tbuckley/cabot-search huggingface dataset:
Evidence of linkage in MSH6-associated region exclusive to high-risk African-American families with prostate cancer.
Authors: Elisa M. Ledet, Oliver Sartor, Rayford Walter, Joan Bailey-Wilson, Diptasri Mandal
Journal: Journal of Clinical Oncology (2017)

180 Background: The significance of germline variants and their implications for prostate cancer (PCa) patients has gained prominence. Mismatch repair (MMR) genes such as MSH6 and MSH2, along with DNA repair genes, may be more important in PCa than previously appreciated. In the present study, we compared linkage results between African American (AA) and Caucasian (CA) PCa families with multiple affected family members. Methods: Study subjects were from 15 large, high-risk, clinically homogenous AA families and 4 CA families from Southern Louisiana. All families had at least ≥ 3 members with family member diagnosed with PCa. Genotyping for linkage analyses was done using Illumina Infinium II SNP HumanLinkage-12 panel. 6,068 SNPs were released for linkage analyses. Parametric linkage analyses were performed using Merlin software, version 1.1.2. An HLOD score &gt; 1.86 was considered suggestive of linkage. Results: A total of 129 individuals from 15 AA families were genotyped including 45 affected men, 44 unaffected men, and 40 women. The average age at diagnosis was 61; 8 of 15 families had more than 4 affected individuals. 50 CA individuals from similar families were genotyped including 12 affected men, 26 presently unaffected men, and 12 women. For CA families, the average age of onset was 66, with at least 5 affected individuals in each family. In AAs, we identified a peak of suggestive linkage at chromosome 2p16 (HLOD = 1.97). Similarly, in CA families, the strongest linkage signal was observed on chromosome 2q14.1 with an HLOD score of 1.94. At the2 q14 linkage region, there was no linkage in AA PCa families (HLOD = 0.0004). Similarly, on 2p16, there was no linkage in the CA cohort (HLOD = 0). Conclusions: The MSH6 gene is located in 2p16 region. MMR gene mutations have been shown to have evidence of microsatellite instability in PCa as well as hereditary nonpolyposis colorectal cancer. MSH6 gene may represent a genetic variant contributing to risk of PCa in high risk AA families. This potentially has therapeutic implications for use of PD1 inhibitors in this population.
Concurrent chemoradiation (CChRT) with bi-weekly docetaxel and cisplatin and thoracic radiotherapy for stage III non-small cell lung cancer (NSCLC): A phase II study from the Galician Lung Cancer Group.
Authors: Joaquin Casal Rubio, EM Brozos, Martin Lázaro Quintela, Sergio Vazquez-Estevez, Jl Firvida, MB Taboada, M Caeiro, JE Castro, Maria Vieito Villar, Clara Senin Estor, MJ Villanueva, Silvia Varela Ferreiro, MC Areses, C Pena, P Calvo, E. Hernandez, N. Martinez, Urbano Anido, Gerardo Huidobro
Journal: Journal of Clinical Oncology (2013)

7549 Background: CChRT is recommended as the evidence-based approach for the management of patients (p) with locally advanced stage III NSCLC and a good performance status, although a clearly superior regimen has not been identified. The aim of our study was to evaluate the effectiveness and toxicities of CChRT with bi-weekly docetaxel (D) and cisplatin (C) and thoracic radiotherapy. Methods: 50 p with histologically confirmed inoperable locally advanced NSCLC, stage IIIAN2/IIIB (no pleural T4), PS 0-1 and adequate lung function (FEV1 &gt; 1.1, V20 &lt; 25%) were included: one cycle of D 75 mg/m2 on day 1 and C 40 mg/m2 days 1-2 followed at 21 days by CChRT with bi-weekly D 40 mg/m2 and C 40 mg/m2 for four courses, during conformal thoracic radiotherapy (66 Gys, 180 cGy/day). The primary objective was overall survival (OS); secondary objectives were progression free survival (PFS), response rate (RR) and toxicity. Median follow-up: 14,5 months. Results: The p characteristics were: mean age 59,1 years (34-75); male/female 44/6; squamous/adeno/large cell carcinoma: 52%/34%/14%; stage IIIAN2 14 p (28%) and stage IIIB 36 p (72%). All p were evaluable for response and toxicity. RR: 4 CR, 36 PR (RR 80%; 95% CI:69-91), 4 SD (8%) and 6 PD (12%). The median PFS was 13 months (95% CI:8-18) and median OS was 19 months (95% CI:14-24). The PFS and OS at 1/2 years were 52%/30% and 79%/40% respectively. A total of 50 cycles of D-C induction chemotherapy were given; main toxicities (NCI-CTC 3.0) per p Grade (g) 1-2/3-4 (%) were as follows: neutropenia 2/16; anemia 12/0; nausea/vomiting 28/2; diarrhea 22/4; there were two episodes of febrile neutropenia. Main toxicities per p in CChRT (D-C doses: 192, 3.8 per p; mean doses RT: 64,6 Gys) were g1-2/3 (%): neutropenia 28/6; anemia 60/0; esophagitis 52/4 and pneumonitis 34/0; there were four episodes of hospitalization: febrile neutropenia, 2 p and g3 esophagitis, 2 p. Conclusions: CChRT with bi-weekly docetaxel and cisplatin and thoracic radiotherapy is a feasible treatment option for inoperable locally advanced stage III NSCLC, showing good clinical efficacy and tolerability with acceptable long-term survival.
Methionine gamma-lyase-encapsulated into red blood cells (ERY-MET) antitumor activity in gastric carcinoma.
Authors: Vanessa Bourgeaux, Karine Sénéchal, Karine Aguera, Fabien Gay, Françoise Horand
Journal: Journal of Clinical Oncology (2017)

78 Background: Methionine (Met) requirement is a cancer specific–metabolic defect that seems a promising target, especially in gastric cancers. Methionine gamma–lyase (MGL), a pyridoxal–5′–phosphate (PLP)–dependent enzyme, is an emerging approach consisting in tumors Met starvation via systemic Met depletion. ERY-MET is a new therapeutic product overcoming the short in vivo half-life of free MGL by its encapsulation into Red Blood Cells (RBCs). Indeed, ERY-MET works as a bioreactor degrading Met that passively diffuses inside the RBC. In addition, entrapped MGL activity can be controlled by supplying Vitamin B6 (PN), the precursor of MGL’s cofactor (PLP), converted inside RBCs. ERY-MET anti-tumor activity was evaluated in vivo in NMRI nudemice bearing subcutaneous gastric carcinoma. Methods: First, in vitro sensitivity of NCI-N87 and AGS human gastric cell lines to free MGL was assessed by IC50 determination using CCK–8 assay. MGL encapsulated into mouse RBCs by hypotonic dialysis was injected once in CD1 mice to determine PK-PD parameters with or without PN supplementation. The anti-tumor activity of weekly ERY-MET injections (x5) at 116 IU/kg ± 25% was assessed with or without PN supplementation in female NMRI nudemice (n = 10/group) xenografted with NCI-N87 cells. Met depletion was determined 6 days after each cumulative injection while tumor growth was followed twice a week by caliper measurement. Results: In vitro studies showed that NCI-N87 as well as AGS cell lines displayed a sensitivity to free MGL with IC50 of 0.35 ± 0.01 and 0.12 ± 0.02 IU/mL, respectively. ERY-MET with daily PN supplementation significantly increased active MGL half-life in vivo (from &lt; 24h to 8–9 days). ERY-MET induced 80% inhibition of tumor growth at day 45 (p &lt; 0.0001). Response rate obtained was 76% of treated mice (15/20). Besides, PN supplementation induced a slow-down of tumor growth during the supplementation period and improved ERY-MET efficacy. Conclusions: Theses results suggest that ERY-MET can induce tumor growth inhibition in mice bearing human gastric adenocarcinoma and that its effect can be regulated by PN supplementation. As such, ERY-MET seems a promising anti-tumor drug to treat gastric cancers.
Impact of patient-specific factors in the development of radiation (RT)-associated cardiac perfusion defects
Authors: R. G. Prosnitz, X. Yu, S. Zhou, D. Kahn, D. R. Hollis, P. H. Hardenbergh, S. Borges-Neto, T. Wong, M. A. Blazing, L. B. Marks
Journal: Journal of Clinical Oncology (2004)

673 Background: Our group is prospectively studying the impact of tangential photon RT to the left breast/chest wall on cardiac function. Using single photon emission computed tomography (SPECT) to assess regional perfusion, we have reported that RT causes dose/volume-dependent perfusion defects in the anterior myocardium. The current analysis addresses the impact of patient-specific factors on the development of RT-associated SPECT cardiac perfusion defects. Methods: Between 1998–2001, 114 patients enrolled onto an IRB-approved prospective study and had pre- and serial post-RT (6–24 months) SPECT scans to assess changes in regional cardiac perfusion. Eighty-three patients had normal pre-RT perfusion scans and available follow-up data. Due to the confounding effect of irradiated volume, patients were divided into 3 subgroups based on the percent of left ventricle within the RT fields: ≤ 1%, 1–5%, and ≥ 5%. Within each volume cohort, the impact of patient-specific factors (Adriamycin based chemotherapy exposure, race, tobacco use, obesity, hypertension, and hypercholesterolemia) on the development of new perfusion defects, was evaluated using logistic regression. Results: With a median follow-up of 18 months (range 6–24 mos), 31/83 (37%) patients developed new perfusion abnormalities. Overall, 73% (8/11) of Africa-American patients developed new perfusion defects vs. 32% (23/72) of Caucasian patients. 42% (22/53) of patients receiving Adriamycin based chemotherapy developed new perfusion defects vs. 30% (9/30) of patients without chemotherapy. Using logistic regression to control for subgroups based on irradiated left ventricular volumes, race remained a significant predictor for new perfusion defects (p=0.04). Other clinical variables (chemotherapy exposure, tobacco use, hypertension, obesity, and Hypercholesterolemia) were not significant. Conclusions: African-American women may be at greater risk for RT-induced cardiac dysfunction than are Caucasians. Longer follow-up and additional study involving larger numbers of patients are needed. Supported in part by Grant DAMD 17–98-1–8071 and BC010663 awarded by DOD. No significant financial relationships to disclose.
Safety and Efficacy of Elotuzumab with Lenalidomide/Dexamethasone for Multiple Myeloma in a Japanese Subpopulation Analysis of the Phase 3 Eloquent-2 Trial
Authors: Kazuteru Ohashi, Kenshi Suzuki, Kazutaka Sunami, Shinsuke Iida, Shinichiro Okamoto, Hiroshi Handa, Kosei Matsue, Masafumi Miyoshi, Eric Bleickardt, Morio Matsumoto, Masafumi Taniwaki
Journal: Blood (2016)
Genome-based outcome prediction in <i>MYCN </i>nonamplified high-risk neuroblastoma.
Authors: Andres Eduardo Morales La Madrid, Thomas Stricker, Peter Pytel, Yasmin C. Gosiengfiao, Jason Shohet, Hiroyuki Shimada, Wayne Lee Furman, Peter E. Zage, Julie R. Park, Elizabeth Perlman, Lisa Guerrero, Helen Salwen, Alexandre Chlenski, Wendy B. London, Susan Lerner Cohn
Journal: Journal of Clinical Oncology (2012)

9534 Background: Less than 40% of children with high-risk neuroblastoma achieve long-term survival, and at diagnosis, it is not possible to identify patients who will be cured. Microarray studies have proposed expression signatures associated with outcome within high-risk cohorts. However, integrating this technology as a clinical test has been difficult, in part due to the lack of available frozen tissue and high quality RNA. The nCounter overcomes this obstacle, using formalin-fixed paraffin embedded tissue (FFPE). Our objective is to test the correlation of a previously published “ultra high-risk” microarray gene signature developed in the MYCN nonamplified high-risk population (Asgharzadeh et al, J Natl Cancer Inst, 2006) with the gene expression signature obtained with the nCounter (NanoString Technologies) using RNA isolated from FFPE MYCN nonamplified high-risk neuroblastoma samples. Methods: FFPE tumor samples linked to clinical outcome data were obtained from 6 collaborative institutions. Tumor content of each sample was assessed morphologically. RNA was isolated using the RNeasy FFPE-kit. Customized probes corresponding to the candidate genes were designed by NanoString. Hybridization reactions were performed in duplicate using 100 ng of RNA. Positive and negative control probes and housekeeping probes were included in every reaction and were used to normalize data for differences in purification, hybridization, and capture efficiencies Results: Forty-two MYCN nonamplified high-risk neuroblastoma samples were analyzed by the nCounter. The cohort 5-year event-free survival and overall survival were 44.6 +/- 8.0% and 53.8 +/- 8.4% respectively. Highly degraded RNA (RIN ~ 1.5-2.8) was obtained. Unsupervised clustering and principle components analysis on normalized expression data showed differential expression of most of the genes with clustering of cases depending upon outcome (FDR = 0.05). Conclusions: Our results demonstrate that the nCounter can yield gene expression profiles that are similar to microarray gene signatures. Further investigation of the clinical utility the nCounter technology to prognosticate outcome in patients with high-risk neuroblastoma is warranted.
<i>NRAS</i> mutations in patients with advanced cancers treated with target-based therapies in early-phase clinical trials.
Authors: Vinu Madhusudanannair, Filip Janku, Gerald Steven Falchook, David S. Hong, Jennifer J. Wheler, Aung Naing, Siqing Fu, Sarina Anne Piha-Paul, Hazem Edmond El-Osta, Rajyalakshmi Luthra, Apostolia Maria Tsimberidou, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2012)

3106 Background: NRAS mutations in cancers increase MAPK signaling. It is plausible that NRAS mutations may be associated with sensitivity to drugs targeting the MAPK pathway. Methods: Tumors from 689 patients with advanced cancers referred to the Clinical Center for Targeted Therapy (phase I program) were screened in a CLIA-certified laboratory for NRAS mutations and if feasible, for PIK3CA, KRAS, BRAF mutations and PTEN aberrations. Whenever possible, patients with NRAS mutations were treated with agents targeting the RAF-MEK pathway. Results: Of the 689 patients, 58 (8%) had NRAS mutations. NRAS mutations were most prevalent in melanoma (26/170, 25%), thyroid (5/26, 19%), endometrial (2/27, 7%), non-small cell lung (1/31, 3%), ovarian (1/60, 2%) and colorectal cancers (1/74, 1%). NRAS mutations were not seen in any of the tested head and neck squamous cell cancers (n = 44); sarcomas (n = 41) and breast cancers (n = 25). None (0/62, 0%) of the patients tested for KRAS had simultaneous NRAS and KRAS mutations, and only 2/42 (5%) tested for BRAF had simultaneous NRAS and BRAF mutations. Of 58 patients with NRAS mutations, 14 (24%) were enrolled in trials that included MEK axis inhibitors. Of these 14 patients, 13 had melanoma and 1 had ovarian cancer and 4/14 (29%) demonstrated tumor shrinkage &gt;10% from baseline. In comparison, only 22/187 (12%) patients with wild-type/unknown NRAS, KRAS and BRAF treated on the same trials demonstrated tumor shrinkage &gt;10% (p=0.086). Conclusions: NRAS mutations are diagnosed in variety of advanced cancers. Patients with NRAS mutations demonstrated a trend to better antitumor activity with MEK axis inhibitors compared to patients without NRAS, KRAS or BRAF mutations. Further studies are warranted to delineate the role of NRAS mutations in patients treated with MEK axis inhibitors.
The prognostic value of an early response in chemoradiation of locally advanced rectal cancer.
Authors: John Ploeen, Jan Lindebjerg, Jens Christian Riis Joergensen, Anders Kristian Moeller Jakobsen
Journal: Journal of Clinical Oncology (2012)

e14134 Background: Preoperative chemoradiation is standard treatment of locally advanced rectal cancer, and there is an obvious need for new methods of assessing the effect. Evaluation by clinical examination with endoscopy is controversial. In most papers the assessment of effect has been performed after the end of treatment. The aim of the present study was to investigate the clinical value of an examination during chemoradiation. Methods: The study included 128 patients with histopathologically verified rectal cancer. Further inclusion criteria were a T3 tumor with a circumferential margin ≤ 5 mm by MRI or a T4 tumor, a distance of &lt; 10 cm from the anal verge and localized diseased only by abdominal and chest CT scan. The treatment was 50.4 Gy/28 fractions or the same treatment with the addition of endorectal brachytherapy 10 Gy/2 fractions in a randomized trial. The concomitant chemotherapy was UFT 300 mg/m 2 and L-leucovorin 22.5 mg daily. Both drugs were given five days a week. Clinical examination with endoscopy was performed week 4 during treatment. The clinical effect was classified into complete response (CR) or not complete response with clinical residual tumor (NCR). The patients were operated eight weeks after end of treatment and the pathological tumor response was classified according to Mandard (TRG). Results: CR was found in 14% of the patients. Comparison with TRG showed that 82% with CR had TRG1 as compared to the NCR group where only 9% had TRG1 (p&lt;10 -4 ). The risk of lymph node metastasis was also different with 94% pN 0 in the group with CR compared to 57% in the NCR group (p=0.02). The rate of CR translated to a major difference in the risk of recurrence (local and distant). No patients with CR experienced recurrence as compared to 19% in the NCR group (p&lt;0.05). The CR also correlated with cancer specific survival. None of the patients with CR died from rectal cancer with a median observation time of 36 months compared to 30% in the NCR group. Conclusions: CR is a major prognostic parameter in locally advanced rectal cancer treated with chemoradiation. Early CR should be considered in the selection of patients for Watchful Waiting.
Rotavirus Vaccines — A New Hope
Authors: Mathuram Santosham, Duncan Steele
Journal: New England Journal of Medicine (2017)

Diarrhoea due to Rotavirus is the leading cause of mortality among children less than 5 years of age in developing countries. Though Rotavirus vaccine has been approved by FDA since 2006 it has not been incorporated in the EPI schedule of Pakistan. Objective of our study was to explore the clinical efficacy, cost effectiveness and safety of Rotavirus vaccine in infants and children against diarrhoea caused by Rotavirus. Online search yielded a total of 103 articles out of which 31 articles were included for perusal. Newly-developed vaccines have been found to have combined efficacy of 61.2-64.6% in African Countries and 82.1-84.7% in Europe and Latin America against Rotavirus-induced diarrhoea. Rotavirus vaccine is a very effective option in terms of efficacy, cost and safety against viral diarrhoea caused by Rotavirus. Consideration should be given to include this vaccine in EPI programme of developing countries.
Survivorship care plan (SCP) program development within a large hospital network.
Authors: Natalie Garces, Tara Eaton, Beth York, Chasse Margot Bailey-Dorton, Wendy G. Brick
Journal: Journal of Clinical Oncology (2017)

42 Background: Barriers to SCP delivery are pervasive, with limited data available on strategies to address implementation barriers. Despite the variety of models for SCP-based survivorship care planning, there is a dearth of studies on SCP program development for larger hospital networks. Large networked hospital systems, including the Levine Cancer Institute (LCI), have unique challenges for implementing a SCP program. Methods: Beginning in 2014, LCI implemented a process for delivery of SCPs across its network of 8 Commission on Cancer accredited hospitals. Obstacles to implementation were evaluated and methods of establishing procedures for insuring SCP delivery were reviewed. Improvement in SCP delivery was measured over 3 years. SCP program development involved leveraging technology, developing processes for identifying eligible survivors, and engaging providers and practice managers in this key organizational initiative. Results: In 2014, the SCP program consisted of 3 advanced care providers (ACPs) in 3 LCI medical oncology clinics, delivering SCPs to 67 (2%) of the eligible 3,336 survivors. In the second year of implementation, 14 ACPs and 4 MDs delivered 348 (11%) SCPs to eligible survivors in 14 LCI clinics. By the end of the 2016 calendar year, it is estimated that &gt; 1,029 SCPs ( &gt; 25%) of eligible survivors will receive a SCP throughout the LCI hospital network. Conclusions: While challenging to deliver, SCPs are important both for cancer program accreditation and for communication between patients and physicians. At its large, multi-center cancer program, LCI has implemented a number of methods and protocols to insure that eligible patients receive informative and timely SCPs. LCI’s processes have resulted in an improvement in the number of SCPs delivered and have also served to eliminate obstacles to increasing the number of SCPs that will be delivered in the future. It is recommended that oncology practices consider the methods and interventions that LCI found helpful to improve SCP delivery in large hospital networks. It is also encouraged that oncology practices to continue to share their methods with other centers to promote eventual SCP delivery to eligible survivors.
Do women with <i>BRCA1</i> or <i>BRCA2</i> mutations have reduced ovarian reserve?
Authors: Kelly-Anne Phillips, Ian M. Collins, Roger L Milne, Richard Fisher, Catharyn Stern, Gordon Kannemeyer, Charmaine Smith, Michael Friedlander, Sue-Anne McLachlan, Martha Hickey, John L. Hopper
Journal: Journal of Clinical Oncology (2015)

1537 Background: It is uncertain whether mutations in the DNA repair genes, BRCA1 or BRCA2, result in reduced ovarian reserve. AMH is a surrogate marker of ovarian reserve. This study examined AMH levels of BRCA1 and BRCA2 mutation carriers and their non-carrier blood relatives. Methods: Eligible women were from families segregating BRCA1 or BRCA2 mutations enrolled in the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Each woman had been tested for the family mutation and had completed an epidemiological questionnaire and provided a blood sample at cohort entry. Women were aged 25-45 years, had no personal history of invasive cancer, had two intact ovaries and were not pregnant or breastfeeding at the time of blood draw. AMH was tested on stored plasma samples using an electrochemiluminescence immunoassay platform. Higher AMH levels are associated with greater ovarian reserve. Associations between AMH level and carrier status were tested by linear regression, using the natural logarithm of AMH as the outcome variable, carrier status as the explanatory variable, and adjusting for age at blood draw, oral contraceptive use, BMI and cigarette smoking. Robust standard errors were estimated to account for the inclusion of multiple members from the same family. Results: AMH level was measured for 172 carriers and 216 non-carriers from families carrying BRCA1 mutations, and 147 carriers and 158 non-carriers from families carrying BRCA2 mutations. Within both groups, mutation carriers were younger at blood draw than non-carriers (p ≤ 0.031). Age was negatively associated with AMH level for carriers and non-carriers of BRCA1 and BRCA2 mutations (p < 0.001). BRCA1 mutation carriers had, on average, 25% lower AMH levels than non-carriers (p = 0.022). There was no evidence of an association for BRCA2 mutation carriers (p = 0.94). Results did not change substantially after excluding women who were post-menopausal or taking oral contraceptives at blood draw. Conclusions: This study suggests that women with a germline mutation in BRCA1 have reduced ovarian reserve. This could have implications for their fertility and family planning.