tbuckley/cabot-search huggingface dataset:
Phase II trial of ixazomib combined with gemcitabine and doxorubicin in patients with SMARCB1-deficient kidney malignancies.
Authors: Pavlos Msaouel, Rebecca Slack-Tidwell, Giannicola Genovese, Najat C. Daw, Arlene O. Siefker-Radtke, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2019)

TPS678 Background: SMARCB1 (also known as INI-1, hSNF5, or BAF47) is a potent tumor suppressor inactivated in all cases of renal medullary carcinoma (RMC) and renal cell carcinoma unclassified with medullary phenotype (RCCU-MP), as well as the majority of malignant rhabdoid tumors (MRT). These highly aggressive malignancies often occur in young patients (pts) and are associated with poor prognosis. There are currently no approved therapies targeting SMARCB1 defects. We previously showed that SMARCB1 loss induces a synthetically lethal vulnerability to perturbations of the cellular proteostasis machinery by proteasome inhibitors (Genovese et al. Nature, 542:362-366, 2017). The present study was designed to determine whether the addition of the second-generation proteasome inhibitor ixazomib to cytotoxic chemotherapy with gemcitabine and doxorubicin (IGD regimen) can improve outcomes of pts with aggressive SMARCB1-deficient kidney malignancies. Methods: This single-arm trial uses the Bayesian optimal phase II (BOP2) design (Heng et al. Stat Med 2017) to determine if the IGD regimen will improve the two co-primary endpoints of objective response rate (ORR) to 50% and 28-week disease control rate (DCR) to 30% compared with the historical ORR and 28-week DCR of 29% and 14%, respectively, achieved using gemcitabine plus doxorubicin alone as first-line or salvage therapy in pts with SMARCB1-negative RMC, RCCU-MP, and adult-onset kidney MRTs treated at our institution. Up to 30 pts aged ≥ 12 years old will be enrolled and any number of prior therapies is allowed. Ongoing monitoring for safety and futility will be implemented in 10-patient cohorts. If both the ORR and DCR improve to 50% and 30%, respectively, then there is only a 3.5% chance of stopping early and a 93.1% chance of claiming that IGD is efficacious. Secondary endpoints include progression-free survival, and overall survival. Tissue correlative analyses will be performed to determine whether tumors from pts responding to IGD have increased levels of endoplasmic reticulum stress markers involved in protein turnover. At the time of the abstract submission, 5 pts have been enrolled on this study. Clinical trial information: NCT03587662.
Myc Drives MLL Leukemogenesis in a Human CRISPR/Cas9 Leukemia Model and Indirect Inhibition with JQ1 Diminishes Leukemia Activity
Authors: Kathy-Ann Secker, Hildegard Keppeler, Silke Duerr-Stoerzer, Hannes Schmid, Dominik Schneidawind, Thomas Hentrich, Julia Schulze-Hentrich, Lothar Kanz, Corina Schneidawind
Journal: Blood (2018)
Abstract P132: Establishing a New Observational Study of Cardiovascular Risk Factors and Chronic Diseases in Puerto Rico: The PROSPECT Study
Authors: Josiemer Mattei, Katherine L Tucker, Carlos F Rios-Bedoya, Luis M Falcon, Robert C Kaplan, Jose F Rodriguez-Orengo
Journal: Circulation (2019)

Introduction: Evidence supports a direct link between psychosocial and food-related environmental risk factors, and cardiometabolic conditions. These associations remain markedly understudied at the population level in Puerto Rico (PR), despite the clear and pressing need to alleviate striking disparities in chronic disease in the island. On September 2017, Hurricane Maria devastated PR, imposing urgency for studying trends and associations of risk factors for cardiometabolic conditions under times of distress. Hypothesis and aims: We aimed to design and establish ‘PROSPECT: Puerto Rico Observational Study of Psychosocial, Environmental, and Chronic disease Trends’ to study longitudinal associations in psychosocial, food-related, and cardiometabolic risk factors. Methods: PROSPECT was designed as an island-wide, longitudinal population cohort that is recruiting 2,000 adults ages 30-75y using a multi-frame sampling combining probabilistic plus community approaches, with examinations and interviews done in a network of partner clinics across the island. Trained interviewers are collecting comprehensive data on multiple psychosocial, dietary, and food-related factors, cardiovascular disease (CVD) biological markers, and medical record data, with follow-up at 2-years, using standardized protocols and validated questionnaires. PROSPECT emulates the goals and methods of other US and Caribbean cohorts inclusive of mainland Puerto Ricans and other Latinos for comparison. Results: Expected results include estimates of baseline and 2y prevalence and incidence of psychosocial, dietary, and food environment risk factors, and CVD biological markers; measures of associations between 2y changes in risk factors and CVD biological markers; and estimates of differences in prevalence and 2y changes in risk factors, CVD biological markers, and chronic diseases, with emphasis on CVD, by urban vs. rural area, and pre vs. post-Maria. A supplemental study is investigating how food and water shortages following Hurricane Maria may have triggered allostatic load (i.e. physiological stress) and how social connectedness moderates this in PROSPECT participants, with additional context from qualitative narrative interviews. Conclusions: Ultimately, PROSPECT will create a biorepository and participant database for prospective use, and bolster research, academic, and public health partnerships in PR and the US. The study is yielding seminal data to identify priorities on CVD-related disparities, and address them by tailoring public health programs and policy that will effectively improve cardiovascular health in PR, an island with an underserved and high-risk population, under times of distress.
Neoadjuvant chemotherapy in the real world: A study of 22,819 patients from the Japanese National Clinical Database-Breast Cancer Registry.
Authors: Naoki Niikura, Ai Tomotaki, Hiroaki Miyata, Takayuki Iwamoto, Masaaki S. Kawai, Keisei Anan, Takayuki Kinoshita, Shinobu Masuda, Koichiro Tsugawa, Yutaka Tokuda
Journal: Journal of Clinical Oncology (2015)

588 Background: Recently, neoadjuvant chemotherapy has become a treatment of choice in clinics. Estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) expressions may convert from positive to negative and vice versa after neoadjuvant chemotherapy. We investigate the pathological complete response (pCR) rate in each subtype and the discordance rate of ER, PgR, and HER2 before and after neoadjuvant chemotherapy using Japanese breast cancer registry data. Methods: Records for > 300,000 cases from 741 hospitals from 2004 onwards were retrieved from the Japanese National Clinical Database-Breast Cancer Registry. After data cleanup, 22,819 cases without distant metastases, where neoadjuvant chemotherapy was administered between January 1, 2004 and December 31, 2011, were selected. pCR was defined as no invasive tumor in the surgical specimen after neoadjuvant chemotherapy. HER2 overexpression was evaluated (i.e., immunohistochemically 3+ and/or fluorescence in situ hybridization-positive). Results: pCR was achieved in 6.2% of luminal-type (8,995 patients), 26.0% of HER2-type (4,654 patients), and 19.9% of triple-negative (3,786 patients) breast cancer cases. Among the HER2-type cases, pCR was achieved in 33.2% of ER-negative, 18.0% of ER-positive, 32.2% of trastuzumab-treated (as neoadjuvant chemotherapy), and 18.4% of trastuzumab-untreated cases. After neoadjuvant chemotherapy, HER2-negative tumors were found in 626 (21.5%) of the 2,913 patients with HER2-positive pretreatment tumors, and HER2-positive tumors were found in 343 (3.4%) of the 10,178 patients with HER2-negative pretreatment tumors. Furthermore, 536 (4.7%) of the 11,382 patients with ER-positive tumors had ER-negative tumors and 619 (9.6%) of the 5,870 patients with ER-negative tumors had ER-positive tumors after neoadjuvant chemotherapy. Conclusions: We confirmed that in the real world, pCR rates for each subtype follow the same trend in clinical trials. We confirmed that a loss of HER2-positive status in primary tumors could occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer.
Bowel and bladder reproducibility in image-guided SBRT prostate: Results of a patterns of practice survey.
Authors: Jeremy Mandia, Freddy Escorcia, Holly Ning, Kilian Elizabeth Salerno, Deborah E. Citrin, Lindsay S. Rowe
Journal: Journal of Clinical Oncology (2019)

76 Background: Use of prostate stereotactic body radiotherapy (SBRT) as treatment for localized prostate cancer (PCa) is increasing. Given the high dose (&gt;5Gy) per fraction (Fx) being delivered, SBRT requires careful preparation and delivery to ensure accuracy and precision. Guidelines and data on best practice for bowel and bladder preparation are lacking. Therefore, we surveyed practicing radiation oncologists (RO) to document practice patterns for prostate SBRT. Methods: From June to October 2018 we completed a nationwide survey of 1395 American Society for Therapeutic Radiology and Oncology (ASTRO) members who self-identified as managing PCa. A SurveyMonkey link was sent via email, and analysis included practicing RO who treat PCa with SBRT. Results: 204 responses were received with 32% (64/204) using SBRT. 80% (51/64) provided the fractionation used: 33% (17/51) use 35Gy to 36.25Gy, and 17.6% (9/51) use &gt;40Gy in 5 Fx, and 1 used &gt;9Gy Fx. 94% use implantable devices for localization (83% fiducial markers, 17% radiofrequency transponders). 65% (42/64) use a hydrogel spacer. 75% (48/64) use daily cone beam CT (CBCT) for image guidance. The majority use a 5 mm PTV, with 3 mm posteriorly. For bladder and bowel preparation 97% (62/64) provided preferences. For bladder, 90.3% (56/62) required a comfortably full bladder for both simulation and treatment. For simulation, 92% (57/62) have a bowel protocol (BP) to optimize rectal reproducibility. 51.6% (31/62) have patients empty their bowels prior, and 51.6% (31/62) prescribe a BP. Diet alteration was recommended by 77% (48/62). 86% (53/62) used a BP during SBRT treatment. Of those using a BP, 67% (43/64) continued it throughout SBRT with 30% (19/64) continuing BP unless symptoms change management. Only 3% (2/64) stop BP after simulation. Conclusions: The variability of data in the literature on effective BP for treatment reproducibility for PCa is reflected in the varied patterns of practice seen in our survey. Consensus on bladder preparation is seen for a majority of practitioners. A variety of BP regimens are employed.
Incorporating mpMRI Biopsy data into established pre-RP nomograms: Potential impact of an increasingly common clinical scenario.
Authors: Joon Yau Leong, Thenappan Chandrasekar, Elwin Tham, Seth Teplitsky, Costas D. Lallas, Leonard G. Gomella, Edouard John Trabulsi
Journal: Journal of Clinical Oncology (2019)

32 Background: Current pre-radical prostatectomy (RP) nomograms predicting lymph node involvement (LNI) are based on systematic 12-core prostate biopsies (PBx). With the introduction of mpMRI, cognitive or fusion biopsies have become prevalent, often in the absence of systematic cores. We examine the practical application of MR biopsy data using established pre-RP nomograms and the potential implications on RP intra-operative decision making. Methods: Utilizing a prospectively maintained single institution database, all patients who underwent MRI-based PBx prior to RP were identified. Each patient was assessed using the MSKCC Kattan nomogram and the Briganti nomogram using the following iterations: 1) Targeted [T] (targeted cores alone), 2) Targeted &amp; Systematic [TS] and 3) Targeted Augmented [TA]. The TA iteration utilized targeted core data alone and assumed negative remaining systematic cores for a total 12 core. Nomogram outcomes, specifically risk of LNI, was compared across iterations. Clinically significant impact was defined as a change in risk above or below 2% (Δ2) or 5% (Δ5), based on current guidelines recommendations for lymph node dissection. Results: 69 men met inclusion criteria (6 targeted, 63 systematic + targeted PBx). In the 6 men with targeted only biopsies, using the Kattan and Briganti nomograms, Δ2 occurred in 1 patient (16.7%) and Δ5 in 1-2 patients (16.7-33.3%); in all, TA iteration LNI was lower than the T iteration. In the 58 patients with positive targeted biopsy cores, Δ2 and Δ5 were 8.62-32.76% and 25.86-37.93%, respectively. In the subset of 52 patients with both targeted and systematic biopsies, using their TS nomogram as an internal validation, the TA iteration was a better approximation of their TS outcomes than their T iteration in 48% (Kattan) and 67% (Briganti) of patients. Conclusions: mpMRI-based PBx results, and in particular those from targeted biopsy cores alone, yield significantly different results using established pre-RP nomograms. Therefore, future nomograms must better incorporate MRI biopsy data and provide guidelines on how to account for targeted cores. In the interim, augmenting targeted biopsy data may bridge the gap.
Clinical features and outcomes of secondary somatic malignancy (SSM) associated with primary mediastinal nonseminomatous germ cell tumors (PM-NSGCT).
Authors: Lucas W. Dean, Nathan Colin Wong, Shawn Dason, Sumit Isharwal, Mark Donoghue, Liwei Jia, William D. Tap, Gabriella Joseph, Samuel Aaron Funt, Deaglan Joseph McHugh, Hikmat Al-Ahmadie, Victor E. Reuter, Joel Sheinfeld, Dean F. Bajorin, Robert J. Motzer, George J. Bosl, Manjit S. Bains, David Randolph Jones, David B. Solit, Darren R. Feldman
Journal: Journal of Clinical Oncology (2019)

531 Background: The incidence of secondary somatic malignancy (SSM) arising from teratoma is increased in 2 settings; late relapse and primary mediastinal nonseminomatous germ cell tumors (PM-NSGCT). Here, we report the clinical features and outcomes of patients with SSM in the setting of PM-NSGCT. Methods: Between 1985 and 2018, 29 patients with PM-NSGCT and SSM who had sufficient clinical follow-up to evaluate outcome were identified. Clinical and pathologic parameters were reviewed. The Kaplan-Meier method was used to estimate overall survival (OS) from time of SSM diagnosis and the log rank test to compare estimates. Results: Median age was 28 years (range 18-59) and all patients were male. Most presented with local symptoms (n=24, 83%), elevated tumor markers (n=26, 90%), and disease isolated to the mediastinum (n=25, 86%). A total of 39 SSM histologies were present in the 29 cases, with 8 (28%) having 2 (n=6) or 3 (n=2) SSM histologies; 25 (86%) also had viable non-teratomatous GCT in the mediastinal mass. Sarcoma was found in all 29 cases including rhabdomyosarcoma (n=15), angiosarcoma (n=6), sarcoma NOS (n=5), spindle cell (n=4), PNET (n=3), and other (n=3). Non-sarcoma histologies (n=1 each) included AML, SCC, and neuroblastoma. Most patients received GCT-directed chemotherapy followed by an attempt at surgical resection (90%). With a median follow-up of 2 years for survivors, median OS was 1.8 years (95% CI 0-3.9 years), with 18 patients succumbing to disease. Complete surgical resection was achieved in 23 men (79%) and was associated with superior OS (3.1 vs. 0.3 years, p=0.005). At relapse or progression, 11 received SSM histology-directed and 7 GCT-directed chemotherapy with no difference in OS (1.3 vs. 1.2 years, p=0.993). 7 patients developed SSM in the form of leukemia, a finding associated with significantly inferior OS (0.3 vs. 3.0 years, p=0.009). Conclusions: Sarcoma is the predominant SSM histology associated with PM-NSGCT and portends a poor prognosis even with initially localized disease. Complete resection following chemotherapy is critical to achieving long-term survival whereas SSM in the form of leukemia portends especially poor outcome.
A new approach for screening cervical cancer by characterization of transcripts using CAGE technology.
Authors: Kazunori Nagasaka, Ayumi Taguchi, Kei Kawana, Kosuke Hashimoto, Charles Plessy, Hiroe Nakamura, Miranda Thomas, Katsutoshi Oda, Iwao Kukimoto, Piero Carninci, Lawrence Banks, Yutaka Osuga, Tomoyuki Fujii
Journal: Journal of Clinical Oncology (2015)

e16514 Background: Cervical cancer is the third most common female cancer worldwide. Recently, the HPV-DNA test has been approved as a primary screening method in the United States. However, screening with the HPV-DNA test may provoke needless anxiety about a large number of transient infections that pose little or no risk, and might often result in over-treatment. The goal of this study is to develop transcriptome-based diagnostic methods that improve the efficiency of current screening programs. Methods: We performed CAGE (Cap Analysis Gene Expression) analysis to investigated transcriptome start sites (TSSs) from the perspective of both the HPV16 and human genomes. To assess the levels of all the transcriptome levels in HPV16-infected cells, we analyzed cervical carcinoma-derived CaSki and SiHa cells; CIN1-derived W12E cells, containing episomal copies of HPV16 ; and 10 clinical samples (4 CIN2/3 lesions and 6 cervical cancers). cDNA strands are synthesized from the 5’-end of capped RNAs, attached to CAGE ‘bar code’ tags and the sequenced CAGE tags were mapped to the HPV16 (NCBI GI: 333031). CAGE tags were normalized by the total number per sample mapped to the human genome and indicated as Tags per million (TPM). For HPV16 genes, CAGE-tag 5’ coordinates were input for Paraclu clustering. Results: We report here two major findings from this study. First, we have identified a novel antisense transcript starting from nt1330 as a non-coding RNA without polyA. Secondly, comparing transcript diversity in the cell-lines, we found only 1 positive-strand tag cluster (TC [regions with > 0.5 TPM/sample]) in the cervical-cancer derived CaSki and SiHa cells, whereas 25 positive-strand and 4 negative-strand TCs were detected in the CIN1-derived W12E cells. Furthermore, a comparison of viral transcriptome expression between biopsied CIN2/3 lesions and cervical cancers shows a significant diversity that would be lost upon viral genome integration and disease progression. Conclusions: Using the CAGE method, we have successfully established unbiased analyses of reproducible TSSs across the HPV16 genome. Further validation and identification of possible biomarkers are warranted to predict the outcome of infections with HPV.
Platelet Integrin αIIbβ3 Activation Kinetics in Inherited Platelet Functional Disorders ∼ the Role of ADP Receptor P2Y12, Caldag-GEFI and Kindlin-3 αIIbβ3 Activation By inside-out Signaling
Authors: Hisashi Kato, Nobuko Nishiura, Keigo Akuta, Hirokazu Kashiwagi, Koichi Kokame, Toshiyuki Miyata, Yuzuru Kanakura, Yoshiaki Tomiyama
Journal: Blood (2018)
Robot-assisted radical cystectomy (RARC) versus open radical cystectomy (ORC): Oncological outcomes in 469 patients with a mean follow-up of five years.
Authors: Kassem Faraj, Kyle Rose, Haidar Abdul-Muhsin, Anojan Navaratnam, Michael Patton, Scott Cheney, Mark D. Tyson, Erik P. Castle
Journal: Journal of Clinical Oncology (2019)

492 Background: There is scant information about intermediate and long-term comparative outcomes between RARC and ORC, with the exception of a recent, small randomized-trial. We present our experience with RARC and ORC in managing bladder cancer patients who require cystectomy. Methods: A query of all patients who underwent radical cystectomy for a primary bladder tumor between 01/2007 and 6/2017 at our institution yield 469 patients. Data was collected on patient demographics, pre-operative information, operative details, pathology, and follow-up. Most RARCs were performed by a high-volume robotic surgeon who preferentially used the robotic approach at the start of all cases. Statistical analyses were generated using SPSS 22.0. Any open conversions were analyzed in the RARC cohort. Results: In 469 total patients, 197 (42.0%) and 272 (58.0%) underwent RARC and ORC, respectively. There were 163 (82.7%) and 224 (82.4%) males in each group and the mean ages (SD) were 71.5 (8.6) and 70.2 (10.5) years. Mean follow-up (SD) was 75 (37.7) and 61 (35.7) months, respectively. There were 130 (66.0%) and 172 (63.2%) patients who presented with T2 or greater disease (p=0.605). Soft-tissue margin rates were 4.1% for RARC and 6.7% for ORC patients (p=0.232). Neoadjuvant chemotherapy was used in 56.9% of RARC and 45.9% of ORC patients with ≥ cT2 disease (p=0.058). The 5-year overall survival was 60.0% vs 57.0% and the 10-year overall survival was 40.3% vs 44.8% for RARC vs. ORC patients, respectively (p=0.283). The 5-year recurrence-free survival was survival (RFS) was 71.7% vs 65.7% and the 10-year RFS was 70.5% vs 62.3% for the RARC vs. open groups, respectively (p=0.078). Aggressive histological variants, which were associated with greater likelihood for recurrence, were more common in the ORC group (13.7 vs. 22.4% p=0.013). Atypical recurrences (i.e. peritoneal, extrapelvic nodes) occurred in 6 (3.0%) and 14 (5.1%) RARC and ORC patients, respectively (p=0.266). Conclusions: In experienced hands, intermediate and long-term outcomes of RARC appear equivalent to ORC with regards to recurrence free survival, overall survival, and risk of atypical recurrences.
Impact of hemoglobin level and self-reported symptom burden in patients with lung cancer.
Authors: Christian S. Adonizio, Jezza Malik, Preston Biegley, Mark Wojtowicz, Jonathan Darer, James Wade
Journal: Journal of Clinical Oncology (2015)

e17692 Background: There has been limited research defining the differences between the effects of liberal (8-10 g/dL) and restrictive (7-8 g/dL) transfusion hemoglobin thresholds on outcomes of ambulatory patients with cancer. Methods: As part of routine work-flow, all patients with a cancer diagnosis were asked to complete an electronic, patient self-reported survey using the validated MD Anderson Symptom Inventory (MDASI) at each ambulatory physician encounter in Medical and Radiation Oncology at two centers within Geisinger Health System. Analysis was restricted to patients with a diagnosis of lung cancer, because it was thought that this population would experience the effects of anemia most acutely. Each MDASI completed was matched with the laboratory-reported hemoglobin specific to that day. Results: There were 850 MDASI completed between 1/22/14 and 1/16/15 for which there was a corresponding hemoglobin result. There were 256 MDASI from 147 individual patients with lung cancer (Table 1). Applying a Minimal Important Difference, MID, (previously validated for this tool) of 0.98 to 1.21 for the symptoms of fatigue, shortness of breath, general activity, mood, and work interference, there was no significant difference noted between hemoglobin levels of 8-12 g/dL. This observation did not change when patients were stratified by age. There were insufficient responses from patients with Hgb < 8.0 g/dL. Conclusions: There was no significant difference in the symptoms of fatigue, shortness of breath, general activity, mood, and work interference with hemoglobin levels of 8-12 g/dL as self-reported by patients. There were insufficient responses to draw conclusions about patients with hemoglobin levels less than 8 g/dL. Results are consistent with the current ASH and ASCO guidelines for transfusion of patients with cancer. MDASI values from patients w/ lung cancer and anemia. HEMOGLOBIN VALUE SURVEYS PATIENTS PATIENTS W/ LUNG CANCER FATIGUE AVERAGE SHORTNESS OF BREATH AVERAGE GENERAL ACTIVITY AVERAGE MOOD AVERAGE WORK AVERAGE 7-7.99 1 1 1 10.0 8.0 3.0 10.0 8.0 8-8.99 21 20 20 6.0 4.6 4.7 3.9 5.0 9-9.99 31 25 25 5.3 4.4 4.7 3.2 4.6 10-11.99 72 52 52 4.7 3.6 4.1 3.2 4.1 12+ 131 86 86 5.0 3.5 3.4 2.8 3.5 TOTAL 256 147 147 5.1 3.7 3.9 3.1 4.0