tbuckley/cabot-search huggingface dataset:
Metronomic chemotherapy (MC): Results of two feasibility trials in patients (pts) with HER2 positive (HER2+) and negative (HER2-) locally advanced breast cancer (LABC).
Authors: Vanessa Petry, Alessandro Leal, Roberto J. Arai, Jose R. Piato, Felipe Andrade, Marcelo Paiva, Marcio R. Ferraz, Simone Marinho, Paulo Marcelo Hoff, Max S. Mano
Journal: Journal of Clinical Oncology (2012)

e11513 Background: In SWOG0012, MC improved pathologic complete response (pCR) compared to standard neoadjuvant chemotherapy (NC). We evaluated the feasibility of MC with a taxane→anthracycline schedule, which has also been shown potentially superior to the inverse sequence. We also evaluated the feasibility of MC in combination with trastuzumab. Methods: The primary objective was feasibility (defined as a febrile neutropenia (FN) rate ≤10%). Secondary objectives were cardiac safety, tolerability and efficacy as measured by objective response and pCR. The original accrual goal was 25 Her2+ pts and 40 Her2- pts. Her2- pts received paclitaxel (100mg/m2) x8 weeks followed by doxorubicin (24mg/m2) x9 weeks combined with oral cyclophosphamide (100mg/day), without G-CSF. Her2+ pts also received weekly trastuzumab (4 mg/kg followed by 2mg/kg) concurrently with the entire CT. Results: Most pts were stage III (Her+: 8/9; Her-: 4/11). The Her2+ cohort was prematurely closed after 2(22%) pts developed G3 pneumonitis (both during the MC phase). Both recovered completely. There was 1 case of asymptomatic LVEF drop to below 50% (during the taxane phase); 1 pt had G2 hand-foot skin reaction (HFS) and another had G2 mucositis. The Her2- cohort was also prematurely closed with only 11 pts due to high rates of mucocutaneous toxicity (G3 HFS in 36%, G3 rash in 9%) and also because of SWOG0221 negative results. There were 2(18%) cases of FN, but no cases of pneumonitis. 1/11(9%) Her2- and 5/9(55%) Her2 + pts had a pCR. VEGF-related biomarkers were collected and will be presented at a later date. Conclusions: The proposed MC schedules proved too toxic to be considered for further clinical development. In addition, MC resulted in unexpectedly high rates of severe pulmonary toxicity when given in combination with trastuzumab. Her2+ but not Her2- pts had an impressively high pCR rate.
Phase III multicenter, randomized study of utidelone plus capecitabine versus capecitabine alone for heavily pretreated, anthracycline- and taxane-refractory metastatic breast cancer.
Authors: Binghe Xu, Pin Zhang, Tao Sun, Qingyuan Zhang, Zefei Jiang, Zhongyu Yuan, Xiaojia Wang, Shude Cui, Yuee Teng, Xi-Chun Hu, Junlan Yang, Hongming Pan, Zhongsheng Tong, Huiping Li, Qiang Yao, Yongsheng Wang
Journal: Journal of Clinical Oncology (2018)

1003 Background: Utidelone, a genetically engineered epothilone analog, showed excellent efficacy in phase II and III trials in terms of PFS as a primary end point and ORR as a secondary end point. In this multi-center phase III trial, we sought to determine whether utidelone plus capecitabine (CAP) could improve overall survival (OS) compared with CAP alone in patients with metastatic breast cancer (MBC) previously treated with anthracycline and taxanes. Methods: A total of 405 patients with MBC previously treated with anthracycline and taxanes were randomly assigned with a 2:1 ratio to either utidelone (30mg/m2/d intravenously on d1-d5) plus CAP (1,000 mg/m2 orally bid on d1-d14) or CAP alone (1,250 mg/m2 orally bid on d1-d14) given every three weeks. Kaplan-Meier methods were used to estimate the median OS, 2-year survival rate and corresponding 95% confidence intervals (CI) in the intention-to-treat (ITT) population between the two groups by means of two-sided log-rank tests. Survival HR (two-sided 95% CI) is computed using Cox proportional hazards model for the comparisons. Results: By March 9, 2018, 281 patients had died with 180 (66.7%) in the combination group and 101 (74.8%) in the CAP alone. In the ITT population, median OS was 14.75 months (95%CI 13.08-16.69) with combination group and 12.22 months (95%CI 11.14-14.26) with CAP alone. OS was significantly improved for the combination group vs CAP alone (HR 0·63, 95% CI 0·45─0·88;p = 0·0047). The 2-year survival rate was 39.0% (95% CI 33.2%, 45.1%) vs 26.6% (19.4%, 35.0%), which was significantly improved by 12.4% (1.9%- 22.4%;p = 0.015) for utidelone plus CAP. Peripheral neuropathy was the only grade 3 adverse event associated with utidelone that occurred at a prominent rate (25%), but was manageable and reversible, in the combination arm. Notably, utidelone caused very mild myelosuppression and no liver toxicities. This is the first study to show a significant OS benefit of an epothilone, and utidelone is the first microtubule inhibitor to demonstrate non-significant myelosuppression with a superior safety profile compared with ixabepilone. Conclusions: Utidelone plus CAP significantly improved OS in this heavily pretreated population with no significant increase in myelosuppression and most other adverse events compared to CAP alone. Clinical trial information: NCT02253459.
Racial and ethnic disparities in presentation, treatment, and outcomes for minority populations with diagnosis of lung cancer.
Authors: Luis E. Raez, Candice Sareli, Mark I. Block, Francisco Tarrazzi, Evelio Velis, Srinath Sundadaraman, Raja Mudad
Journal: Journal of Clinical Oncology (2013)

e17540 Background: There are differences in the presentation, treatment and outcome of lung cancer patients (pts), based on ethnicity, however there are not enough publications regarding these issues. Methods: Registry data on 2,255 pts with non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) treated during last 10 years (2002-2011) at Memorial Health Care System was obtained. The main objective of the study was to evaluate differences in lung cancer survival according to ethnicity. Chi-square was used to compare distribution of tumor stage. Survival curves were compared using log-rank test for each of the tumor stages. Adjusted hazard ratios (AHR) and 95% confidence intervals (95% CI) were reported based on the results of a multivariate Cox regression model for overall survival (OS) with adjustment for gender, age at diagnosis, race, stage and health insurance. Results: A total of 1940 pts (86%) had the diagnosis of NSCLC, the rest were SCLC. There were 1170 (52%) females. Non-Hispanic whites (NHW) were 1,791 pts (79%), Hispanics (H) 266 (12%) and African-American (AA) 149 (7%). Fifty eight percent of patients had stage III/IV at diagnosis. 2054 of the pts were insured (91%). There was a significant difference in age at diagnosis among H (66.5 y), AA (64.4y) and WNH (69.5y). The probability of being diagnosed at a late stage (IIIB/IV) was two times higher among AA compared to NHW (OR= 1.77, P&lt;0.05) or H (OR = 1.67, p&lt;0.05). There was no survival difference between NSCLC and SCLC (19m vs. 16m). Females with NSCLC lived significantly longer than males (Adjusted Hazard ratio (AHR= 1.14 p&lt;0.01). The same was true for SCLC (AHR = 1.43 p &lt; 0.01). Significant predictors for worse survival for patients with NSCLC were: older age at diagnosis (AHR = 1.01, p&lt;0.001), male gender (AHR=1.12, p&lt;0.05) and late stage at diagnosis (AHR=2.27, p&lt;0.001). Insurance and ethnicity were not significant predictors of of survival. Conclusions: There are significant disparities in presentation and outcomes among minority patients with lung cancer. We will further evaluate if other social or genetic factors can explain these disparities.
Psychosexual functioning in sexually active female survivors of childhood cancer.
Authors: Kari L. Bjornard, Carrie R Howell, James L. Klosky, Wassim Chemaitilly, Deo Kumar Srivastava, Tara M. Brinkman, Daniel M. Green, Victoria W Willard, Lisa M Jacola, Matthew J. Krasin, Melissa M. Hudson, Leslie L. Robison, Kirsten K. Ness
Journal: Journal of Clinical Oncology (2018)

136 Background: Childhood cancer survivors (CCS) may be at risk for low psychosexual function. We estimated the prevalence of low psychosexual function among female CCS, and evaluated associations with treatment exposures. Methods: 712 female CCS (mean age at assessment 31.2±7.71 years, at diagnosis 7.00±5.58 years; 31.3% acute lymphoblastic leukemia, 12.5% Hodgkin lymphoma) and 122 non-cancer controls enrolled in the St. Jude Lifetime Cohort Study completed a clinical assessment, reported sexual activity with or without a partner in the preceding month, and filled out the Sexual Functioning Questionnaire (SFQ) (25 items averaged to create overall and subscale scores ranging 0-5; lower is worse). CCS with SFQ scores &lt; 10 th percentile of controls were classified as low function. Linear models, adjusted for age, were used to compare SFQ scores. Associations between CCS characteristics and psychosexual function were evaluated using logistic regression. Results: 19.9% of CCS had low psychosexual function with a lower mean overall SFQ score than controls (3.19 vs. 3.47, effect size 0.4; p &lt; 0.01). The most common impairments among CCS were performance problems (27.4%), orgasm (24.2%), satisfaction (17.6%), interest (17.2%), desire (15.4%), and arousal (12.5%). Survivors with low function reported poor quality of life in both physical (21.1% vs. 12.7%, p = 0.01) and mental health (36.5% vs. 18.2%, p &lt; 0.01) domains compared to those without. Untreated hypogonadism was associated with low function (OR 3.20, 95% CI 1.69-6.42) for the performance problems subscale. Compared to controls, CCS with germ cell tumors (OR 8.82, 95% CI 3.17-24.50), renal tumors (OR 4.49, 95% CI 1.89-10.67) and leukemia (OR 3.09, 95% CI 1.50-6.38) were at greatest risk for low function. Though 40.7% of CCS perceived a higher risk for low psychosexual function compared to other women their age, only 2.9% reported receiving an intervention. Conclusions: Low psychosexual function is prevalent among female CCS. CCS with low psychosexual function also report poorer quality of life and more psychological symptoms. Research is necessary to identify additional risk factors that characterize high-risk survivors who would benefit from targeted screening and intervention.
Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma
Authors: Reinaldo Franqui-Machin, Mu Hao, Hua Bai, Zhimin Gu, Xin Zhan, Hasem Habelhah, Yogesh Jethava, Lugui Qiu, Ivana Frech, Guido Tricot, Fenghuang Zhan
Journal: Journal of Clinical Investigation (2018)

Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification-mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization. Increased NEK2 kinase levels activated the canonical NF-κB signaling pathway through the PP1α/AKT axis. Newly diagnosed myeloma patients with activated NF-κB signaling through increased NEK2 activity had poorer event-free and overall survivals based on multiple independent clinical cohorts. We also found that NEK2 activated heparanase, a secreted enzyme, responsible for bone destruction in an NF-κB-dependent manner. Intriguingly, both NEK2 and USP7 inhibitors showed great efficacy in inhibiting myeloma cell growth and overcoming NEK2-induced and -acquired drug resistance in xenograft myeloma mouse models.
Trends in triple negative breast cancer in California over 15 years.
Authors: Carol Parise, Vincent Caggiano
Journal: Journal of Clinical Oncology (2018)

e12569 Background: ER+/PR+/HER2- is the most common subtype and has the best survival and triple negative breast cancer (TNBC) is the second most common subtype and has the worst survival. The purpose of this study was to assess trends in diagnosis of TNBC versus ER+/PR+/HER2- over 15 years. Methods: We identified 221,205 cases of first primary female invasive breast cancer from the California Cancer Registry 2000-2014. 130,758 (59.7%) were ER+/PR+/HER2-, 27,278 (12.3%) were TNBC and the remaining 63,169 (28.6%) were the six remaining subtypes. The ratio of ER+/PR+/HER2- to TNBC cases diagnosed per year was computed. Results: The number of cases of both subtypes increased over time. TNBC was diagnosed at a higher percentage in 2000-2009 than it was in 2010-2014. The opposite was true for ER+/PR+/HER2- (Table 1). The ratio of diagnoses of ER+/PR+/HER2- to TNBC increased 48% over the 15 year period. Conclusions: The number of cases of ER+/PR+/HER2-, the subtype with the best survival continues to increase over time while the incidence of TNBC, the subtype with the worst survival, appears to have stabilized. Year N % of ER+/PR+/ HER2- % of ER+/PR+/ HER2-/year N % of TNBC % of TNBC/year Ratio Total 2,000 4,887 3.7% 80.5% 1,187 4.4% 19.5% 4.12 6,074 2,001 5,855 4.5% 81.2% 1,359 5.0% 18.8% 4.31 7,214 2,002 5,895 4.5% 81.2% 1,366 5.0% 18.8% 4.32 7,261 2,003 6,491 5.0% 79.7% 1,656 6.1% 20.3% 3.92 8,147 2,004 6,294 4.8% 78.9% 1,682 6.2% 21.1% 3.74 7,976 2,005 6,900 5.3% 80.1% 1,717 6.3% 19.9% 4.02 8,617 2,006 8,112 6.2% 80.5% 1,968 7.2% 19.5% 4.12 10,080 2,007 9,147 7.0% 82.2% 1,977 7.2% 17.8% 4.63 11,124 2,008 9,680 7.4% 81.6% 2,177 8.0% 18.4% 4.45 11,857 2,009 9,825 7.5% 82.3% 2,113 7.7% 17.7% 4.65 11,938 2,010 10,306 7.9% 83.6% 2,019 7.4% 16.4% 5.10 12,325 2,011 11,320 8.7% 84.7% 2,041 7.5% 15.3% 5.55 13,361 2,012 11,779 9.0% 85.5% 2,004 7.3% 14.5% 5.88 13,783 2,013 12,175 9.3% 85.7% 2,037 7.5% 14.3% 5.98 14,212 2,014 12,092 9.2% 86.0% 1,975 7.2% 14.0% 6.12 14,067 Total 130,758 27,278 158,036
Spontaneous regression of mantle cell lymphoma: a report of four cases
Authors: Haige Ye, Aakash Desai, Tiejun Gong, Dongfeng Zeng, Krystle Nomie, Wendy Chen, Wei Wang, Jorge Romaguera, Michael L. Wang
Journal: Cancer Communications (2018)

Abstract Background Spontaneous regression has been reported in some indolent forms of lymphoma. Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm and has a poor prognosis. However, approximately 30% of MCL patients can exhibit indolent clinical behavior. To date, complete spontaneous regression of MCL has not been reported. Case presentation We describe four cases of spontaneous regression of MCL. At the time of presentation, these patients were asymptomatic, with lymph node enlargement and mild to moderate fluorodeoxyglucose (FDG) uptake on FDG‐positron emission tomography combined with computed tomography. One of the possible mechanisms of spontaneous regression of the tumor could be due to the host immune response through humoral and cellular immunity, which may have a role in the clearance of tumor cells. Conclusions In this report, we support the use of a “wait and watch” strategy for MCL patients with no risk factors and indolent behavior. This strategy helps spare patients from further potentially harmful chemotherapy. In addition, we describe the phenomenon of spontaneous regression in MCL patients who are asymptomatic and have low‐volume disease.
Identification of Targetable Driver Mutations In Molecularly Selected Never Smoker Lung Adenocarcinomas
Authors: C Bennati, D Aisner, R Chiari, M Varella Garcia, S Kako, G Metro, Guido Bellezza, Minotti, Ludovini, De Angelis, L Marcomigni, L. Crinò
Journal: Journal of Thoracic Oncology (2013)
PRDM16 isoforms differentially regulate normal and leukemic hematopoiesis and inflammatory gene signature
Authors: David J. Corrigan, Larry L. Luchsinger, Mariana Justino de Almeida, Linda J. Williams, Alexandros Strikoudis, Hans-Willem Snoeck
Journal: Journal of Clinical Investigation (2018)

PRDM16 is a transcriptional coregulator involved in translocations in acute myeloblastic leukemia (AML), myelodysplastic syndromes, and T acute lymphoblastic leukemia that is highly expressed in and required for the maintenance of hematopoietic stem cells (HSCs), and can be aberrantly expressed in AML. Prdm16 is expressed as full-length (fPrdm16) and short (sPrdm16) isoforms, the latter lacking the N-terminal PR domain. The role of both isoforms in normal and malignant hematopoiesis is unclear. We show here that fPrdm16 was critical for HSC maintenance, induced multiple genes involved in GTPase signaling, and repressed inflammation, while sPrdm16 supported B cell development biased toward marginal zone B cells and induced an inflammatory signature. In a mouse model of human MLL-AF9 leukemia, fPrdm16 extended latency, while sPrdm16 shortened latency and induced a strong inflammatory signature, including several cytokines and chemokines that are associated with myelodysplasia and with a worse prognosis in human AML. Finally, in human NPM1-mutant and in MLL-translocated AML, high expression of PRDM16, which negatively impacts outcome, was associated with inflammatory gene expression, thus corroborating the mouse data. Our observations demonstrate distinct roles for Prdm16 isoforms in normal HSCs and AML, and identify sPrdm16 as one of the drivers of prognostically adverse inflammation in leukemia.
Vector competence of Aedes albopictus for the Indian Ocean lineage (IOL) chikungunya viruses of the 2007 and 2017 outbreaks in Italy: a comparison between strains with and without the E1:A226V mutation
Authors: Claudia Fortuna, Luciano Toma, Maria Elena Remoli, Antonello Amendola, Francesco Severini, Daniela Boccolini, Roberto Romi, Giulietta Venturi, Giovanni Rezza, Marco Di Luca
Journal: Eurosurveillance (2018)

We compared the vector competence of an Italian population of Aedes albopictus for two strains of chikungunya virus (CHIKV), with and without E1:A226V mutation, responsible for outbreaks in 2007 in the Emilia Romagna region and 2017 in the Lazio and Calabria regions, respectively. Ae. albopictus showed similar vector competence for both viral strains indicating that E1:A226V mutation is not exclusively responsible for ability of CHIKV to replicate well in this mosquito species.
JAK2, Calr and MPL Mutation Status Predicts the Survival Outcome of Patients with Primary Myelofibrosis
Authors: Uri Rozovski, Taghi Manshouri, Vilma Dembitz, Ksenija Bozinovic, Sherry Pierce, Hagop M. Kantarjian, Zeev Estrov, Srdan Verstovsek
Journal: Blood (2014)
Hexavalent Chromium–Induced Chromosome Instability Drives Permanent and Heritable Numerical and Structural Changes and a DNA Repair–Deficient Phenotype
Authors: Sandra S. Wise, Abou El-Makarim Aboueissa, Julieta Martino, John Pierce Wise
Journal: Cancer Research (2018)

Abstract A key hypothesis for how hexavalent chromium [Cr(VI)] causes cancer is that it drives chromosome instability (CIN), which leads to neoplastic transformation. Studies show chronic Cr(VI) can affect DNA repair and induce centrosome amplification, which can lead to structural and numerical CIN. However, no studies have considered whether these outcomes are transient or permanent. In this study, we exposed human lung cells to particulate Cr(VI) for three sequential 24-hour periods, each separated by about a month. After each treatment, cells were seeded at colony-forming density, cloned, expanded, and retreated, creating three generations of clonal cell lines. Each generation of clones was tested for chromium sensitivity, chromosome complement, DNA repair capacity, centrosome amplification, and the ability to grow in soft agar. After the first treatment, Cr(VI)-treated clones exhibited a normal chromosome complement, but some clones showed a repair-deficient phenotype and amplified centrosomes. After the second exposure, more than half of the treated clones acquired an abnormal karyotype including numerical and structural alterations, with many exhibiting deficient DNA double-strand break repair and amplified centrosomes. The third treatment produced new abnormal clones, with previously abnormal clones acquiring additional abnormalities and most clones exhibiting repair deficiency. CIN, repair deficiency, and amplified centrosomes were all permanent and heritable phenotypes of repeated Cr(VI) exposure. These outcomes support the hypothesis that CIN is a key mechanism of Cr(VI)-induced carcinogenesis. Significance: Chromium, a major public health concern and human lung carcinogen, causes fundamental changes in chromosomes and DNA repair in human lung cells. Cancer Res; 78(15); 4203–14. ©2018 AACR.
Anthropometric factors and Breslow thickness: prospective data on 2570 cases of cutaneous melanoma in the population-based Janus Cohort
Authors: J.S. Stenehjem, M.B. Veierød, L.T. Nilsen, R. Ghiasvand, B. Johnsen, T.K. Grimsrud, R. Babigumira, N.C. Støer, J.R. Rees, T.E. Robsahm
Journal: British Journal of Dermatology (2018)

Breslow thickness is the most important prognostic factor of localized cutaneous melanoma (CM), but associations with anthropometric factors have been sparsely and incompletely investigated.To examine prediagnostic body mass index (BMI), body surface area (BSA), and height, weight and weight change in relation to Breslow thickness, overall and by anatomical site and histological subtype; and to assess possible nonlinear associations between these anthropometric factors and Breslow thickness.CMs in the Janus Cohort were identified between 1972 and 2014. Linear regression was used to estimate geometric mean ratios (GMRs) of Breslow thickness with 95% confidence intervals (CIs) according to anthropometric factors. Restricted cubic splines in generalized linear models predicted adjusted mean Breslow thickness, and were used to assess possible nonlinear relationships.Of 2570 cases of CM, obese patients had a GMR of 1·16 (95% CI 1·04-1·30) of Breslow thickness vs. normal-weight patients. For BSA and weight, quintile 5 showed GMRs of 1·13 (95% CI 1·00-1·27) and 1·17 (95% CI 1·03-1·33) of Breslow thickness vs. quintile 1, respectively. Associations seemed restricted to superficial spreading melanomas and CMs on the trunk and lower limbs. The associations plateaued at an adjusted mean Breslow thickness of about 2·5 mm (BMI 29 kg m-2 , BSA 2·05 m2 and weight 90 kg), before declining for the highest values. No associations were found for height and weight change.This large case-series of incident CM demonstrated positive associations between BMI, BSA, weight and Breslow thickness, and suggested that behavioural or other mechanisms apply at high values.
Targeting energy metabolism via the mitochondrial pyruvate carrier as a novel approach to attenuate neurodegeneration
Authors: Emmanuel Quansah, Wouter Peelaerts, J. William Langston, David K. Simon, Jerry Colca, Patrik Brundin
Journal: Molecular Neurodegeneration (2018)

Several molecular pathways are currently being targeted in attempts to develop disease-modifying therapies to slow down neurodegeneration in Parkinson's disease. Failure of cellular energy metabolism has long been implicated in sporadic Parkinson's disease and recent research on rare inherited forms of Parkinson's disease have added further weight to the importance of energy metabolism in the disease pathogenesis. There exists a new class of anti-diabetic insulin sensitizers in development that inhibit the mitochondrial pyruvate carrier (MPC), a protein which mediates the import of pyruvate across the inner membrane of mitochondria. Pharmacological inhibition of the MPC was recently found to be strongly neuroprotective in multiple neurotoxin-based and genetic models of neurodegeneration which are relevant to Parkinson's disease. In this review, we summarize the neuroprotective effects of MPC inhibition and discuss the potential putative underlying mechanisms. These mechanisms involve augmentation of autophagy via attenuation of the activity of the mammalian target of rapamycin (mTOR) in neurons, as well as the inhibition of neuroinflammation, which is at least partly mediated by direct inhibition of MPC in glia cells. We conclude that MPC is a novel and potentially powerful therapeutic target that warrants further study in attempts to slow Parkinson's disease progression.