Τετάρτη 8 Νοεμβρίου 2017

Healthcare Utilization and Costs During the Initial Phase of Care Among Elderly Women With Breast Cancer

Background: Understanding the patterns of healthcare utilization and costs during the initial phase of care (12 months after breast cancer [BC] diagnosis) in older women (aged ≥65 years) is crucial in the allocation of Medicare resources. The objective of this study was to determine healthcare utilization and costs during the initial phase of care in older, female, Medicare fee-for-service beneficiaries diagnosed with BC, and to determine the factors associated with higher costs. Methods: A retrospective observational study using the SEER-Medicare linked database was conducted in 69,307 women aged ≥66 years diagnosed with primary incident BC in 2003–2009 to determine healthcare utilization, average costs, and costs for specific services during the initial phase of care. Generalized linear model regression was conducted to identify the factors associated with higher costs in a multivariate framework. Results: A total of 96% of women were treated with surgery during the initial phase of BC care, whereas 21% and 54% underwent chemotherapy and radiotherapy, respectively. Costs during the initial phase of care totalled $28,075 in 2012 USD, comprising $13,344 for physician services and $7,456 for outpatient services. Factors associated with higher costs during the initial phase of care were younger age (66–69 years), African American race, higher household income, advanced stages of BC, initial BC treatment, higher number of primary care physician visits, and presence of comorbidities and/or a mental condition. Conclusions: The economic burden of BC is substantial during the initial phase of care. Physician and outpatient services accounted for the highest proportion of costs. Predisposing factors, need-related factors, healthcare use, and external environmental healthcare factors significantly predicted costs during the initial phase of care.



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Do Published Data in Trials Assessing Cancer Drugs Reflect the Real Picture of Efficacy and Safety?

Background: The reporting quality of publications is of vital importance to ensure accurate evidence dissemination. This study aimed to compare the consistency of results reporting between the ClinicalTrials.gov results database and the respective matching publications. Methods: We identified 323 phase III/IV cancer drug trials with a randomized controlled design and searched PubMed for publications in a 50% random sample (n=160). Data were extracted independently from ClinicalTrials.gov and publications. A scoring system was applied to determine characteristics associated with reporting quality. Results: Of 117 reviewed trials with publications, result reporting was significantly more complete in ClinicalTrials.gov for efficacy measurement (92.3% vs 90.6%), serious adverse events (SAEs; 100% vs 43.6%), and other adverse events (OAEs; 100% vs 62.4%). For trials with both posted and published results for design information (n=117), efficacy measurements (n=98), SAEs (n=51), and OAEs (n=73), discrepancies were found in 16 (13.7%), 38 (38.8%), 26 (51.0%), and 54 (74.0%) trials, respectively. Overreporting of treatment effects (7 trials) and alteration of primary end points favoring statistically significant outcomes (11 trials) were the major discrepancies in efficacy reporting; incomplete (66 trials) and underreporting (20 trials) of SAEs were the predominant issues in benefit/risk reporting. Median quality score was 21 (range, 14–28). Trials that had parallel assignment, were phase IV, had primary funding by industry, were completed after 2009, and had earlier results posted possessed better reporting quality. Conclusions: Although most trials showed reasonable completeness and consistency, some discrepancies are prevalent and persistent, jeopardizing evidence-based decision-making. Our findings highlight the need to consult results systematically from both ClinicalTrials.gov and publications.



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NCCN News



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Oncology Research Program



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Who's Watching the Kids?



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Addition of Definitive Radiotherapy to Chemotherapy in Patients With Newly Diagnosed Metastatic Nasopharyngeal Cancer

Background: Management of metastatic (M1) nasopharyngeal cancer (NPC) is controversial; data suggest high overall survival (OS) rates with definitive chemoradiotherapy (CRT). Herein, we evaluated OS in patients with M1 NPC undergoing chemotherapy alone versus CRT. Methods: The National Cancer Data Base was queried for M1 NPC cases. Patients undergoing no/unknown chemotherapy and/or with unknown/nondefinitive radiotherapy (RT) doses (<60 Gy) were excluded. Logistic regression analysis ascertained clinical factors associated with RT administration. Kaplan-Meier analysis evaluated OS between both cohorts; Cox proportional hazards modeling assessed factors associated with OS. Survival was then evaluated between matched populations using inverse-probability–weighted regression adjustment. OS between groups was also measured in patients surviving ≥1 and ≥3 years to address bias from poor-prognostic subsets (eg, widely disseminated disease), and those receiving CRT ≤30 and ≤60 days of each other (surrogates for concurrent CRT) versus >30 and >60 days (sequential) of each other. Results: Of 555 patients, 296 (53%) received chemotherapy alone and 259 (47%) underwent CRT. Patients undergoing CRT more often had private insurance (P=.001) and lived in areas with higher education levels (P=.028). Median OS in the chemotherapy-only and CRT cohorts were 13.7 and 25.8 months, respectively (P<.001); differences persisted between matched populations (P<.001). On multivariate analysis, receipt of additional RT independently predicted for improved OS (P<.001). OS differences between cohorts remained apparent when evaluating patients surviving for ≥1 (P<.001) and ≥3 (P=.002) years. Patients who received concurrent or sequential CRT displayed improved OS over those receiving chemotherapy alone, for both the 30-day (P<.001) and 60-day cutoffs (P<.001). Conclusions: Patients with M1 NPC undergoing definitive RT and chemotherapy experienced higher survival than those receiving chemotherapy alone. Risk stratification and patient selection for such combined modality interventions is critical.



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Letter to the Editor: Defining "Standard of Care"



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Emerging Role of CAR T Cells in Non-Hodgkin's Lymphoma

Adoptive T-cell therapy with chimeric antigen receptor T cells (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies, and several groups have published positive results using anti-CD19 CAR-Ts for the treatment of B-cell acute lymphoblastic leukemia. Recently, new data from clinical trials have demonstrated the benefits of CAR-T therapy in the non-Hodgkin's lymphoma (NHL) setting. This review describes some of the most recent and promising advances in engineered T-cell therapy, with particular emphasis on the clinical benefits of NHL treatment.



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Sexual Health Is Paramount in the Counseling of Women at Risk for Breast or Ovarian Cancer Undergoing Risk-Reducing Surgery



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Nonadherence to Statins and Antihypertensives and Hospitalizations Among Elderly Medicare Beneficiaries With Incident Cancer

Background: Incident cancer diagnosis may increase the risk of coronary artery disease (CAD)–related hospitalizations, especially in older individuals. Adherence to statins and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs)/β-blockers reduces CAD-related hospitalizations. This study examined the relationship between medication adherence and CAD-related hospitalizations immediately following cancer diagnosis. Patients and Methods: A retrospective observational longitudinal study was conducted using SEER-Medicare data. Elderly Medicare fee-for-service beneficiaries with preexisting CAD and incident breast, colorectal, or prostate cancer (N=12,096) were observed for 12 months before and after cancer diagnosis. Hospitalizations measured every 120 days were categorized into CAD-related hospitalization, other hospitalization, and no hospitalization. Medication adherence was categorized into 5 mutually exclusive groups: adherent to both statins and ACEIs/ARBs/β-blockers (reference group), not adherent to both statins and ACEIs/ARBs/β-blockers, adherent to either statins or ACEIs/ARBs/β-blockers, use of one medication class and adherent to that class, and use of one medication class and not adherent to that class. The relationship between medication adherence and hospitalization was analyzed using repeated measures multinomial logistic regressions. Inverse probability treatment weights were used to control for observed group differences among medication adherence categories. Results: Adherence to both statins and ACEIs/ARBs/β-blockers was estimated at 31.2% during the 120-day period immediately following cancer diagnosis; 13.7% were not adherent to both medication classes during the same period, and 27.4% had CAD-related hospitalizations immediately after cancer diagnosis, which declined to 10.6% during the last 4 months of the postdiagnosis period. In the adjusted analyses, those not adherent to both statins and ACEIs/ARBs/β-blockers were more likely to have CAD-related hospitalization compared with those adherent to both medication classes (adjusted odds ratio, 1.82; 95% CI, 1.72–1.92; P<.0001). Conclusions: Given the complexity of interaction between CAD and cancer, it is important to routinely monitor medication adherence in general clinical practice and to provide linkages to support services that can increase medication adherence.



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Time to Change: Supporting Sexual and Gender Minority People--An Underserved, Understudied Cancer Risk Population



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Sexual and Gender Minority Issues Across NCCN Guidelines: Results From a National Survey

Background: The lesbian, gay, bisexual, transgender, queer/questioning (LGBTQ) population is at higher risk for multiple types of cancers compared with the heterosexual population. Expert NCCN panels lead the nation in establishing clinical practice guidelines addressing cancer prevention, early detection, and treatment of cancer sites and populations. Given the emergence of new data identifying cancer disparities in the LGBTQ population, this study examined the inclusion of medical and/or psychosocial criteria unique to LGBTQ within NCCN Guidelines. Methods: Data were collected for 32 of the 50 NCCN Guidelines. Results: NCCN panel members reported that neither sexual orientation (84%) nor gender identity (94%) were relevant to the focus of their guidelines; 77% responded that their panels currently do not address LGBTQ issues, with no plans to address them in the future. Conclusions: Greater consideration should be given to the needs of LGBTQ patients across the cancer care continuum. Given that research concerning LGBTQ and cancer is in its infancy, additional empirical and evidence-based data are needed to bolster further integration of LGBTQ-specific criteria into clinical care guidelines.



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Exceptional Response to Temsirolimus in a Metastatic Clear Cell Renal Cell Carcinoma With an Early Novel MTOR-Activating Mutation

mTOR pathway inhibitors are important drugs for the treatment of advanced renal cell carcinoma (RCC). However, no valid predictive markers have been identified to guide treatment selection and identify patients who are sensitive to these drugs. Mutations activating the mTOR pathway have been suggested to predict response; however, their predictive value is still unclear. Here, we present the genomic and functional characterization of a patient with metastatic clear cell RCC (ccRCC) who experienced a partial response to temsirolimus after a poor response to 2 previous lines of treatment. At the time of publication, the patient was disease-free 8 years after temsirolimus treatment. Multiregion whole-exome sequencing (WES) on 3 regions of the primary tumor, 1 metastasis, and blood revealed tumor mutations in driver genes in ccRCC: a missense mutation in VHL (p.W88L), a loss-of-function mutation in BAP1 (p.E454Rfs*15), and a novel missense mutation in MTOR (p.Y1974H). The MTOR mutation was present in all tumor regions, with similar allele frequency as the VHL mutation, and in vitro functional assessment of the MTOR variant demonstrated that it increased mTORC1 activity. Consistently, immunohistochemistry in the tumor samples demonstrated increased levels of phospho-S6. In conclusion, multiregion WES identified a novel MTOR mutation acquired early during tumor development as the event leading to a high sensitivity to temsirolimus treatment. This study supports tumor multiregion sequencing to detect truncal mutations in the mTOR pathway to identify patients sensitive to mTOR inhibitors.



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Apoyo con Carino: Strategies to Promote Recruiting, Enrolling, and Retaining Latinos in a Cancer Clinical Trial

Background: We present and describe tailored strategies to address known barriers to minority participation in clinical trial research. The strategies used allowed our team to engage communities and successfully recruit, enroll, and retain a diverse underserved population of Latinos with advanced cancer for this clinical trial. Methods: Participants were recruited from 3 urban and 7 rural sites. We identified 4 critical barriers to recruitment for this underserved population: (1) mistrust; (2) language and communication barriers; (3) lack of access to academic cancer center; and (4) inability to participate due to transportation, childcare, or work responsibilities. We developed tailored strategies to engage referring sites and patients to participate in the clinical trial. Results: We identified 318 potentially eligible participants; 34 were found to be ineligible, and 223 consented to participate in the study, representing a 79.0% enrollment rate. All patients (100%) self-identified as Latino, and 47.5% spoke Spanish as their primary language. Patients were socioeconomically disadvantaged: 53.6% had an annual income <$15,000 USD, and 50.2% had less than a high school education. A total of 177 participants completed the 3-month follow-up; 26 died before the 3-month follow interview, and 20 did not complete the follow-up evaluation (9% withdrawal rate). Conclusions: Our community-informed strategies were highly effective for recruiting, enrolling, and retaining an underserved diverse population of Latinos. The barriers we identified and the strategies we used have the potential to inform research to increase minority participation in cancer clinical trials. ClinicalTrials.gov identifier: NCT01695382



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Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.



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Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.



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NCCN Guidelines Insights: Central Nervous System Cancers, Version 1.2017

For many years, the diagnosis and classification of gliomas have been based on histology. Although studies including large populations of patients demonstrated the prognostic value of histologic phenotype, variability in outcomes within histologic groups limited the utility of this system. Nonetheless, histology was the only proven and widely accessible tool available at the time, thus it was used for clinical trial entry criteria, and therefore determined the recommended treatment options. Research to identify molecular changes that underlie glioma progression has led to the discovery of molecular features that have greater diagnostic and prognostic value than histology. Analyses of these molecular markers across populations from randomized clinical trials have shown that some of these markers are also predictive of response to specific types of treatment, which has prompted significant changes to the recommended treatment options for grade III (anaplastic) gliomas.



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Truth in Advertising: Do Clinical Trial Publications Tell It All?



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Effects of Proton Center Closure on Pediatric Case Volume and Resident Education at an Academic Cancer Center

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James Galle, David Long, Tim Lautenschlaeger, Richard Zellars, Gordon Watson, Susannah Ellsworth
PurposeChanges in radiation oncology infrastructure influence referral/practice patterns, which may affect resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education.MethodsThis was a review of 412 consecutive pediatric (≤18 years) cases treated at a single institution from 2012-2016. Residents' Accreditation Council for Graduate Medical Education case logs for the same years were also analyzed. Characteristics of the patient population and resident case volumes before and after closure of the PTC are reported.ResultsOverall pediatric new starts declined by about 50%, from 35-70 per 6 months in 2012-2014 to 22-30 per 6 months in 2015-2016. CNS case volume declined sharply, from 121 patients treated in 2012-2015 to 18 patients in 2015-2016. In 2012-2014, our institution treated 36, 24, and 17 patients for medulloblastoma/intracranial PNET, ependymoma, and low grade glioma (LGG), respectively, compared to 0, 1, and 1 patients in 2015-2016. 49 patients were treated with craniospinal radiation (CSI) from 2012-2014, while only 2 patients underwent CSI between 2015-2016. Hematologic malignancy patient volume and use of total body irradiation remained relatively stable. Patients treated when the PTC was open were significantly younger (9.1 vs 10.7 years, p=0.010) and their radiation courses were longer (35.4 vs 20.9 days, p<0.0001) than those treated after its closure. Resident case logs showed only a small decline in total pediatric cases, as the percentage of pediatric cases covered by residents increased after PTC closure; however, residents logged fewer CNS cases after PTC closure vs. before.ConclusionsOverall pediatric case volume decreased following PTC closure, as did the number of patients treated for potentially curable CNS tumors. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become increasingly concentrated at specialized centers.

Teaser

Changes in radiation oncology infrastructure influence referral/practice patterns and resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education. We demonstrate a sharp decrease in overall pediatric cases and potentially curable CNS tumors treated at our center following PTC closure. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become concentrated at specialized centers.


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Delineation of neck clinical target volume specific to nasopharyngeal carcinoma based on lymph node distribution and the international consensus guidelines

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Li Lin, Yao Lu, Xiao-Ju Wang, Hui Chen, Sha Yu, Jiao Tian, Guan-Qun Zhou, Lu-Lu Zhang, Zhen-Yu Qi, Jiang Hu, Jun Ma, Ying Sun
PurposeTo establish regional lymph node (LN) distribution probability map and draw neck clinical target volume (CTV) specific to nasopharyngeal carcinoma (NPC).Methods and MaterialsOne thousand patients with pathologically-proven NPC between January 2010 and December 2011 were enrolled. Center points of LNs with a minimal axial diameter (MID) ≥ 4 mm were marked on one single treatment planning computed tomography scan. Neck node levels I – X based on the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. Relationships between LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to NPC.ResultsA total of 10651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, the majority of node levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% (11/83) cases had LNs beyond the posteromedial border; for level VIIa (retropharyngeal LN), 1.5% (12/819) cases had LNs above the cranial boundary and 5 cases had LNs emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of level Ib, II, IVa and Vc. Accordingly, a new level VIIc was proposed to include medial group of retropharyngeal LNs, and moderate extended boundaries for levels Vb and VIIa were recommended, while reduced boundaries were possibly adaptable for levels Ib, II, IV and Vc.ConclusionThe majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. While, we propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggested that boundaries for levels Ib, II, IV and Vc might be reduced.

Teaser

Neck node distribution probability maps and curves for NPC were established based on 10651 nodes from 956 patients. Relationships between node distribution and international consensus guidelines for delineation of neck node levels were analyzed. Our findings demonstrate that the majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggest that boundaries for levels Ib, II, IV and Vc might be reduced.


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Dietary nutrient intake, ethnicity, and epigenetic silencing of lung cancer genes detected in sputum in New Mexican smokers

Lung cancer (LC) gene methylation detected in sputum assesses field cancerization and predicts LC incidence. Hispanic smokers have higher LC susceptibility compared to non-Hispanic Whites (NHW). We aimed to identify novel dietary nutrients affecting LC gene methylation and determine the degree of ethnic disparity in methylation explained by diet. Dietary intakes of 139 nutrients were assessed using a validated Harvard food frequency questionnaire in 327 Hispanics and 1502 NHWs from the Lovelace Smokers cohort (LSC). Promoter methylation of twelve LC genes was assessed in sputum DNA. A global association was identified between dietary intake and gene methylation (Ppermutation=0.003). Seventeen nutrient measurements were identified with magnitude of association with methylation greater than that seen for folate. A stepwise approach identified B12, manganese, sodium, and saturated fat as the minimally correlated set of nutrients whose optimal intakes could reduce the methylation by 36% (Ppermutation<0.001). Six protective nutrients included vitamin D, B12, manganese, magnesium, niacin, and folate. Approximately 42% of ethnic disparity in methylation was explained by insufficient intake of protective nutrients in Hispanics compared to NHWs. Functional validation of protective nutrients showed an enhanced DNA repair capacity towards double-strand DNA breaks, a mechanistic biomarker strongly linked to acquisition of LC gene methylation in smokers. Dietary intake is a major modifiable factor for preventing promoter methylation of LC genes in smokers' lungs. Complex dietary supplements could be developed based on these protective nutrients for LC chemoprevention in smokers. Hispanic smokers may benefit the most from this complex for reducing their LC susceptibility.



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Healthcare Utilization and Costs During the Initial Phase of Care Among Elderly Women With Breast Cancer

Background: Understanding the patterns of healthcare utilization and costs during the initial phase of care (12 months after breast cancer [BC] diagnosis) in older women (aged ≥65 years) is crucial in the allocation of Medicare resources. The objective of this study was to determine healthcare utilization and costs during the initial phase of care in older, female, Medicare fee-for-service beneficiaries diagnosed with BC, and to determine the factors associated with higher costs. Methods: A retrospective observational study using the SEER-Medicare linked database was conducted in 69,307 women aged ≥66 years diagnosed with primary incident BC in 2003–2009 to determine healthcare utilization, average costs, and costs for specific services during the initial phase of care. Generalized linear model regression was conducted to identify the factors associated with higher costs in a multivariate framework. Results: A total of 96% of women were treated with surgery during the initial phase of BC care, whereas 21% and 54% underwent chemotherapy and radiotherapy, respectively. Costs during the initial phase of care totalled $28,075 in 2012 USD, comprising $13,344 for physician services and $7,456 for outpatient services. Factors associated with higher costs during the initial phase of care were younger age (66–69 years), African American race, higher household income, advanced stages of BC, initial BC treatment, higher number of primary care physician visits, and presence of comorbidities and/or a mental condition. Conclusions: The economic burden of BC is substantial during the initial phase of care. Physician and outpatient services accounted for the highest proportion of costs. Predisposing factors, need-related factors, healthcare use, and external environmental healthcare factors significantly predicted costs during the initial phase of care.



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NCCN News



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Who's Watching the Kids?



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Addition of Definitive Radiotherapy to Chemotherapy in Patients With Newly Diagnosed Metastatic Nasopharyngeal Cancer

Background: Management of metastatic (M1) nasopharyngeal cancer (NPC) is controversial; data suggest high overall survival (OS) rates with definitive chemoradiotherapy (CRT). Herein, we evaluated OS in patients with M1 NPC undergoing chemotherapy alone versus CRT. Methods: The National Cancer Data Base was queried for M1 NPC cases. Patients undergoing no/unknown chemotherapy and/or with unknown/nondefinitive radiotherapy (RT) doses (<60 Gy) were excluded. Logistic regression analysis ascertained clinical factors associated with RT administration. Kaplan-Meier analysis evaluated OS between both cohorts; Cox proportional hazards modeling assessed factors associated with OS. Survival was then evaluated between matched populations using inverse-probability–weighted regression adjustment. OS between groups was also measured in patients surviving ≥1 and ≥3 years to address bias from poor-prognostic subsets (eg, widely disseminated disease), and those receiving CRT ≤30 and ≤60 days of each other (surrogates for concurrent CRT) versus >30 and >60 days (sequential) of each other. Results: Of 555 patients, 296 (53%) received chemotherapy alone and 259 (47%) underwent CRT. Patients undergoing CRT more often had private insurance (P=.001) and lived in areas with higher education levels (P=.028). Median OS in the chemotherapy-only and CRT cohorts were 13.7 and 25.8 months, respectively (P<.001); differences persisted between matched populations (P<.001). On multivariate analysis, receipt of additional RT independently predicted for improved OS (P<.001). OS differences between cohorts remained apparent when evaluating patients surviving for ≥1 (P<.001) and ≥3 (P=.002) years. Patients who received concurrent or sequential CRT displayed improved OS over those receiving chemotherapy alone, for both the 30-day (P<.001) and 60-day cutoffs (P<.001). Conclusions: Patients with M1 NPC undergoing definitive RT and chemotherapy experienced higher survival than those receiving chemotherapy alone. Risk stratification and patient selection for such combined modality interventions is critical.



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Letter to the Editor: Defining "Standard of Care"



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Emerging Role of CAR T Cells in Non-Hodgkin's Lymphoma

Adoptive T-cell therapy with chimeric antigen receptor T cells (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies, and several groups have published positive results using anti-CD19 CAR-Ts for the treatment of B-cell acute lymphoblastic leukemia. Recently, new data from clinical trials have demonstrated the benefits of CAR-T therapy in the non-Hodgkin's lymphoma (NHL) setting. This review describes some of the most recent and promising advances in engineered T-cell therapy, with particular emphasis on the clinical benefits of NHL treatment.



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Sexual Health Is Paramount in the Counseling of Women at Risk for Breast or Ovarian Cancer Undergoing Risk-Reducing Surgery



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Nonadherence to Statins and Antihypertensives and Hospitalizations Among Elderly Medicare Beneficiaries With Incident Cancer

Background: Incident cancer diagnosis may increase the risk of coronary artery disease (CAD)–related hospitalizations, especially in older individuals. Adherence to statins and/or angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin II receptor blockers (ARBs)/β-blockers reduces CAD-related hospitalizations. This study examined the relationship between medication adherence and CAD-related hospitalizations immediately following cancer diagnosis. Patients and Methods: A retrospective observational longitudinal study was conducted using SEER-Medicare data. Elderly Medicare fee-for-service beneficiaries with preexisting CAD and incident breast, colorectal, or prostate cancer (N=12,096) were observed for 12 months before and after cancer diagnosis. Hospitalizations measured every 120 days were categorized into CAD-related hospitalization, other hospitalization, and no hospitalization. Medication adherence was categorized into 5 mutually exclusive groups: adherent to both statins and ACEIs/ARBs/β-blockers (reference group), not adherent to both statins and ACEIs/ARBs/β-blockers, adherent to either statins or ACEIs/ARBs/β-blockers, use of one medication class and adherent to that class, and use of one medication class and not adherent to that class. The relationship between medication adherence and hospitalization was analyzed using repeated measures multinomial logistic regressions. Inverse probability treatment weights were used to control for observed group differences among medication adherence categories. Results: Adherence to both statins and ACEIs/ARBs/β-blockers was estimated at 31.2% during the 120-day period immediately following cancer diagnosis; 13.7% were not adherent to both medication classes during the same period, and 27.4% had CAD-related hospitalizations immediately after cancer diagnosis, which declined to 10.6% during the last 4 months of the postdiagnosis period. In the adjusted analyses, those not adherent to both statins and ACEIs/ARBs/β-blockers were more likely to have CAD-related hospitalization compared with those adherent to both medication classes (adjusted odds ratio, 1.82; 95% CI, 1.72–1.92; P<.0001). Conclusions: Given the complexity of interaction between CAD and cancer, it is important to routinely monitor medication adherence in general clinical practice and to provide linkages to support services that can increase medication adherence.



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Time to Change: Supporting Sexual and Gender Minority People--An Underserved, Understudied Cancer Risk Population



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Apoyo con Carino: Strategies to Promote Recruiting, Enrolling, and Retaining Latinos in a Cancer Clinical Trial

Background: We present and describe tailored strategies to address known barriers to minority participation in clinical trial research. The strategies used allowed our team to engage communities and successfully recruit, enroll, and retain a diverse underserved population of Latinos with advanced cancer for this clinical trial. Methods: Participants were recruited from 3 urban and 7 rural sites. We identified 4 critical barriers to recruitment for this underserved population: (1) mistrust; (2) language and communication barriers; (3) lack of access to academic cancer center; and (4) inability to participate due to transportation, childcare, or work responsibilities. We developed tailored strategies to engage referring sites and patients to participate in the clinical trial. Results: We identified 318 potentially eligible participants; 34 were found to be ineligible, and 223 consented to participate in the study, representing a 79.0% enrollment rate. All patients (100%) self-identified as Latino, and 47.5% spoke Spanish as their primary language. Patients were socioeconomically disadvantaged: 53.6% had an annual income <$15,000 USD, and 50.2% had less than a high school education. A total of 177 participants completed the 3-month follow-up; 26 died before the 3-month follow interview, and 20 did not complete the follow-up evaluation (9% withdrawal rate). Conclusions: Our community-informed strategies were highly effective for recruiting, enrolling, and retaining an underserved diverse population of Latinos. The barriers we identified and the strategies we used have the potential to inform research to increase minority participation in cancer clinical trials. ClinicalTrials.gov identifier: NCT01695382



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Activity of Entrectinib in a Patient With the First Reported NTRK Fusion in Neuroendocrine Cancer

Despite advances in genomic analysis, the molecular origin of neuroendocrine tumors (NETs) is complex and poorly explained by described oncogenes. The neurotrophic TRK family, including NTRK1, 2, and 3, encode the proteins TRKA, TRKB, TRKC, respectively, involved in normal nerve development. Because NETs develop from the diffuse neuroendocrine system, we sought to determine whether NTRK alterations occur in NETs and whether TRK-targeted therapy would be effective. A patient with metastatic well-differentiated NET, likely of the small intestine, was enrolled on the STARTRK2 trial (ClinicalTrials.gov identifier: NCT02568267) and tissue samples were analyzed using an RNA-Seq next-generation sequencing platform. An ETV6:NTRK3 fusion was identified and therapy was initiated with the investigational agent entrectinib, a potent oral tyrosine kinase inhibitor of TRKA, TRKB, and TRKC. Upon treatment with entrectinib, the patient experienced rapid clinical improvement; his tumor response was characterized by initial tumor growth and necrosis. This is the first report of an NTRK fusion in NETs. Our patient's response to entrectinib suggests that NTRK fusions can be important in the pathogenesis of NETs. Recent DNA-based genomic analyses of NETs may have missed NTRK fusions due its large gene rearrangement size and multiple fusion partners. The tumor's initial pseudoprogression may represent a unique response pattern for TRK-targeted therapies. An effort to characterize the prevalence of NTRK fusions in NETs using optimal sequencing technology is important.



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Hairy Cell Leukemia, Version 2.2018, NCCN Clinical Practice Guidelines in Oncology

Hairy cell leukemia (HCL) is a rare type of indolent B-cell leukemia, characterized by symptoms of fatigue and weakness, organomegaly, pancytopenia, and recurrent opportunistic infections. Classic HCL should be considered a distinct clinical entity separate from HCLvariant (HCLv), which is associated with a more aggressive disease course and may not respond to standard HCL therapies. Somatic hypermutation in the IGHV gene is present in most patients with HCL. The BRAF V600E mutation has been reported in most patients with classic HCL but not in those with other B-cell leukemias or lymphomas. Therefore, it is necessary to distinguish HCLv from classic HCL. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of classic HCL.



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Truth in Advertising: Do Clinical Trial Publications Tell It All?



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Effects of Proton Center Closure on Pediatric Case Volume and Resident Education at an Academic Cancer Center

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): James Galle, David Long, Tim Lautenschlaeger, Richard Zellars, Gordon Watson, Susannah Ellsworth
PurposeChanges in radiation oncology infrastructure influence referral/practice patterns, which may affect resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education.MethodsThis was a review of 412 consecutive pediatric (≤18 years) cases treated at a single institution from 2012-2016. Residents' Accreditation Council for Graduate Medical Education case logs for the same years were also analyzed. Characteristics of the patient population and resident case volumes before and after closure of the PTC are reported.ResultsOverall pediatric new starts declined by about 50%, from 35-70 per 6 months in 2012-2014 to 22-30 per 6 months in 2015-2016. CNS case volume declined sharply, from 121 patients treated in 2012-2015 to 18 patients in 2015-2016. In 2012-2014, our institution treated 36, 24, and 17 patients for medulloblastoma/intracranial PNET, ependymoma, and low grade glioma (LGG), respectively, compared to 0, 1, and 1 patients in 2015-2016. 49 patients were treated with craniospinal radiation (CSI) from 2012-2014, while only 2 patients underwent CSI between 2015-2016. Hematologic malignancy patient volume and use of total body irradiation remained relatively stable. Patients treated when the PTC was open were significantly younger (9.1 vs 10.7 years, p=0.010) and their radiation courses were longer (35.4 vs 20.9 days, p<0.0001) than those treated after its closure. Resident case logs showed only a small decline in total pediatric cases, as the percentage of pediatric cases covered by residents increased after PTC closure; however, residents logged fewer CNS cases after PTC closure vs. before.ConclusionsOverall pediatric case volume decreased following PTC closure, as did the number of patients treated for potentially curable CNS tumors. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become increasingly concentrated at specialized centers.

Teaser

Changes in radiation oncology infrastructure influence referral/practice patterns and resident educational experiences. This study aimed to analyze effects of closure of an academic proton treatment center (PTC) on pediatric case volume, distribution, and resident education. We demonstrate a sharp decrease in overall pediatric cases and potentially curable CNS tumors treated at our center following PTC closure. Our findings raise important questions regarding resident training in pediatric radiation oncology as these cases become concentrated at specialized centers.


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Delineation of neck clinical target volume specific to nasopharyngeal carcinoma based on lymph node distribution and the international consensus guidelines

Publication date: Available online 8 November 2017
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Li Lin, Yao Lu, Xiao-Ju Wang, Hui Chen, Sha Yu, Jiao Tian, Guan-Qun Zhou, Lu-Lu Zhang, Zhen-Yu Qi, Jiang Hu, Jun Ma, Ying Sun
PurposeTo establish regional lymph node (LN) distribution probability map and draw neck clinical target volume (CTV) specific to nasopharyngeal carcinoma (NPC).Methods and MaterialsOne thousand patients with pathologically-proven NPC between January 2010 and December 2011 were enrolled. Center points of LNs with a minimal axial diameter (MID) ≥ 4 mm were marked on one single treatment planning computed tomography scan. Neck node levels I – X based on the 2013 updated international consensus guidelines were also contoured. LN distribution probability maps and distribution curves were established. Relationships between LN distribution and consensus guidelines were analyzed to propose modifications for CTV boundaries specific to NPC.ResultsA total of 10651 LNs from 959 patients were marked. Based on the distribution of LNs and consensus guidelines, the majority of node levels defined in the 2013 updated consensus guidelines were confirmed to be comprehensive and applicable for NPC. However, for level Vb, 13.3% (11/83) cases had LNs beyond the posteromedial border; for level VIIa (retropharyngeal LN), 1.5% (12/819) cases had LNs above the cranial boundary and 5 cases had LNs emerged in the medial group. Moreover, we confirmed that no LN had been detected in certain areas of level Ib, II, IVa and Vc. Accordingly, a new level VIIc was proposed to include medial group of retropharyngeal LNs, and moderate extended boundaries for levels Vb and VIIa were recommended, while reduced boundaries were possibly adaptable for levels Ib, II, IV and Vc.ConclusionThe majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. While, we propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggested that boundaries for levels Ib, II, IV and Vc might be reduced.

Teaser

Neck node distribution probability maps and curves for NPC were established based on 10651 nodes from 956 patients. Relationships between node distribution and international consensus guidelines for delineation of neck node levels were analyzed. Our findings demonstrate that the majority of node levels in the 2013 updated consensus guidelines are comprehensive and applicable for NPC. We propose a new level VIIc to include medial group of retropharyngeal LNs, recommend moderate extended boundaries for levels Vb and VIIa, and suggest that boundaries for levels Ib, II, IV and Vc might be reduced.


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Venetoclax is effective in small cell lung cancers with high BCL-2 expression

Purpose: Small cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% five-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets. Experimental Design: We used a high-throughput drug screen to identify a venetoclax sensitive SCLC sub-population, and validated the findings with multiple patient-derived xenografts of SCLC. Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of SCLC patients could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs. Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2 expressing SCLCs.



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Venetoclax is effective in small cell lung cancers with high BCL-2 expression

Purpose: Small cell lung cancer (SCLC) is an often-fatal neuroendocrine carcinoma usually presenting as extensive disease, carrying a 3% five-year survival. Despite notable advances in SCLC genomics, new therapies remain elusive, largely due to a lack of druggable targets. Experimental Design: We used a high-throughput drug screen to identify a venetoclax sensitive SCLC sub-population, and validated the findings with multiple patient-derived xenografts of SCLC. Results: Our drug screen consisting of a very large collection of cell lines demonstrated that venetoclax, an FDA-approved BCL-2 inhibitor, was found to be active in a substantial fraction of SCLC cell lines. Venetoclax induced BIM-dependent apoptosis in vitro and blocked tumor growth and induced tumor regressions in mice bearing high BCL-2-expressing SCLC tumors in vivo. BCL-2 expression was a predictive biomarker for sensitivity in SCLC cell lines and was highly expressed in a subset of SCLC cell lines and tumors, suggesting that a substantial fraction of SCLC patients could benefit from venetoclax. Mechanistically, we uncover a novel role for gene methylation that helped discriminate high BCL-2-expressing SCLCs. Conclusions: Altogether, our findings identify venetoclax as a promising new therapy for high BCL-2 expressing SCLCs.



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Complement activation via a C3a receptor pathway alters CD4+ T lymphocytes and mediates lung cancer progression

The complement cascade is a part of the innate immune system which acts primarily to remove pathogens and injured cells. However, complement activation is also peculiarly associated with tumor progression. Here we report mechanistic insights into this association in multiple immunocompetent orthotopic models of lung cancer. After tumor engraftment, we observed systemic activation of the complement cascade as reflected by elevated levels of the key regulator C3a. Notably, growth of primary tumors and metastases was both strongly inhibited in C3-deficient mice (C3-/- mice), with tumors undetectable in many subjects. Growth inhibition was associated with increased numbers of IFNγ+/TNFα+/IL-10+ CD4+ and CD8+ T cells. Immunodepletion of CD4+ but not CD8+ T cells in tumor-bearing subjects reversed the inhibitory effects of C3 deletion. Similarly, antagonists of the C3a or C5a receptors inhibited tumor growth. Investigations using multiple tumor cell lines in the orthotopic model suggested the involvement of a C3/C3 receptor autocrine signaling loop in regulating tumor growth. Overall, our findings offer functional evidence that complement activation serves as a critical immunomodulator in lung cancer progression, acting to drive immune escape via a C3/C5-dependent pathway.

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Oncolytic virotherapy blockade by microglia and macrophages requires STAT1/3

The first oncolytic virotherapy employing HSV-1 (oHSV-1) was approved recently by the FDA to treat cancer, but further improvements in efficacy are needed to eradicate challenging refractory tumors such as glioblastomas (GBM). Microglia/macrophages comprising ~40% of a GBM tumor may limit virotherapeutic efficacy. Here we show these cells suppress oHSV-1 growth in gliomas by internalizing the virus through phagocytosis. Internalized virus remained capable of expressing reporter genes while viral replication was blocked. Macrophage/microglia formed a nonpermissive OV barrier, preventing dissemination of oHSV-1 in the glioma mass. The deficiency in viral replication in microglial cells was associated with silencing of particular viral genes. Phosphorylation of STAT1/3 was determined to be responsible for suppressing oHSV-1 replication in macrophages/microglia. Treatment with the oxindole/imidazole derivative C16 rescued oHSV-1 replication in microglia/macrophages by inhibiting STAT1/3 activity. In the U87 xenograft model of GBM, C16 treatment overcame the microglia/macrophage barrier, thereby facilitating tumor regression without causing a spread of the virus to normal organs. Collectively, our results suggest a strategy to relieve a STAT1/3 dependent therapeutic barrier and enhance oHSV-1 oncolytic activity in GBM.

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IDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients

Host immunity influences the impact of radiotherapy (RT) in cancer but mechanistic connections remain obscure. In this study, we investigated the relationship of indoleamine 2,3-dioxygenase (IDO) systemic activity on clinical outcomes in RT-treated non-small cell lung cancer (NSCLC). IDO-mediated production of kynurenine and the kynurenine:tryptophan ratio in patient blood serum were determined for stage III NSCLC patients at times before, during and after RT administration and then correlated to overall survival (OS), progression-free survival and disease progression rate in patients. We found the impact of RT on these serum IDO markers to be heterogeneous in patients. On average, kynurenine:tryptophan ratios were reduced during RT but restored after RT. Notably, both baseline levels of kynurenine:tryptophan and changes in the levels of kynurenine after RT were significantly associated with OS. When combined, favorable change and favorable baseline corresponded with very long-term OS (median OS was not reached after 57 months median follow-up). Favorable change combined with unfavorable baseline still corresponded with a lack of distant metastases. Our results suggest that RT alters IDO-mediated immune status in NSCLC patients and that changes in this serum biomarker may be useful to predict outcomes and perhaps personalize RT dosage to improve survival.

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Oncolytic virotherapy blockade by microglia and macrophages requires STAT1/3

The first oncolytic virotherapy employing HSV-1 (oHSV-1) was approved recently by the FDA to treat cancer, but further improvements in efficacy are needed to eradicate challenging refractory tumors such as glioblastomas (GBM). Microglia/macrophages comprising ~40% of a GBM tumor may limit virotherapeutic efficacy. Here we show these cells suppress oHSV-1 growth in gliomas by internalizing the virus through phagocytosis. Internalized virus remained capable of expressing reporter genes while viral replication was blocked. Macrophage/microglia formed a nonpermissive OV barrier, preventing dissemination of oHSV-1 in the glioma mass. The deficiency in viral replication in microglial cells was associated with silencing of particular viral genes. Phosphorylation of STAT1/3 was determined to be responsible for suppressing oHSV-1 replication in macrophages/microglia. Treatment with the oxindole/imidazole derivative C16 rescued oHSV-1 replication in microglia/macrophages by inhibiting STAT1/3 activity. In the U87 xenograft model of GBM, C16 treatment overcame the microglia/macrophage barrier, thereby facilitating tumor regression without causing a spread of the virus to normal organs. Collectively, our results suggest a strategy to relieve a STAT1/3 dependent therapeutic barrier and enhance oHSV-1 oncolytic activity in GBM.

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IDO Immune Status after Chemoradiation May Predict Survival in Lung Cancer Patients

Host immunity influences the impact of radiotherapy (RT) in cancer but mechanistic connections remain obscure. In this study, we investigated the relationship of indoleamine 2,3-dioxygenase (IDO) systemic activity on clinical outcomes in RT-treated non-small cell lung cancer (NSCLC). IDO-mediated production of kynurenine and the kynurenine:tryptophan ratio in patient blood serum were determined for stage III NSCLC patients at times before, during and after RT administration and then correlated to overall survival (OS), progression-free survival and disease progression rate in patients. We found the impact of RT on these serum IDO markers to be heterogeneous in patients. On average, kynurenine:tryptophan ratios were reduced during RT but restored after RT. Notably, both baseline levels of kynurenine:tryptophan and changes in the levels of kynurenine after RT were significantly associated with OS. When combined, favorable change and favorable baseline corresponded with very long-term OS (median OS was not reached after 57 months median follow-up). Favorable change combined with unfavorable baseline still corresponded with a lack of distant metastases. Our results suggest that RT alters IDO-mediated immune status in NSCLC patients and that changes in this serum biomarker may be useful to predict outcomes and perhaps personalize RT dosage to improve survival.

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Treating Recurrent Glioma with Toca 511 [News in Brief]

Selectively replicating retroviral vector delivers high local concentrations of 5-FU directly to brain tumors.



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Papillary Adenocarcinoma in a Gastric Duplication Cyst

Abstract

Gastric duplication cysts are rare and mostly present in the first year of life. In adulthood presentation is in the form of obstruction, ulceration, bleeding, fistulization etc. Malignancy is extremely rare with only 12 cases reported to date. We came across a gastric duplication cyst with papillary adenocarcinoma in a 63 year old man. He underwent cyst excision with radical subtotal gastrectomy. The awareness of such a condition made it possible for us to have a suspicion of malignancy preoperatively based on imaging and thus a radical surgery was performed. High index of suspicion is necessary to diagnose this condition preoperatively on CT scan. Literature review revealed that this is the first case to be reported from India.



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Papillary Adenocarcinoma in a Gastric Duplication Cyst

Abstract

Gastric duplication cysts are rare and mostly present in the first year of life. In adulthood presentation is in the form of obstruction, ulceration, bleeding, fistulization etc. Malignancy is extremely rare with only 12 cases reported to date. We came across a gastric duplication cyst with papillary adenocarcinoma in a 63 year old man. He underwent cyst excision with radical subtotal gastrectomy. The awareness of such a condition made it possible for us to have a suspicion of malignancy preoperatively based on imaging and thus a radical surgery was performed. High index of suspicion is necessary to diagnose this condition preoperatively on CT scan. Literature review revealed that this is the first case to be reported from India.



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Correction to: Relative abundance of β-thalassemia-related mutations in southern China correlates with geographical coordinates

Abstract

Figure 1c. is with numeric error. The error can not result in any change of discussion and conclusion. The proper figures corresponding to Fig 1c are in supplement file, see figure 5 and 6.



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Glyphosate Use and Cancer Incidence in the Agricultural Health Study

Abstract
Background
Glyphosate is the most commonly used herbicide worldwide, with both residential and agricultural uses. In 2015, the International Agency for Research on Cancer classified glyphosate as "probably carcinogenic to humans," noting strong mechanistic evidence and positive associations for non-Hodgkin lymphoma (NHL) in some epidemiologic studies. A previous evaluation in the Agricultural Health Study (AHS) with follow-up through 2001 found no statistically significant associations with glyphosate use and cancer at any site.
Methods
The AHS is a prospective cohort of licensed pesticide applicators from North Carolina and Iowa. Here, we updated the previous evaluation of glyphosate with cancer incidence from registry linkages through 2012 (North Carolina)/2013 (Iowa). Lifetime days and intensity-weighted lifetime days of glyphosate use were based on self-reported information from enrollment (1993–1997) and follow-up questionnaires (1999–2005). We estimated incidence rate ratios (RRs) and 95% confidence intervals (CIs) using Poisson regression, controlling for potential confounders, including use of other pesticides. All statistical tests were two-sided.
Results
Among 54 251 applicators, 44 932 (82.8%) used glyphosate, including 5779 incident cancer cases (79.3% of all cases). In unlagged analyses, glyphosate was not statistically significantly associated with cancer at any site. However, among applicators in the highest exposure quartile, there was an increased risk of acute myeloid leukemia (AML) compared with never users (RR = 2.44, 95% CI = 0.94 to 6.32, Ptrend = .11), though this association was not statistically significant. Results for AML were similar with a five-year (RRQuartile 4 = 2.32, 95% CI = 0.98 to 5.51, Ptrend = .07) and 20-year exposure lag (RRTertile 3 = 2.04, 95% CI = 1.05 to 3.97, Ptrend = .04).
Conclusions
In this large, prospective cohort study, no association was apparent between glyphosate and any solid tumors or lymphoid malignancies overall, including NHL and its subtypes. There was some evidence of increased risk of AML among the highest exposed group that requires confirmation.

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CLDN6 promotes chemoresistance through GSTP1 in human breast cancer

Claudin-6 (CLDN6), a member of CLDN family and a key component of tight junction, has been reported to function as a tumor suppressor in breast cancer. However, whether CLDN6 plays any role in breast cancer ch...

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STAT3-blocked whole-cell hepatoma vaccine induces cellular and humoral immune response against HCC

Whole-cell tumor vaccines have shown much promise; however, only limited success has been achieved for the goal of eliciting robust tumor-specific T-cell responses.

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A prospective evaluation of hippocampal radiation dose volume effects and memory deficits following cranial irradiation

To prospectively evaluate hippocampal radiation dose volume effects and memory decline following cranial irradiation.

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Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer

Research studies show tests that analyze tumor DNA in blood, called liquid biopsies, may help detect cancer early, guide precision cancer treatment, and tracking treatment response.



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Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer

Research studies show tests that analyze tumor DNA in blood, called liquid biopsies, may help detect cancer early, guide precision cancer treatment, and tracking treatment response.



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Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer

Research studies show tests that analyze tumor DNA in blood, called liquid biopsies, may help detect cancer early, guide precision cancer treatment, and tracking treatment response.



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Liquid Biopsy: Using DNA in Blood to Detect, Track, and Treat Cancer

Research studies show tests that analyze tumor DNA in blood, called liquid biopsies, may help detect cancer early, guide precision cancer treatment, and tracking treatment response.



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Correction to: Improved plan quality with automated radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG 0933 trial

In the original publication [1] figure legends 2 and 4 have been swapped. The original article was updated to rectify this error.

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Quantitative assessment of radiation dose and fractionation effects on normal tissue by utilizing a novel lung fibrosis index model

Normal lung tissue tolerance constitutes a limiting factor in delivering the required dose of radiotherapy to cure thoracic and chest wall malignancies. Radiation-induced lung fibrosis (RILF) is considered a c...

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Correction to: Improved plan quality with automated radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG 0933 trial

In the original publication [1] figure legends 2 and 4 have been swapped. The original article was updated to rectify this error.

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Quantitative assessment of radiation dose and fractionation effects on normal tissue by utilizing a novel lung fibrosis index model

Normal lung tissue tolerance constitutes a limiting factor in delivering the required dose of radiotherapy to cure thoracic and chest wall malignancies. Radiation-induced lung fibrosis (RILF) is considered a c...

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A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D–culture methods for hepatocellular carcinoma

Abstract

Background

Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D–culture system (CD-DST).

Methods

Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5-furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated.

Results

HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 ± 0.45 μg/ml, 0.03 ± 0.02 μg/ml, 1.15 ± 0.75 μg/ml, 0.09 ± 0.03 μg/ml, or 1.76 ± 0.44 μg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC.

Conclusions

The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients.



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Journal Club.

No abstract available

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Scheduled Intravenous Acetaminophen Improves Patient Satisfaction With Postcraniotomy Pain Management: A Prospective, Randomized, Placebo-controlled, Double-blind Study.

Background: Postcraniotomy pain can be difficult to manage with opioids due to opioid-related side effects, including drowsiness, nausea/vomiting, confusion, and pupillary changes, potentially masking the signs of postoperative neurological deterioration. Intravenous (IV) acetaminophen, a nonopioid analgesic, has been reported to have opioid-sparing effects after abdominal and orthopedic surgeries. This study investigates whether IV acetaminophen has similar effects after craniotomy. Materials and Methods: In this prospective, randomized, placebo-controlled, double-blind clinical trial, 100 adult patients scheduled to undergo supratentorial craniotomy for excision of a brain mass were randomized to receive either IV acetaminophen or placebo preincision and then every 6 hours for a total of 24 hours after surgery. Total 24-hour opioid consumption, pain scores, satisfaction with overall pain management, time to meet postanesthesia care unit discharge criteria, and incidence of opioid-related side effects were compared. Results: There was no difference in the 24-hour postoperative opioid consumption in morphine equivalents between the IV acetaminophen group (median, 11 mg; n=45) and the placebo group (median, 10.1 mg; n=41). No statistically significant difference of visual analog scale pain score was observed between 2 treatment groups. Patient satisfaction with overall postoperative pain management was significantly higher in the IV acetaminophen group than the placebo group on a 1 to 10 scale (8.1+/-0.4 vs. 6.9+/-0.4; P=0.03). There was no significant difference in secondary outcomes, including the incidence of opioid-related side effects. Conclusions: IV acetaminophen, as adjunctive therapy for craniotomy procedures, did not show an opioid-sparing effect in patients for the 24 hours after craniotomy; however, it was associated with improved patient satisfaction regarding overall pain control. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved

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A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D–culture methods for hepatocellular carcinoma

Abstract

Background

Patients suffering from advanced stage hepatocellular carcinoma (HCC) often exhibit a poor prognosis or dismal clinical outcomes due to ineffective chemotherapy or a multi-drug resistance (MDR) process. Thus, it is urgent to develop a new chemotherapeutic sensitivity testing system for HCC treatment. The presence study investigated the potential application of a novel chemotherapeutic sensitivity-testing system based on a collagen gel droplet embedded 3D–culture system (CD-DST).

Methods

Primary cells were separating from surgical resection specimens and then tested by CD-DST. To identify whether HCC cell lines or cells separating from clinical specimens contain MDR features, the cells were treated with an IC 50 (half maximal inhibitory concentration) or IC max (maximal inhibitory concentration) concentration of antitumor agents, e.g., 5-furuolouracil (5-FU), paclitaxel (PAC), cisplatin (CDDP), epirubicin (EPI), or oxaliplatin (L-OHP), and the inhibitory rates (IRs) were calculated.

Results

HepG2 cells were sensitive to 5-FU, PAC, CDDP, EPI, or L-OHP; the IC 50 value is 0.83 ± 0.45 μg/ml, 0.03 ± 0.02 μg/ml, 1.15 ± 0.75 μg/ml, 0.09 ± 0.03 μg/ml, or 1.76 ± 0.44 μg/ml, respectively. Only eight (8/26), nine (9/26), or five (5/26) patients were sensitive to the IC max concentration of CDDP, EPI, or L-OHP; whereas only three (3/26), four (4/26), or two (2/26) patients were sensitive to the IC 50 concentration of CDDP, EPI, or L-OHP. No patients were sensitive to 5-FU or PAC.

Conclusions

The in vitro drug sensitivity exanimation revealed the MDR features of HCC and examined the sensitivity of HCC cells from clinical specimens to anti-tumor agents. CD-DST may be a useful method to predict the potential clinical benefits of anticancer agents for HCC patients.



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Overcoming barriers to radiotherapy in at-risk urban populations: primary language as a driver of initiation disparity

Abstract

Objective

Delays in radiotherapy initiation are associated with increased local recurrence rates, but demographic drivers of initiation disparity have not been evaluated. Patient demographics have been shown to drive treatment disparities in radiotherapy, negatively influencing treatment recommendations, initiation, and compliance, indicating significant barriers to treatment in at-risk urban populations. Recent studies evaluating the effect of primary language on these disparities have produced conflicting results; studies have focused on specific disease sites and included varying treatment modalities in addition to radiotherapy. We examined time from diagnosis to initiation in all radiotherapy-receiving patients in an urban safety net hospital, stratified by primary language.

Methods

Demographic data, 1- and 5-­year mortality, disease extent, days from diagnosis to initiation (DtI), and primary language of 342 unique patients presenting to the Brookdale University Hospital Medical Center Department of Radiation Oncology from 2008 to 2012 were collected. Records with incomplete or outlying data were excluded from analysis. Data was de-identified and coded before analysis in SPSS v. 24 with a 95% confidence interval using ANOVA for data with normalized distribution and Mann-Whitney U/Kruskal-Wallis tests for differences in non-normally distributed data, as determined by the Shapiro-Wilk test.

Results

We found no difference in DtI between English-, Spanish-, and Haitian Creole-speaking patient populations. Age at diagnosis was greater in the Haitian Creole-speaking population (p < 0.001); gender (p < 0.05), disease extent (p < 0.001), and month of initiation (p < 0.001) had an effect on DtI. Race, age at diagnosis, and ethnicity did not have a significant effect on DtI.

Conclusion

Patient primary language does not have an effect on radiotherapy initiation time in an urban safety net hospital. At-risk urban patient populations face barriers to treatment that may confound previously reported differences in English- and non-English-speaking patients.



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Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update

Summary

Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field.



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Anti-angiogenic therapies for the treatment of angiosarcoma: a clinical update

Summary

Angiosarcomas are rare aggressive endothelial tumours, and are associated with a poor prognosis. Due to their vascular nature, there is great interest in their response to anti-angiogenic agents. A number of small prospective studies have reported angiosarcoma response to vascular-targeted agents, including agents that target vascular endothelial growth factor. To date, the response to these agents has been disappointing, and similar to the response observed in other soft tissue sarcoma subtypes. This short review will summarise the recent data in this field.



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Acknowledgement to Referees



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The Predictive Values of Lesion Size, F-18 FDG Avidity and I-131 Avidity for the Clinical Outcome of I-131 Treatment in Patients with Metastatic Differentiated Thyroid Carcinoma Only in the Lung

Abstract

Purpose

We aimed to evaluate the prognostic values of radiography, F-18 FDG PET, and I-131 whole body scans in patients with lung-only metastasis from differentiated thyroid carcinoma (DTC).

Methods

Between 1998 and 2013, we included 31 patients (F: 26, M: 5) with lung-only metastasis from DTC who had been treated with I-131 and underwent PET. Lung metastasis was categorized according to the size (macronodular ≥1.0 cm vs. micronodular <1.0 cm), FDG avidity (avid vs. non-avid), and I-131 avidity (avid vs. non-avid). Progression-free survival (PFS) was evaluated for each patient.

Results

Among 31 patients, seven (23%) had macronodular lung metastasis, 26 (84%) had FDG avid lung metastasis, and 16 (52%) had I-131 avid lung metastasis. During the median follow-up period of 9.4 y, median PFS was 6.1 y. Based on Kaplan-Meier analysis, macronodular lung metastasis (p = 0.017) and I-131 non-avid lung metastasis (p = 0.059) were significantly associated with worse outcomes, but FDG avid lung metastasis was not (p = 0.135). Patients with FDG non-avid lung metastasis did not experience disease progression during follow-up, while 11 of 26 patients (42%) experienced disease progression. Based on univariate analysis, the hazard ratio for a poor prognosis was 3.78 (p = 0.029) for macronodular lung metastasis and 3.29 (p = 0.079) for I-131 non-avid lung metastasis.

Conclusions

Macronodular and I-131 non-avid lung metastasis were associated with a poor prognosis in lung-only metastasis from DTC. Although FDG avid lung metastasis may be associated with a poor prognosis, a larger-scale study is needed.



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The Predictive Values of Lesion Size, F-18 FDG Avidity and I-131 Avidity for the Clinical Outcome of I-131 Treatment in Patients with Metastatic Differentiated Thyroid Carcinoma Only in the Lung

Abstract

Purpose

We aimed to evaluate the prognostic values of radiography, F-18 FDG PET, and I-131 whole body scans in patients with lung-only metastasis from differentiated thyroid carcinoma (DTC).

Methods

Between 1998 and 2013, we included 31 patients (F: 26, M: 5) with lung-only metastasis from DTC who had been treated with I-131 and underwent PET. Lung metastasis was categorized according to the size (macronodular ≥1.0 cm vs. micronodular <1.0 cm), FDG avidity (avid vs. non-avid), and I-131 avidity (avid vs. non-avid). Progression-free survival (PFS) was evaluated for each patient.

Results

Among 31 patients, seven (23%) had macronodular lung metastasis, 26 (84%) had FDG avid lung metastasis, and 16 (52%) had I-131 avid lung metastasis. During the median follow-up period of 9.4 y, median PFS was 6.1 y. Based on Kaplan-Meier analysis, macronodular lung metastasis (p = 0.017) and I-131 non-avid lung metastasis (p = 0.059) were significantly associated with worse outcomes, but FDG avid lung metastasis was not (p = 0.135). Patients with FDG non-avid lung metastasis did not experience disease progression during follow-up, while 11 of 26 patients (42%) experienced disease progression. Based on univariate analysis, the hazard ratio for a poor prognosis was 3.78 (p = 0.029) for macronodular lung metastasis and 3.29 (p = 0.079) for I-131 non-avid lung metastasis.

Conclusions

Macronodular and I-131 non-avid lung metastasis were associated with a poor prognosis in lung-only metastasis from DTC. Although FDG avid lung metastasis may be associated with a poor prognosis, a larger-scale study is needed.



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Bromoethylindole (BEI-9) redirects NF-κB signaling induced by camptothecin and TNFα to promote cell death in colon cancer cells

Abstract

Chemotherapeutic regimens containing camptothecin (CPT), 5-fluorouracil, and oxaliplatin are used to treat advanced colorectal cancer. We previously reported that an indole derivative, 3-(2-bromoethyl)indole (BEI-9), inhibited the proliferation of colon cancer cells and suppressed NF-κB activation. Here, we show that a combination of BEI-9 with either CPT or tumor necrosis factor alpha (TNFα) enhances cell death. Using colorectal cancer cells, we examined the activation of NF-κB by drugs, the potential of BEI-9 for inhibiting drug-induced NF-κB activation, and the enhancement of cell death by combination treatments. Cells were treated with the chemotherapeutic drugs alone or in combination with BEI-9. NF-κB activation, cell cycle profiles, DNA-damage response, markers of cell death signaling and targets of NF-κB were evaluated to determine the effects of single and co-treatments. The combination of BEI-9 with CPT or TNFα inhibited NF-κB activation and reduced the expression of NF-κB-responsive genes, Bcl-xL and COX2. Compared to CPT or BEI-9 alone, sequential treatment of the cells with CPT and BEI-9 significantly enhanced caspase activation and cell death. Co-treatment with TNFα and BEI-9 also caused more cytotoxicity than TNFα or BEI-9 alone. Combined BEI-9 and TNFα enhanced cell death through caspase activation and cleavage of the switch-protein, RIP1 kinase. BEI-9 reduced the expression of COX2 both alone and in combination with CPT or TNF. We postulate that BEI-9 enhances the effects of these drugs on cancer cells by turning off or redirecting NF-κB signaling. Therefore, the combination of BEI-9 with drugs that activate NF-κB needs to be evaluated for clinical applications.



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The prostate cancer screening clinic in the Bahamas: a model for low- and middle-income countries

Abstract

Purpose

Grand Bahama (pop. 51,000) is an island within the Bahamas archipelago. A local chapter of International Us TOO Prostate Cancer Support Group (UTGB) has led an annual community-based prostate cancer screening clinic in Grand Bahama each September since 2009. Features of this initiative, characteristics of attendees, and a description of found cancers were summarized to determine the clinic's value and to guide improvements.

Method

We analyzed the established clinic from 2012 to 2015, wherein UTGB attracted corporate funding, volunteers managed clinics, and health professionals provided healthcare services. An explicit algorithm was used to sort clients by age, comorbidities, and findings from digital rectal examinations, and prostate-specific antigen (PSA) values, to determine which clients would undergo secondary assessment and prostate biopsy.

Results

Overall, 1,844 males were registered (mean age 57.6 years), and only 149 men attended on more than one occasion for a total of 1,993 clinic visit. The urologist reviewed 315 men in secondary follow-up, for elevated PSA and/or an abnormal digital rectal examination. Of these, 45 men fulfilled criteria for trans-rectal ultrasound biopsy, and there were 40 found cases of prostate cancer, for a positive-predictive value of 89%. By D'Amico risk-stratification, these 40 cases were low (10%), intermediate (40%), and high risk (50%). The urologist counseled all 40 cases and facilitated access to standard care.

Conclusion

This study suggests that low-resource countries can advance cost-effective screening clinics, apply policy guidelines, and provide services within acceptable standards of care. It is the expectation, with a sustained effort and community participation over the ensuing years, that earlier disease presentation will occur and, consequently, a concomitant decrease in the disease-specific mortality.



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Correction to: Improved plan quality with automated radiotherapy planning for whole brain with hippocampus sparing: a comparison to the RTOG 0933 trial

Abstract

In the original publication [1] figure legends 2 and 4 have been swapped. The original article was updated to rectify this error.



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Systematic analyses of glutamine and glutamate metabolisms across different cancer types

Glutamine and glutamate are known to play important roles in cancer biology. However, no detailed information is available in terms of their levels of involvement in various biological processes across differe...

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Prognostic value of plasma Epstein–Barr virus DNA level during posttreatment follow-up in the patients with nasopharyngeal carcinoma having undergone intensity-modulated radiotherapy

The value of Epstein–Barr virus (EBV) DNA assay during posttreatment follow-up of the patients with nasopharyngeal carcinoma (NPC) presenting with different pretreatment plasma EBV DNA levels remains unclear. ...

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Prognostic value of plasma Epstein–Barr virus DNA level during posttreatment follow-up in the patients with nasopharyngeal carcinoma having undergone intensity-modulated radiotherapy

The value of Epstein–Barr virus (EBV) DNA assay during posttreatment follow-up of the patients with nasopharyngeal carcinoma (NPC) presenting with different pretreatment plasma EBV DNA levels remains unclear. ...

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The impact of physical activity on fatigue and quality of life during and after adjuvant treatment for breast cancer

BACKGROUND

Although physical activity (PA) can alleviate fatigue and improve quality of life (QoL) in patients with breast cancer (BC), not all domains of PA may have equal impact. The objective of the current study was to examine the longitudinal impact of PA components on the evolution of fatigue and QoL during and after adjuvant treatment for BC.

METHODS

The women included in the study were participants in the 2-year longitudinal FATSEIN ("Fatigue dans le cancer du Sein") study. Fatigue and QoL were measured using the Multidimensional Fatigue Inventory and the European Organization for Research and Treatment of Cancer 30-item QoL questionnaire, respectively. Group-based trajectory analysis was used to determine patterns of PA evolution (frequency, duration, and intensity). Cross-sectional and longitudinal associations between PA patterns and fatigue and QoL were analyzed by using multivariable linear regression and a mixed model.

RESULTS

Among the 424 women who were included (mean ± standard deviation age, 57.1 ± 10.4 years), 2 trajectories were identified for each of the 3 PA components: low and insufficient frequency (51.2%) or regular and moderate frequency (48.8%), low and insufficient duration (47.6%) or regular and moderate duration (52.4%), and low intensity (47.2%) or low to moderate intensity (52.8%). Overall, during treatment, fatigue was increased and QoL was decreased, and the reverse was observed after treatment. During treatment, increased fatigue and decreased QoL were limited by regular PA frequency (β = −8.71 for total fatigue; β = 14.59 for emotional function), but the results were less significant after treatment.

CONCLUSIONS

PA, especially its frequency, is an important determinant of fatigue and QoL during adjuvant treatment for BC. The promotion of regular PA among women who are receiving treatment for BC may be an effective way to reduce fatigue and improve QoL. Cancer 2017. © 2017 American Cancer Society.



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Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors

Abstract

Daytime sleepiness is recognized in childhood brain tumor survivors. Our objective was to determine prevalence, risk factors for PSG/MLST proven hypersomnia/narcolepsy, and response to stimulants in childhood brain tumor survivors. Standard PSG/MSLT criteria were used to diagnose hypersomnia/narcolepsy. Medical records of brain tumor survivors having undergone a PSG/MSLT were reviewed for the diagnostic code of hypersomnia/narcolepsy. Survivors with hypersomnia/narcolepsy were matched with 2–3 survivors without reported hypersomnia/narcolepsy by age at tumor diagnosis, gender, and time from tumor diagnosis. Between January 2000 to April 2015, 39 of the 2336 brain tumor patients treated at our institution were diagnosed with hypersomnia/narcolepsy for a prevalence rate of 1670/100,000. Hypersomnia/narcolepsy was diagnosed at a median of 6.1 years (range 0.4–13.2) from tumor diagnosis and 4.7 years (range − 1.5 to 10.4) from cranial radiation. Midline tumor location (OR 4.6, CI 1.7–12.2, p = 0.002) and anti-epilepsy drug (AED) use (OR 11, CI 2.4–54) correlated with hypersomnia/narcolepsy while radiation dose > 30 Gray trended towards significance (OR 1.8, CI 0.9–3.6); posterior fossa tumor location reduced the risk (OR 0.1, CI 0.04–0.5, p = 0.002). AED use also correlated with midline tumor location. Thirty-seven survivors were treated with stimulants and reported improved wakefulness and school performance [response rate CI 0.97 (0.86–0.99) and 0.83 (0.65–0.94)]. Prevalence of hypersomnia/narcolepsy among childhood brain tumor survivors was higher than the general population. Tumor location and radiation dose were possible risk factors, and stimulants were reported to be beneficial.



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The impact of physical activity on fatigue and quality of life during and after adjuvant treatment for breast cancer

BACKGROUND

Although physical activity (PA) can alleviate fatigue and improve quality of life (QoL) in patients with breast cancer (BC), not all domains of PA may have equal impact. The objective of the current study was to examine the longitudinal impact of PA components on the evolution of fatigue and QoL during and after adjuvant treatment for BC.

METHODS

The women included in the study were participants in the 2-year longitudinal FATSEIN ("Fatigue dans le cancer du Sein") study. Fatigue and QoL were measured using the Multidimensional Fatigue Inventory and the European Organization for Research and Treatment of Cancer 30-item QoL questionnaire, respectively. Group-based trajectory analysis was used to determine patterns of PA evolution (frequency, duration, and intensity). Cross-sectional and longitudinal associations between PA patterns and fatigue and QoL were analyzed by using multivariable linear regression and a mixed model.

RESULTS

Among the 424 women who were included (mean ± standard deviation age, 57.1 ± 10.4 years), 2 trajectories were identified for each of the 3 PA components: low and insufficient frequency (51.2%) or regular and moderate frequency (48.8%), low and insufficient duration (47.6%) or regular and moderate duration (52.4%), and low intensity (47.2%) or low to moderate intensity (52.8%). Overall, during treatment, fatigue was increased and QoL was decreased, and the reverse was observed after treatment. During treatment, increased fatigue and decreased QoL were limited by regular PA frequency (β = −8.71 for total fatigue; β = 14.59 for emotional function), but the results were less significant after treatment.

CONCLUSIONS

PA, especially its frequency, is an important determinant of fatigue and QoL during adjuvant treatment for BC. The promotion of regular PA among women who are receiving treatment for BC may be an effective way to reduce fatigue and improve QoL. Cancer 2017. © 2017 American Cancer Society.



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Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model

Abstract

High-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the therapeutic model, intratumorally inhibiting tumor-derived HMGB1 (causing downstream loss of TSLP production) attenuated Treg activation, unleashed tumor-specific CD8 T cell responses, and elicited CD8α+/CD103+DC- and T cell-dependent antitumor activity. These results suggest a new pathway for the activation of Treg involving in tumor-derived HMGB1 and TSLP, and have important implications for incorporating HMGB1 inhibitors into cancer immunotherapy.



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Transcription factor E2F1 promotes EMT by regulating ZEB2 in small cell lung cancer

Abstract

Background

Epithelial-mesenchymal transition (EMT) is an early event in tumour invasion and metastasis, and widespread and distant metastasis at early stages is the typical biological behaviour in small cell lung cancer (SCLC). Our previous reports showed that high expression of the transcription factor E2F1 was involved in the invasion and metastasis of SCLC, but the role of E2F1 in the process of EMT in SCLC is unknown.

Methods

Immunohistochemistry was performed to evaluate the expressions of EMT related markers. Immunofluorescence was used to detect the expressions of cytoskeletal proteins and EMT related markers when E2F1 was silenced in SCLC cell lines. Adenovirus containing shRNA against E2F1 was used to knock down the E2F1 expression, and the dual luciferase reporter system was employed to clarify the regulatory relationship between E2F1 and ZEB2.

Results

In this study, we observed the remodelling of cytoskeletal proteins when E2F1 was silenced in SCLC cell lines, indicating that E2F1 was involved in the EMT in SCLC. Depletion of E2F1 promoted the expression of epithelial markers (CDH1 and CTNNB1) and inhibited the expression of mesenchymal markers (VIM and CDH2) in SCLC cell lines, verifying that E2F1 promotes EMT occurrence. Next, the mechanism by which E2F1 promoted EMT was explored. Among the CDH1 related inhibitory transcriptional regulators ZEB1, ZEB2, SNAI1 and SNAI2, the expression of ZEB2 was the highest in SCLC tissue samples and was highly consistent with E2F1 expression. ChIP-seq data and dual luciferase reporter system analysis confirmed that E2F1 could regulate ZEB2 gene expression.

Conclusion

Our data supports that E2F1 promotes EMT by regulating ZEB2 gene expression in SCLC.



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Carbon ion radiotherapy for 80 years or older patients with hepatocellular carcinoma

Abstract

Background

To evaluate the safety and efficacy of carbon ion radiotherapy (C-ion RT) for 80 years or older patients with hepatocellular carcinoma (HCC).

Methods

Eligibility criteria of this retrospective study were: 1) HCC confirmed by histology or typical hallmarks of HCC by imaging techniques of four-phase multidetector-row computed tomography or dynamic contrast-enhanced magnetic resonance imaging; 2) no intrahepatic metastasis or distant metastasis; 3) no findings suggesting direct infiltration of the gastrointestinal tract; 4) performance status ≤2 by Eastern Cooperative Oncology Group classification; and 5) Child-Pugh classification A or B. Patients received C-ion RT with 52.8 Gy (RBE) or 60.0 Gy (RBE) in four fractions for usual cases and 60.0 Gy (RBE) in 12 fractions for close-to-gastrointestinal tract cases. Toxicities were classified using the National Cancer Institute's Common Terminology Criteria for Adverse Events (Version 4.0).

Results

Between March 2011 and November 2015, 31 patients were treated. The median follow-up period of all patients was 23.2 months (range: 8.4–55.3 months). Median age at the time of registration of C-ion RT was 83 years (range: 80–95 years). Child-Pugh grade A and B were 27 patients and 4 patients, respectively.

The 2-year estimated overall survival, local control, and progression-free survival rates were 82.3%, 89.2%, and 51.3%, respectively. No patients had Grade 2 or higher acute toxicities (within 3 months after C-ion RT). One patient experienced progression in Child-Pugh classification from A to B within 3 months after C-ion RT. In late toxicities, Grade 3 encephalopathy was observed in 3 patients, and 2 improved with medication.

Conclusions

C-ion RT was effective with minimal toxicities for 80 years or older patients with hepatocellular carcinoma.

Trial registration

UMIN000020571: date of registration, 14 January 2016, retrospectively registered.



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Trastuzumab resumption after extremely severe cardiotoxicity in metastatic breast cancer patient: a case report

Abstract

Background

Trastuzumab-related cardiotoxicity has been reported in patients receiving trastuzumab concurrently with other agents, especially with anthracyclines. Cardiac function damage is generally rare, precox and mild with trastuzumab alone.

Case presentation

We report the case of a 49 year-old woman affected by metastatic breast cancer who developed trastuzumab-related cardiogenic shock due to pump failure (with LVEF of about 15%) after three months of treatment. After a long hospitalization in the cardiac intensive care unit and a proper treatment, LVEF increased to 50% and, due to a severe progression of disease, trastuzumab was resumed and continued for more than one year.

Conclusion

This is a case of particularly severe cardiotoxicity related to trastuzumab treatment, which was recovered with pharmacological treatment and the temporary discontinuation of the treatment. Trastuzumab was safely resumed after clinical and echocardiographic parameters improvement.



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Synchronous occurrence of hereditary gastric adenocarcinoma, gastrointestinal stromal tumor, and esophageal small cell and squamous carcinoma in situ: an extremely rare case report

Abstract

Background

Hereditary diffuse gastric carcinoma (HDGC) accounts for 1–3% of all gastric carcinomas. Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal (GI) tract but they comprise fewer than 1% of all GI malignancies. Small-cell carcinoma (SmCC) is a rare histological type of esophageal carcinoma, accounting for 0.4% to 2.8% of all esophageal tumors. Co-occurrence of SmCC with esophageal tumors caused by squamous carcinoma is also very uncommon. Although multiple primary malignancies are no longer rare in clinical practice, the simultaneous appearance of HDGC, GIST, esophageal small cell and squamous carcinoma in situ is extremely rare and very few cases have been reported.

Case presentation

We present a case of a 53 year-old woman with synchronous occurrence of four malignancies including HDGC, GIST, esophageal small cell- and local squamous carcinoma in situ. A total gastrectomy with D2 lymph node dissection and postoperative adjuvant chemotherapy with oxaliplatin and paclitaxel liposome were performed. After a 1-year follow-up, this patient was still in good condition with no evidence of recurrence.

Conclusion

This is the unique case that describes the co-existence of the aforementioned four types of neoplasm. This case demonstrates that a diagnosis of gastric cancer does not preclude the presence of other malignancies and every case should be thoroughly analyzed to avoid missing other problems, which may worsen the prognosis.



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Does hair dye use really increase the risk of prostate cancer?

Abstract

Recently, Shu-Yu Tai et al. reported that personal hair dye use increased risk of prostate cancer with a dose-response effect. Although hair dyes were identified as carcinogenic in animals and increased risk of some cancers among hairdressers, the existing epidemiological data did not support that personal hair dye use increased risk of cancers, even for bladder cancer. Given that Tai et al.'s report of a potential hazard of personal hair dye use on risk of prostate cancer was particular, the methodology of the study was scrutinized and some flaws were found including the issue of external validity.



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Guanylate-binding protein-1 is a potential new therapeutic target for triple-negative breast cancer

Abstract

Background

Triple-negative breast cancer (TNBC) is characterized by a lack of estrogen and progesterone receptor expression (ESR and PGR, respectively) and an absence of human epithelial growth factor receptor (ERBB2) amplification. Approximately 15–20% of breast malignancies are TNBC. Patients with TNBC often have an unfavorable prognosis. In addition, TNBC represents an important clinical challenge since it does not respond to hormone therapy.

Methods

In this work, we integrated high-throughput mRNA sequencing (RNA-Seq) data from normal and tumor tissues (obtained from The Cancer Genome Atlas, TCGA) and cell lines obtained through in-house sequencing or available from the Gene Expression Omnibus (GEO) to generate a unified list of differentially expressed (DE) genes. Methylome and proteomic data were integrated to our analysis to give further support to our findings. Genes that were overexpressed in TNBC were then curated to retain new potentially druggable targets based on in silico analysis. Knocking-down was used to assess gene importance for TNBC cell proliferation.

Results

Our pipeline analysis generated a list of 243 potential new targets for treating TNBC. We finally demonstrated that knock-down of Guanylate-Binding Protein 1 (GBP1 ), one of the candidate genes, selectively affected the growth of TNBC cell lines. Moreover, we showed that GBP1 expression was controlled by epidermal growth factor receptor (EGFR) in breast cancer cell lines.

Conclusions

We propose that GBP1 is a new potential druggable therapeutic target for treating TNBC with enhanced EGFR expression.



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MicroRNA expression patterns in canine mammary cancer show significant differences between metastatic and non-metastatic tumours

Abstract

Background

MicroRNAs may act as oncogenes or tumour suppressor genes, which make these small molecules potential diagnostic/prognostic factors and targets for anticancer therapies. Several common oncogenic microRNAs have been found for canine mammary cancer and human breast cancer. On account of this, large-scale profiling of microRNA expression in canine mammary cancer seems to be important for both dogs and humans.

Methods

Expression profiles of 317 microRNAs in 146 canine mammary tumours of different histological type, malignancy grade and clinical history (presence/absence of metastases) and in 25 control samples were evaluated. The profiling was performed using microarrays. Significance Analysis of Microarrays test was applied in the analysis of microarray data (both unsupervised and supervised data analyses were performed). Validation of the obtained results was performed using real-time qPCR. Subsequently, predicted targets for the microRNAs were searched for in miRBase.

Results

Results of the unsupervised analysis indicate that the primary factor separating the samples is the metastasis status. Predicted targets for microRNAs differentially expressed in the metastatic vs. non-metastatic group are mostly engaged in cell cycle regulation, cell differentiation and DNA-damage repair. On the other hand, the supervised analysis reveals clusters of differentially expressed microRNAs unique for the tumour type, malignancy grade and metastasis factor.

Conclusions

The most significant difference in microRNA expression was observed between the metastatic and non-metastatic group, which suggests a more important role of microRNAs in the metastasis process than in the malignant transformation. Moreover, the differentially expressed microRNAs constitute potential metastasis markers. However, validation of cfa-miR-144, cfa-miR-32 and cfa-miR-374a levels in blood samples did not follow changes observed in the non-metastatic and metastatic tumours.



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Seropositivity to herpes simplex virus type 2, but not type 1 is associated with cervical cancer: NHANES (1999–2014)

Abstract

Background

Herpes simplex virus types 1 and 2 (HSV1 and HSV2) are infectious agents, and their association with cancer occurrence in human is a controversial topic for decades. We addressed this subject using all available continuous National Health and Nutrition Examination Survey (NHANES) cross-sectional data from 1999 to 2014.

Methods

Eight data cycles (1999–2000, 2001–2002, 2003–2004, 2005–2006, 2007–2008, 2009–2010, 2011–2012, and 2013–2014) were employed, and a sample of 8184 female participants was used in this study according to the availability of cancer history and HSV serostatus.

Results

The seroprevalences of HSV1 and HSV2 were 60.73 ± 0.89 and 25.02 ± 0.64, respectively, and the numbers increased with age (P < 0.01). In confounder-adjusted logistic regression analysis, association between HSV1 seropositivity and uterine cancer was identified (adjusted odds ratio-ORadjusted = 6.03; 95% CI: 1.52, 23.87). HSV2 seropositivity was associated with cancer occurrence (ORadjusted = 1.47; 95% CI: 1.01, 2.14), cervical cancer (ORadjusted = 1.72; 95% CI: 1.06, 2.79) and uterine cancer (ORadjusted = 3.49; 95% CI: 1.03, 11.85). Moreover, HSV2 was persistently associated with cervical cancer after further adjusting high-risk human papillomavirus (HPV) as confounder (ORadjusted = 1.90; 95% CI: 1.09, 3.34). Relative risk (RR)-based interaction measurement between HSV2 and HPV on the additive scale suggests higher RR for cervical cancer in participants with seropositivity for HPV only (RRadjusted = 2.98; 95% CI: 1.23, 7.20; P = 0.02), HSV2 only (RRadjusted = 2.79; 95% CI: 1.31, 5.96; P = 0.01) or both viruses (RRadjusted = 3.44; 95% CI: 1.50, 7.86; P < 0.01) when setting participants with seronegativity for both HPV and HSV2 as reference.

Conclusions

The finding of current study provides epidemiological evidence that serostatus of HSV2 can serve as an independent predictor for cervical cancer.



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