tbuckley/cabot-search huggingface dataset:
Comprehensive preclinical testing for neuroblastoma using orthotopic xenografts of a patient tumor.
Authors: Sara Michele Federico, Elizabeth Stewart, Rachel Christine Brennan, Cori Bradley, Fan Wang, Burgess B. Freeman, Clinton F. Stewart, Jianrong Wu, Michael A. Dyer
Journal: Journal of Clinical Oncology (2012)

e13584 Background: Neuroblastoma is an aggressive malignancy that accounts for 15% of pediatric cancer deaths. There are limited well characterized neuroblastoma models for use in preclinical trials. We characterized a human neuroblastoma orthotopic xenograft, performed comprehensive preclinical studies, and evaluated the pharmacokinetics of drugs targeting the PI3K pathway. Methods: Tumor tissue (MAST3) was obtained from a 2 year old with stage IV metastatic MYCN amplified neuroblastoma. Using ultrasound guidance, MAST3 cells were injected into the para-adrenal space of nod-scid mice. Tumors were monitored for growth with routine ultrasound and passaged. The initial patient tumor (MAST3) and tumor from each passage were extensively analyzed including: histology, electron microscopy (EM), gene expression profiling, single nucleotide polymorphism (SNP ) microarrays, whole genome sequencing (WGS), and spectral karyotyping (SKY). Using this orthotopic xenograft model, a randomized preclinical trial was conducted to evaluate the response to standard chemotherapeutic agents. Pharmacokinetic studies of oral BEZ-235, BKM-120, OSI-906 and everolimus were conducted. Results: Analysis of the histology, EM, gene expression profiling, SNP microarrays, WGS, and SKY showed minimal variability between the MAST3 tumor and the passaged tumors in the orthotopic xenografts. Notably, MAST3 metastasized to the liver, lung and spleen in vivo. Administering standard chemotherapeutic agents every 3 weeks for a total of 6 courses, we observed a significant response in 40% of treated mice. Further ongoing preclinical trials will evaluate the comparative efficacy of IGFR/PI3K/mTOR molecular targeted therapies. Conclusions: We developed the first well characterized neuroblastoma orthotopic xenograft. Our comprehensive characterization of this xenograft indicates that it retains many of the molecular, cellular and genetic properties of the primary lesion. A preclinical trial using standard chemotherapeutic agents has provided a valuable baseline for comparison with novel therapeutics and will inform our selection of the most promising agents to move into clinical trials.
PopNet: A Markov Clustering Approach to Study Population Genetic Structure
Authors: Javi Zhang, Asis Khan, Andrea Kennard, Michael E. Grigg, John Parkinson
Journal: Molecular Biology and Evolution (2017)

With the advent of low cost, high-throughput genome sequencing technology, population genomic data sets are being generated for hundreds of species of pathogenic, industrial, and agricultural importance. The challenge is how best to analyze and visually display these complex data sets to yield intuitive representations capable of capturing complex evolutionary relationships. Here we present PopNet, a novel computational method that identifies regions of shared ancestry in the chromosomes of related strains through clustering patterns of genetic variation. These relationships are subsequently visualized within a network by a novel implementation of chromosome painting. We apply PopNet to three diverse populations that feature differential rates of recombination and demonstrate its ability to capture evolutionary relationships as well as associate traits to specific loci. Compared with existing tools, PopNet provides substantial advances by both removing the need to predefine a single reference genome that can bias interpretation of population structure, as well as its ability to visualize multiple evolutionary relationships, such as recombination events and shared ancestry, across hundreds of strains.
Novel combination chemotherapy with topotecan, doxorubicin and vincristine (TAV) in patients with advanced lung cancer
Authors: E. S. Santos, L. E. Raez, S. Padmanabhan, M. F. Rosado, I. Reis
Journal: Journal of Clinical Oncology (2004)

7251 Background: Topotecan has a role in the second-line therapy of small cell lung cancer (SCLC), and has activity in advanced non-small cell lung cancer (NSCLC). The objective of this study was to determine the safety and maximum tolerated dose (MTD) of a novel combined chemotherapy regimen: topotecan (T), doxorubicin [Adriamycin (A)], and vincristine (V), for the development of Phase II trial. Methods: Patients (pts) with advanced SCLC or NSCLC who had incurable disease were enrolled.Pts should have failed palliative chemotherapy first, unless they have extensive disease (ED). The schema used for therapy was: T was escalated from 0.75 mg/m2 days 1–5 every four weeks; fixed doses of V and A were given at 1 mg/m2 days 1 and 5, and 30 mg/m2 day five only, respectively. Each cohort had three pts. Dose limiting toxicity (DLT) was defined as grade 4 hematological toxicity persisting for more than 7 days or any grade 4 non-hematological toxicity. Results: Fifteen pts were enrolled: 8 males and 7 females, with a median age of 53 years (35–72 years). Thirteen pts were white, and 11 had a Hispanic origin. Nine pts had NSCLC and six SCLC. A total of 36 cycles of TAV were given. The combination was well tolerated. No DLT were seen in the 0.75 mg/m2 or 1 mg/m2 cohorts. Only 1/6 pts developed DLT in the 1.25 mg/m2 cohort with grade 4 neutropenia and thrombocytopenia. We stopped accrual in the 1.5 mg/m2 cohort; we did not consider necessary to increase the dose of T because this is the dose commonly used as a single agent. From the 9 pts with NSCLC: all were stage IV, 4/9 had received at least 2 lines of palliative chemotherapy, 4/9 had failed radiation, and 1/9 pt had a sustained PR (11%). Among the 6 pts with SCLC: 5 had ED (3 already treated with chemotherapy), and one with limited disease that had relapsed. The overall response rate was 2/6 (33.3%): 1 CR and 1 PR, with another patient who attained SD (16.7%). Conclusions: The MTD for T is close to 1.25 mg/m2 for this combination based on our experience and the data in the literature. The activity seen in ED-SCLC (50% clinical benefit) may justify the development of a Phase II trial in this setting. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline
Should colorectal cancer screening guidelines account for gender and race/ethnicity?
Authors: C. P. Theuer, T. Taylor, W. Brewster, H. Anton-Culver
Journal: Journal of Clinical Oncology (2004)

1022 Objectives: The recommended age to begin colorectal screening is 50 for all Americans at “average” risk, regardless of gender or race/ethnicity. However, the natural history of colorectal cancer differs between men and women and across major racial/ethnic groups. Therefore the optimum starting age for colorectal screening may depend upon gender and race/ethnicity. We compare the total cost-effectiveness of different starting ages for colorectal screening by gender and race/ethnicity to address this issue. Methods: We determined age-specific colorectal cancer incidence rates, the proportion of left-sided cancers, and the proportion of localized cancers in Asian, Black, Latino, and White men and women using the California Cancer Registry. We incorporated these data and available data for life expectancy and colorectal cancer survival to model the cost-effectiveness of two 35-year colorectal cancer-screening interventions. Results: Age-specific colorectal cancer incidence rates were highest in Black men and lowest in Latino women. Screening beginning at age 50 was most cost-effective in Black men and least cost-effective in Latino women (measured as dollars spent per year of life saved) using annual fecal occult blood testing combined with flexible sigmoidoscopy every 5 years and using colonoscopy every 10 years. The cost-effectiveness of a 35-year screening program in Black men beginning at age 45 was similar to the cost-effectiveness of screening White men and Black women beginning at age 50 and more cost-effective than screening non-Black women as well as Asian and Latino men beginning at age 50. Conclusions: Screening is most cost-effective in Black men because of high age-specific colorectal cancer incidence rates. Initiation of colorectal cancer screening in this group prior to age 50 should be strongly considered, and could mimic prostate cancer screening recommendations in this high-risk group. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Annals Story Slam - Humanism in Medical Education
Authors: Anthony J. Mazzarelli
Journal: Annals of Internal Medicine (2017)

Web Exclusives4 April 2017Annals Story Slam - Humanism in Medical EducationFREEAnthony J. Mazzarelli, MDAnthony J. Mazzarelli, MDFrom Cooper University Hospital, Camden, New Jersey.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W17-0038 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Humanism in Medical Education "Humanism in Medical Education," by Dr. Anthony J. Mazarelli (Duration 4:33)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: From Cooper University Hospital, Camden, New Jersey.Current Author Address: Anthony J. Mazzarelli, MD, Cooper University Hospital; e-mail, [email protected]edu. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 4 April 2017Volume 166, Issue 7Page: SS1KeywordsMedical education ePublished: 4 April 2017 Issue Published: 4 April 2017 Copyright & PermissionsCopyright © 2017 by American College of Physicians. All Rights Reserved.Loading ...
Incidence, detection, and management of cardiac metastasis in pediatric sarcoma patients
Authors: D. P. Hughes, M. Crutchley, W. I. Douglas, M. F. Munsell, A. A. Vaporciyan, C. Herzog, F. W. Tsai, W. Huh
Journal: Journal of Clinical Oncology (2009)

10060 Background: Sarcoma metastasizing to the heart is a difficult and complicated clinical problem, yet local control is feasible and effective for select patients with cardiac metastasis. Diligence is required to detect these lesions while still amenable to treatment, and echocardiogram remains the best tool for detecting cardiac disease. Methods: We reviewed all echocardiograms (1330) performed on 307 pediatric sarcoma patients treated at UT M. D. Anderson Cancer Center between 1997 and 2008. Measures of cardiac function and pathology (including size of ventricles and atria, function of ventricles and valves, presence of metastasis, and presence of pericardial effusion) were assigned numerical values. Fisher's exact test and the Wilcoxon rank-sum test compared clinical characteristics of patients with and without cardiac metastases. Results: The prevalence of cardiac metastases was 1.6% (5/307) with 95% confidence interval 0.5% to 3.8%. The presence of cardiac metastasis positively correlated with pericardial effusion (p = 0.001) and tricuspid valve insufficiency (p = 0.014). The probability of a patient with pericardial effusion having a cardiac metastasis was 28.6% (95% CI: 3.7%-71%). Of the 5 patients with documented sarcoma metastasis to the heart, 3 had widespread refractory disease, were given no cardiac-specific therapy, and rapidly died from disease. One patient who had widespread disease controlled with chemotherapy and radiation had open resection of 2 cardiac metastases which resulted in site-specific disease control for 6 months before succumbing to progressive extra-cardiac disease. Another patient had isolated cardiac metastasis, treated with open resection of 2 metastases followed by adjuvant chemotherapy, and has been without recurrent cardiac metastases for 5 years and 9 months. Conclusions: Durable local control for sarcoma metastasizing to the heart is possible and effective for select patients. Pericardial effusion merits evaluation for potential associated cardiac metastasis. Echocardiogram monitoring of sarcoma patients remains important, and should include screening for possible cardiac metastasis. No significant financial relationships to disclose.
Hepatitis B virus screening in patients receiving intravenous chemotherapy.
Authors: Mylene Hernandez Remo, Wadih Chacra, Sandra Cuellar, Janet Golick, Phuc Nguyen, Emily Armgardt, Neeta K. Venepalli
Journal: Journal of Clinical Oncology (2017)

205 Background: Patients with chronic hepatitis B (HBV) who undergo chemotherapy without antiviral prophylaxis may develop HBV reactivation, hepatitis, liver injury, and even death. The University of Illinois Cancer Center (UICC) lacks a standardized guideline for screening patients for HBV prior to chemotherapy initiation. A retrospective chart review was conducted on chemotherapy orders submitted to UICC pharmacy over 4 weeks for both hematological and solid tumor malignancies. Of 63 new orders for intravenous chemotherapy, only 14 patients (22%) underwent HBV screening prior to chemotherapy initiation. We aimed to increase HBV screening from 22% to 50% over 2 months. Methods: A multidisciplinary taskforce comprised of hematology/oncology and hepatology physicians, clinical pharmacy, and nursing was created. An ideal process map was created identifying a clear management schema for HBV screening including differences in screening tests for various populations and management recommendations for positive test results. Two Plan-Do-Study-Act (PDSA) cycles were tested with post intervention data collected over eight weeks. Results: Of 192 chemotherapy orders submitted to outpatient pharmacy over 8 weeks, 62 patients (32%) were determined to be appropriate for HBV screening prior to initiation of chemotherapy. Of these, 36 patients (58%) were screened appropriately for HBV. Additionally, a subset analysis revealed 100% of patients successfully screened for HBV prior to initiation of anti-CD20 therapies. Conclusions: At UICC, a multidisciplinary team created and successfully piloted the implementation of a HBV screening policy in both hematological and solid tumor malignancies. Our initial aim was reached after 8 weeks of implementation, and ongoing efforts are being conducted to further improve HBV screening rates to 90%.
Adherence to ASTRO ‘Choosing Wisely’ recommendations for radiation therapy in low-risk endometrial cancer.
Authors: Joshua A. Roth, Jean A. McDougall, Lia Moriguchi Halasz, Catherine R. Fedorenko, Qin Sun, Bernardo H. L. Goulart, Shilpen A. Patel
Journal: Journal of Clinical Oncology (2017)

240 Background: The American Society for Radiation Oncology (ASTRO) ‘Choosing Wisely’ (CW) list notes radiation interventions lacking evidence of benefit in cancer care. This study characterizes adherence to the 2014 CW item to ‘not recommend radiation following hysterectomy in low-risk endometrial cancer’ (Stage I, Grade 1-2). No studies have previously evaluated adherence to this CW item. Methods: SEER records for patients age &gt;65 at first primary diagnosis of Stage I (Grade 1-2) endometrial cancer between 2008-2011 were linked with Medicare files. Included cases had Medicare Part A and B coverage for ≥12 months before/after diagnosis and had a hysterectomy 1 month prior to 4 months following diagnosis. We used logistic regression to evaluate associations between socio-demographic and clinical characteristics (Table 1) and receipt of radiation therapy within 1 year of diagnosis. Results: Among 2,938 women meeting eligibility criteria, mean age was 74, 90% were white, and 55% lived in a ‘big metro’ area (population &gt;1m). The non-adherent fraction was 24%. Among non-adherent cases, 76% received brachytherapy. In adjusted analyses (Table 1), only tumor grade was associated with non-adherence. Conclusions: More than 20% of low-risk endometrial cancer cases in our sample were non-adherent to ASTRO CW recommendations, and this only varied significantly by tumor grade. Therefore, use of radiation therapy following hysterectomy appears to be a widespread issue. This is important because non-adherence may result in side effects or substantial cost without commensurate clinical benefit. This study’s follow-up period was prior to the ASTRO CW list, but similar recommendations existed in ASCO, ESMO and NCCN guidelines at the time—suggesting work is need to align practice with guidelines. Our findings provide a baseline measure against which future studies can measure progress. [Table: see text]
Cardiac safety in patients (pts) with metastatic breast cancer (MBC) treated with lapatinib (L) and trastuzumab (TRA)
Authors: A. M. Storniolo, M. Koehler, A. Preston, E. Rappold, J. Byrne, M. S. Ewer
Journal: Journal of Clinical Oncology (2007)

514 Background: Clearly defined standards for assessing cardiac toxicity do not exist for newer agents used as treatment for BC, e.g., tyrosine kinase inhibitors. To evaluate the usefulness of increased cardiac monitoring and cardiac function (LVEF) in pts treated with L+TRA, data from 4 trials were analyzed. Methods: From July 2003 to Dec 2006, 238 pts received L+TRA (n=203) or L+TRA with paclitaxel or docetaxel (n=35) for HER2-positive MBC. LVEF was evaluated at screening, every 8 weeks after starting L+TRA, and at withdrawal via multiple-gated acquisition scans or echocardiograms. Rate of symptomatic cardiac events (CE; NCI CTCAE Grade 3 or 4 LV systolic dysfunction) or asymptomatic LVEF decreases (=20% relative to baseline and below the institution’s lower limit of normal) were assessed. Results: None of the 238 pts had a symptomatic CE. Four pts had a single asymptomatic LVEF decrease and 1 pt had 2 asymptomatic LVEF decreases, totaling 6 decreases in 5 (2.1%) pts. These pts were women aged 36–64 years and had previously received anthracyclines (A; n=2), A+TRA (n=2), or unknown therapy (n=1). Median time to onset of LVEF decrease was 83 days; all but 1 decrease occurred within 75 days after initiating L+TRA (range: 18–221 days). Baseline LVEFs of 62%, 60%, 62%, 74% and 58% decreased to 47%, 46%, 45%, 45%, and 45%, respectively. L+TRA was temporarily interrupted in 3 pts and continued in 2 pts despite LVEF decrease. Per investigators, LVEF decrease resolved with no further sequelae in 4 pts (59%, 56%, 60%, and 50%) and was ongoing in 1 pt. Conclusion: Initial data indicate L+TRA or L+TRA with taxanes does not constitute a serious incremental cardiac risk and may not require more stringent cardiac monitoring than is used for A or TRA alone. The combined effect of HER2 inhibition with L+TRA appears not to increase the risk of CE in this population. No significant financial relationships to disclose.
XPD, XPA, ERCC1 and XPG/ERCC5 single nucleotide polymorphisms (SNPs) in oxaliplatin-treated colorectal cancer (CRC)
Authors: J. M. Vila, I. Moreno, M. Monzo, R. Ibeas, J. Moreno, M. Pinuaga, F. Martinez, A. Navarro, E. Pou, J. Sole Monne
Journal: Journal of Clinical Oncology (2004)

3677
Intestinal IgA as a modulator of the gut microbiota
Authors: Shinsaku Okai, Fumihito Usui, Misa Ohta, Hiroshi Mori, Ken Kurokawa, Satoshi Matsumoto, Tamotsu Kato, Eiji Miyauchi, Hiroshi Ohno, Reiko Shinkura
Journal: Gut Microbes (2017)

Accumulating evidence suggests that dysbiosis plays a role in the pathogenesis of intestinal diseases including inflammatory bowel disease (IBD) as well as extra-intestinal disorders. As a modulator of the intestinal microbiota, we isolated a mouse monoclonal IgA antibody (clone W27) with high affinities for multiple commensal bacteria, but not for beneficial bacteria such as Lactobacillus casei (L. casei). Via specific recognition of an epitope in serine hydroxymethyltransferase (SHMT), a bacterial metabolic enzyme, W27 IgA selectively inhibited the in vitro growth of bound bacteria, including Escherichia coli (E. coli), while having no effect on unbound beneficial bacteria such as L. casei. By modulating the gut microbiota in vivo, oral administration of W27 IgA effectively prevented development of colitis in several mouse models. Here we discuss how intestinal IgA modulates the gut microbiota through recognition of SHMT.
Hereditary cancer families’ perceptions about biobanking as a healthy control.
Authors: Gwendolyn P. Quinn, Clement K Gwede, Ivana Sehovic, Tuya Pal, Cathy Meade
Journal: Journal of Clinical Oncology (2013)

e12556 Background: Biobanks are a promising way to identify links between genetic and environmental factors in relation to disease, particularly cancer. However, there has been skepticism among the general public about the purpose of biospecimen donation. Healthy people are beginning to be approached for participation in biobanking based on NIH initiative to establish national repositories. There is a great need to address public concerns about biospecimen donation. There may be additional and unique concerns among families with a history of hereditary cancer. Methods: Participants were recruited through research networks of families across the US who had received genetic counseling/testing. At-risk individuals (18 and over, no personal cancer diagnosis, first degree family member with cancer, had a test for hereditary cancer) completed a 15-item biobanking statement rating worksheet, selecting from 1 (strongly disagree), 2 (agree), 3 (not sure), 4 (disagree) and 5 (strongly agree). Results: 39 participants (100% white, 92.5% female) completed the worksheet. Most participants (87%) agreed confidentiality with medical information was important. 89% thought genetic research and biobanks were useful even if they only produced scientific knowledge instead of cancer cures. 87% felt the public should be consulted on ethical issues in biospecimen research, and permission should be acquired before conducting research on their samples (74%). 56% were unsure if they were exposing themselves to risk if they donated a specimen, while 46% were concerned that their specimen would be connected to their identity. Participants were uncertain if researchers should explain the use of each biospecimen (36% agreed, 33% unsure, 31% disagreed). 92% felt public education about biobanking would increase biospecimen donation. Conclusions: While participants were supportive of genetic research and biobanks, concerns regarding confidentiality and loss of privacy remain among unaffected carriers. There is a need to enhance existing training for researchers to improve understanding of high genetic risk community members’ perceptions about biobanking.