tbuckley/cabot-search huggingface dataset:
Natural history of clinical complete response to neoadjuvant chemotherapy for urothelial carcinoma of the bladder: Updated single-institution experience.
Authors: Justin T. Matulay, Marissa C. Velez, Ifeanyi Onyeji, Alexa R. Meyer, Arindam RoyChoudhury, Mitchell C. Benson, Sven Wenske, Christopher B. Anderson, James M. McKiernan, Guarionex Joel DeCastro
Journal: Journal of Clinical Oncology (2016)

4537 Background: Approximately 30-40% of patients with muscle-invasive bladder cancer (MIBC) who undergo neoadjuvant chemotherapy (NAC) have a complete pathologic response at radical cystectomy. It is unknown if patients identified via endoscopic evaluation as complete responders can safely undergo surveillance. We describe our updated experience with a cohort of such patients. Methods: Retrospective review of 44 patients with proven MIBC (≥cT2) and clinical complete response (cCR) to NAC. Each patient underwent platinum based NAC and cCR was defined as negative urine cytology, normal TURBT, and normal cross-sectional imaging. Patients were followed post-NAC with cytology, cystoscopy with biopsy, and cross-sectional imaging. Results: Mean age of the cohort was 67.2 ± 9.6 years with a median follow-up of 37.4 ± 38.3 months. The NAC regimens were: MVAC 47.7% (21), gemcitabine/cisplatin 31.8% (14), other 18.2% (7), and unknown 2.3% (1). Table 1 summarizes the clinical stage and outcomes of the cohort. Kaplan-Meier analysis shows a 5-yr cancer-specific survival (CSS) for the immediate and non-immediate RC groups of 87.5% vs. 100%, p=0.182, respectively. The overall mean CSS is 134.1 ± 10.2 months. The mean CSS for immediate RC versus non-immediate RC is 134.1 months and 99.4 months, respectively, but the difference is not statistically significant. Conclusions: In a highly select subgroup of patients who have no evidence of measurable disease following NAC for MIBC, vigilant surveillance results in a 57% chance of avoiding radical surgery and an overall survival of 72.7% after a median follow-up of 38.5 months. Future studies should focus on identifying the clinical, pathologic, and molecular factors associated with a durable complete response. Clinical stage and post-cT0 outcomes. Immediate Cystectomy Delayed Cystectomy Recurrence with Bladder in situ Bladder preserved, NED No. pts 8 11 11 14 Pre-NAC clinical stage (No. pts) cT2 (8) cT3 (1), cT2 (10) cT2 (11) cT3 (1). cT2 (13) Median days from MIBC diagnosis to NAC (range) 55 (5-103) 20 (1-78) 27 (3-121) 47 (11-118) No. death/total No. 4/8 4/11 3/11 1/14 No. cancer related death/total No. 2/8 3/11 0/11 0/14
Epididymal Cystadenomas in von Hippel-Lindau Disease Showing Increased Activity on 68Ga DOTATATE PET/CT
Authors: Georgios Z. Papadakis, Corina Millo, Samira M. Sadowski, Ulas Bagci, Nicholas J. Patronas
Journal: Clinical Nuclear Medicine (2016)

von Hippel-Lindau (VHL) disease is a familial cancer syndrome characterized by the development of a variety of malignant and benign tumors, including epididymal cystadenomas. We report a case of a VHL patient with bilateral epididymal cystadenomas who was evaluated with Ga DOTATATE PET/CT, showing intensely increased activity (SUVmax, 21.6) associated with the epididymal cystadenomas, indicating cell-surface overexpression of somatostatin receptors. The presented case supports the usefulness of somatostatin receptor imaging using Ga DOTA-conjugated peptides for detection and follow-up of VHL manifestations, as well as surveillance of asymptomatic gene carriers.
Cost-effectiveness of neoadjuvant (NeoAdj) versus adjuvant (Adj) therapies for resectable pancreatic cancer (PC).
Authors: R. T. Shroff, M. M. Javle, S. Krishnan, S. B. Cantor, J. E. Lee, J. B. Fleming, G. R. Varadhachary, J. L. Abbruzzese, R. A. Wolff, L. S. Elting
Journal: Journal of Clinical Oncology (2010)

4125 Background: The median survival (MS) after resection for localized PC is 18 mos. An estimated 60 % of resected patients (pts) receive Adj therapy. The standard of care in the US is Adj chemotherapy (CT) + radiation therapy (RT) whereas in Europe, it is AdjCT. Our institutional standard is NeoAdj CT+RT because it enables early treatment of micrometastases, avoids surgery for pts with aggressive tumor biology and may improve the margin negative resection rate. MS of pts who progress on NeoAdj CT+RT is 7 mos vs. 34 mos for pts who undergo resection; overall (intent-to-treat) MS is 22 mos for NeoAdjCT+RT (J Clin Oncol 2008; 26:3496). SEER Medicare data with PC reported a MS of 23 mos with NeoAdj RT vs. 17 mos with Adj RT (IJROBP 2008;72:1128). No prospective randomized trials (RCTs) have compared the effectiveness or cost of these regimens. Methods: We constructed a decision-analytic model of costs and effectiveness of 4 regimens: 1) NeoAdj weekly gemcitabine (Gem) + EBRT 50.4 Gy; 2) the same regimen with EBRT 30 Gy; 3) AdjCT+RT (per RTOG 9704); 4) Adj Gem (per ESPAC-3). Effectiveness was measured as MS (from large, published cohort and clinical studies). Cost was measured from the payer's (Medicare) perspective in 2009 US dollars and included pancreatic resection and its complications (from the National Inpatient Sample), CT (average wholesale price + 6%), RT (Medicare allowable cost), and continuing and palliative care (from published literature). Physician fees were not included. A standard benchmark of $100,000/life-year (LY) gained was used to determine cost-effectiveness. Results: The estimated cost of the AdjCT regimen was $74,649. The addition of RT to AdjCT resulted in an incremental cost of > $5,000 without survival benefit. The MS figure with NeoAdj therapy exceeded that with AdjCT by 4 mos with incremental costs of $30,028 (50.4 Gy) and $15,566 (30 Gy) per LY gained. Thus both regimens compared favorably to AdjCT. This finding was not sensitive to variation in Medicare allowable RT costs. Conclusions: While analysis is limited by a lack of RCTs comparing the regimens, our results (based on published reports) suggest that NeoAdjCT + RT in resectable PC may be cost-effective as compared with AdjCT and AdjCT+RT. No significant financial relationships to disclose.
Abstract 2536: Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines
Authors: Elliott Kahen, Diana Yu, Christopher Cubitt, Dan Sullivan, Damon R. Reed
Journal: Cancer Research (2015)

Abstract Background: Malignant Peripheral Neural Sheath Tumors (MPNST) are a type of sarcoma that arise spontaneously from a peripheral nerve or plexiform neurofibroma. Approximately 1 in 10 people with a constitutional mutation in the NF1 gene, a negative regulator of RAS function, develop MPNST with a peak incidence in the adolescent and young adult years. Available chemotherapy treatment for MPNST has low response rates, and the prognosis for unresectable or metastatic tumors is poor. A clinically relevant system to rapidly evaluate the efficacy of many agents and combinations of agents on MPNSTs which can be translated into clinical trials is needed. Methods: Here, we seek to identify promising single drug and combination therapies using FDA approved and other agents of interest via high-throughput screening platforms, based on established MPNST cell line models (SNF02.2, SNF10.1, SNF94.3, and SNF96.2). Taking into consideration past lessons learned from in vitro experiments, we designed stringent screening conditions that assess the candidate compounds and combinations at clinically-relevant concentrations and exposure times that mimic the in vivo pharmacokinetics in an effort to maximize the translational potential of these results. Fifty-four agents with roughly ¼ inhibitors of the RAS downstream pathways, another ¼ kinase inhibitors, and the remainder a representation of many classes of agents with diverse mechanisms of action were screened across 4 cell lines with biological replicates. The majority of the agents are FDA approved. Others are in active clinical trials, demonstrate a promising mechanism of action, or have published preclinical data in MPNST models. CellTiter Glo assays were used to assess cell viability at the maximal achievable serum concentration from phase I studies and at two lower concentrations. Promising agents were then studied in two-drug combinations to evaluate for synergy in addition to efficacy of the combination. The combinations were selected with careful attention to known drug-drug interactions, metabolism, schedule and non-overlapping toxicities. Results: Our screening results indicate that a number of FDA approved chemotherapy agents, evaluated at clinically relevant concentrations and exposure times, significantly reduced cell viability across all cell lines tested. These findings suggest promising opportunities for developing combination clinical trials. Citation Format: Elliott Kahen, Diana Yu, Christopher Cubitt, Dan Sullivan, Damon R. Reed. Assessing combinations of FDA approved chemotherapy in malignant peripheral nerve sheath tumor (MPNST) cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2536. doi:10.1158/1538-7445.AM2015-2536
Abstract 3944: Combining tumor glypican-3 expression and CD16 Expression on NK cells from peripheral blood to identify patients responding to codrituzumab/GC33/RO5137382
Authors: Gong Chen, Ya-Chi Chen, Bernhard Reis, Anton Belousov, Lori Jukofsky, Christine Rossin, Axel Muehlig, Chao Xu, Laurent Essioux, Toshihiko Ohtomo, Laura Di Laurenzio, Oscar Puig, Ray Lee
Journal: Cancer Research (2016)

Abstract Background &amp; Aims: Codrituzumab (GC33 or RO5137382), a monoclonal antibody targeting an oncofetal protein glypican-3 (GPC3) expressed on the cell surface of hepatocellular carcinoma (HCC), induces antibody-dependent cellular cytotoxicity (ADCC) and inhibits tumor growth in preclinical studies. Based on this mechanism of codrituzumab, two biomarkers GPC3 and CD16 of the NK cells, which are the effector cells of ADCC, were investigated to correlate with clinical efficacy of codrituzumab in patients with advanced HCC. Methods: Data from a phase II clinical trial of codrituzumab were used for this analysis. GPC3 expression was determined by immunohistochemistry (IHC) analysis of tumor biopsies, and CD16 expression on NK cells were quantified by a flow cytometry analysis of peripheral blood mononuclear cells. Overall survival of patients with high exposure of codrituzumab or placebo (n = 113) was used to compare different patient subgroups stratified by high or low expression of GPC3 and CD16. Results: In individual-biomarker analyses, longer survival after codrituzumab treatment correlates with either high expression level of GPC3 in tumors (n = 97, HR = 0.39, 95%CI = 0.21 - 0.70, p = 0.00081) or a relatively high level of CD16 expressed on NK cells (n = 80, HR = 0.44, 95%CI = 0.23 - 0.83, p = 0.0056) at baseline. Furthermore, joint analyses of the two biomarkers reveal that both high levels of GPC3 and CD16 are required for patients to benefit from codrituzumab treatment (n = 67, HR = 0.29, 95%CI = 0.13 - 0.62, p = 0.00074), and lack of either one of them leads to a loss of codrituzumab therapeutic effect. Conclusions: The retrospective analysis supports the mechanism of ADCC, in which the combination of high GPC3 expression in tumors and high CD16 expression in NK cells from peripheral blood is associated with prolonged overall survival given treatment of codrituzumab. This result supports the usage of both GPC3 and CD16 as potential biomarkers to select HCC patients for codrituzumab treatment. Citation Format: Gong Chen, Ya-Chi Chen, Bernhard Reis, Anton Belousov, Lori Jukofsky, Christine Rossin, Axel Muehlig, Chao Xu, Laurent Essioux, Toshihiko Ohtomo, Laura Di Laurenzio, Oscar Puig, Ray Lee. Combining tumor glypican-3 expression and CD16 Expression on NK cells from peripheral blood to identify patients responding to codrituzumab/GC33/RO5137382. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3944.
Prevalence of Prediabetes and Type 2 Diabetes in Children With Nonalcoholic Fatty Liver Disease
Authors: Kimberly P. Newton, Jiayi Hou, Nancy A. Crimmins, Joel E. Lavine, Sarah E. Barlow, Stavra A. Xanthakos, Jonathan Africa, Cynthia Behling, Michele Donithan, Jeanne M. Clark, Jeffrey B. Schwimmer
Journal: JAMA Pediatrics (2016)

<h3>Importance</h3> Nonalcoholic fatty liver disease (NAFLD) is a major chronic liver disease in children in the United States and is associated with insulin resistance. In adults, NAFLD is also associated with type 2 diabetes. To our knowledge, the prevalence of type 2 diabetes in children with NAFLD is unknown. <h3>Objective</h3> To determine the prevalence of type 2 diabetes and prediabetes in children with NAFLD and assess type 2 diabetes and prediabetes as risk factors for nonalcoholic steatohepatitis (NASH). <h3>Design, Setting, and Participants</h3> This was a multicenter, cross-sectional study at 12 pediatric clinical centers across the United States participating in the National Institute of Diabetes and Digestive and Kidney Diseases NASH Clinical Research Network. Children younger than 18 years with biopsy-confirmed NAFLD enrolled in the NASH Clinical Research Network. <h3>Main Outcomes and Measures</h3> The presence of type 2 diabetes and prediabetes as determined by American Diabetes Association screening criteria using clinical history and fasting laboratory values. <h3>Results</h3> There were 675 children with NAFLD included in the study with a mean age of 12.6 years and mean body mass index (calculated as weight in kilograms divided by height in meters squared) of 32.5. Most of the children were boys (480 of 675) and Hispanic (445 of 675).The estimated prevalence of prediabetes was 23.4% (95% CI, 20.2%-26.6%), and the estimated prevalence of type 2 diabetes was 6.5% (95% CI, 4.6%-8.4%). Girls with NAFLD had 1.6 (95% CI, 1.04-2.40) times greater odds of having prediabetes and 5.0 (95% CI, 2.49-9.98) times greater odds of having type 2 diabetes than boys with NAFLD. The prevalence of NASH was higher in those with type 2 diabetes (43.2%) compared with prediabetes (34.2%) or normal glucose (22%) (<i>P</i> &lt; .001). The odds of having NASH were significantly higher in those with prediabetes (OR, 1.9; 95% CI, 1.21-2.9) or type 2 diabetes (OR, 3.1; 95% CI, 1.5-6.2) compared with those with normal glucose. <h3>Conclusions and Relevance</h3> In this study, nearly 30% of children with NAFLD also had type 2 diabetes or prediabetes. These children had greater odds of having NASH and thus were at greater long-term risk for adverse hepatic outcomes.
CRISPR/Cas9 Screens Reveal Requirements for Host Cell Sulfation and Fucosylation in Bacterial Type III Secretion System-Mediated Cytotoxicity
Authors: Carlos J. Blondel, Joseph S. Park, Troy P. Hubbard, Alline R. Pacheco, Carole J. Kuehl, Michael J. Walsh, Brigid M. Davis, Benjamin E. Gewurz, John G. Doench, Matthew K. Waldor
Journal: Cell Host & Microbe (2016)
The Role of a Vascular Surgeon
Authors: Ying Wei Lum, James H. Black
Journal: JAMA Surgery (2016)

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A Case of Euglycemic Diabetic Ketoacidosis Following Long-term Empagliflozin Therapy
Authors: Peter D. Farjo, Kacie M. Kidd, Josephine L. Reece
Journal: Diabetes Care (2016)

In 2015, the U.S. Food and Drug Administration (FDA) released a statement associating the use of sodium–glucose cotransporter 2 (SGLT2) inhibitors and the incidence of diabetic ketoacidosis (DKA) in cases with relatively normal or mildly elevated glucose levels (euglycemic DKA [euDKA]) (1). This warning along with a review of more recent publications reveals possible triggers of this complication (2–4). Our report highlights a case of euDKA in a patient with type 2 diabetes, after over 6 months of empagliflozin treatment, presenting in respiratory alkalosis with krill oil use as a possible precipitating factor.

A 57-year-old man with a 10-year history of type 2 diabetes presented to the emergency room with lightheadedness. He had been using empagliflozin alone for 189 days, decreasing his HbA1c from 7.0% …
Prognostic factors in the treatment of mild hypertension. The Management Committee of the Australian National Blood Pressure Study.
Journal: Circulation (1984)

In the Australian therapeutic trial in patients with mild diastolic hypertension, univariate analysis of possible prognostic characteristics (covariates) at the time of entry into the study showed a higher incidence of trial end points, mainly events due to ischemic heart disease and cerebrovascular disease, in older subjects, men, cigarette smokers, and those with higher systolic blood pressures and lower body mass indexes than in their complementary groups. There was a lower incidence of these events in actively treated subjects than in control subjects at both high and low levels of incidence of each covariate considered, but treatment benefit was most marked in those with lower serum cholesterol levels and lower systolic blood pressures. Multivariate regression analyses of data from men and women separately, performed with the Cox proportional-hazards model, confirmed that the incidence of trial end points increased with age and with systolic blood pressure, and showed higher rates in cigarette smokers, which increased markedly with decreasing body weight. With respect to the effects of treatment, the multivariate analysis showed an increasing benefit with decreasing body weight in smokers. The apparent relationship of treatment benefit to systolic blood pressure in the univariate analysis did not reach statistical significance in the multivariate analysis. The greater benefit from treatment related to lower levels of serum cholesterol found in the univariate analysis was also found in several preliminary multivariate analyses, but did not reach statistical significance in the final model. However, this relationship should be tested in other therapeutic trials in progress or recently completed.(ABSTRACT TRUNCATED AT 250 WORDS)
High-Dose Therapy in AL Amyloidosis: A Prospective Phase II Study by the Dutch-Belgian Cooperative Group (HOVON)
Authors: Bouke P.C. Hazenberg, Sandra Croockewit, Ron van der Holt, Sonja Zweegman, Gerard Bos, Peter Vandenberghe, Pieter Sonneveld, Jan J. Cornelissen, Edo Vellenga, Pierre W. Wijermans, Roelof Willemze, Marinus H.J. Van Oers, Okke de Weerdt, Fokje M. Spoelstra, Henk Lokhorst
Journal: Blood (2008)
Venous thromboembolism in metastatic urothelial carcinoma.
Authors: Patrik Palacka, Jan Luha, Michal Mego, Viera Stvrtinova, Zuzana Sycova-Mila, Jana Obertova, Daniela Svetlovska, Katarina Rejlekova, Michal Chovanec, Jozef Mardiak
Journal: Journal of Clinical Oncology (2016)

e16029 Background: Cancer is established risk factor for development of venous thromboembolism (VTE). Objective of this study was to identify prevalence of VTE in patients (pts) with metastatic urothelial carcinoma (MUC) and to determine its impact on overall survival depending on prognostic factors (Karnofsky index ˂ 80%, presence of visceral metastases). Methods: From January 2000 to September 2015, 209 pts (49 women, 23.4%) with MUC (bladder 173 pts, renal pelvis 25 pts, ureter 5 pts, and e loco ignoto6 pts) treated with first-line platinum-based chemotherapy were enrolled in this study. Median age was 65 years (range 37–86 years), median metastatic sites was 2 (range 1–5), median Karnofsky index was 90% (range 40–100%). Overall survival (OS) was estimated by Kaplan-Meier method and groups were compared by log rank test (Mantel-Cox). Results: In this study, totally 42 (20.1%) VTE events were established including 13 (31.0%) PE (pulmonary embolism) and 30 DVT (deep vein thrombosis) cases (71.4%). Symptomatic VTE events were identified in 28 pts (66.7%). Median OS was better in pts without VTE vs pts with VTE [10.4 months (95% CI 8.9-11.8) vs9.5 months (95% CI 6.8-12.3), P = 0.071]. In subgroup analysis, pts with Karnofsky index (KI) ˂ 80% without VTE had significantly better OS compared to pts with VTE (median OS not reached vs 2.1 months, < 0.0001). However, VTE was not associated with survival in pts with KI ≥ 80% or based on presence of visceral metastases. Conclusions: This study showed high prevalence of VTE events in MUC patients treated with first-line platinum-based chemotherapy. VTE led to significant decrease of overall survival in patients with Karnofsky index ˂ 80%. In this subgroup, prevention of VTE seems to be reasonable.
Different Mutant Splicing Factors Cause Distinct Missplicing Events and Give Rise to Different Clinical Phenotypes in Myelodysplastic Syndromes
Authors: Yusuke Shiozawa, Luca Malcovati, Aiko Sato-Otsubo, Anna Gallì, Kenichi Yoshida, Tetsuichi Yoshizato, Yusuke Sato, Keisuke Kataoka, Masashi Sanada, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Satoru Miyano, Eva Hellström Lindberg, Seishi Ogawa, Mario Cazzola
Journal: Blood (2015)