tbuckley/cabot-search huggingface dataset:
Assessment of Molecular Relapse Detection in Early-Stage Breast Cancer
Authors: Isaac Garcia-Murillas, Neha Chopra, Iñaki Comino-Méndez, Matthew Beaney, Holly Tovey, Rosalind J. Cutts, Claire Swift, Divya Kriplani, Maria Afentakis, Sarah Hrebien, Giselle Walsh-Crestani, Peter Barry, Stephen R. D. Johnston, Alistair Ring, Judith Bliss, Simon Russell, Abigail Evans, Anthony Skene, Duncan Wheatley, Mitch Dowsett, Ian E. Smith, Nicholas C. Turner
Journal: JAMA Oncology (2019)

<h3>Importance</h3> Current treatment cures most cases of early-stage, primary breast cancer. However, better techniques are required to identify which patients are at risk of relapse. <h3>Objective</h3> To assess the clinical validity of molecular relapse detection with circulating tumor DNA (ctDNA) analysis in early-stage breast cancer. <h3>Design, Setting, and Participants</h3> This prospective, multicenter, sample collection, validation study conducted at 5 United Kingdom medical centers from November 24, 2011, to October 18, 2016, assessed patients with early-stage breast cancer irrespective of hormone receptor and ERBB2 (formerly HER2 or HER2/neu) status who were receiving neoadjuvant chemotherapy followed by surgery or surgery before adjuvant chemotherapy. The study recruited 170 women, with mutations identified in 101 patients forming the main cohort. Secondary analyses were conducted on a combined cohort of 144 patients, including 43 patients previously analyzed in a proof of principle study. <h3>Interventions</h3> Primary tumor was sequenced to identify somatic mutations, and personalized tumor-specific digital polymerase chain reaction assays were used to monitor these mutations in serial plasma samples taken every 3 months for the first year of follow-up and subsequently every 6 months. <h3>Main Outcomes and Measures</h3> The primary end point was relapse-free survival analyzed with Cox proportional hazards regression models. <h3>Results</h3> In the main cohort of 101 female patients (mean [SD] age, 54 [11] years) with a median follow-up of 35.5 months (interquartile range, 27.9-43.0 months), detection of ctDNA during follow-up was associated with relapse (hazard ratio, 25.2; 95% CI, 6.7-95.6;<i>P</i> &lt; .001). Detection of ctDNA at diagnosis, before any treatment, was also associated with relapse-free survival (hazard ratio, 5.8; 95% CI, 1.2-27.1;<i>P</i> = .01). In the combined cohort, ctDNA detection had a median lead time of 10.7 months (95% CI, 8.1-19.1 months) compared with clinical relapse and was associated with relapse in all breast cancer subtypes. Distant extracranial metastatic relapse was detected by ctDNA in 22 of 23 patients (96%). Brain-only metastasis was less commonly detected by ctDNA (1 of 6 patients [17%]), suggesting relapse sites less readily detectable by ctDNA analysis. <h3>Conclusions and Relevance</h3> The findings suggest that detection of ctDNA during follow-up is associated with a high risk of future relapse of early-stage breast cancer. Prospective studies are needed to assess the potential of molecular relapse detection to guide adjuvant therapy.
Brentuximab vedotin for relapsed or refractory non-Hodgkin lymphoma: Preliminary results from a phase II study.
Authors: Ranjana Advani, Yasuhiro Oki, Andrei R. Shustov, Laurie E. Grove, Nancy Bartlett
Journal: Journal of Clinical Oncology (2012)

8070 Background: Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for the treatment of Hodgkin lymphoma and systemic anaplastic large cell lymphoma (ALCL) after failure of other therapies. Based on the high objective response rate observed in patients with systemic ALCL, a type of non-Hodgkin lymphoma that is characterized by homogeneous CD30 expression, a study was initiated in other non-Hodgkin lymphomas that express the CD30 target. Methods: A phase 2 open-label single-arm study is underway in patients with relapsed or refractory CD30-positive non-Hodgkin lymphoma, excluding ALCL (NCT01421667). Brentuximab vedotin is administered IV at 1.8 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint is objective response rate assessed by the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Tumor specimens are assessed by central lab in order to characterize the relationship of CD30 expression with antitumor activity. Results: Ten patients (age range 28–83; 5 M, 5 F) have enrolled to date. Diagnoses include diffuse large B-cell lymphoma (DLBCL, n=2), EBV-positive DLBCL of the elderly (n=3), primary mediastinal B-cell lymphoma (n=2), peripheral T-cell lymphoma NOS (n=2), and angioimmunoblastic T-cell lymphoma (AITL). Patients had received 1–6 prior chemotherapy regimens; 3 patients had prior stem cell transplants. Of 6 patients who have completed the cycle 2 response assessment, 2 attained complete remission, 1 with DLBCL (90% CD30+) and 1 with AITL (8% CD30+), 1 had stable disease, and 3 had progressive disease. Treatment-related serious adverse events observed to date were rash, febrile neutropenia, and mastoiditis. Conclusions: Preliminary results suggest that brentuximab vedotin may have antitumor activity in patients with relapsed or refractory CD30-expressing non-Hodgkin lymphomas, in addition to the efficacy previously observed in systemic ALCL. Updated study results will be presented.
Survival analysis of Hispanics with hepatocellular carcinoma at a large academic institution.
Authors: Daniel Lin, Andreas Kaubisch, Sanjay Goel, Yungtai Lo, Santiago Aparo
Journal: Journal of Clinical Oncology (2012)

e14682 Background: Hepatocellular carcinoma (HCC) appears to have worse prognosis among Hispanics in the United States who have a higher mortality when compared toBlacks and Non-Hispanic Whites based on statistics from the Surveillance Epidemiology and End Results (SEER) database. There is paucity of data directly comparing Hispanics vs. Non-Hispanics. The aim of this study is to compare the overall survival (OS) of Hispanics and Non-Hispanics with HCC at a large academic institution. Methods: Men and women diagnosed and treated for HCC at Montefiore Medical Center (MMC) from 2000 to 2009 were identified using data from the MMC Cancer Registry. Patient’s characteristics obtained included age at diagnosis, gender, race, tumor stage, Model for End-stage Liver Disease (MELD) scores, Hepatitis B, C and HIV status, alcohol use, presence of cirrhosis, alpha-feto protein levels, performance status and treatment. A Cox proportional-hazard model was used to assess survival differences between Hispanics and Non-Hispanics adjusting for clinically relevant and statistically significant variables. Results: A total of 513 patients were identified from the Cancer Registry database. 76 patients were excluded (58 due to inability to confirm the diagnosis of HCC based on current radiologic criteria, 18 due to unavailable ethnicity data). The remaining 437 patients were used for modeling and final analysis. Of the final cohort of 437 patients, 49% (n=212) were Hispanic and 51% (n=225) were Non-Hispanic. Among Non-Hispanics, 55% were Black, 35% were White and 10% were “other” race. Median time of follow up for Hispanics was 13.5 months and for Non-Hispanics was 12.1 months. The median OS among Hispanics was 14.5 months and was not statistically different from the Non-Hispanic group (median OS of 13.1 months) with a p value of 0.49. In a multivariate analysis model the hazard ratio (HR) for survival among Hispanics was 0.81 (95% CI 0.61 to 1.07, p= 0.15) when compared to Non-Hispanics; after adjusting for gender, age at diagnosis, tumor stage, treatment, alpha-feto protein levels and MELD scores. Conclusions: Hispanics diagnosed and treated with HCC at Montefiore Medical Center do not seem to have worse survival when compared to Non-Hispanics.
The Covalent CDK7 Inhibitor THZ1 Potently Induces Apoptosis in Multiple Myeloma Cells <i>In Vitro</i> and <i>In Vivo</i>
Authors: Yu Zhang, Liang Zhou, Dipankar Bandyopadhyay, Kanika Sharma, Alexander Joseph Allen, Maciej Kmieciak, Steven Grant
Journal: Clinical Cancer Research (2019)

The goal of this study was to characterize the activity of the covalent CDK7 inhibitor THZ1 in multiple myeloma models.Multiple myeloma lines were exposed to varying THZ1 concentrations alone or with carfilzomib or ABT-199, after which apoptosis was monitored by flow cytometry, protein expression by Western blot analysis, mRNA by RT-PCR. Analogous studies were performed in cells ectopically expressing c-MYC, MCL-1, or BCL-XL, or CRISPER-Cas CDK7 sgRNA knockout. Primary multiple myeloma cells were exposed to THZ1 ± carfilzomib or ABT-199. In vivo effects of THZ1 were examined in a systemic U266 xenograft model.THZ1 markedly diminished multiple myeloma cell proliferation and survival despite bortezomib or stromal cell resistance in association with G2-M arrest, inactivation of CTD RNA Pol II, dephosphorylation of CDKs 7 as well as 1, 2, and 9, and MCL-1, BCL-xL, and c-MYC mRNA or protein downregulation. Ectopic MCL-1, c-MYC, or BCL-XL expression significantly protected cells from THZ1 lethality. Both THZ1 and CRISPR-Cas CDK7 knockout sharply diminished multiple myeloma cell proliferation and significantly increased carfilzomib and ABT-199 lethality. Parallel effects and interactions were observed in primary CD138+ (N = 22) or primitive multiple myeloma cells (CD138-/CD19+/CD20+/CD27+; N = 16). THZ1 administration [10 mg/kg i.p. twice daily (BID), 5 days/week] significantly improved survival in a systemic multiple myeloma xenograft model with minimal toxicity and induced similar events observed in vitro, for example, MCL-1 and c-MYC downregulation.THZ1 potently reduces multiple myeloma cell proliferation through transcriptional downregulation of MCL-1, BCL-XL, and c-MYC in vitro and in vivo. It warrants further attention as a therapeutic agent in multiple myeloma.
Abstract 4495: Role of base excision repair (BER) pathway in regulation of KRAS expression in pancreatic cancer
Authors: Suravi Pramanik, Shrabasti Roychoudhury, Hannah Harris, Heyu Song, Kishor K. Bhakat
Journal: Cancer Research (2019)

Abstract Activating mutations in KRAS proto-oncogene, a signature event driving the development, progression and therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC), remains undruggable. The occurrence of guanine oxidation (8-oxoguanine) in the KRAS promoter and up-regulation of KRAS gene transcription under oxidative stress has been shown to be associated with KRAS expression and cancer development and progression. However, the molecular mechanism by which 8-oxoguanine damage regulates KRAS expression is largely unknown. Here, we show that the base excision repair (BER) pathway, a fundamental DNA damage repair pathway that processes most of the endogenous damages including oxidative base damage is involved in regulation of KRAS expression and survival of PDAC. We show that Apurinic/apyrimidinic endonuclease (APE1), a key enzyme of the BER pathway, is highly elevated in pancreatic cancer tissue samples. To elucidate the role of active BER pathway in the regulation of KRAS expression, we used real-time PCR (RT-PCR) analysis. Inflicting cells with oxidative damage using glucose oxidase increased KRAS gene expression in control cells but not in APE1 downregulated cells. ChIP assay showed enhanced occupancy of APE1 in KRAS promoter upon oxidative stress. Consistent with this, using synthetic oligonucleotide containing the KRAS promoter region, we showed that APE1 could bind and cleave AP site in KRAS promoter. Further, ChIP-qPCR analysis showed decreased occupancy of MAZ, a transcription factor, to the KRAS promoter in APE1 downregulated cells. Down-regulation of APE1 also resulted in decreased KRAS expression and increased sensitivity of pancreatic cancer cells to routinely used chemotherapeutic agents such as Gemcitabine, 5-Fluorouracil, Oxaliplatin, etc., suggesting that targeting APE1 and in turn, BER can sensitize pancreatic cancer cells. Our study suggests that BER pathway or APE1 plays a significant role in the tumor-selective regulation of gene expression and sensitization of cancer cells to chemotherapy, and supports the further investigation of novel treatments that target this pathway for cancer therapy. Citation Format: Suravi Pramanik, Shrabasti Roychoudhury, Hannah Harris, Heyu Song, Kishor K. Bhakat. Role of base excision repair (BER) pathway in regulation of KRAS expression in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4495.
Alternative splicing is required for stage differentiation in malaria parasites
Authors: Lee M. Yeoh, Christopher D. Goodman, Vanessa Mollard, Emma McHugh, V. Vern Lee, Angelika Sturm, Anton Cozijnsen, Geoffrey I. McFadden, Stuart A. Ralph
Journal: Genome biology (2019)

In multicellular organisms, alternative splicing is central to tissue differentiation and identity. Unicellular protists lack multicellular tissue but differentiate into variable cell types during their life cycles. The role of alternative splicing in transitions between cell types and establishing cellular identity is currently unknown in any unicellular organism. To test whether alternative splicing in unicellular protists plays a role in cellular differentiation, we conduct RNA-seq to compare splicing in female and male sexual stages to asexual intraerythrocytic stages in the rodent malaria parasite Plasmodium berghei. We find extensive changes in alternative splicing between stages and a role for alternative splicing in sexual differentiation. Previously, general gametocyte differentiation was shown to be modulated by specific transcription factors. Here, we show that alternative splicing establishes a subsequent layer of regulation, controlling genes relating to consequent sex-specific differentiation of gametocytes. We demonstrate that alternative splicing is reprogrammed during cellular differentiation of a unicellular protist. Disruption of an alternative splicing factor, PbSR-MG, perturbs sex-specific alternative splicing and decreases the ability of the parasites to differentiate into male gametes and oocysts, thereby reducing transmission between vertebrate and insect hosts. Our results reveal alternative splicing as an integral, stage-specific phenomenon in these protists and as a regulator of cellular differentiation that arose early in eukaryotic evolution.
PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+CD38hi cells and anti-PD-1 resistance
Authors: Vivek Verma, Rajeev K Shrimali, Shamim Ahmad, Winjie Dai, Hua Wang, Sumin Lu, Rahul Nandre, Pankaj Gaur, Jose Lopez, Moshe Sade-Feldman, Keren Yizhak, Stacey L. Bjorgaard, Keith T. Flaherty, Jennifer A. Wargo, Genevieve M. Boland, Ryan J. Sullivan, Gad Getz, Scott A. Hammond, Ming Tan, Jingjing Qi, Phillip Wong, Taha Merghoub, Jedd Wolchok, Nir Hacohen, John E. Janik, Mikayel Mkrtichyan, Seema Gupta, Samir N. Khleif
Journal: Nature Immunology (2019)
Hypertension care in India: a nationally representative cross-sectional study among individuals aged 15 to 49 years
Authors: Jonas Prenissl, Jennifer Manne-Goehler, Lindsay M Jaacks, Prabhakaran Dorairaj, Ashish Awasthi, Anne Christine Bischops, Rifat Atun, Till Bärnighausen, Justine Davies, Sebastian Vollmer, Pascal Geldsetzer
Journal: PLoS Medicine (2019)
5FU/LV with or without irinotecan in patients with resected stage II-III rectal cancer: Final analysis of R98 intergroup study.
Authors: Catherine Delbaldo, Marc Ychou, Ayman Zawadi, Jean-Yves Douillard, Thierry André, Veronique Guerin-Meyer, Céline Lepère, Olivier Dupuis, Roger Faroux, Annie Jouhaud, Emmanuel Quinaux, Pascal Piedbois
Journal: Journal of Clinical Oncology (2013)

3542 Background: The goal of the study was to test whether adding Irinotecan to a 5-FU/LV adjuvant regimen improves disease free survival (DFS) or overall survival (OS) in optimally resected stages II-III rectal cancers. Primary end-point was DFS. Methods: Six hundred patients were planned to be randomized between 5-FU/LV (control arm) or 5-FU/LV + irinotecan (experimental arm). As only 357 patients had been included from 03/1999 to 12/2005 (178 in control and 179 in experimental arm), the IDMC recommended to close accrual. The trial was stratified by control arm: Mayo-Clinic regimen (A: LV 20 mg/m², 5-FU 425 mg/m² bolus days (d) 1- 5 reapeted at d29,57,92,127 and 162) or LV5-FU2 regimen (A’: LV 200 mg/m², 5-FU 400 mg/m² bolus and 5-FU 600 mg/m² 22-hours infusion d1-2, q 2 w for 12 cycles). The experimental arm (B) was LV5-FU2 + irinotecan 180 mg/m² d1. Results: All 357 randomized patients were evaluable for efficacy. Patient characteristics were well balanced (median age 62 years, stage II 31 %, stage III 69 %, N0 31 %, 68 % received preoperative radiotherapy, and 80 % had sphincter conservation). With follow-up of 156 months, DFS and OS are not statistically increase (81vs 92 events for DFS in experimental and control arm, hazard ratio (HR)=0.805, p=0.154;63 vs 72 events for OS, HR=0.874, p=0.433). Patients allocated to the experimental arm had more grade 3-4 neutropenia when compared with the LV5FU2 control (33 % vs 16 %, p=0.03), but not when compared with the Mayo Clinic arm (32% vs 36%, p=0.84). Grade 3-4 diarrhea tend to be higher in the experimental arm, but analyses stratified by control arm or by radiotherapy failed to show significant differences across strata (test for interaction p=0.44). Conclusions: In patients with resected stage II-III rectal cancer, adding irinotecan to 5FU/LV led to a non significant increase of DFS and OS. The analysis was planned to have a 60 % power to detect a significant difference with 220 events. With a long term follow up of 8 years only 173 events were observed in our trial. Lack of power and good patient prognosis (thirty one percent of node negative patients) may have impacted the results.
Phase 1 Results from ZUMA-6: Axicabtagene Ciloleucel (axi-cel; KTE-C19) in Combination with Atezolizumab for the Treatment of Patients with Refractory Diffuse Large B Cell Lymphoma (DLBCL)
Authors: Frederick L. Locke, Jason R. Westin, David B. Miklos, Alex F. Herrara, Caron A. Jacobson, Jennifer Lee, John M. Rossi, Adrian Bot, Allen Xue, Lynn Navale, Jeff S. Aycock, Jeffrey S. Wiezorek, Zachary J. Roberts
Journal: Blood (2017)
Use of analysis of iron metabolism with CRP-dependent ferritin index and reticulocyte hemoglobin to determine treatment strategy for chemotherapy-related anemia
Authors: T. Steinmetz, S. Schmitz, A. Tsamaloukas, R. Rohrberg, L. Thomas
Journal: Journal of Clinical Oncology (2009)

e20510 Background: Intravenous iron (IV Fe) can increase the efficacy of erythropoiesis stimulating agents (ESA). However it is still unsettled whether all patients (pts) do so. We conducted a phase II trial to analyze various parameters for the addition of IV Fe to ESA in chemotherapy treated anemic cancer pts. Methods: Pts with an indication for ESA following the EORTC guidelines and a serum ferritin (SF) level ≥20ng/ml were screened in a central laboratory. Those with a C-reactive protein (CRP)-dependent ferritin index (FI = soluble transferrin receptor (sTFR)/log ferritin ratio) above threshold (* FI ≥3.2 if CRP &lt;5mg/l, or FI &gt;2.0 if CRP ≥5 mg/l) were treated with iron only. Those with a sub-threshold FI received Epoetin beta (Epo) 30.000E/wk sc., and from these, those with a reticulocyte hemoglobin (Hb) content (CHr) ≤28pg/ml additionally received Fe-saccharat 200mg/wk iv up to 1g. Results: 11 centers recruited 303 pts (median age 65y, male 41%) from 10/04 to 10/06; 230 (76%) had a sub threshold FI (group Q I+IV), of whom 23 (8%, Q IV) had a CHr ≤28pg. 73 pts (24%) had an increased FI (Q II+III), indicating relative iron deficiency, of whom 27 (9%, Q III) had a CHr ≤28pg. There was no correlation between assignment to one of the groups (Q I-IV) and age, gender, body-mass-index, type or stage of tumor, endogenous Epo level, and hematokrit. In 265 pts evaluable for response Hb on d1 was 9.8 ±1.2 g/dl (mean ± SD) and 10.7 ±1.3 g/dl in 4 th week. Mean increase of Hb from d1 to 8 th week was 1.4 ± 1.7 g/dl. 36% pts received a transfusion within 12 weeks and 18% after the 4 th week. The table shows response according to groups. Conclusions: At study onset we expected nearly all pts to receive Epo and searched for those who might have a benefit from additional IV Fe. However, we conclude in synopsis with other studies, that all pts might have a benefit from IV Fe but only 76%, those with a sub-threshold FI, have a benefit from Epo. [Table: see text] [Table: see text]
In vivo isolation of circulating tumor cells in non-small cell lung cancer (NSCLC) patients by a medical device.
Authors: Lukasz Gasiorowski, Stefanie Herold, Phillip Sangwook Kim, Arndt Schmitz, Thomas Krahn, Nils G. Morgenthaler, Grzegorz Dworacki, Klaus Luecke, Wojciech Dyszkiewicz
Journal: Journal of Clinical Oncology (2012)

10536 Background: Currently, circulating tumor cells (CTCs) are isolated in vitro from small limited volumes of blood samples. Furthermore, CTC results for NSCLC as a prognostic and stratification biomarker are scarce. The aim of the study was to assess a functionalized and structured medical wire (FSMW) for in vivo isolation of CTCs directly from the blood of NSCLC patients, and to compare it to the Cell Search method. Methods: The device was inserted in a cubital vein through a standard cannula for thirty minutes. The interaction of target CTCs with the FSMW was mediated by an antibody directed against the epithelial cell adhesion molecule (EpCAM). To confirm the CTCs binding to the wire, the immunohistochemical staining against EpCAM as well as CD45 for negative cell selection was performed. There were 72 applications of the wire in 48 stage I-IIIB NSCLC patients (12 double applications) and 12 non cancer patients. Enumeration data was available for 34 NSCLC patients and 8 non cancer patients. For 34 patients, samples were also tested in the Cell Search system. Results: The device was well tolerated in all 72 applications without side effects. We obtained in vivo isolation of CTCs in 32 of 34 NSCLC patients (94.1%) with a median (range) of 13 (0-300) CTCs. The sensitivity was similar for early and late stage NSCLC patients. In the non-cancer patients, no CTCs were detected (100 % specificity). In 2 of 34 samples (5.8%), CTCs were detected by the Cell Search method. In all matched pairs, the FSMW detected the same number or more CTCs compared to the Cell Search method. Conclusions: Whilst well tolerated without side effects, the CTC detection rate of the FSMW in NSCLC patients was &gt;90%. In contrast, &lt;10% detection was obtained using the Cell Search analysis. No CTCs were detected in non-cancer patients. This proof of concept study may have important clinical implications, as the implementation of the device into clinical practice may improve early detection, prognosis and therapy monitoring of NSCLC patients. The method may also allow the molecular analysis of the CTCs, with the possibility of establishing more personalized treatment regiments.