tbuckley/cabot-search huggingface dataset:
Soft tissue sarcomas: A challenge for oncology.
Authors: Maria Jesus Blanco Sánchez, Samuel Hernandez Sarmiento, Pedro Jimenez Gallego, Marta Mori de Santiago, Saray Galvan Ruiz, Maria Hernandez Sosa, Salvador Saura Grau, David Aguiar Bujanda, Enrique Grande, Uriel Bohn
Journal: Journal of Clinical Oncology (2014)

e21512 Background: Soft tissue sarcomas (STS) are rare tumors with a heterogeneous behaviour due their origin in mesenquimal tissues. The prognosis depend on their histopatologic characteristics and they often have an aggressive development. Methods: Retrospective study of patients with diagnostic of STS treated at the Medical Oncology of the Hospital Universitario de Gran Canaria Doctor Negrín between 2000-2013. Survival was analyzed with the Kaplan–Meier method and compared between groups with the log-rank test. Results: From January 2000 to September 2013, 53 patients were analyzed (Table). Clinical presentation more frequent was tumor without pain (60.4%) and less frequent was pain (22.6%) or secondary symptoms by local grown (17%). The most common site of distant metastases was the lung (53,3%). 47% patients were treated with surgery and 23.5% with chemotherapy. To date there have been 24 relapses (70,6% of grade 3 tumors). The most frequent place for first relapse was local in 60% while the lung was the second one. 5-year overall survival by histologic grade was 40% in patients with G3 tumors, 70% G2 and 90% G1 (p=0,017). Median survival time between recurrent and death was 8 months. At this time 28 patients are alive without disease. Conclusions: In our experience, the prognosis and the risk of relapse depends on surgical margins, size, histology and grade of the tumor. Our data show a statistically significance difference for overall survival according to tumor grade. The poor outcomes of patients at relapse highlights the need to improve treatment options and continuing the search for new agent therapies for these patients. Median age 53y Range 18-87 Tumor size n (%) <50 23 (43,4%) <5cm 12 (22,6%) ≥50 30 (56,6%) ≥5cm 41(77,4%) Stage n (%) Grade n (%) IA 6 (11,3%) Grade 1 9 (17%) IB 5 (9,4%) Grade 2 8(15,1%) IIA 6 (11,3%) Grade 3 36 (67,9%) IIB 3 (5,7%) III 19 (35,9%) IV 14 (26,4%) Histologic type Site n (%) n (%) n (%) Leiomyosarcoma Pleomorphic sarcoma Liposarcoma Synovial Sarcoma Angiosarcoma MPNST Others 13 (24,5%) 12 (22,6%) 9 (17%) 5 (9,4%) 3 (5,7%) 3 (5,7%) 8 (15%) Head-Neck Trunk wall Abdominal wall Extremities 3 (5,7%) 13 (24,5%) 8 (15,1%) 29 (54,8%) Superficial Deep 7 (13,2%) 46 (86,8%)
Association of diabetes and cancer-diagnoses in primary care practices in Germany.
Authors: Nina Schmidt, Karel Kostev, Volker Ziller, Bernd Kowall, Wolfgang Rathmann
Journal: Journal of Clinical Oncology (2014)

1604 Background: Previously published studies suggest that type 2 diabetes is associated with an increased risk of cancer, particularly in the case of breast, colorectal, bladder and pancreatic cancers. In the present study the incidence of 14 different cancer types was compared among diabetes vs. none-diabetes patients. Methods: We used data from the IMS Health Disease Analyzer database focusing on two different groups of patients: patients diagnosed with diabetes and patients without diabetes who were treated in a general practice in Germany. The analysis was performed retrospectively. The proportion of patients with a primary cancer diagnosis following initial diagnosis of diabetes (or in the same period for patients with no diabetes) was determined. The Hazard ratios (HR; Cox regression) for the risk of cancer in diabetic versus none-diabetic patients (follow-up:. maximum of 12 years) were adjusted for demographic and clinical variables. Results: 78,599 patients diagnosed with diabetes and 392,995 patients without diabetes were identified. The study population was matched in terms of age (68 ± 11 years) and gender (male: 47%). The overall risk of cancer was slightly higher in diabetes-patients than in patients without diabetes (HR: 1.06; CI: 1.04 to 1.09). The risk of getting cancer was significantly increased for patients with diabetes with regard to pancreatic cancer (HR: 2.17; CI: 1.86 to 2.52), esophageal cancer (HR: 1.32; CI: 1.03 to 1.69), kidney cancer (HR: 1.30; CI: 1.11 to 1.52), lung cancer (HR: 1.15; CI: 1.05 to 1.28), colorectal cancer (HR: 1.13, CI: 1.04 to 1, 22) and endometrial cancer in women (HR: 1.43; CI: 1.08 to 1.90). In breast, prostate, liver, stomach, thyroid, urinary bladder, gall bladder cancer and non-Hodgkin lymphoma no significant increase in risk was observed. Conclusions: In this retrospective database analysis, with a maximum of 12 year observation period, type 2 diabetes was associated with an increased risk of cancer. However, it is not yet clear at this point whether the diabetes or rather certain antidiabetic drugs increase the risk of cancer. Further research is required to understand these correlations.
Geospatial Mapping of Sickle Cell Disease in Northwest Tanzania: The Tanzania Sickle Surveillance Study (TS3)
Authors: Emmanuela E. Ambrose, Luke R. Smart, Mwesige Charles, Arielle G. Hernandez, Adolfine Hokororo, Teresa Latham, Medard Beyanga, Erius Tebuka, Erasmus Kamugisha, Thad A. Howard, Russell E. Ware
Journal: Blood (2018)
Prostate brachytherapy technique and long-term urinary incontinence: 5-year outcomes of a prospective comparative cohort study.
Authors: James Austin Talcott, Jack A. Clark, Judith Manola, Ronald C. Chen, Irving D. Kaplan, Anthony L. Zietman, Anthony Victor D'Amico
Journal: Journal of Clinical Oncology (2014)

e16016 Background: Prostate brachytherapy (BT) causes long-term urinary incontinence. Altered techniques may improve patient outcomes. Methods: We prospectively studied three Boston-area patient BT cohorts: 1 cohort with MRI imaging, target volume avoids transition zone (MRBT) and 2 with standard ultrasound imaging and planning techniques (USBT1 and USBT2). We surveyed patients pretreatment and at intervals after, using the validated PCSI scales for urinary incontinence (incont), obstruction/irritation (obstir) bowel problems, sexual dysfunction and the quality of life (QOL) effect of incont on their lives (incontQOL). Based on early results showing increased acute urinary toxicity, USBT2 providers adopted an element of USBT1 technique that improved results. We report final 5-year follow-up. Results: Of 286 eligible patients, 73 MRBT patients and 190 USBT patients (99 USBT1 and 91 USBT2 patients) completed at least 3-month surveys. Patient differed by age (median: MRBT 65.3 years vs. USBT 68.3 p=0.005, USBT2 65.3 vs. USBT1 68.3 p=0.004) and education (MRBT 8%≤high school vs. USBT 23%, p<0.001) but other demographic and clinical variables were similar. MRBT patients had more pretreatment obstir symptoms and better sexual function pretreatment. USBT2 patients had greater increases in acute (3-month) obstir (28.8 vs. 20.0, p=0.01) and incont (12.2 vs. 7.1, p=0.01) than USBT1 but were similar at 5 years. Changing USBT2 technique eliminated the acute urinary differences in subsequent patients. Compared to USBT, MRBT patients had greater increases in acute urinary morbidity (obstir 28.8 vs. 20.0, p=0.01; incont 9.6 vs. 2.2, p=0.002; incontQOL 10.2 vs. 2.4, p=0.0002) and long-term incontinence (incont 7.5 vs. 3.3, p=0.05; incontQOL 5.6 vs. 1.2, p=0.01). Other outcomes did not differ. Age and other QOL variables varied by outcome. Conclusions: QOL outcomes vary by BT technique, even if nominally similar. Measuring QOL may provide useful information for patients selecting treatment and providers evaluating their technique. Clinical trial information: NCT00681694.
Abstract 18700: Cardiac Fibroblast Co-Culture Promotes More Adult-Like Electrophysiological Properties in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
Authors: Christopher Kane, Cesare M Terracciano
Journal: Circulation (2016)

Cardiac fibroblasts can influence cardiomyocyte structure and function through direct physical interaction and/or by the secretion of soluble factors. Here we assessed the effects of fibroblast co-culture on cardiomyocyte electrophysiology. Ventricular fibroblasts from failing human hearts (DCM, n=4) were seeded onto human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) at a ratio of 2:1 and cultured for 24 hours. iPS-CMs alone were used as control. Ca2+ transients (CaT) and action potential duration (APD) were assessed optically using fluo-4 AM and di-8-ANEPPS. Data are presented as percentage change from control where appropriate. iPS-CM CaT duration was significantly reduced with fibroblasts (-8.4±2.2% n=12 p<0.01). Sarcoplasmic reticulum (SR) Ca2+ uptake was highly upregulated (2.07±0.12s-1 vs 0.63±0.07s-1 in control n=26, 23 p<0.001), associated with a greater in SR Ca2+ content (F/F0: 3.74±0.11 vs 2.97±0.11 in control n=37, 32 p<0.001) and SERCA2a protein (1.02±0.08 vs 0.55±0.01 n=3 p...
Surgery for central nervous system tumors in the Brazilian National Health Care System: A review of 57,361 cases in DATASUS.
Authors: Julio Leonardo Barbosa Pereira, Luciola De Barros Pontes, Antonio A. F. De Salles, Alessandra Gorgulho, Ana Moura, Diana Lara Pinto de Santana, Benjamin Haaland, Gilberto Lopes
Journal: Journal of Clinical Oncology (2014)

2064 Background: In low- and middle-income countries, resource limitations make the management of central nervous system (CNS) tumors challenging, particularly in Brazil, a country with major socioeconomic and health access disparities. We aimed to evaluate cancer-related neurosurgical procedures in the public health care system. Methods: Based on Brazilian’s public health system database (DATASUS), we collected data for neurosurgical procedures related to CNS tumors performed between January 2008 and November 2013. Information about number of procedures, costs, length of stay and number of inpatient deaths were analyzed for each State and then correlated to State specific population, gross domestic product (GDP) per capita and number of procedures. Results: 57,361 procedures were performed, the majority (45.9%) in the Southeast region. Total cost was $108,363,829.00; average cost per admission was $1,889.00. Average cost in each State, for a fixed number of procedures and population, tended to decrease as GDP per capita increased (OR -0.14; 95% CI -0.4 to -0.1; p=0.001). The mean length of hospital stay was 14.4 days, longer for patients treated at the North of the country (19.9 days). On multivariate analysis, number of procedures, GDP per capita, and population had an independent association with days of hospitalization. A total of 4,079 patients died, translating into an inpatient mortality rate of 7.11%, higher than expected based on US and European data. Northern States had the highest rates (12.76% for the region and 17.6% for the State with the highest mortality). Mortality rates decreased as number of procedures (p<0.001), GDP per capita (p<0.001) or State population increased (p<0.001). On multivariate analysis, only number of procedures (OR 0.93; 95% CI 0.91 to 0.96; p<0.001) and State population (OR 1.25; 95% CI 1.13 to 1.38; p<0.001) had an independent association with mortality. Conclusions: This is the first study to evaluate disparities in CNS tumor surgery in a middle income country, confirming that regional disparities exist and that clinical and economic outcomes correlate with income level, number of procedures and state population.
Impact of treatment-free interval (TFI) and disease control rate (DCR) on survival outcome in relapsed malignant pleural mesothelioma (MPM).
Authors: Vanesa Gregorc, Alessandra Bulotta, Maria Grazia Viganò, Domenico Ghio, Gilda Rossoni, Claudio Sallemi, Floriana Fontana, Cristina Ammannati, Scialini Colombi, Antonio Lambiase, Claudio Bordignon
Journal: Journal of Clinical Oncology (2014)

7584 Background: Both TFI (the time elapsing from end of first line to start of second line therapy) and DCR (the nonprogression rate at first tumor evaluation) have been found to predict overall survival (OS) in some tumor types. Methods: The impact of TFI and DCR on the outcome of relapsed MPM patients who had failed a pemetrexed-based regimen was tested in an individual patient data pooled analysis. Second line therapy (n=450) was single agent NGR-hTNF (n=50, ph 2 trial) or chemotherapy (gemcitabine, vinorelbine or doxorubicin) plus NGR-hTNF/placebo (n=400; ph 3 trial). In both trials, tumor evaluation was done every 6 weeks by MPM-modified RECIST. OS was computed from second line therapy and median follow-up time was 19.3 months. TFI data were treated as a continuous or dichotomous variable using the median value as cutpoint (4.6 months; 95% CI 4.0-5.0). In multivariable models, hazard ratios (HR) for OS were derived from Cox models adjusted for baseline factors: age (median, 66 years), sex (men, 75%), PS (1-2, 66%), histology (nonepithelial, 19%), EORTC score (≥ 1.27, 35%), best response to first line therapy (DCR, 74%), neutrophil to lymphocyte ratio (NLR; median, 4). Results: TFI data individually predicted for OS when tested as continuous (HR=1.02; p=0.005) or median value (HR=1.35; p=0.005). A TFI shorter than 4.6 months remained independent predictor of poor OS on multivariate analysis (HR=1.38; p=0.01) along with male sex (1.70; 0.001), PS of 1-2 (1.48; 0.004), nonepithelioid histology (1.77; 0.002), EORTC score ≥ 1.27 (1.36; 0.05) and NLR ≥ 4 (2.1; <0.0001). A short TFI was also related to worse progression free survival (adjusted HR=1.36; p=0.009) and DCR (adjusted odds ratio=0.62; p=0.02). After second line therapy, the 6-week DCR was 54%, while 46% of cases had early progression or were unevaluable. Using DCR at 6 weeks as a time dependent covariate, the nonprogression rate was univariately associated with OS improvement (HR=0.58; p<0.0001), which persisted after adjusting for baseline risk factors (HR=0.61; p<0.0001). Conclusions: In relapsed MPM, a prior short TFI is an independent predictor of poor prognosis and the 6-week DCR can be used as early surrogate endpoint for survival. Clinical trial information: NCT00484276-NCT01098266.
Functional significance of the platelet immune receptors GPVI and CLEC-2
Authors: Julie Rayes, Steve P. Watson, Bernhard Nieswandt
Journal: Journal of Clinical Investigation (2019)

Although platelets are best known for their role in hemostasis, they are also crucial in development, host defense, inflammation, and tissue repair. Many of these roles are regulated by the immune-like receptors glycoprotein VI (GPVI) and C-type lectin receptor 2 (CLEC-2), which signal through an immunoreceptor tyrosine-based activation motif (ITAM). GPVI is activated by collagen in the subendothelial matrix, by fibrin and fibrinogen in the thrombus, and by a remarkable number of other ligands. CLEC-2 is activated by the transmembrane protein podoplanin, which is found outside of the vasculature and is upregulated in development, inflammation, and cancer, but there is also evidence for additional ligands. In this Review, we discuss the physiological and pathological roles of CLEC-2 and GPVI and their potential as targets in thrombosis and thrombo-inflammatory disorders (i.e., disorders in which inflammation plays a critical role in the ensuing thrombosis) relative to current antiplatelet drugs.
Preclinical Validation Studies Support Causal Machine Learning Based Identification of Novel Drug Targets for High-Risk Multiple Myeloma
Authors: Arnold Bolomsky, Fred Gruber, Kathrin Stangelberger, Leon Furchtgott, Dominik Arnold, Puja Raut, Diane Wuest, Karl Runge, Iya Khalil, Niklas Zojer, Nikhil Munshi, Boris Hayete, Heinz Ludwig
Journal: Blood (2018)
Analysis of epithelial ovarian cancer morphology, adhesion and migration in response to bone morphogenetic protein 4
Authors: Brigitte L. Theriault, Mark W. Nachtigal
Journal: Cancer Research (2005)

3770  Introduction Bone morphogenetic proteins (BMPs) are members of the transforming growth factor beta (TGFβ) superfamily of secreted ligands. We have identified a functional BMP signaling pathway in human ovarian surface epithelial (OSE) and epithelial ovarian cancer (EOC) cells. Most ovarian cancers arise from the OSE, which forms a monolayer covering the ovarian surface and rests on a basement membrane composed of extracellular matrix (ECM) proteins such as collagen IV and laminin. OSE and EOC cells express integrin receptors and focal adhesion proteins that facilitate adhesion to the ECM. These molecules likely play a role in repair mechanisms following the rupture of the OSE after ovulation and may contribute to EOC metastasis. We have shown that the treatment of EOC cells with BMP4 results in altered cell morphology characterized by increased cell spreading. We hypothesize that BMP4 signaling induces changes in cell morphology, adhesion and migration by altering the cytoskeleton, integrin receptors and ECM. Methods Primary human EOC cells were left untreated or grown in the presence of 10 ng/mL BMP4 for 7 days. Cytoskeletal changes were visualized through staining of filamentous actin (F-actin), while integrin receptor and focal adhesion protein localization was observed by immunofluorescence. Quantitative PCR was used to assess mRNA levels of integrin receptors, focal adhesion proteins and ECM proteins. Motility of EOC cells in response to BMP4 was evaluated using an in vitro wounding assay while cell adhesion was observed using a tritiated amino acid incorporation assay. Results Consistent with cell spreading, increased stress fiber formation occurred in response to BMP4 treatment. In addition, localization of vinculin to an apparent greater number of focal contacts along with colocalization to actin stress fibers was observed. Changes in the staining pattern of integrins α3, α5, αV and β1 were seen with BMP4 treatment. Quantitative PCR analysis showed modest increases in integrin receptor and focal adhesion protein mRNA after 7 days of treatment, while marked increases in collagen I, collagen IV and filamin mRNA levels were seen as early as 24hrs following BMP4 treatment. EOC cells demonstrated increased motility in the presence of BMP4, while showing decreased cell adhesion. Conclusions Taken together, this data shows that BMP4 can induce changes in molecules involved in cell morphology, adhesion and motility, translating into changes in cellular behavior. Future work will examine these behaviors with BMP4 treated EOC cells in response to culture on various ECM substrates, and comparison with normal OSE samples. These experiments will enhance our understanding of how BMP4 signaling may contribute to metastasis.
The role of next-generation sequencing (NGS) to integrate identified genomic alterations (GA) into cancer treatment decisions in gastrointestinal (GI) tumors.
Authors: Madappa N. Kundranda, Donald Peter Braun, Kim Kramer, Edgar Donald Staren, Brad Tan, Bruce G. Gershenhorn, Eiko Klimant, Brion Vincent Randolph, Maurie Markman
Journal: Journal of Clinical Oncology (2014)

e22115 Background: GI cancers account for about 20% of all cancers diagnosed in the US. Therapeutic options in relapsed/refractory disease are limited and the outcomes are poor. Advanced therapeutic approaches including integrating NGS in treatment decisions could be a possible consideration. Methods: A retrospective chart review was performed on all GI patients (pts) evaluated with NGS through Foundation One (Foundation Medicine Inc., MA) to assess for GA for which therapies could be initiated. Results: Between Nov 2012 - Dec 2013; 278 pts with gastric and GE junctional (GGE) (n=67, 24%), pancreatic (PC) (n=47, 15%), hepatobiliary (HB) (n=30, 11%) and colorectal (CR) (n=140, 50%) had NSG testing. 271 (97%) of the total cohort had GA; 43% were females; median age was 54yrs (range: 20-81).GA were reported in 144 genes with the most common being TP53 64%; KRAS 50%; APC 39%; CDKN2A 15%; PIK3CA 14%; SMAD4 12%; MYC 9% and CCND1 8%. Distribution of the 3 most common GA by tumor type were: GGE - TP53 58%; KIT 36%; CARD11 18%. PC - KRAS 80%; TP53 71%; CDKN2A 29%. HB - CDKN2A 30%; TP53 27%; MCL1 23%. CR - APC 76%; TP53 72%; KRAS 56%. Of the 271 pts who harbored >1 GA; 34 % had an FDA approved drug for the same cancer; 75% had an FDA approved drug for another cancer type; 33% had an FDA approved drug for same cancer type and also had an FDA approved drug in another cancer type and 95% had a potential clinical trial available. Thus, 73% (n=207/278) had an ‘actionable’ GA. In this cohort of 271 pts, 9 pts were treated: 5 are currently on treatment with clinical responses (CR, PR or SD); 3 had progression; and 1 is currently enrolled in a clinical trial. The median follow up on these 9 pts is <4 months. Conclusions: NGS was successful in identifying ‘actionable’ GA 73% of the time. Even with FDA approved drugs; barriers to specific therapies not being instituted include: 1) having received it already 2) unavailability of the drug 3) lack of insurance coverage 4) decision of the treating physician and 5) patient preference. The role of genomic profiling to tailor cancer therapy is rapidly evolving and needs prospective follow up of patients on treatment to determine the utilization benefit in treating cancer patients.
Prospective assessment of neurocognitive outcomes in children and young adults with progressive/residual benign and low-grade brain tumors treated with high-precision conformal or conventional radiotherapy: Results of a randomized clinical trial.
Authors: Rakesh Jalali, Tejpal Gupta, Uday Krishna, Savita Goswami, Jayita Deodhar, Debnarayan Dutta, Sadhna Kannan, Atul Goel, Rajiv Sarin
Journal: Journal of Clinical Oncology (2014)

2035 Background: Evidence for modern conformal partial brain radiotherapy is largely on retrospective or small case-series. We report longitudinal detailed neuropsychological outcomes from a prospective randomized trial comparing high-precision conformal radiotherapy (CRT) versus conventional radiotherapy (Conv RT) in children and young adults with progressive/residual benign and low-grade brain tumors (NCT00517959). Methods: Between 2001-10, 200 patients (132 males, 68 females; median age 13 years) were randomized to receive CRT (n=105; multiple non-coplanar fields using micromultileaf collimators under stereotactic guidance) or Conv RT (n=95; 2-4 open fields and beam modification) by 6 MV to dose of 54 Gy/30 fractions. Age-appropriate battery included full-scale IQ (FSIQ), verbal quotient (VQ), performance quotient (PQ), memory quotient (MQ>16 years of age) by Wechsler scores, LOTCA and anxiety-depression tests. Serial evaluations were done at pre-RT, 6-months and 2, 3 and 5 years and analyzed using generalized linear-mixed model (GLMM). Results: The most common histology was craniopharyngioma and low-grade astrocytoma. Baseline characteristics were well balanced between two arms. A substantial proportion of patients had low intelligence (FSIQ <69) in both arms (CRT-17%; Conv RT-16%) before RT. GLMM for repeated measures demonstrated significantly better preservation of FSIQ over time in patients treated with CRT compared to Conv RT at 3 year (p=0.003) and 5 year post-RT evaluation (p=0.012,Hyunh-Feldt test), as also in VQ (p=0.047) and MQ (p=0.049). Decline in LOTCA scores at 5-years (mainly in visuo-motor organization and attention-concentration) was significantly higher in Conv RT than CRT (p=0.019). Children <16 years had lesser depression in conformal arm (p=0.01) with no differences in anxiety between two arms. Conclusions: Our randomized trial provides high-quality evidence supporting use of high-precision conformal radiotherapy in children and young adults with progressive and residual benign and/or low-grade brain tumors. Clinical trial information: NCT00517959.