tbuckley/cabot-search huggingface dataset:
Prognostic significance of lactate dehydrogenase-5 expression in patients with prostate cancer treated with androgen deprivation therapy and androgen receptor axis-targeted agents.
Authors: Wataru Fukuokaya, Takahiro Kimura, Mariko Honda, Hiroyuki Inaba, Kosuke Iwatani, Mori Keiichiro, Shun Sato, Hiroyuki Takahashi, Shin Egawa
Journal: Journal of Clinical Oncology (2019)

300 Background: Evidence suggests that hypoxic zones are prevalent in prostate cancer (PC). Recent clinical data showed that the expression of lactate dehydrogenase-5 (LDH5), a tumor hypoxia marker, affected the outcome of PC treated with radiation therapy. However, the impact of its expression on hormone therapy remains unclear. We investigated the predictive value of LDH5 expression in biopsy specimens from patients with PC treated with hormone therapy. Methods: Baseline data were available from 50 patients with PC treated with both androgen deprivation therapy (ADT) and novel androgen receptor axis-targeted agents (ARATs). LDH5 expression in the biopsy specimens was analyzed using immunohistochemical staining. Patients were stratified according to LDH5 expression in needle biopsy specimens. The relationships between LDH5 expression and baseline data at diagnosis, time to emergence of castration resistance, prostate-specific antigen (PSA) progression, and overall survival from induction of ADT and ARATs were examined. Results: Biopsy specimens from 19 patients highly expressed LDH5. High LDH5 expression was significantly associated with high Gleason scores (≥8) (p = 0.03), high clinical T stage (p = 0.008), and the likelihood of having at least one lymph node (p = 0.019) and metastatic lesion (p = 0.024). In a multivariate logistic regression model, LDH5 expression was significantly associated with high clinical T stage (p = 0.038), the presence of lymph node metastasis (p = 0.013), and high neutrophil-to-lymphocyte ratio (p = 0.016). Multivariate Cox regression analysis showed that high LDH5 expression was a significant predictor of time to emergence of castration resistance (hazard ratio [HR] 2.45, 95% confidence interval [CI] 1.12–5.36, p = 0.025) and overall survival (HR 9.3, 95% CI 2.17–39.8, p = 0.003). No significant association was observed between LDH5 expression and time to PSA progression from the induction of ARATs in univariate Cox regression analysis (p = 0.28). Conclusions: The results of this study suggest that LDH5 expression is a predictor of treatment outcomes in patients with PC treated with ADT.
Assessment of second-line VEGF-inhibitor therapy in radioiodine-refractory (RAIR) differentiated thyroid cancer (DTC).
Authors: Lara Dunn, Alan Loh Ho, Sofia Haque, Matthew G. Fury, Shrujal S. Baxi, Grace Cullen, David G. Pfister, Eric Jeffrey Sherman
Journal: Journal of Clinical Oncology (2015)

e17064 Background: Multiple small molecule kinase inhibitors that target VEGF are NCCN compendium approved for treatment of recurrent/metastatic RAIR DTC. After first-line therapy that includes VEGF inhibition, the benefit from second-line VEGF inhibitors has not been well evaluated. Methods: The study population included patients (pts) with RAIR DTC treated at MSKCC on three phase II studies (VEGF Trap, sorafenib/temsirolimus, or sorafenib/everolimus), who received two lines of therapy with VEGF inhibition. In the second line, only single-agent therapy was allowed. Results: 37 pts received at least 2 lines of VEGF inhibitors; non-protocol agents included pazopanib, sorafenib, sunitinib, and vandetanib, while PTC299 was through a phase I trial. 24 pts came off first-line therapy for progression; 13 pts for toxicity or withdrawal of consent. Rate of benefit with second-line therapy was similar in both of these groups: 45.8% and 53.8%, respectively, had a partial response (PR)/stable disease (SD) > 6 months. Considering all 37 pts, the median duration on first and second-line VEGF inhibitors was 6.3 months (range 0.5–53.9) and 4.8 months (range 0.3–47.8), respectively. The best response per RECIST v1.1 on first-line therapy was 18.9% PR, 2.7% unconfirmed (U) PR, 70.2% SD, 8.1% progression of disease (POD); the best response on second-line therapy was 2.7% PR, 8.1% UPR, 62.2% SD, 27.0% POD. 54.1% and 48.7% of pts had PR/SD for > 6 months on first- and second-line treatment, respectively. Thyroglobulin level, gender, duration on first-line treatment, and best response on first-line treatment showed no significant correlation with duration on second-line treatment, but tumors with BRAF mutations appeared to have less durable benefit (P < 0.05, log-rank). 48.6% of pts received pazopanib and 40.5% sorafenib in the second-line; median duration on these agents was not significantly different. Conclusions: Approximately half of the pts in our study had durable PR/SD on second-line VEGF inhibitors; BRAF mutation status may be predictive of benefit. Further study is needed to elucidate the contributions of disease natural history versus treatment effect mediated by VEGF or other targets.
Comparative analysis of biopsy proven lymph node positive bladder cancer patients to those with biopsy proven lymph node negative disease prior treatment.
Authors: Amy Lim, Vikram M Narayan, Mohamed Seif, Justin T. Matulay, Colin P.N. Dinney, Neema Navai
Journal: Journal of Clinical Oncology (2019)

475 Background: Many studies assessing the efficacy of chemotherapy before surgery include few clinically node positive patients or completely exclude them which make response rates in this particular subset of patients difficult to determine. Additionally, these patients are clinically node positive, making true nodal response rates unable to be determined. We report a descriptive analysis of patients with clinically node positive disease who underwent lymph node biopsy prior to any treatment and their outcomes. Methods: Data was obtained retrospectively from patients with cTanyN1-3M0 bladder cancer from 2006-2017 who underwent radical cystectomy at MD Anderson. SPSS was used for statistical analysis. Results: Among the 120 patients with cTanyN1-3M0 (median follow up 27.4 months), 40 patients underwent lymph node biopsy (LNBx). 26 (65%) patients had a positive LNBx, 14 (35%) were negative. 100% of the patients with a positive LNBx underwent primary chemotherapy. On final cystectomy, 9 (34.6%) of those patients had complete nodal response (pN0) and 9 (34.6%) had complete bladder response (pT0). 7 were pT0N0. Of the patients with a negative LNBx, 11 (78.6%) underwent neoadjuvant chemotherapy and of those patients, 7 (63.6%) were pN0 and 4 (36.4%) were pT0. Of patients that did not undergo LNBx that received primary chemotherapy (78 patients), 41 (52.6%) were pN0 and 22 (28.2%) were T0. There was no significant difference in overall or recurrence free survival between patients with a positive or negative biopsy or who did not undergo biopsy (p = .474). There was a significant improvement in overall and recurrence free survival in patients with negative nodal disease on final pathology compared to those with positive nodal disease (p &lt; 0.001). Conclusions: Patients that had a negative LNBx were less likely to undergo primary chemotherapy. Pathologic bladder response rates correlate with nodal response rates. In cN+ patients, overall survival and recurrence free rates are not significantly different in patients without a lymph node biopsy, a positive biopsy or a negative biopsy. Finally, advanced final pathologic stage predicts worse outcomes.
Abstract P091: Short-term Increased Dietary Potassium From Potato and Potassium Gluconate Has No Effect on Blood Pressure and Microcirculation in Pre-hypertensive-to-hypertensive Adults
Authors: Michael S Stone, Berdine R Martin, George P McCabe, Linda D McCabe, Connie M Weaver
Journal: Circulation (2019)

Potassium is an essential nutrient of concern according to recent Dietary Guidelines for Americans Advisory Committees, with less than 3% of the population meeting the current adequate intake (AI) level of 4700mg/d. Increases in potassium intake have been linked to improvements in cardiovascular and other metabolic health outcomes. Blood pressure (BP) is currently the primary criterion for determining potassium requirements. In this clinical trial, we assessed the effects of increasing potassium intake on BP and microcirculation (endothelial function). Thirty pre-hypertensive-to-hypertensive (Systolic BP ≥ 120mmHg) men (N=15) and Women (N=15) with a mean ± SD age, BMI, and BP (systolic(SBP)/ diastolic(DBP)) of 48.2 ± 15 y, 31.4 ± 6.1, and 136.3 ± 11.9/ 86.1 ± 7.1 mmHg, respectively, were enrolled in a cross-over randomized control diet trial. Participants were assigned to a random order of four 16-day dietary potassium interventions including a basal diet (control) of 2300mg/d(~60mmol/d), and three periods of an additional 1000mg/d(3300mg/d(~85mmol/d) total) of potassium in the form of potatoes (baked, boiled, or pan-heated with no additional fat), French fries, or a potassium gluconate supplement. Each intervention period was separated by two or more weeks of wash out. Blood pressure was measured in triplicate using manual auscultation on days 1, 4, 6, 8, 11, 13, 15, 16, and 17 of each intervention. Microvascular and endothelial function were assessed via thermal hyperemia, utilizing laser Doppler flowmetry (LDF), at baseline and at the end of each intervention. Results for differences in both SBP and DBP ± SE were assessed at the end treatment (average of day 15, 16, and 17 measurements) using a mixed model with repeated measures and Dunnett adjustment (P &lt; 0.05), with no significant differences among groups (control: 128.7 ± 2.1/ 83.6 ± 1.6, French fries: 127.7 ± 2.2/ 83.7 ± 1.6, potatoes: 127.6 ± 2.3/ 85.1 ± 1.6, supplement: 128.0 ± 2.2/ 83.7 ± 1.7). Utilizing the same statistical analysis, there were also no significant differences in endothelial function (measured as percent of cutaneous vascular conductance max (%CVCmax) ± SE) among groups (control: 87.4 ± 1.5%, French Fries: 87.7 ± 1.4%, potatoes: 88.3 ± 1.1%, supplement: 88.9 ± 1.0%). In this small, controlled feeding study of short duration, increased potassium from potatoes or supplement achieved 70% of recommended intakes, but had no significant benefit to blood pressure or microvascular function in men and women with higher cardiometabolic risk.
South African physician emigration, return migration, and shared migration, 1991–2017: a registry-based analysis
Authors: Joseph Nwadiuko, Ligia Paina
Journal: The Lancet Global Health (2019)

BackgroundPhysician emigration—the so-called brain drain—is a topic of great concern to health workforce planners. South Africa has a high number of physician emigrants, yet there are few registry-based studies that have analysed whether these physicians remain abroad permanently. In this study, we aimed to use a registry-based approach to analyse return migration and shared migration in South African physicians.MethodsWe extracted information from registry records about South African trained physicians who had registered in Australia, Canada, New Zealand, the USA, or the UK (ACNUU nations) between 1991 and 2017. We used an attrition-based model to identify non-retiree dropouts from UK, New Zealand, and US registries and cross-referenced with a South African physician registry to determine return migration from these countries. Return migration counts in Canada were derived from secondary data from Canadian Medical Association surveys. Physicians who had active simultaneous registration in South Africa and one other nation were counted as shared migrants.FindingsAs of December, 2017, there were 11 224 South African trained physicians actively registered to practise in ACNUU nations, around a third (30·2%) fewer than the peak of 16 095 in 2003. Of these, 3596 (32·0%) held dual active registration (shared migration) in an ACNUU nation and South Africa. In 2017, 5008 physicians met criteria for return migration—that is, 30·1% of all non-retired South African physicians with a history of practising medicine in ACNUU countries. There has been a five-fold drop in emigration rates from South Africa between 1991 and 2017 (from 1·8% to 0·3% per year; UK −88·9%, non-UK −74·2%), negatively correlated with a substantial rise in GDP per capita growth within South Africa in time-adjusted models (–0·36% per $100 increase [p=0·01; 95% CI −0·089 to −0·632]). We noted a temporary increase in return migration between 1995 and 2009 and a simultaneous sustained increase in shared migration.InterpretationA registry-based approach allows simultaneous assessment of physician emigration, return migration, and shared migration. Our findings of decreasing rates of emigration and increasing return and shared migration rates suggest a mobility transition in medical migration in South Africa.FundingWorld Bank.
The timing from perioperative chemotherapy and disease recurrence could have clinical impact on survival in bladder cancer patients treated with salvage chemotherapy.
Authors: Eiji Kikuchi, Nozomi Hayakawa, Koichirou Ogihara, Minami Omura, Ryuichi Mizuno, Mototsugu Oya
Journal: Journal of Clinical Oncology (2019)

444 Background: Our aim was to clarify whether the duration between perioperative chemotherapy and disease recurrence could affect therapeutic efficacy of salvage chemotherapy in bladder cancer patients treated with radical cystectomy. Methods: We retrospectively identified 201 patients treated with radical cystectomy and perioperative chemotherapy of neoadjuvant chemotherapy (NAC) and/or adjuvant chemotherapy (AC) for bladder cancer at our 7 institutions between 2003 and 2015. Of them 56 patients received salvage chemotherapy for disease recurrence and were included in the present analysis. We classified these patients according to the time from perioperative chemotherapy received to disease recurrence ( &lt; 12 months, 12-24 months, and 24 &lt; months) and compared their clinical characteristics and survival outcomes. Results: Overall, 33, 14, and 9 patients developed disease recurrence in &lt; 12 months, 12-24 months, and &lt; 24 months, respectively after perioperative chemotherapy. Patients in the 12-24 months group had a higher smoking rate compared to those in the other two groups, and were higher rate of female in comparison to the &lt; 24 months group. Twenty-four (42.8%) patients received NAC alone, 23 (41.1%) received AC alone, and 9 (16.1%) received both NAC and AC. Twenty-two (66.7%), 9 (64%), and 4 (44.4%) patients received NAC in the &lt; 12 months group, the 12-24 months group, and the &lt; 24 months group, respectively. Furthermore, 19 (57.6%), 7 (50%), and 6 (66.7%) patients received AC in the &lt; 12 months group, the 12-24 months group, and the &lt; 24 months group, respectively. The 5 year overall survival in the &lt; 12 months group was 26.6%, which was significantly lower than those in the 12-24 months group (51.1%, p &lt; 0.001) and in the 24 months group (46.9%, p = 0.014). Multivariate Cox regression analysis revealed that disease recurrence after perioperative chemotherapy within 12 months was the only independent prognostic indicator for overall death (p = 0.032). Conclusions: Bladder cancer patients with disease recurrence within 12 months from their perioperative chemotherapy have a worse overall survival after salvage chemotherapy.
Glucocorticoid receptor antagonist Org34517 as a chemosensitizing agent for ovarian cancer.
Authors: Neil David Theise, Stephen Gately, Matthew Witman, Paul Gonzales, Anthony Arment, Maggie Valenzuela
Journal: Journal of Clinical Oncology (2015)

e16556 Background: Anti-tumor activity has been predicted for glucocorticoid receptor antagonists (GRAs) for some solid organ malignanies. Org34517, the first selective GRA studied in humans, has shown no prohibitive effects in phase 1/2 clinical trials. We evaluated Org34517 anti-tumor activity with and without Paclitaxel (Pac) in a human ovarian tumor xenograft model. Methods: Female athymic nude mice were inoculated with A2780 human ovarian tumor line. Org34517 doses of 600 (Org600) and 900 mg/kg (Org-900), with and without 10 mg/kg Paclitaxel (Pac), were given. Vehicle Control (VC) and Org34517 were given once daily for 12 days. Pac was given once daily for 5 days. Seven days following inoculation, tumors reached a mean mass of 148 mg and were randomized into 6 treatment groups (VC/VC, VC/Pac, VC/Org600, VC/Org900, Pac/Org600, Pac/Org900). Body and tumor weights (TW) were recorded 3x weekly. The study ended at 18 days. Mean tumor growth inhibition (TGI) was calculated and differences between groups confirmed by Student’s t-test. All procedures were carried out under the institutional guidelines of TGen Drug Development Institutional Animal Care and Use Committee (Protocol #13057). Results: Body weights for all groups showed no significant decline. No significant morbidities/mortalities were associated with any drug administration. Conclusions: Higher dose Org34517, but not lower dose, showed significant TGI, statistically equivalent to Pac alone; due to direct cytotoxicity and/or to prevention of tumor stimulatory effects by endogenous cortisol. Both Org34517 doses synergized with Pac, doubling TGI, suggesting chemosensitization of tumor cells. Further pre-clinical and clinical trials are needed to evaluate a wider of range of dosing, as single agents and with Pac (or other chemotherapies). Given the safety of both compounds in phase 2 clinical trials, ovarian carcinoma treatment supplementation with Org could be amenable to expedited clinical assessment. Treatment Mean TW ± SEM % TGI Veh/Veh 2859.9 ± 143.5 --- Veh/Org600 2919.2 ± 165.1 0 Veh/Org900 2417.7 ± 152.3* 16 Pac 2331.1 ± 232.7* 20 Pac/Org600 1879.1 ± 356.4* 36 Pac/Org900 1720.8 ± 91.1** 42 *P < 0.05 vs Control; **P < 0.05 vs. Control and vs. Paclitaxel alone.
Abstract 20189: Redefining the Blanking Period After the Maze Procedure for Atrial Fibrillation
Authors: Jin Hee Choi, Ki Won Hwang, Soon Myung Jung, Yeon Seong Kim, Soo Yong Lee, Min Ku Chon, Sang Hyun Lee, Jeong Su Kim, Yong-Hyun Park, June Hong Kim, Kook Jin Chun, Hyung Gon Je, Sang Kwon Lee
Journal: Circulation (2017)

Introduction & Hypothesis: Early recurrence (ER) of atrial tachyarrhythmia (ATA) is common after atrial fibrillation ablation. There is well unknown about current guidelines of blanking period after maze procedure. We aimed to investigate the significance of ER after maze procedure is a predictor of late recurrence (LR) and determine whether it varies according to timing. Methods: From 2009 to 2016, a total of 290 patients underwent the open heart surgery with concomitant maze procedure were analyzed. Data were obtained from 12-lead electrocardiograms and Holter monitoring during follow-up. Patients with atrial ATA ≥30 seconds within post procedure 3 month were stratified according to the timing of ER. Results: A total of 146 patients (50.3%) experienced their last episode of ER during the first the first (n=82), second (n=15), or third (n=49) month of the 3-month blanking period. One-year freedom from ATAs was 97.7% in patients without ER compared with 96.9%, 76.9%, and 10.4% in patients with ER 1, 2, an...
Safeguarding the Patient’s Own Blood Supply
Authors: Michelle P. Zeller, Richard M. Kaufman
Journal: JAMA (2019)

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Circulating tumor (ct) DNA-based genomic profile of prostate cancer (PCa) patients with elevated carcinoembryonic antigen (CEA).
Authors: Pannaga G. Malalur, Theodore Stewart Gourdin, Ali Roberts, Michael B. Lilly
Journal: Journal of Clinical Oncology (2019)

218 Background: Neuroendocrine (aggressive variant) PCa patients often have elevated CEA (40-85%), which is associated with poor outcomes. We used ctDNA analysis to identify a genomic pattern for PCa patients with elevated CEA (CEA+ PCa). Methods: We analyzed ctDNA-based genomic profiles (Guardant 360) from 32 patients with CEA+ PCa. Profiles were compared with genomic profiles from the TCGA database, ctDNA profiles for 50 consecutive PCa patients with normal CEA levels (CEAnl PCa), and ctDNA profiles for GI tumors associated with elevated CEA. Results: CEA+ PCa patient profiles showed concordance with TCGA database genomic profiles for neuroendocrine PCa. There was high similarity in genes amplified; however many more single-nucleotide variants (SNVs) were detected with ctDNA analysis. For ctDNA profiles of CEA+ PCa, the most commonly amplified genes were AR, PIK3CA, MYC, CDK6, BRAF, MET; the most common clonal SNVs were in TP53, PTEN, APC, PIK3CA, and MET. Serial ctDNA analyses were done in 23 CEA+ PCa patients, of which 8 showed conversion from CEAnl to CEA+ PCa. This change was accompanied by emergence of new amplifications (62.5%; AR, MET, MYC, BRAF, EGFR, CDK6) or SNVs (tumor suppressor genes [ APC, TP53] or mitogen signaling pathways [ BRAF, ERBB2, KRAS, MET, PIK3CA]). Clonal mutations present in CEAnl PCa frequently persisted after emergence of a CEA+ phenotype. CEA+ PCa differed from CEAnl PCa by the higher prevalence of AR amplifications (p = 0.033), higher AR copy number (p = 0.004), and lower number of AR clonal mutations (p = 0.0017). AR amplification was significantly more frequent in CEA+ PCa (50%) than in another CEA+ malignancy, colon cancer (3%). AR amplification copy number was also much higher in CEA+ PCa than in colon cancer (p = 0.0023). Conclusions: ctDNA analysis shows AR amplifications as highly associated with CEA+ and neuroendocrine PCa. New amplifications occur during evolution from CEAnl to CEA+ PCa. Genomic profile obtained using ctDNA (within limits) is comparable to TCGA database. AR amplification is characteristic of CEA+ PCA and may distinguish this entity from other cancers with elevated CEA.