tbuckley/cabot-search huggingface dataset:
Impact of zoledronate on FMAU positron emission tomography (PET) scanning results in metastatic prostate cancer.
Authors: Omid Saeed Tehrani, Ulka N. Vaishampayan, Jawana Lawhorn-Crews, Lance K. Heilbrun, Kimberlee Dobson, Daryn W. Smith, Brenda Dickow, Anthony Frank Shields
Journal: Journal of Clinical Oncology (2015)

e16069 Background: We conducted a pilot trial utilizing a [18F]FMAU [(1-(2′-deoxy-2′-fluoro-β-D-arabinofuranosyl)thymine] PET as a tumor tracer to evaluate its reproducibility and changes in maximum and mean standardized uptake value (SUVmax and SUVmean) with zoledronate therapy in castrate resistant prostate cancer (PC) with bone metastasis (BM). Methods: Eligible patients had PC with radiographic evidence of BM and creatinine clearance > 30 ml/min. Two baseline FMAU-PET scans (about 1 week apart, range 2 - 12 days) were obtained for testing reproducibility. Therapy started within 7 days of the second scan. Zoledronate, 4 mg IV was infused over 15 minutes and PET scan was obtained 7 days later. Bony lesion with highest uptake on the first scan was compared in later scans. Bone turnover markers and PSA were obtained pre and post therapy. Response was defined as decline in SUV of ≥ 15% after zoledronate. Results: 11 patients consented; median age 65 years; 5 African American and 6 Caucasians; median PSA level 113.7 ng/ml (range 1 - 1209.3). The median change in SUVmax between baseline scans was -10.5% (range -66.8% to +30.0%) and in SUVmean was -6.6% (range -47.3% to +56.8%). Regardless of the choice of SUV or baseline scan, uptakes were highly variable (Table 1). Overall zolendronate did not appreciably change FMAU uptake. PSA declined in 4 patients, with maximum drop of 34%. Urine N- telopeptide was markedly decreased in all patients. Bone alkaline phosphatase changed minimally: median -0.2% (-7.3% to +10.8%). Conclusions: FMAU tracer was able to detect bone metastases in PC. Zoledronate did not produce an appreciable change in scans. Response determination with other novel therapies is ongoing. Clinical trial information: NCT01205646.Median percent change in SUV, its range, and PET response rate. Reproducibility Pre/post zolendronate treatment comparison Scan 2 vs. Scan 1 Scan 3 vs. Scan 1 Scan 3 vs. Scan2 SUVmax ≥15% decline -10.5% (-66.8% to +30.0%) 3 (27%) -10.1% (-43.8% to +54.8%) 3 (27%) +7.3% (-32.2% to +33.5%) 2 (18%) SUVmean ≥15% decline -6.6% (-47.3% to +56.8%) 3 (27%) -8.9% (-44.6% to +82.6%) 4 (36%) +5.2% (-29.3% to +29.9%) 1 (9%)
Consequences of passages: Mitotic indices and centrosome amplification levels variance between patients’ tumors and cancer cells cultured in vitro.
Authors: Vaishali Pannu, Shashi Donthamsetty, Karuna Mittal, Padmashree C.G. Rida, Guilherme Henrique Cantuaria, Michelle D. Reid, Xiaoxian Li, Ritu Aneja
Journal: Journal of Clinical Oncology (2015)

e13518 Background: The correct choice of preclinical model is absolutely vital for the success of anticancer drugs in clinical trials. Recently, mitosis-targeting drugs performed dismally in human trials. This calls into question the validity of mitosis as a “druggable target” and underscores the need to examine other cancer-specific targets and better preclinical testing models. Methods: Using indirect immunofluoresence confocal imaging, we compared the number of mitotic figures (phosphohistone H3 staining) and centrosome amplification (CA) (γ-tubulin staining), in 20 paraffin-embedded clinical cancer specimens (breast, pancreas and bladder), immortalized cancer cell lines (MDA-MB-231-breast, MiaPaCa-pancreas and T24-bladder) and a patient derived cell line (breast). We further tested the susceptibility of patient derived cell line to centrosome declustering drugs like CW069 and Griseofulvin. Results: While clinical specimens showed < 2% of cells in mitotic phase, mitotic cells ranged from 5-20% in in vitro cultured cells. In contrast, CA ranged from 40-50% in clinical tumor samples as opposed to 5-15% in cell culture. Patient-derived tumor cells displayed high degree of CA (~50%) only at low passage number and the extent of CA alarmingly decreased with increase in passage number. Furthermore, lower passage number cells were more susceptible to centrosome declustering drugs compared to high passage number cells. This is the first report to substantiate mitotic and centrosomal incongruity between various model systems ranging from human tumors, patient-derived primary cell lines, and cancer cells in continuous culture. Conclusions: Here we demonstrate the previously unrecognized striking discordance in the extent of mitotic activity and CA between clinical tumor specimens and cancer cells cultured in vitro. Our findings emphasize that CA, a cancer-cell specific trait, could be a superior therapeutic target for cancer therapy. Furthermore, we highlight the importance of low-passage patient-derived cell line system as most representative of the clinical scenario and a good preclinical model for testing centrosome-targeting drugs.
The natural history, treatment pattern, and survival of the patients with sarcomatoid bladder carcinoma: A pooled analysis.
Authors: Midhun Malla, Jue Wang
Journal: Journal of Clinical Oncology (2015)

e15532 Background: Sarcomatoid bladder carcinoma (SRBC) is a rare variant of urothelial cancer. Current data is limited on clinical features, appropriate management and outcomes. Methods: A retrospective review of our experience of managing SRBC was performed in conjunction with a systematic literature search.Literature review was performed on the MEDLINE database using the key words ‘bladder cancer’, ‘sarcomatoid carcinoma’, ‘carcinosarcoma’, ‘diagnosis’, ‘treatment’, and ‘prognosis’. Clinical characteristics, treatment, and survival were compared between the cohorts from SEER and single institutional cohorts. Results: No clinical trials on SRBC were reported in the English literature so far.Two SEER registry and thirteen single institution retrospective studies have been identified. The final cohort for the study included 835 patients: 522 from two registry studies and 313 from 13 case series. Five single institution studies contained adequate clinical follow up information. SRBC usually presented in sixth to seventh decades (age range: 30-91) and was more common in males (M:F 1.3-16:1). Gross hematuria (70-100%) was the most common symptom. Both population and case series showed that these patients present with a high grade tumor, advanced stage and was associated with poor prognosis. Tumor stage was identified as the significant predictor for cancer-specific survival in UNMC, Mayo, Turkey studies and one of the SEER studies (Wang et al). In UNMC series, aggressive multimodality therapy lead to a better cancer control and improved survival. Significant differences existed in the demographic characteristics (age at diagnosis, M:F ratio), tumor stage, treatment pattern (rate of cystectomy, radiation and chemotherapy), and median survival, when comparing single-institution studies to the SEER cohorts, likely reflecting differences in practice patterns. Conclusions: Patients diagnosed with this rare, aggressive malignancy should be referred to a cancer center with an extensive experience in the management of SRBC. The results of this analysis help to increase awareness of this rare malignancy and serve as a baseline for future clinical studies.
Reproducibility of homologous recombination deficiency (HRD) scores in biopsies of triple negative breast cancer (TNBC) tumors.
Authors: Kirsten Timms, Anees B. Chagpar, Vikram Wali, Veerle Bossuyt, Julia E. Reid, Alexander Gutin, Christopher Neff, Erin Wysong Hofstatter, Jerry S. Lanchbury, Lajos Pusztai
Journal: Journal of Clinical Oncology (2015)

1091 Background: The HRD score is the sum of three previously described (Abkevich et al, Birkbak et al, Popova et al) metrics that quantitate genomic rearrangements. The HRD score is significantly associated with both tumor BRCA1/2 mutations (tmBRCA) and response to DNA damaging agents in TNBC. This study assesses the consistency of the HRD score in multiple biopsies obtained from the same cancer to examine the impact of spatial heterogeneity and sampling on the results. Methods: HRD scores, tmBRCA, and BRCA1 promoter methylation were assessed in 96 samples from 32 surgically resected, stage II-III breast cancers; each cancer was biopsied in three distinct areas. HR deficiency was defined as having either high HRD score ( ≥ 42) or tmBRCA positive. Results: A total of 81 samples (31 tumors) yielded DNA for sequencing and generated 81 tmBRCA calls and 76 BRCA1 methylation values passing QC metrics. HRD scores were obtained for 70 (86%) samples, leaving 16 triplets and 7 duplicates available for reproducibility analysis, and 8 singles. High HRD scores were observed in all biopsies that were tmBRCA positive (3 triplets; 1 single) or BRCA1 methylation positive (2 triplets). BRCA1/2 mutation and BRCA1 methylation were consistent within all replicates. BRCA1/2 wild type tumors without BRCA1methylation had high HRD scores in 4 tumor sets (1 triplet; 3 pairs). The average standard deviation (SD) within replicates was 2.6 with a coefficient of variation (CV) of 9%. SD was slightly higher in samples with higher scores but the difference between low and high HRD scores was not significant (Wilcoxon p = 0.18). HR deficiency status was the same in different biopsies from each of the 31 tumors; however, observable differences were apparent between the genomic profiles. Conclusions: All HRD metrics examined were consistent across the multiple repeat biopsies from different regions of the same cancer. While observable changes in the genomic profiles of matched samples were noted indicating subtle within-tumor spatial genomic heterogeneity, the HRD scores were highly conserved.
Abstract P403: Role of Modifiable and Non-modifiable Risk Factors in the Association of Kidney Function With Stroke Risk in Multi-ethnic Study of Atherosclerosis (MESA)
Authors: Sanaz Sedaghat, Michael Bancks, Ian H. de Boer, Holly Kramer, Orlando Gutierrez, WT Longstreth, Kiarri N. Kershaw, Mercedes Carnethon
Journal: Circulation (2019)

Introduction: Persons with chronic kidney disease have up to 8 times higher risk of stroke. A role for shared vascular risk factors, such as aging, sex, hypertension, and diabetes has been implicated in this association. We aim to explore the contribution of non-modifiable and modifiable vascular risk factors to this association. Hypothesis: We hypothesize that non-modifiable and modifiable vascular risk factors could explain part, but not all, of the association between kidney function and incidence of stroke. Methods: We included 6404 participants (mean age 62 yrs, 51% women, 38% white). Kidney function was assessed by estimated glomerular filtration rate (eGFR) and albumin-to-creatinine ratio (ACR). Participants were followed for an average of 12±4 yrs for incidence of stroke. Multiple Cox regression models, adjusted for baseline non-modifiable (age, sex and race) and modifiable (BMI, smoking, SBP, diabetes, cholesterol, alcohol intake, physical activity, and healthy diet score) risk factors were used to estimate the association of kidney function with incidence of stroke. Results: During follow-up, 284 (4.4%) fatal and non-fatal stroke cases were adjudicated. Among them, 233 (3.6%) were non-fatal stroke. Non-modifiable vs. modifiable risk factors were associated with greater reduction in HRs from a crude model for association of each SD lower eGFR with risk of stroke. (25% vs. 12% for non-fatal and 33% vs. 14% for all stroke). Non-modifiable vs. modifiable risk factors were associated with a lower reduction in HRs from a crude model for association of doubling ACR with risk of stroke (6% vs. 12% for both non-fatal and all stroke) (Figure). After adjusting for all factors, worse kidney function remained associated with risk of stroke. Conclusions: Findings suggest that conventional modifiable and non-modifiable vascular risk factors do not fully explain the higher risk of stroke in relation to worse kidney function. This finding warrants exploring other potential novel mechanisms of this association.
Esophageal cancer in Israel: A unique clinicopathological entity?
Authors: Michal Sarfaty, Ofer Purim, Yulia Kundel, Olga Ulitsky, Nikolai Menasherov, Hanoch Kashtan, Aaron Sulkes, Baruch Brenner
Journal: Journal of Clinical Oncology (2015)

e15050 Background: Esophageal cancer (EC) comprises two histopathological subtypes: squamous cell carcinoma (SqCC), usually located in the upper 2/3 of the esophagus, and adenocarcinoma (AdenoCa), usually located in the lower 1/3 of the esophagus. While in western countries the incidence of SqCC tumors has declined with an increase in AdenoCas, it remains the leading histology in endemic areas such as Turkey, Iran, the former Soviet Union, and northern China. Data regarding EC in Israel are limited, mostly from registry reports, which lack individual patient information. The aim of this study was therefore to characterize EC in Israel, as compared with the Western world and endemic areas. Methods: This is a retrospective study of all consecutive EC patients treated at our institution between 1998 and 2010. Epidemiological and clinicopathological data were retrieved from the patients’ medical files and the institutional electronic database and analyzed using standard statistical methods. Results: 137 EC patients were included in the study. 62.5% were males, 58.8% were Ashkenazi Jews, 30.8% were Sephardic Jews, and 0.7% were Arabs. The median age was 72 years (range: 36-92); 32% had a family history of cancer and 19.8% had second malignancies. SqCC was the dominant histology (58.8% versus 34.5% with AdenoCa), though 63.1% had distal tumors (including gastroesophageal junction). Unexpectedly, 55.3% of lower 1/3 tumors were SqCC and only 43% were AdenoCas. Most patients (59.9%) were diagnosed with advanced disease, either locally (36.5%) or with overt distant metastases (23.4%). With a median follow up of 58.5 months (range: 14-185.8 months), 103 patients (75.7%) had died of disease; median overall survival was 14.9 months, one-year survival was 62.9% and 3-year survival was 25%. Conclusions: Most features of EC in Israel, as depicted from our institutional database, are in accordance with the international literature on the disease. Still, the typical location and histological subtype observed in this study raise the possibility that EC in Israel represents a unique entity, not entirely identical to either the endemic or the Western disease subtypes. However, more data on EC in Israel are needed before the features of this entity are clearly defined.
Cholesterol-Lowering Agents
Authors: Savvas Hadjiphilippou, Kausik K. Ray
Journal: Circulation Research (2019)

Cardiovascular disease (CVD) remains the leading cause of death worldwide. To date, decades of research has established LDL-C (low-density lipoprotein cholesterol) as a causal factor in the development of atherosclerotic CVD. Statin therapy, supported by a broad evidence base, has demonstrated its superior efficacy in reducing LDL-C and subsequent cardiovascular risk. It therefore currently forms the mainstay of lipid-lowering therapy as recommended by international guidelines. Statin therapy is indicated in the secondary prevention of atherosclerotic CVD, as well as genetic causes of dyslipidemia (such as familial hypercholesterolemia). Although this strategy targets those most at risk, it merely addresses those most susceptible and does not account for the fact that most cardiovascular events occur in those at moderate to low risk. In addition, there is evidence for use in primary prevention such as in those with diabetes mellitus, chronic kidney disease, and high risk of future atherosclerotic CVD as determined by risk prediction calculators. Risk prediction tools, however, are far from perfect and do not accurately account for those at low short-term but high lifelong risk. Considering the log-linear relationship between LDL-C reductions and reductions in risk of atherosclerotic CVD, even in those at very low risk of future events, a clinical question posed is can we and should we shift the entire risk distribution by treating everyone? The present review discusses these issues in more detail outlining arguments for and against each approach.
The outcome of loco-regional radiotherapy in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate.
Authors: Berna Yildirim, Onal Cem, Fatih KOse, Ezgi Oymak, Ali Murat Sedef, Ali Ayberk Besen, Sercan Aksoy, Ozan Cem Guler, Ahmet Taner Sumbul, Huseyin Mertsoylu, Gokhan Ozyigit
Journal: Journal of Clinical Oncology (2019)

316 Background: To evaluate the potential benefit of curative radiotherapy (RT) to primary tumor in metastatic castration resistant prostate cancer (mCRPC) patients treated with abiraterone. Methods: The clinical parameters of 106 mCRPC patients treated with abiraterone in the either pre- or post-chemotherapy setting were retrospectively evaluated. All patients had PSA progression or radiographic progression suitable for metastasis according to the RECIST guidelines with or without PSA progression. Patients were either oligometastatic (≤5 metastases) at diagnosis or became oligometastatic after systemic treatment were analyzed. Local RT to primary tumor and pelvic lymphatics was delivered in 44 patients (41%), while 62 patients (59%) did not have RT to primary tumor. Results: Median follow-up times for patients overall and for those who survived were 14.2 months (range, 2.3–54.9 months) and median OS for entire cohort was 21.9 months. The median OS was significantly higher in patients treated with local RT to primary tumor compared to patients without local RT (p = 0.04). Local RT to prostate and pelvic lymphatics significantly diminished local recurrence rate ( p = 0.003). In univariate analysis, a decline in PSA levels ≥50% of baseline was significant prognostic factor for both OS and PFS in entire cohort and in patients receiving prostate RT. In multivariate analysis, PSA response ≥50 of baseline obtained ≥3 weeks after abiraterone therapy is the only significant prognostic factor for better OS and PFS. Additionally, local RT to prostate is nearly significant prognosticator for improved OS. Patients treated with primary RT to prostate had significantly less progression under abiraterone and longer abiraterone period compared to patients without local prostate RT. Conclusions: Local prostate RT significantly improves OS and local control but not PFS, in mCRPC treated with abiraterone. Patients treated with primary RT to prostate had significantly less progression under abiraterone and longer abiraterone period compared to patients without local prostate RT.
Hypoxia: Evaluating CAR‐T Cell Therapy in a Hypoxic 3D Tumor Model (Adv. Healthcare Mater. 5/2019)
Authors: Yuta Ando, Elizabeth L. Siegler, Hoang P. Ta, Gunce E. Cinay, Hao Zhou, Kimberly A. Gorrell, Hannah Au, Bethany M. Jarvis, Pin Wang, Keyue Shen
Journal: Advanced Healthcare Materials (2019)

Hypoxia is a feature of most solid tumor microenvironments. Chimeric antigen receptor T (CAR-T) cell therapy has not been successful in solid tumors, partially due to the tumor microenvironment. In article number 1900001 by Keyue Shen and co-workers, an in vitro hypoxic tumor model with an oxygen gradient is engineered, which allows for quantitative assessment of CAR-T cell cytotoxicity and infiltration under the heterogeneous oxygen landscape in solid tumors.
The role of radiomics in the preoperative diagnosis of renal cell carcinoma with sarcomatoid dedifferentiation (sRCC).
Authors: Chalairat Suk-Ouichai, Aikaterini Kotrotsou, Tagwa Idris, Srishti Abrol, Eric Umbreit, Andrew G. McIntosh, Christopher G. Wood, Rivka R. Colen, Jose A. Karam
Journal: Journal of Clinical Oncology (2019)

621 Background: sRCC is an aggressive renal malignancy, with poor survival and limited response to therapy. Preoperative identification of sRCC would be helpful for counselling patients, and clinical trial enrollment. This study aims at assessing the potential of radiomics to discriminate clear cell sRCC from non-sarcomatoid clear cell RCC (nsRCC). Methods: The study included 49 sRCC and 41 nsRCC patients treated with surgery between 2007-2016, who had contrast-enhanced CT available. An experienced radiologist delineated the entire tumor using 3D Slicer ( http://www.slicer.org ). The extracted 3D region of interest was imported in our in-house radiomic pipeline. A total of 310 features (10 histogram-based and 300 second-order features) were calculated. Second-order radiomic features were calculated using the Grey Level Cooccurrence Matrix (GLCM) and 20 Haralick features were obtained from the GLCM. To account for directionality, the mean, variance and range of the features across different directions were calculated. Finally, different number of gray levels were also considered in the analysis (N = 8, 16, 32, 64, 256). Core features were obtained using a feature selection based on Least Absolute Shrinkage and Selection Operator (LASSO). Selected features were used to build a classification model for prediction of sRCC versus nsRCC (XGboost). To evaluate the robustness of the estimates, Leave One Out Cross-Validation (LOOCV) was conducted on the patient set. Results: Overall, median tumor size was 10.0 cm and most patients had pT3a (68%). There was no significant difference of age, gender, race, tumor size and stages between sRCC and nsRCC cohorts. The prediction of sRCC using LOOCV was significant with p-value &lt; 0.0001. Area under the curve, sensitivity, and specificity for identification of sRCC were 96.8%, 92.6% and 93.8% respectively. Conclusions: This study demonstrates that CT radiomic features can accurately discriminate between sRCC and nsRCC. The proposed tool has the potential to advance clinical management strategies. In addition to being noninvasive, this methodology can be applied to scans obtained during routine clinical care. Further external validation is warranted.