibulin-3, mesothelin, and osteopontin were also measured in nonhealthy individuals.

Results: HMGB1 serum levels reliably distinguished malignant mesothelioma patients, asbestos-exposed individuals, and unexposed controls. Total HMGB1 was significantly higher in malignant mesothelioma patients and asbestos-exposed individuals compared with healthy controls. Hyperacetylated HMGB1 was significantly higher in malignant mesothelioma patients compared with asbestos-exposed individuals and healthy controls, and did not vary with tumor stage. At the cut-off value of 2.00 ng/mL, the sensitivity and specificity of serum hyperacetylated HMGB1 in differentiating malignant mesothelioma patients from asbestos-exposed individuals and healthy controls was 100%, outperforming other previously proposed biomarkers. Combining HMGB1 and fibulin-3 provided increased sensitivity and specificity in differentiating malignant mesothelioma patients from patients with cytologically benign or malignant non–mesothelioma pleural effusion.

Conclusions: Our results are significant and clinically relevant as they provide the first biomarker of asbestos exposure and indicate that hyperacetylated HMGB1 is an accurate biomarker to differentiate malignant mesothelioma patients from individuals occupationally exposed to asbestos and unexposed controls. A trial to independently validate these findings will start soon. Clin Cancer Res; 22(12); 3087–96. ©2016 AACR.

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POLE Mutations in Endometrial Cancer

Purpose: The aim of this study was to confirm the prognostic significance of POLE exonuclease domain mutations (EDM) in endometrial carcinoma patients. In addition, the effect of treatment on POLE-mutated tumors was assessed.

Experimental Design: A retrospective patient cohort of 496 endometrial carcinoma patients was identified for targeted sequencing of the POLE exonuclease domain, yielding 406 evaluable tumors. Univariable and multivariable analyses were performed to determine the effect of POLE mutation status on progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS). Combining results from eight studies in a meta-analysis, we computed pooled HR for PFS, DSS, and OS.

Results: POLE EDMs were identified in 39 of 406 (9.6%) endometrial carcinomas. Women with POLE-mutated endometrial carcinomas were younger, with stage I (92%) tumors, grade 3 (62%), endometrioid histology (82%), and frequent (49%) lymphovascular invasion. In univariable analysis, POLE-mutated endometrial carcinomas had significantly improved outcomes compared with patients with no EDMs for PFS, DSS, and OS. In multivariable analysis, POLE EDMs were only significantly associated with improved PFS. The effect of adjuvant treatment on POLE-mutated cases could not be determined conclusively; however, both treated and untreated patients with POLE EDMs had good outcomes. Meta-analysis revealed an association between POLE EDMs and improved PFS and DSS with pooled HRs 0.34 [95% confidence interval (CI), 0.15–0.73] and 0.35 (95% CI, 0.13–0.92), respectively.

Conclusions: POLE EDMs are prognostic markers associated with excellent outcomes for endometrial carcinoma patients. Further investigation is needed to conclusively determine if treatment is necessary for this group of women. Clin Cancer Res; 22(12); 2865–73. ©2016 AACR.

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Selected Articles from This Issue

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Phase I Cancer Study of PI3K-mTOR Inhibitor Apitolisib

Purpose: This first-in-human phase I trial assessed the safety, tolerability, and preliminary antitumor activity of apitolisib (GDC-0980), a dual inhibitor of class I PI3K, and mTOR kinases.

Experimental Design: Once-daily oral apitolisib was administered to patients with solid tumors for days 1 to 21 or 1 to 28 of 28-day cycles. Pharmacokinetic and pharmacodynamic parameters were assessed.

Results: Overall, 120 patients were treated at doses between 2 and 70 mg. The commonest ≥G3 toxicities related to apitolisib at the recommended phase 2 dose (RP2D) at 40 mg once daily included hyperglycemia (18%), rash (14%), liver dysfunction (12%), diarrhea (10%), pneumonitis (8%), mucosal inflammation (6%), and fatigue (4%). Dose-limiting toxicities (1 patient each) were G4 fasting hyperglycemia at 40 mg (21/28 schedule) and G3 maculopapular rash and G3 fasting hyperglycemia at 70 mg (21/28 schedule). The pharmacokinetic profile was dose-proportional. Phosphorylated serine-473 AKT levels were suppressed by ≥90% in platelet-rich plasma within 4 hours at the MTD (50 mg). Pharmacodynamic decreases in fluorodeoxyglucose positron emission tomography uptake of >25% occurred in 66% (21/32) of patients dosed at 40 mg once daily. Evidence of single-agent activity included 10 RECIST partial responses (PR; confirmed for peritoneal mesothelioma, PIK3CA mutant head-and-neck cancer, and three pleural mesotheliomas).

Conclusions: Apitolisib exhibited dose-proportional pharmacokinetics with target modulation at doses ≥16 mg. The RP2D was 40 mg once-daily 28/28 schedule; severe on-target toxicities were apparent at ≥40 mg, particularly pneumonitis. Apitolisib was reasonably tolerated at 30 mg, the selected dose for pleural mesothelioma patients given limited respiratory reserve. Modest but durable antitumor activity was demonstrated. Clin Cancer Res; 22(12); 2874–84. ©2016 AACR.

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IL18 plus anti-PD-L1 and anti-CTLA-4 Antibodies

Purpose: Recent clinical trials and animal models demonstrated that immune checkpoint blockade enhanced effector cell responses and tumor rejection; however, further development and improvement of cancer immunotherapy is necessary for more favorable objective responses. In this study, we examined the effect of IL18 on the antitumor effect of immune checkpoint inhibitors.

Experimental Design: We examined the effect of IL18 on the peritoneal dissemination of CT-26 cells or tail vein injection metastasis of B16/F10 cells using antiprogrammed death-1 ligand-1 (αPD-L1) and/or anti-CTL–associated antigen-4 (αCTLA-4) mAbs.

Result: Massive ascites developed after intraperitoneal inoculation of CT-26, resulting in animal death within 30 days. Treatment of mice with αPD-L1 and/or αCTLA-4 significantly prolonged their survival, and a combination of the antibodies and IL18 provided a much greater therapeutic benefit. The combination modality led to the accumulation of precursor of mature natural killer (pre-mNK) cells in the peritoneal cavity together with increased CD8⁺ T and decreased CD4⁺CD25⁺Foxp3⁺ T cells. Depletion of the pre-mNK cells abrogated the therapeutic effects and increased the number of CD4⁺CD25⁺Foxp3⁺ T cells. The combination treatment also suppressed tail vein injection metastasis of B16/F10 cells.

Conclusions: The results demonstrated that IL18 enhanced therapeutic effects of immune checkpoint blockade against peritoneal dissemination of carcinoma or tail vein injection metastasis of melanoma through accumulation of pre-mNK cells, memory-type CD8⁺ T cells, and suppression of CD4⁺CD25⁺Foxp3⁺ T cells. A combination of immune checkpoint inhibitors with IL18 may give a suggestion to the development of next-generation cancer immunotherapy. Clin Cancer Res; 22(12); 2969–80. ©2016 AACR.

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GVAX for Recurrent Malignant Glioma

Purpose: Recurrent malignant glioma carries a dismal prognosis, and novel therapies are needed. We examined the feasibility and safety of vaccination with irradiated autologous glioma cells mixed with irradiated GM-K562 cells in patients undergoing craniotomy for recurrent malignant glioma.

Experimental Design: We initiated a phase I study examining the safety of 2 doses of GM-K562 cells mixed with autologous cells. Primary endpoints were feasibility and safety. Feasibility was defined as the ability for 60% of enrolled subjects to initiate vaccination. Dose-limiting toxicity was assessed via a 3+3 dose-escalation format, examining irradiated tumor cells mixed with 5 x 10⁶ GM-K562 cells or 1 x 10⁷ GM-K562 cells. Eligibility required a priori indication for resection of a recurrent high-grade glioma. We measured biological activity by measuring delayed type hypersensitivity (DTH) responses, humoral immunity against tumor-associated antigens, and T-lymphocyte activation.

Results: Eleven patients were enrolled. Sufficient numbers of autologous tumor cells were harvested in 10 patients, all of whom went on to receive vaccine. There were no dose-limiting toxicities. Vaccination strengthened DTH responses to irradiated autologous tumor cells in most patients, and vigorous humoral responses to tumor-associated angiogenic cytokines were seen as well. T-lymphocyte activation was seen with significantly increased expression of CTLA-4, PD-1, 4-1BB, and OX40 by CD4⁺ cells and PD-1 and 4-1BB by CD8⁺ cells. Activation was coupled with vaccine-associated increase in the frequency of regulatory CD4⁺ T lymphocytes.

Conclusions: Vaccination with irradiated autologous tumor cells mixed with GM-K562 cells is feasible, well tolerated, and active in patients with recurrent malignant glioma. Clin Cancer Res; 22(12); 2885–96. ©2016 AACR.

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PlGF/VEGFR-1 Mediates Obesity-Induced Tumor Progression

Purpose: Obesity promotes pancreatic and breast cancer progression via mechanisms that are poorly understood. Although obesity is associated with increased systemic levels of placental growth factor (PlGF), the role of PlGF in obesity-induced tumor progression is not known. PlGF and its receptor VEGFR-1 have been shown to modulate tumor angiogenesis and promote tumor-associated macrophage (TAM) recruitment and activity. Here, we hypothesized that increased activity of PlGF/VEGFR-1 signaling mediates obesity-induced tumor progression by augmenting tumor angiogenesis and TAM recruitment/activity.

Experimental Design: We established diet-induced obese mouse models of wild-type C57BL/6, VEGFR-1 tyrosine kinase (TK)-null, or PlGF-null mice, and evaluated the role of PlGF/VEGFR-1 signaling in pancreatic and breast cancer mouse models and in human samples.

Results: We found that obesity increased TAM infiltration, tumor growth, and metastasis in pancreatic cancers, without affecting vessel density. Ablation of VEGFR-1 signaling prevented obesity-induced tumor progression and shifted the tumor immune environment toward an antitumor phenotype. Similar findings were observed in a breast cancer model. Obesity was associated with increased systemic PlGF, but not VEGF-A or VEGF-B, in pancreatic and breast cancer patients and in various mouse models of these cancers. Ablation of PlGF phenocopied the effects of VEGFR-1-TK deletion on tumors in obese mice. PlGF/VEGFR-1-TK deletion prevented weight gain in mice fed a high-fat diet, but exacerbated hyperinsulinemia. Addition of metformin not only normalized insulin levels but also enhanced antitumor immunity.

Conclusions: Targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment and inhibits obesity-induced acceleration of tumor progression. Clin Cancer Res; 22(12); 2993–3004. ©2016 AACR.

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Nested quantitative PCR approach for urinary cell-free EZH2 mRNA and its potential clinical application in bladder cancer

Abstract

EZH2 is overexpressed in bladder cancer (BC) and plays important roles in tumor development and progression. Recent studies show cell free (cf) RNAs released from cancer cells can reflect tissues changes, and are stable and detectable in urine. Although conventional quantitative real-time PCR (qPCR) is highly sensitive, low abundances of urinary cf-RNAs usually result in false-negatives. Thus, this study develops a nested qPCR (nqPCR) approach to quantify cf-EZH2 mRNA in urine, and further assess its clinical significance for BC. Forty urine samples were first selected to evaluate feasibility of nqPCR. Then, levels of urinary cf-EZH2 mRNA were detected using developed method in an independent cohort of subjects with 91 healthy, 81 cystitis, 169 non-muscle invasive BC (NMIBC), and 103 muscle-invasive BC (MIBC). In cf-EZH2 mRNA detection, nqPCR method was significantly associated with qPCR, but it could detect more urine samples and increase detection limit three orders of magnitude. Based on nqPCR method, cf-EZH2 mRNA levels have been found to be increased in urine of NMIBC and MIBC patients (P<0.001). Compared with cytology, cf-EZH2 mRNA showed higher diagnostic ability for MIBC (P<0.001) while not for NMIBC (P>0.05). Moreover, it also could distinguish MIBC from NMIBC, with AUC of 0.787. For MIBC patients, high expression of cf-EZH2 mRNA associated with advanced stage, and was an independent predictor of reduced disease free survival or overall survival. In conclusion, detection of cf-EZH2 mRNA in urine by nqPCR is a sensitive and noninvasive approach, and may be used for diagnosis and prognosis prediction of MIBC. This article is protected by copyright. All rights reserved.

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The TGFβ pathway stimulates ovarian cancer cell proliferation by increasing IGF1R levels

ABSTRACT

In a search for new therapeutic targets for treating epithelial ovarian cancer we analyzed the Transforming Growth Factor Beta (TGFβ) signaling pathway in these tumors. Using a TMA with patient samples we found high Smad2 phosphorylation in ovarian cancer tumoral cells, independently of tumor subtype (high-grade serous or endometrioid). To evaluate the impact of TGFβ receptor inhibition on tumoral growth, we used different models of human ovarian cancer orthotopically grown in nude mice (OVAs). Treatment with a TGFβRI&II dual inhibitor, LY2109761, caused a significant reduction in tumor size in all these models, affecting cell proliferation rate. We identified Insulin Growth Factor (IGF)1 receptor as the signal positively regulated by TGFβ implicated in ovarian tumor cell proliferation. Inhibition of IGF1R activity by treatment with a blocker antibody (IMC-A12) or with a tyrosine kinase inhibitor (linsitinib) inhibited ovarian tumoral growth in vivo. When IGF1R levels were decreased by shRNA treatment, LY2109761 lost its capacity to block tumoral ovarian cell proliferation. At the molecular level TGFβ induced mRNA IGF1R levels. Overall, our results suggest an important role for the TGFβ signaling pathway in ovarian tumor cell growth through the control of IGF1R signaling pathway. Moreover, it identifies anti-TGFβ inhibitors as being of potential use in new therapies for ovarian cancer patients as an alternative to IGF1R inhibition. This article is protected by copyright. All rights reserved.

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Low-dose radiation may be a novel approach to enhance the effectiveness of cancer therapeutics

Abstract

It has been generally accepted that both natural and man-made sources of ionizing radiation contribute to human exposure and consequently pose a possible risk to human health. However, accumulating evidence has shown that the biological effects of low-dose radiation (LDR) are different from those of high-dose radiation. LDR can stimulate proliferation of normal cells and activate their defense systems, while these biological effects are not observed in some cancer cell types. Although there is still no concordance on this matter, the fact that LDR has the potential to enhance the effects of cancer therapeutics and reduce the toxic side effects of anti-cancer therapy has garnered significant interest. Here, we provide an overview of the current knowledge regarding the experimental data detailing the different responses of normal and cancer tissues to LDR, the underlying mechanisms, and its significance in clinical application. This article is protected by copyright. All rights reserved.

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Chemotherapy Options for Poor Responders to Neoadjuvant Chemotherapy for Orbital Granulocytic Sarcoma

Opinion statement

Granulocytic sarcoma (GS) is a rare manifestation of myeloid proliferation, characterized by formation of a mass comprised of immature cells of myeloid origin. Orbital granulocytic sarcoma is rarer still, with only a small fraction of GS patients having orbital involvement. Given the rarity of orbital GS, no unified therapy plan has been identified, as large prospective trials are not feasible, but it is widely accepted that patients with GS ought to be treated with systemic intensive chemotherapy consistent with standard of care regimens for acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML). Development of a treatment plan for GS in poor responders involves a systemic leukemia plan as novel therapeutics have not been investigated for treatment GS per se, but used more widely for AML. GS is most commonly associated with AML and thus will be addressed in that context in this review. Patients with GS associated with CML should receive CML-specific therapy. When conventional and traditional cytotoxic GS/AML chemotherapy regimens are insufficient, patients often require a combination of novel therapeutics, stem cell transplantation (SCT), and radiation. Much of the recent advancement in AML therapy, as well as in AML translational research, has been in targeting molecular facets of the disease and enabling more specificity with treatment. The aim of treating patients for whom conventional treatment was unsuccessful with personalized therapy has not yet been realized, but many of the novel therapeutics reviewed below have demonstrated promise and are cause for optimism. In our center, when a GS/AML patient is refractory to frontline therapy, we rely on novel chemotherapy therapeutic options as outlined below.

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Editorial Board

Publication date: July 2016
Source:Critical Reviews in Oncology/Hematology, Volume 103





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Detection of Recurrent Prostate Cancer after Primary Radiation Therapy: an Evaluation of the Role of Multiparametric 3T MRI imaging with Endorectal Coil

Publication date: Available online 14 June 2016
Source:Practical Radiation Oncology
Author(s): Fabio Zattoni, Akira Kawashima, Alessandro Morlacco, Brian J. Davis, Avinash Nehra, Lance Mynderse, Adam Froemming, R. Jeffrey Karnes
ObjectiveThe value of multiparametric MRI (mpMRI) in staging prostate cancer (PCa) prior to salvage prostatectomy (sRP) is currently unclear, due to minimal data comparing mpMRI results to final pathologic stage at surgery. The aim of the study is to determine the diagnostic performance of mpMRI in characterizing viable recurrent tumor and lymph node metastasis following radiation therapy (RT) failure.MethodsBetween 01/2007-07/2014, nineteen patients with biopsy proven recurrent PCa after primary RT underwent 3 Tesla mpMRI and subsequent sRP with extended pelvic lymphadenectomy. mpMRI images were independently reviewed by two GU MRI radiologists (R1 and R2), blinded to the pathology results, to evaluate extraprostatic extension (EPE), seminal vesicle invasion (SVI), and pelvic lymph node metastasis (PLNM). Sensitivity, specificity, PPV, NPV, ROC curves and interobserver agreement (R1 and R2) were evaluated for each outcome on a per-patient basis. Final pathologic results were used as a gold standard for comparison in all patients. A multivariate analysis was conducted to assess the relationship between the index lesion's ADC value and its enhancement characteristics with the Gleason Score.ResultsEPE was found in 14 (73.7%) patients, SVI in 13 (68.4%), and PLNM in 5 (26.3%). mpMRI sensitivity for PLNM was 60.0 % (R1 &R2) with specificity of 85.7 % (R1) and 92.8 % (R2). With regards to SVI, the sensitivity was 61.5 % (R1) and 76.9 % (R2) with specificity of 66.6 % (R1 and R2). Sensitivity for EPE was 50.0% (R1) and 71.43% (R2) with specificity of 80.0%(R1) and 100.00 %(R2).No significant associations were found at multivariate analysis. The evaluation of PLNM, SVI, and PCa recurrence within the prostate demonstrated moderate interobserver agreement (k: 0.51–0.57).ConclusionsmpMRI has good accuracy for detecting PLNM, SVI and ECE after RT. MpMRI provides useful information in locally-recurrent PCa following primary radiotherapy.



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A phase II trial evaluating the effects and intra-tumoral penetration of bortezomib in patients with recurrent malignant gliomas

Abstract

One resistance mechanism in malignant gliomas (MG) involves nuclear factor-κB (NF-κB) activation. Bortezomib prevents proteasomal degradation of NF-κB inhibitor α (NFKBIA), an endogenous regulator of NF-κB signaling, thereby limiting the effects of NF-κB on tumor survival and resistance. A presurgical phase II trial of bortezomib in recurrent MG was performed to determine drug concentration in tumor tissue and effects on NFKBIA. Patients were enrolled after signing an IRB approved informed consent. Treatment was bortezomib 1.7 mg/m² IV on days 1, 4 and 8 and then surgery on day 8 or 9. Post-operatively, treatment was Temozolomide (TMZ) 75 mg/m² PO on days 1–7 and 14–21 and bortezomib 1.7 mg/m² on days 7 and 21 [1 cycle was (1) month]. Ten patients were enrolled (8 M and 2 F) with 9 having surgery. Median age and KPS were 50 (42–64) and 90 % (70–100). The median cycles post-operatively was 2 (0–4). The trial was stopped as no patient had a PFS-6. All patients are deceased. Paired plasma and tumor bortezomib concentration measurements revealed higher drug concentrations in tumor than in plasma; NFKBIA protein levels were similar in drug-treated vs. drug-naïve tumor specimens. Nuclear 20S was less in the cytoplasm in postoperative samples. Postoperative treatment with TMZ and bortezomib did not show clinical activity. Bortezomib appears to sequester in tumor but pharmacological effects on NFKBIA were not seen, possibly obscured due to downregulation of NFKBIA during tumor progression. Changes in nuclear 20S could be marker of bortezomib effect on tumor.

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Erratum to: Altered expression of stromal interaction molecule (STIM)-calcium release-activated calcium channel protein (ORAI) and inositol 1,4,5-trisphosphate receptors (IP 3 Rs) in cancer: will they become a new battlefield for oncotherapy?

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Association between periodontitis and ischemic stroke: a systematic review and meta-analysis

Abstract

Several observational studies have suggested an association between periodontitis and cerebral ischemia. This meta-analysis aimed to investigate whether this link exists, and if so, the degree to which it is significant. The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline for systematic review was used. The search strategy included using electronic databases and hand searching works published up to March 2015. MEDLINE via PubMed, EMBASE, Proceedings Web of Science and Current Contents Connect were searched by two independent reviewers. Case-control, cross-sectional or cohort studies including patients with measures of periodontitis and ischemic stroke were eligible to be included in the analysis. Quality assessments of selected studies were performed. From a total of 414 titles and abstracts, 57 potentially relevant full text papers were identified. After inclusion criteria were applied, 8 studies were included in the present systematic review (5 case-control and 3 cohort studies). Although it was not the intention, cross-sectional studies were excluded due to eligibility criteria were not accomplished. Therefore, meta-analyses were conducted with data retrieved from the 8 studies included. These meta-analyses showed statistically significant association between periodontitis and ischemic stroke in both cohort pooled relative risks at 2.52 (1.77–3.58), and case-control studies pooled relative risks at 3.04 (1.10–8.43). In conclusion, the present meta-analysis demonstrated an association between periodontitis and ischemic stroke. However, well-designed prospective studies should be carried out to provide robust evidence of the link between both diseases. In regards to ischemic stroke subtypes, further case-control studies should be carried out to investigate whether there is any association between the different subtypes of cerebral infarcts and periodontitis.

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Overweight duration in older adults and cancer risk: a study of cohorts in Europe and the United States

Abstract

Recent studies have shown that cancer risk related to overweight and obesity is mediated by time and might be better approximated by using life years lived with excess weight. In this study we aimed to assess the impact of overweight duration and intensity in older adults on the risk of developing different forms of cancer. Study participants from seven European and one US cohort study with two or more weight assessments during follow-up were included (n = 329,576). Trajectories of body mass index (BMI) across ages were estimated using a quadratic growth model; overweight duration (BMI ≥ 25) and cumulative weighted overweight years were calculated. In multivariate Cox models and random effects analyses, a longer duration of overweight was significantly associated with the incidence of obesity-related cancer [overall hazard ratio (HR) per 10-year increment: 1.36; 95 % CI 1.12–1.60], but also increased the risk of postmenopausal breast and colorectal cancer. Additionally accounting for the degree of overweight further increased the risk of obesity-related cancer. Risks associated with a longer overweight duration were higher in men than in women and were attenuated by smoking. For postmenopausal breast cancer, increased risks were confined to women who never used hormone therapy. Overall, 8.4 % of all obesity-related cancers could be attributed to overweight at any age. These findings provide further insights into the role of overweight duration in the etiology of cancer and indicate that weight control is relevant at all ages. This knowledge is vital for the development of effective and targeted cancer prevention strategies.

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Diagnosing native liver fibrosis and esophageal varices using liver and spleen stiffness measurements in biliary atresia: a pilot study

Abstract

Background

Biliary atresia commonly leads to liver fibrosis and cirrhotic complications, including esophageal varices.

Objective

To evaluate liver and spleen stiffness measurements using acoustic radiation force impulse (ARFI) imaging for diagnosing grade of liver fibrosis and predicting the presence of esophageal varices in patients treated for biliary atresia.

Materials and methods

ARFI imaging of the spleen and native liver was performed in 28 patients with biliary atresia. We studied the relation between ARFI imaging values and liver histology findings (n=22), upper gastrointestinal endoscopy findings (n=16) and several noninvasive test results. Diagnostic accuracy was assessed using receiver operating characteristic curve analyses.

Results

Liver stiffness measurements exhibited a significant difference among the different grades of liver fibrosis (P=0.009), and showed higher values in patients with high-risk esophageal varices than in the other patients (P=0.04). The areas under the receiver operating characteristic curves of liver stiffness measurements for liver fibrosis grades  ≥ F2, ≥F3 and = F4 were 0.83, 0.93 and 0.94, respectively. Patients with high-risk esophageal varices were preferentially diagnosed by the combined liver and spleen stiffness measurements (area under the curve, 0.92).

Conclusion

Liver and spleen stiffness measurements using ARFI imaging are potential noninvasive markers for liver fibrosis and esophageal varices in patients treated for biliary atresia.

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Rho GTPases: RAC1 polymorphisms affected platinum-based chemotherapy toxicity in lung cancer patients

Abstract

Purpose

Lung cancer is the leading cause of cancer deaths in the world. The toxicity of platinum-based chemotherapy is a main reason limiting its clinical effects. RAC1, as a member of the Rho family of small guanosine triphosphatases (GTPases), was reported to be related to most cancers, such as breast cancer, gastric cancer, testicular germ cell cancer, and lung cancer. Its potential of becoming a drug target in cancer treatment has been investigated in recent years. The aim of this study was to investigate the association between genetic polymorphisms and platinum-based chemotherapy toxicity.

Methods

We enrolled 317 lung cancer patients randomly. Nineteen polymorphisms of HSP genes and Rho family genes were genotyped by Sequenom MassARRAY. The logistic regression was performed by PLINK to compare the relevance of polymorphisms and toxicity outcome.

Results

We found that the polymorphisms of RAC1 rs836554, rs4720672, and rs12536544 were significantly associated with platinum-based chemotherapy toxicity (p = 0.018, p = 0.044, and p = 0.021, respectively).

Conclusions

RAC1 rs836554, rs4720672, and rs12536544 polymorphisms may be novel and useful genetic markers to predict the toxicity induced by platinum-based chemotherapy in lung cancer patients.

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A Phase I study of safety and pharmacokinetics of fruquintinib, a novel selective inhibitor of vascular endothelial growth factor receptor-1, -2, and -3 tyrosine kinases in Chinese patients with advanced solid tumors

Abstract

Purpose

Fruquintinib (HMPL-013) is a novel oral small molecule compound that selectively inhibits vascular endothelial growth factor receptors-1, -2, and -3 with potent inhibitory effects on multiple human tumor xenografts. This first-in-human study was conducted to assess the maximum tolerated dose and dose-limiting toxicities, safety and tolerability, pharmacokinetics, and preliminary anti-tumor activity of fruquintinib.

Methods

Patients 18–70 years old with advanced solid tumors refractory to standard therapies were recruited. Fruquintinib was administered orally in 4-week repeating cycles in two regimens, either once daily continuously or once daily for 3-week on/1-week off, until discontinuation due to toxicity or tumor progression. Adverse events were assessed using National Cancer Institute Common Terminology Criteria for Adverse Events v4.0.3. Pharmacokinetic parameters were measured after a single dose and in multiple dosing. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors v1.0.

Results

Forty patients were enrolled into 5 cohorts in continuous regimen and 2 cohorts in 3-week-on/1-week-off regimen. The most common grade 3/4 adverse events were hand–foot skin reaction, hypertension, and thrombocytopenia. PK analysis showed good and rapid absorption followed by slow terminal elimination with a mean half-life of approximately 42 h which was consistent across all dose groups. Thirty-four patients were evaluable for tumor response, including 14 with partial response and 14 with stable disease.

Conclusions

Fruquintinib showed an acceptable safety profile and preliminary evidence of anti-tumor activity in patients with advanced solid tumors. The recommended dose was determined to be either 4 mg QD on a continuous regimen or 5 mg QD on a 3-week-on/1-week-off regimen.

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The clinicopathological significance of miR-149 and PARP-2 in hepatocellular carcinoma and their roles in chemo/radiotherapy

Abstract

Hepatocellular carcinomas (HCC) are commonly diagnosed at an advanced stage with unresectable tumors. Although numerous non-surgical approaches have been developed to treat HCC, the prognosis of patients with HCC is still poor. This study investigated the expression of miR-149 and PARP-2 in HCC tumor tissues and their roles in sensitizing chemo/radiotherapy. The expression of miR-149 was measured by real-time PCR, and PARP-2 protein was measured by immunohistochemistry and Western blot. The xenograft HCC mouse model was established by inoculating Hep G2 cells. Increased PARP-1 and decreased miR-149 expression was observed in HCC tissues compared to peritumoral tissues. Positive PARP-2 and low miR-149 expression correlated with larger tumor mass size (P < 0.001), capsular and vascular invasion (P < 0.001), lymph node metastasis (P = 0.02), high histological grade (P < 0.001), TNM (P < 0.001), and BCLC grade (P = 0.001). The Kaplan-Meier survival analysis showed a negative correlation between high PARP-2 expression or low miR-149 expression in HCC tissues with the survival of patients. High PARP-2 and low miR-149 correlated with a low 5-year survival rate and are poor prognosis factors. Overexpression of miR-149 or inhibition of PARP-2 expression could inhibit tumor growth but was more effective in sensitizing chemotherapy and radiotherapy in xenograft HCC animal models. Increased PARP-2 expression and loss of miR-149 expression are involved in the pathogenesis of HCC and are poor prognosis factors in patients with HCC. Although both miR-149 overexpression and PARP-2 inhibitor exert some antitumoral effect, PARP-2 inhibitor is a chemo/radio sensor and can be used to enhance chemotherapy and radiotherapy in patients with HCC.

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Biological imaging in clinical oncology—introduction

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Use of complementary and alternative medicine by patients with cancer: a cross-sectional study at different points of cancer care

Abstract

Complementary and alternative medicine (CAM) is widely used by cancer patients. In order to learn more on the usage of CAM, its reasons and motifs as well as sources of information along the trajectory of treatment, we decided to evaluate the prevalence and predictors for the use of CAM by cancer patients while being under active treatment with chemo- or radiotherapy or in aftercare. We distributed a standardized questionnaire among patients attending a department of radio-oncology, an ambulance for oncology and offices of general practitioners (GPs). Five hundred and six patients took part. Most attributed cancer to stress and trauma (23.7 and 16.4 %) or genes (20.8 %). Forty-four percentage reported knowing a physician with competence in CAM, and in all settings, most patients named the GP. Fifty-one percentage admitted using CAM, 35 % informed the oncologist about using CAM, 56 % informed the GP, and 26 % did not inform any physician. Most often used CAM was vitamin D (17 %) and selenium (16 %). Most important goals were to strengthen the immune system (59 %) and become active (52 %). Most patients were satisfied with the CAM methods they used. Yet, with some methods, dissatisfaction was up to 30 %. The GP has an important function concerning CAM in oncology as most patients believe the GP to have best knowledge in CAM. In order to integrate complementary medicine into evidence-based medicine, physicians should be trained on how to communicate on CAM with the patient and with each other. Explaining cancer and cancer therapies in a way lay persons are able to understand may be helpful. Physicians should actively address patients' needs of involvement not only in decision making, but also actively in the therapy.

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Inhibition of Dopamine Receptor D4 Impedes Autophagic Flux, Proliferation, and Survival of Glioblastoma Stem Cells

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Sonam Dolma, Hayden J. Selvadurai, Xiaoyang Lan, Lilian Lee, Michelle Kushida, Veronique Voisin, Heather Whetstone, Milly So, Tzvi Aviv, Nicole Park, Xueming Zhu, ChangJiang Xu, Renee Head, Katherine J. Rowland, Mark Bernstein, Ian D. Clarke, Gary Bader, Lea Harrington, John H. Brumell, Mike Tyers, Peter B. Dirks
Glioblastomas (GBM) grow in a rich neurochemical milieu, but the impact of neurochemicals on GBM growth is largely unexplored. We interrogated 680 neurochemical compounds in patient-derived GBM neural stem cells (GNS) to determine the effects on proliferation and survival. Compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected GNS growth. In particular, dopamine receptor D4 (DRD4) antagonists selectively inhibited GNS growth and promoted differentiation of normal neural stem cells. DRD4 antagonists inhibited the downstream effectors PDGFRβ, ERK1/2, and mTOR and disrupted the autophagy-lysosomal pathway, leading to accumulation of autophagic vacuoles followed by G0/G1 arrest and apoptosis. These results demonstrate a role for neurochemical pathways in governing GBM stem cell proliferation and suggest therapeutic approaches for GBM.

Graphical abstract

Teaser

Dolma et al. show that compounds that modulate dopaminergic, serotonergic, and cholinergic signaling pathways selectively affected glioblastoma neural stem cells (GNS). In particular, dopamine receptor D4 antagonists disrupt the autophagy-lysosomal pathway of GNS, leading to growth arrest and apoptosis.


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ΔNp63/DGCR8-Dependent MicroRNAs Mediate Therapeutic Efficacy of HDAC Inhibitors in Cancer

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Marco Napoli, Avinashnarayan Venkatanarayan, Payal Raulji, Brooke A. Meyers, William Norton, Lingegowda S. Mangala, Anil K. Sood, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Harina Vin, Madeleine Duvic, Michael B. Tetzlaff, Jonathan L. Curry, Alain H. Rook, Hussein A. Abbas, Cristian Coarfa, Preethi H. Gunaratne, Kenneth Y. Tsai, Elsa R. Flores
ΔNp63 is an oncogenic member of the p53 family and acts to inhibit the tumor-suppressive activities of the p53 family. By performing a chemical library screen, we identified histone deacetylase inhibitors (HDACi) as agents reducing ΔNp63 protein stability through the E3 ubiquitin ligase, Fbw7. ΔNp63 inhibition decreases the levels of its transcriptional target, DGCR8, and the maturation of let-7d and miR-128, which we found to be critical for HDACi function in vitro and in vivo. Our work identified Fbw7 as a predictive marker for HDACi response in squamous cell carcinomas and lymphomas, and unveiled let-7d and miR-128 as specific targets to bypass tumor resistance to HDACi treatment.

Graphical abstract

Teaser

Napoli et al. show that HDAC inhibitors (HDACi) target the ΔNp63/DGCR8 axis to inhibit ΔNp63-dependent tumors, especially those lacking functional p53. ΔNp63 inhibition decreases DGCR8 expression and maturation of let-7d and miR-128. They also identify Fbw7 level as a predictive marker for HDACi response.


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miRNA-126 Orchestrates an Oncogenic Program in B Cell Precursor Acute Lymphoblastic Leukemia

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Silvia Nucera, Alice Giustacchini, Francesco Boccalatte, Andrea Calabria, Cristiana Fanciullo, Tiziana Plati, Anna Ranghetti, Jose Garcia-Manteiga, Davide Cittaro, Fabrizio Benedicenti, Eric R. Lechman, John E. Dick, Maurilio Ponzoni, Fabio Ciceri, Eugenio Montini, Bernhard Gentner, Luigi Naldini
MicroRNA (miRNA)-126 is a known regulator of hematopoietic stem cell quiescence. We engineered murine hematopoiesis to express miRNA-126 across all differentiation stages. Thirty percent of mice developed monoclonal B cell leukemia, which was prevented or regressed when a tetracycline-repressible miRNA-126 cassette was switched off. Regression was accompanied by upregulation of cell-cycle regulators and B cell differentiation genes, and downregulation of oncogenic signaling pathways. Expression of dominant-negative p53 delayed blast clearance upon miRNA-126 switch-off, highlighting the relevance of p53 inhibition in miRNA-126 addiction. Forced miRNA-126 expression in mouse and human progenitors reduced p53 transcriptional activity through regulation of multiple p53-related targets. miRNA-126 is highly expressed in a subset of human B-ALL, and antagonizing miRNA-126 in ALL xenograft models triggered apoptosis and reduced disease burden.

Graphical abstract

Teaser

Nucera et al. show that sustained miRNA-126 expression across differentiation stages during murine hematopoiesis results in leukemia. Human B-ALL is also dependent on miRNA-126, which orchestrates an oncogenic program by downregulating p53-dependent pathways and maintaining blasts in a B cell precursor state.


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DNMT3A Loss Drives Enhancer Hypomethylation in FLT3-ITD-Associated Leukemias

Publication date: 13 June 2016
Source:Cancer Cell, Volume 29, Issue 6
Author(s): Liubin Yang, Benjamin Rodriguez, Allison Mayle, Hyun Jung Park, Xueqiu Lin, Min Luo, Mira Jeong, Choladda V. Curry, Sang-Bae Kim, David Ruau, Xiaotian Zhang, Ting Zhou, Michael Zhou, Vivienne I. Rebel, Grant A. Challen, Berthold Göttgens, Ju-Seog Lee, Rachel Rau, Wei Li, Margaret A. Goodell
DNMT3A, the gene encoding the de novo DNA methyltransferase 3A, is among the most frequently mutated genes in hematologic malignancies. However, the mechanisms through which DNMT3A normally suppresses malignancy development are unknown. Here, we show that DNMT3A loss synergizes with the FLT3 internal tandem duplication in a dose-influenced fashion to generate rapid lethal lymphoid or myeloid leukemias similar to their human counterparts. Loss of DNMT3A leads to reduced DNA methylation, predominantly at hematopoietic enhancer regions in both mouse and human samples. Myeloid and lymphoid diseases arise from transformed murine hematopoietic stem cells. Broadly, our findings support a role for DNMT3A as a guardian of the epigenetic state at enhancer regions, critical for inhibition of leukemic transformation.

Graphical abstract

Teaser

Yang et al. show that expression of FLT3-ITD in mouse Dnmt3a^−/− and Dnmt3a^+/− hematopoietic stem cells preferentially induces lymphoid and myeloid leukemia, respectively. They show that mouse and human leukemias with DNMT3A mutations have reduced DNA methylation predominantly at hematopoietic enhancer regions.


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Total versus partial splenectomy in pediatric hereditary spherocytosis: A systematic review and meta-analysis

Abstract

To compare the clinical effectiveness of total splenectomy (TS) or partial splenectomy (PS) in pediatric hereditary spherocytosis, a systematic review and meta-analysis was performed (PROSPERO registration CRD42015030056). There were 14 observational studies comparing pre- and postoperative hematologic parameters. Secondary outcomes include in-hospital infections, surgical complications, symptomatic recurrence, and biliary disease. TS is more effective than PS to increase hemoglobin (3.6 g/dl vs. 2.2 g/dl) and reduce reticulocytes (12.5% vs. 6.5%) after 1 year; outcomes following PS are stable for at least 6 years. There were no cases of overwhelming postsplenectomy sepsis. A population-based patient registry is needed for long-term follow-up.

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Coping with a newly diagnosed high-grade glioma: patient-caregiver dyad effects on quality of life

Abstract

Patients with high-grade gliomas (HGG) and their caregivers have to confront a very aggressive disease that produces major lifestyle disruptions. There is an interest in studying the ability of patients and their caregivers to cope with the difficulties that affect quality of life (QoL). We examine, in a sample of patient-caregiver dyads in the specific context of newly diagnosed cases of HGG, whether the QoL of patients and caregivers is influenced by the coping processes they and their relatives use from a specific actor–partner interdependence model (APIM). This cross-sectional study involved 42 dyads with patients having recent diagnoses of HGG and assessed in the time-frame between diagnosis and treatment initiation. The self-reported data included QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology QoL), emotional status, and coping strategies (BriefCope). The APIM was used to test the dyadic effects of coping strategies on QoL. Coping strategies, such as social support, avoidance, and problem solving, exhibited evidence of either an actor effect (degree to which the individual's coping strategies are associated with their own QoL) or partner effect (degree to which the individual's coping strategies are associated with the QoL of the other member of the dyad) for patients or caregivers. For positive-thinking coping strategies, actor and partner effect were not observed. This study emphasizes that the QoL for patients and their caregivers was directly related to the coping strategies they used. This finding suggests that targeted interventions should be offered to help patients and their relatives to implement more effective coping strategies.

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Pencil-beam scanning for pediatric rhabdomyosarcoma: Promise and precautions

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Comparison of clinical features and outcomes in patients with extraskeletal versus skeletal localized Ewing sarcoma: A report from the Children's Oncology Group

Abstract

Background

The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES.

Methods

Patients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan–Meier method, compared using the log-rank test, and modeled using Cox multivariate regression.

Results

Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P < 0.001), less likely to have tumors >8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50–0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS.

Conclusion

Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.

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[Measures of parental stress in cases of pediatric cancer].

Related Articles

[Measures of parental stress in cases of pediatric cancer].

Bull Cancer. 2016 Jun 9;

Authors: Labrell F, Chevignard M, Câmara Costa H

Abstract
This paper aims firstly to introduce a definition of parental stress (PS) and to detail the criteria of PS in case of pediatric cancers. Several reports have shown that pediatric cancers lead to posttraumatic stress symptoms (PTSS) for all parents and induce stress trajectories throughout diagnosis, treatment and recovery or relapse. Secondly, several predictors of SP are presented, such as parent's perceptions of children's medical treatment, psychological characteristics (e.g. anxiety) and sociodemographic factors. Lastly, several measures of PS are reviewed, which underline the existence of specific tools aimed at evaluating PS in pediatric cancers; however, the availability of a French version of these tools remains scarce. This review advocates systematic measures of PS in order to provide better care for children with cancer through the improvement of their family's feelings about the injury.

PMID: 27291717 [PubMed - as supplied by publisher]

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Ascites modulates cancer cell behavior, contributing to tumor heterogeneity in ovarian cancer

Abstract

The ascites of cancer is a unique tumor-microenvironment, providing a physical structure for the accumulation of cellular and acellular components. Ascites is initiated and maintained by physical and biological factors resulting from underlying disease and forms an ecosystem that contributes to disease progression. It has been demonstrated that the cellular contents and the molecular signatures of ascites change continuously, during the course of a disease. Over the last decade, increasing attention has been given to the characterization of components of ascites and their role in the progression of ovarian cancer, the most malignant gynecologic cancer in women. This review will discuss the role of ascites in disease progression, in terms of modulating cancer cell behavior and contributing to tumor heterogeneity from molecular levels to clinical implication in ovarian cancer.

This article is protected by copyright. All rights reserved.

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LAG-3, an important immune checkpoint in cancer

Abstract

Immunotherapy has recently become widely used in lung cancer. Many oncologists are focused on cytotoxic T lymphocyte antigen-4 (CTLA-4), programmed cell death ligand-1 (PD-L1), and programmed cell death-1 (PD-1). Immunotherapy targeting the PD-1/PD-L1 checkpoints has shown promising efficacy in non-small cell lung cancer (NSCLC), but questions remain to be answered. Among them is whether the simultaneous inhibition of other checkpoints could improve outcomes. Lymphocyte-activation gene-3 (LAG-3) is another vital checkpoint that may have a synergistic interaction with PD-1/PD-L1. Here we review the LAG-3 function in cancer, clinical trials with agents targeting LAG-3, and the correlation of LAG-3 with other checkpoints.

This article is protected by copyright. All rights reserved.

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Framing research for state policymakers who place a priority on cancer

Abstract

Purpose

Despite the potential for reducing the cancer burden via state policy change, few data exist on how best to disseminate research information to influence state legislators' policy choices. We explored: (1) the relative importance of core framing issues (source, presentation, timeliness) among policymakers who prioritize cancer and those who do not prioritize cancer and (2) the predictors of use of research in policymaking.

Methods

Cross-sectional data were collected from US state policymakers (i.e., legislators elected to state houses or senates) from January through October 2012 (n = 862). One-way analysis of variance was performed to investigate the association of the priority of cancer variable with outcome variables. Multivariate logistic regression models examined predictors of the influence of research information.

Results

Legislators who prioritized cancer tended to rate characteristics that make research information useful higher than those who did not prioritize cancer. Among differences that were statistically significant were three items in the "source" domain (relevance, delivered by someone respected, supports one's own position), one item in the "presentation" domain (telling a story related to constituents) and two items in the "timeliness" domain (high current state priority, feasible when information is received). Participants who prioritized cancer risk factors were 80 % more likely to rate research information as one of their top reasons for choosing an issue on which to work.

Conclusions

Our results suggest the importance of narrative forms of communication and that research information needs to be relevant to the policymakers' constituents in a brief, concise format.

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Chemotherapy Options for Poor Responders to Neoadjuvant Chemotherapy for Orbital Granulocytic Sarcoma

Opinion statement

Granulocytic sarcoma (GS) is a rare manifestation of myeloid proliferation, characterized by formation of a mass comprised of immature cells of myeloid origin. Orbital granulocytic sarcoma is rarer still, with only a small fraction of GS patients having orbital involvement. Given the rarity of orbital GS, no unified therapy plan has been identified, as large prospective trials are not feasible, but it is widely accepted that patients with GS ought to be treated with systemic intensive chemotherapy consistent with standard of care regimens for acute myelogenous leukemia (AML) or chronic myelogenous leukemia (CML). Development of a treatment plan for GS in poor responders involves a systemic leukemia plan as novel therapeutics have not been investigated for treatment GS per se, but used more widely for AML. GS is most commonly associated with AML and thus will be addressed in that context in this review. Patients with GS associated with CML should receive CML-specific therapy. When conventional and traditional cytotoxic GS/AML chemotherapy regimens are insufficient, patients often require a combination of novel therapeutics, stem cell transplantation (SCT), and radiation. Much of the recent advancement in AML therapy, as well as in AML translational research, has been in targeting molecular facets of the disease and enabling more specificity with treatment. The aim of treating patients for whom conventional treatment was unsuccessful with personalized therapy has not yet been realized, but many of the novel therapeutics reviewed below have demonstrated promise and are cause for optimism. In our center, when a GS/AML patient is refractory to frontline therapy, we rely on novel chemotherapy therapeutic options as outlined below.

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American Journal of Cancer Research; +21 new citations

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

American Journal of Cancer Research

These pubmed results were generated on 2016/06/14

PubMed comprises more than 24 million citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

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Psychosocial morbidity in women with abnormal cervical cytology managed by cytological surveillance or initial colposcopy: longitudinal analysis from the TOMBOLA randomised trial

Abstract

Objective

To compare psychosocial outcomes (follow-up related worries and satisfaction with follow-up related information and support) over 30 months of two alternative management policies for women with low-grade abnormal cervical cytology.

Methods

Women aged 20–59 years with low-grade cytological abnormalities detected in the National Health Service Cervical Screening Programme were randomised to cytological surveillance or initial colposcopy. A total of 3399 women who completed psychosocial questionnaires at recruitment were invited to complete questionnaires at 12, 18, 24 and 30 months. Linear mixed models were used to investigate differences between arms in the two psychosocial outcomes. Each outcome had a maximum score of 100, and higher scores represented higher psychosocial morbidity.

Results

On average, over 30 months, women randomised to colposcopy scored 2.5 points (95%CI −3.6 to −1.3) lower for follow-up related worries than women randomised to cytological surveillance. Women in the colposcopy arm also scored significantly lower for follow-up related satisfaction with information and support (−2.4; −3.3 to −1.4) over 30 months. For both outcomes, the average difference between arms was greatest at 12th- and 18th-month time points. These differences remained when the analysis was stratified by post-school education.

Conclusions

Women with low-grade cytology, irrespective of their management, have substantial initial psychosocial morbidity that reduces over time. Implementation of newer screening strategies, which include surveillance, such as primary HPV screening, need to consider the information and support provided to women. © 2016 The Authors. Psycho-Oncology published by John Wiley & Sons Ltd.

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The trajectory of the blood DNA methylome ageing rate is largely set before adulthood: evidence from two longitudinal studies

Abstract

The epigenetic clock, defined as the DNA methylome age (DNAmAge), is a candidate biomarker of ageing. In this study, we aimed to characterize the behaviour of this marker during the human lifespan in more detail using two follow-up cohorts (the Young Finns study, calendar age i.e. cAge range at baseline 15–24 years, 25-year-follow-up, N = 183; The Vitality 90+ study, cAge range at baseline 19–90 years, 4-year-follow-up, N = 48). We also aimed to assess the relationship between DNAmAge estimate and the blood cell distributions, as both of these measures are known to change as a function of age. The subjects' DNAmAges were determined using Horvath's calculator of epigenetic cAge. The estimate of the DNA methylome age acceleration (Δ-cAge-DNAmAge) demonstrated remarkable stability in both cohorts: the individual rank orders of the DNAmAges remained largely unchanged during the follow-ups. The blood cell distributions also demonstrated significant intra-individual correlation between the baseline and follow-up time points. Interestingly, the immunosenescence-associated features (CD8+CD28− and CD4+CD28− cell proportions and the CD4/CD8 cell ratio) were tightly associated with the estimate of the DNA methylome age. In summary, our data demonstrate that the general level of Δ-cAge-DNAmAge is fixed before adulthood and appears to be quite stationary thereafter, even in the oldest-old ages. Moreover, the blood DNAmAge estimate seems to be tightly associated with ageing-associated shifts in blood cell composition, especially with those that are the hallmarks of immunosenescence. Overall, these observations contribute to the understanding of the longitudinal aspects of the DNAmAge estimate.

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Germline mutations of BRCA1 gene exon 11 are not associated with platinum response neither with survival advantage in patients with primary ovarian cancer: understanding the clinical importance of one of the biggest human exons. A study of the Tumor Bank Ovarian Cancer (TOC) Consortium

Abstract

Germline mutations in BRCA1 gene have been reported in up to 20 % of epithelial ovarian cancer (EOC) patients. Distinct clinical characteristics have been attributed to this special EOC population. We hypothesized that mutations in different BRCA1 gene exons may differently affect the clinical course of the disease. The aim of this study was to analyze, in a large cohort of primary EOCs, the clinical impact of mutations in BRCA1 gene exon 11, the largest exon of the gene sequence encoding the 60 % of BRCA1 protein. Two hundred sixty-three primary EOC patients, treated between 2000 and 2008 at Charité University Hospital of Berlin, were included. Patients' blood samples were obtained from the Tumor Ovarian Cancer (TOC) Network (www.toc-network.de). Direct sequencing of BRCA1 gene exon 11 was performed for each patient to detect mutations. Based on their BRCA1 exon 11 mutational status, patients were compared regarding clinico-pathological variables and survival. Mutations in BRCA1 exon 11 were found in 18 out of 263 patients (6.8 %). Further 10/263 (3.8 %) cases showed variants of uncertain significance (VUS). All exon 11 BRCA1-positive tumors (100 %) were Type 2 ovarian carcinomas (p = 0.05). Age at diagnosis was significantly younger in Type 2 exon 11 mutated patients (p = 0.01). On multivariate analysis, BRCA1 exon 11 mutational status was not found to be an independent predictive factor for optimal cytoreduction, platinum response, or survival. Mutations in BRCA1 gene exon 11 seem to predispose women to exclusively develop a Type 2 ovarian cancer at younger age. Exon 11 BRCA1-mutated EOC patients showed distinct clinico-pathological features but similar clinical outcome with respect to sporadic EOC patients.

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