tbuckley/cabot-search huggingface dataset:
National multidisciplinary tumor board (MTB): Report of the first 526 questions raised within RYTHMIC, the network for thymic malignancies in France.
Authors: Benjamin Besse, Eric Pichon, Eric Dansin, Pascal Alexandre Thomas, Hervé Lena, Gerard Zalcman, Julien Mazieres, Gilbert Massard, Luc Thiberville, Virginie Westeel, Xavier Quantin, Christelle Clement-Duchene, Pierre Fournel, Hélène Senellart, Quan Tran, Thierry Jo Molina, Nicolas Girard
Journal: Journal of Clinical Oncology (2014)

7605 Background: RYTHMIC (Réseau tumeurs THYMiques et Cancer) is a nationwide network for thymic malignancies, which was funded in 2012 by the French National Cancer Institute. The objectives of the network include a territorial coverage by regional expert centers, elaboration of recommendations, dissemination of knowledge and promotion of collaborative research. All patients diagnosed with thymic malignancy in France have to be discussed on a real-time basis at a reference web-based national MTB or regional MTB. Patient’s data from the MTB were prospectively entered in a database. Methods: We report the patient’s and tumor’s characteristics and treatment modalities of the patients included during the first 2 years of MTB. Questions raised during the MTB were reviewed. Results: From January to December 2013, 383 patients were included in the RYTHMIC database. There were 197 (51%) men and 186 (49%) women. Among 304 cases, histology was thymoma for 198 (65%) patients (16 (5%) type A, 31 (10%) type AB, 38 (12%) type B1, 46 (15%) type B2, 35 (12%) type B3, 38 (12%) mixed type, 4 unknown), and thymic carcinoma for 34 (11%) patients, 7 (2%) carcinoïds; other histologies were diagnosed for 65 (21%) patients. Among 206 cases, Masaoka-Koga stage was I, IIA, IIB, III, IVA, and IVB in 46 (22%), 33 (16%), 28 (13%), 37 (18%), 44 (21%), and 18 (9%) patients, respectively. 71 (18%) patients presented with autoimmune disorder, consisting of myasthenia gravis in 60% of the cases. Surgery was performed for 229 patients, mostly using a median sternotomy approach (52% of cases), video-assisted surgery accounted for 9% of the cases. Among the 526 questions addressed during the MTB, the most frequent were the indication of post-operative radiotherapy (29%), recurrence management (18%) and indication of surgery of a mediastinal lesion (17%). Conclusions: The RYTHMIC prospective cohort demonstrates the feasibility of a national MTB for thymic malignancies. It provides with a comprehensive tool to monitor dedicated actions to improve the management of patients in the future, increase the quality-of-care (mostly regarding locoregional treatment), and screen patients for future clinical trials.
Retrospective analysis of circulating tumor DNA of archived plasma samples.
Authors: Wei Shen, Grace Q. Zhao, Zhonglin Liang, Venkata Yellapantula, Sam Sun, Ling Fung Paul Tang, Shengrong Lin, Kang Ying, Ryan C. Fields, Li Ding
Journal: Journal of Clinical Oncology (2016)

e23175 Background: Retrospective clinical studies using circulating tumor DNA (ctDNA) from banked blood samples may hold the key to unlocking the world of cancer genomics. Unfortunately, some archived samples have been collected using methods incompatible with current ctDNA protocols. Two such examples are (1) the use of blood collection tubes containing heparin and (2) insufficient volumes of plasma. We have addressed these challenges using a modified version of the Firefly platform, our high precision sequencing technology equipped with a unique error correction mechanism. Methods: To address heparin contamination, ctDNA was extracted from blood samples from 2 metastatic colorectal cancer (mCRC) patients and 3 pancreatic cancer patients using heparin- and EDTA-coated tubes. After heparin removal, the yield and detected mutations from the pairs were compared. With regard to managing small volumes, we analyzed ctDNA obtained from 1ml plasma samples that were over 2 years old for 6 mCRC patients. Blood samples were collected from each patient before and after chemotherapy. Resulting ctDNA mutation profiles acquired by panel NGS were then correlated with each patient’s treatment outcomes. Results: We validated our approach to heparin contamination by matching detected mutations from ctDNA extracted from tubes containing heparin and EDTA tubes, the current industry standard. For the 6 mCRC patients, all 4 patients were either with partial response (PR) or stable disease (SD) exhibited an interval decrease in minor allele frequency (MAF) for multiple cancer-associated mutations. In comparison, the remaining 2 progressive disease (PD) patients had an increase in mutations MAF post-treatment. Of the 3 patients who were unresponsive to chemotherapy or relapsed within 6 months of completing treatment, 2 had mutation profiles with high TP53 mutation rates ( > 1%). Conclusions: We have demonstrated the feasibility of ctDNA analysis of banked blood which has either (1) been contaminated with heparin or (2) very low volume. And using 1ml of plasma, we are able to monitor treatment in mCRC patients. In addition, our early findings suggest the detection of the TP53 mutation may have prognostic value for mCRC patients undergoing chemotherapy.
Persistent vasomotor symptoms and breast cancer in the Women’s Health Initiative (WHI).
Authors: Rowan T. Chlebowski, Joanne E. Mortimer, Carolyn Crandall, Kathy Pan, JoAnn E Manson, Rebecca A. Nelson, Karen Johnson, Mara Vitolins, Dorothy Lane, Jean Wactawski-Wende, Karen W. Kwan, Marcia L. Stefanick
Journal: Journal of Clinical Oncology (2018)

e13567 Background: Vasomotor symptoms (VMS) including hot flashes and night sweats are common during menopausal transition and may persist. While pathophysiology of VMS is complex, estrogen's efficiency as VMS therapy suggests hormonal environment change may influence this process. As studies of VMS and breast cancer are inconsistent, we examined associations between persistent VMS and breast cancer incidence and mortality in postmenopausal women. Methods: The analytic sample included 25499 postmenopausal women aged 50-79 enrolled in the WHI between 1993-1998 at 40 US clinical centers. Eligible were women without current/former menopausal hormone therapy use and for whom information on VMS status was available. VMS data were collected by questionnaire including: "age at first and last VMS episode" and "VMS in last 4 weeks" (yes/no) to categorize participants as never VMS or persistent VMS. Breast cancers were verified by medical record review. Cause of death was determined by medical record and death certificate review, enhanced by serial National Death Index queries. The associations between VMS status and breast cancer incidence and deaths from breast cancer (deaths directly attributed to the cancer) and deaths after breast cancer (death from all causes) were determined using time dependent Cox regression analyses adjusted for breast cancer risk factors including physical activity. Results: After 17.9 years (median) follow- up with 1399 incident breast cancers, women with persistent VMS (n = 9715), compared to women with never VMS (n = 15784), had a higher breast cancer incidence (hazard ratio [HR] 1.13, 95% confidence interval [CI] 1.02-1.27) with more estrogen receptor negative cancers (18% vs 13.2%, P = 0.02) and regional/distant involvement (26.5% vs 19.5%, P = 0.002). While the risk of death from breast cancer was somewhat higher in women with persistent VMS (HR 1.33, 95% CI 0.88-2.02), the difference was not statistically significant. VMS status (persistent versus never) had no influence on deaths after breast cancer (HR 1.02, 95% CI 0.81-1.29). Conclusions: Compared to women who never experienced VMS, women with persistent VMS are more likely to be diagnosed with breast cancer, but not more likely to die from breast cancer.
Overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer
Authors: Zhuoyu Gu, Yixin Li, Xiaoya Yang, Meisheng Yu, Zhanru Chen, Chan Zhao, Lixin Chen, Liwei Wang
Journal: Journal of Hematology & Oncology (2018)

Recently, many potential prognostic biomarkers for gastric cancer (GC) have been identified, but the prognosis of advanced GC patients remains poor. Chloride channels are promising cancer biomarkers, and their family member chloride channel-3 (CLC-3) is involved in multiple biological behaviors. However, whether CLC-3 is a prognostic biomarker for GC patients is rarely reported. The molecular mechanisms by which CLC-3 is regulated in GC are unclear. The expression of CLC-3 and XRCC5 in human specimens was analyzed using immunohistochemistry. The primary biological functions and pathways related to CLC-3 were enriched by RNA sequencing. A 5'-biotin-labeled DNA probe with a promoter region between - 248 and + 226 was synthesized to pull down CLC-3 promoter-binding proteins. Functional studies were detected by MTS, clone formation, wound scratch, transwell, and xenograft mice model. Mechanistic studies were investigated by streptavidin-agarose-mediated DNA pull-down, mass spectrometry, ChIP, dual-luciferase reporter assay system, Co-IP, and immunofluorescence. The results showed that CLC-3 was overexpressed in human GC tissues and that overexpression of CLC-3 was a poor prognostic biomarker for GC patients (P = 0.012). Furthermore, higher expression of CLC-3 was correlated with deeper tumor invasion (P = 0.006) and increased lymph node metastasis (P = 0.016), and knockdown of CLC-3 inhibited cell proliferation and migration in vitro. In addition, X-ray repair cross-complementing 5 (XRCC5) was identified as a CLC-3 promoter-binding protein, and both CLC-3 (HR 1.671; 95% CI 1.012-2.758; P = 0.045) and XRCC5 (HR 1.795; 95% CI 1.076-2.994; P = 0.025) were prognostic factors of overall survival in GC patients. The in vitro and in vivo results showed that the expression and function of CLC-3 were inhibited after XRCC5 knockdown, and the inhibition effects were rescued by CLC-3 overexpression. Meanwhile, the expression and function of CLC-3 were promoted after XRCC5 overexpression, and the promotion effects were reversed by the CLC-3 knockdown. The mechanistic study revealed that knockdown of XRCC5 suppressed the binding of XRCC5 to the CLC-3 promoter and subsequent promoter activity, thus regulating CLC-3 expression at the transcriptional level by interacting with PARP1. Our findings indicate that overexpression of CLC-3 is regulated by XRCC5 and is a poor prognostic biomarker for gastric cancer. Double targeting CLC-3 and XRCC5 may provide the promising therapeutic potential for GC treatment.
Opioid Death Rate Acceleration in Jurisdictions Legalizing Marijuana Use—Reply
Authors: Ashley C. Bradford, Amanda Abraham, Grace Bagwell Adams
Journal: JAMA Internal Medicine (2018)

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Disclosure of secondary germline findings from clinical tumor-normal paired somatic mutation profiling.
Authors: Molly S. Daniels, Karen H. Lu, Banu Arun, Mark Routbort, Russell Broaddus
Journal: Journal of Clinical Oncology (2018)

1510 Background: Accurate identification of cancer somatic mutations is facilitated by tumor-normal subtractive analysis. Tumor-normal paired testing (TNPT) can also lead to significant secondary germline findings. We report the secondary germline outcomes from clinical TNPT of 4923 patients at a single institution. Methods: TNPT via the Oncomine platform was performed in-house when ordered by patients’ clinicians. Potential secondary germline findings were flagged and sent to clinical cancer genetics (CCG) for review. Pathogenic germline mutations in high penetrance hereditary cancer genes were selected by database and literature review. Medical records were reviewed to determine whether standalone germline testing (SGT) had already identified the mutation. If not, CCG contacted the patient and offered confirmatory SGT via outside reference laboratory. Results: From January 2016 to January 2018, 62/4923 (1.3%) of TNPTs were flagged for CCG review. 41/62 (66%) mutations were selected for follow-up (see table). 16/28 (57%) of patients with previously unknown mutations returned for confirmatory SGT. In 28/29 (97%) cases where both TNPT and SGT results were available, they were concordant. The exception was an MSH2 mutation found on TNPT but not on SGT; further analysis revealed that the TNPT result had been a low confidence call. Conclusions: Clinical TNPT identified germline mutations in 0.8% of tested patients, many of which were not already known to patients and/or occurred in cancers outside the typical spectrum for that gene. Effective communication between pathology and CCG facilitates classification of mutations as well as patient notification. Offering secondary germline findings from clinical TNPT to patients is feasible and affords families the opportunity to benefit from predictive genetic testing. Gene Mutation previously found on SGT (13) Mutation newly identified on TNPT (28) BRCA1 Ovary (4) Sebaceous(1), ovary (1), lung (2), colon (1) BRCA2 Breast (1), ovary (3), prostate (2), lung (1), pancreatic (1) Ovary (1), colon (5), lung (4), prostate (3), glioma (1), ampullary (1) TP53 0 Sarcoma (2), colon (1), thymoma (1), pancreatic (1) EGFR T790M 0 Lung (1), colon (1) MSH2 Ovary (1) Kidney (1)
Human Cardiac Gene Therapy
Authors: Kiyotake Ishikawa, Thomas Weber, Roger J. Hajjar
Journal: Circulation Research (2018)

In the past 10 years, there has been tremendous progress made in the field of gene therapy. Effective treatments of Leber congenital amaurosis, hemophilia, and spinal muscular atrophy have been largely based on the efficiency and safety of adeno-associated vectors. Myocardial gene therapy has been tested in patients with heart failure using adeno-associated vectors with no safety concerns but lacking clinical improvements. Cardiac gene therapy is adapting to the new developments in vectors, delivery systems, targets, and clinical end points and is poised for success in the near future.
Profile of cancer-screening resistant individuals (EDIFICE 6).
Authors: Thibault De La Motte Rouge, Jean F. Morere, Sebastien Couraud, Morgan Roupret, Chantal Touboul, Christine Lhomel, Laurent Greillier, François Eisinger, Jerome Viguier
Journal: Journal of Clinical Oncology (2018)

1557 Background: The efficacy of cancer screening (cost effectiveness, reduced mortality) relies on a minimum threshold uptake rate. Target populations are asymptomatic with only average risk, and thus likely to avoid screening. We studied the characteristics of cancer-screening resistant individuals. Methods: The French nationwide observational survey, EDIFICE 6, was conducted online from 26 June-28 July 2017 on a core sample of 12 046 individuals (age 18-69 y). Representativeness was ensured by quota sampling on age, gender, profession, and stratification by geographical area and type of urban district. Multivariate stepwise logistic regression analyses were conducted with a common set of variables to identify factors likely to explain non-uptake of cancer screening. The analysis focused on individuals in the age range of target populations for organized programs: 50-69 y for breast (BC) and colorectal cancer (CRC) (N = 1954 and N = 4300, respectively) and 25-65 y for cervical cancer (CC) (N = 4499). Results: Of those who had never taken part in a screening program, 6% (N = 108) were in the target population for BC screening, 12% (N = 539) for CC, and 38% (N = 1625) for CRC screening. Items associated with not undergoing screening included: for BC, the statement
PSA-recurrence after radical prostatectomy for intermediate/high risk prostate cancer: A helpful parameter or just a patient stress amplifier.
Authors: Martin Spahn, Marianna Kruithof-de Julio, Silvan Boxler, Marc-Alain Furrer, George N. Thalmann, Urs E. Studer
Journal: Journal of Clinical Oncology (2017)

e16535 Background: Development of biochemical recurrence with a rising PSA level after radical prostatectomy causes significant anxiety for patients and treating oncologist. Management of these patients is controversial. Here, we characterize the natural course and pattern of disease progression and survival in men with biochemical recurrence (BCR) after radical prostatectomy (RP) for intermediate and high-risk prostate cancer (PCa) untreated until clinical failure (CF). Methods: Retrospective analysis of consecutive men with BCR after RP for intermediate/high risk PCa. All patients underwent RP+extended pelvic lymph node dissection. A PSA level &gt; 0.2 ng/ml on two consecutive measures was considered BCR. None received neoadjuvant or adjuvant therapy prior to documented clinical failure by body imaging, which was performed at the time point of BCR or symptoms and at least once per year. Results: Of the 622 men with BCR included into the analysis, 267 (43%) had high risk PCa. Median follow-up after RP was 9.4 yrs. (IQR 4.8-15.1) and median time from RP to BCR was 1.4 yrs. (IQR 0.4-3.6). Of the patients 324 (52%) never experienced CF (Æfollow-up from BCR 5.8yr, IQR2.1-11.9); 88 (14%) had local recurrence only; 59 (9%) had lymph node metastasis +/-local recurrence and 151(24%) distant metastasis. The median times from BCR to CF were: 9.5 yrs. (IQR 5.6-13.5) for local failure; 4.9 yrs. (IQR 3.1-8.8) for lymph node failure and 5.6 yrs. (IQR 3-10.5) for distant failure. The 10-yrs cancer specific (CSS) and overall survival (OS) of the entire group from time point of BCR was 78% and 66%, respectively. 5- and 7-yrs conditional CSS from time of CF was strongly depended on recurrence pattern and ranged from 90% and 79% (local only) to 70% and 47% (lymph node+/-local) and 47% and 36% (distant mets), respectively. PSA-doubling time &lt; 12 months and &gt; 2 positive nodes were independent predictors of outcome in multivariate analysis. Conclusions: These data may be useful in informing men with intermediate/high risk PCa regarding the natural course of PSA recurrence and counseling the timing of additional therapies.
Hepatotoxicity of anthracycline chemotherapy in patients with breast cancer.
Authors: Nailya Guskova, Oleg I. Kit, Liubov Yu Vladimirova, Natalya Mikhailovna Tikhanovskaya, Elena A. Sycheva, Anastasia Nozdricheva, Svetlana V. Abakumova, Natalya A Abramova, Anna E Storozhakova, Irina L. Popova, Ludmila A. Ryadinskaya, Aza A. Lyanova, Kristina A. Novoselova, Zinaida P. Lisunova, Kristina Avanesova, Ineya I. Zekhtser, Svetlana V. Belgova, Viktoria Zakharchenko, Irina V. Tselishcheva, Izabella Torpudzhyan
Journal: Journal of Clinical Oncology (2018)

e14505 Background: We monitored some biochemical parameters to assess hepatotoxicity of anthracycline chemotherapy in patients with breast cancer. Methods: The study included 30 patients (32-72 years, median age 52.0±12.8 years) with st. II-III breast cancer receiving 4 cycles of anthracycline (AC) chemotherapy (CT). Serum levels of total protein, albumin, bilirubin and its fractions, alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, C-reactive protein (CRP), alpha-1 antitrypsin (A1AT) (Vitros 5600, USA) and lactate dehydrogenase (LDH) (Cobas Integra 400 plus, Switzerland) were determined before and after anthracycline injections (days 2 and 5) and after 4 CT cycles. Statistical processing of results was performed using the Statistica 6.0 program. Results: The levels of all parameters were within the reference range before treatment, except for 3 pts with moderately increased LDH activity and normal ALT and AST. No changes were observed in 29 (96.7%) pts after cycle 1 CT. 1 (2.6%) patient showed an increase in AST by 2.54 times, in ALT – by 2.88 times on day 2 after AC injection, with restoration to initial values on day 5. Day 2 of the 4th CT cycle: total protein and albumin decreased in 7 (23.3%) pts by 15.8% and 24.3%, respectively; in 30% (9) AST increased by 3 times (p < 0.01) and ALT by 3.2 times (p < 0.01), in 60% (18) LDH increased by 1.4 times (p < 0.01), including pts with initially high LDH. Levels of bilirubin and its fractions did not change significantly. Further increase of AST by 3.6 times (p < 0.001), ALT by 3.8 times (p < 0.05), LDH by 2.2 times (p < 0.05), as well as dysproteinemia, were registered by the end of cycle 4. Levels of CRP and A1AT increased by 2.7 and 2 times (p < 0.05), respectively, in 26.6% (8) pts, including cases with normal enzyme activity, already after the first AC injection. The highest levels were observed by the end of cycle 4: CRP increased by 4 times (p < 0.001), and А1АТ – by 3.4 times (p < 0.05). Conclusions: An increase in levels of CRP and A1AT at the initial stage of anthracycline CT in patients with breast cancer, accompanied by further hyperfermentemia, allows considering these indicators as early predictors of the hepatotoxicity risk.
RNA expression analysis of TCGA data and the limits of genomic features in tumor profiling.
Authors: Ryan Bloom, Raman Talwar, Jon Armstrong, Eric James Duncavage
Journal: Journal of Clinical Oncology (2016)

e23218 Background: Molecular profiling of DNA alterations and mutations has offered unprecedented insight into the causes and treatments of cancer. However, a comprehensive understanding of how these DNA alterations affect the expression of tumor-related genes remains unknown. Methods: We analyzed the expression of 315 cancer related genes across 7 different tumor types using RNA-seq data obtained from The Cancer Genome Atlas (TCGA) database. We compared the expression data to single nucleotide variant (SNV) and structural variants including copy number alterations (CNA) and translocations detected in the genomes of the same samples. Results: We found that, among the cancer-related genes analyzed, 5% of the time a SNV is detected in the DNA, there is no detectable expression of that allele in the RNA We further analyzed the correlation between somatic gene amplifications to the expression levels of the same gene. We found that, overall, CNA status was a very weak predictor of gene expression (r-squared = .00012) with only 8 genes correlated with CNA amplification at a level of r-squared > 0.3. Finally, we examined the expression of ALK, a known oncogene involved in an intrachromosomal fusion (EML4-ALK) in 4-6% of lung adenocarcinomas that results in overexpression of ALK, and is associated with increased response to ALK-inhibitors. We confirmed that the EML4-ALK fusion resulted in ALK overexpression in lung cancer compared to cases with non-rearranged ALK. However, we found that in a subset of patients, particularly in breast cancer, ALK was overexpressed to the same degree (Z-score > 10) as seen in lung cancer EML4-ALK fusions. Conclusions: Our analysis indicates that not all somatic DNA mutations are expressed in tumors, suggesting that concurrent RNA expression profiling could provide additional clinically-actionable information. We further conclude that increased ALK expression may be seen in cancer cases that do not harbor EML4-ALK fusions, raising the possibility of treating such tumors with ALK-inhibitors.