tbuckley/cabot-search huggingface dataset:
Conversion surgery for stage IV gastric cancer: Feasibility, safety, and efficacy results.
Authors: Tsutomu Sato, Ken Nishimura, Norisuke Nakayama, Osamu Motohashi, Kenki Segami, Shigeya Hayashi, Taiichi Kawabe, Toru Aoyama, Tsutomu Hayashi, Takanobu Yamada, Takashi Oshima, Yasushi Rino, Munetaka Masuda, Takashi Ogata, Haruhiko Cho, Takaki Yoshikawa
Journal: Journal of Clinical Oncology (2015)

e15031 Background: Conversion surgery could be an option for stage IV gastric cancer when distant metastasis (M1) is disappeared by palliative chemotherapy, however, feasibility, safety and efficacy of surgery after long-term chemotherapy remains unclear. Methods: This retrospective study examined 21 gastric cancer patients who underwent curative conversion surgery between 2001 and 2013. Postoperative complications were evaluated according to the Clavien-Dindo classification. Overall survival (OS) was estimated by Kaplan-Meier method. Results: Median follow-up period (range) was 43.9 months (7.2-72.1 months). The number of M1 factors was one in 17 patients and two in 4, including metastases to non-regional lymph node in 11, peritoneum in 11, and liver in 3. The regimen of chemotherapy was S-1/CDDP in 11 patients, S-1/Docetaxel/CDDP in 5, S-1/Docetaxel in 2, 5FU/Leucovorin/Paclitaxel in 1, CPT/CDDP in 1, and S-1 monotherapy in 1. The median duration from initiation of chemotherapy to disappearance of M1 factor was 3.5 months and the median duration from initiation of chemotherapy to the operation was 7.5 months. A total of 19 patients (90.4%) underwent over D2 lymphadenectomy including modified D2 in 2 patients, D2 in 16, and D2 plus para-aortic nodal dissection in 3. M1 tumor was not resected except para-aortic nodal dissection in 3 patients. The median operation time and bleeding were 205 minutes and 228 ml, respectively. Grade 2/3/4 morbidities were observed in 5 patients (23.8%); 2 pancreatic fistula (grade 2), 2 abdominal abscess (grade 2 and 3), and 1 anastomotic leakage (grade 3). No mortality was observed. Pathological response of the primary tumor, defined as disappearance of more than two third of the tumor cells, was 66.7% including 19.0% of complete response. The overall survival (OS) after initiation of chemotherapy was 90.5% at 1-year, 85.7% at 2-year, and 75.9% at 3-year with median survival time (MST) of 52.9 months, while OS after surgery was 90.5% at 1 year, 76.2% at 2-year, and 64.5% at 3-year with MST of 40.9 months. Conclusions: Curative conversion gastrectomy for stage IV gastric cancer was feasible and safe. Considering excellent survival, conversion surgery has a value to be evaluated in prospective studies.
Целиакия: современный взгляд на диагностику и лечение
Authors: Yu.M. Stepanov, А.V. Salenko
Journal: GASTROENTEROLOGY (2019)

В статье представлен анализ этиопатогенетических механизмов возникновения целиакии. Освещены современные методы диагностики данной патологии, проанализирован алгоритм их использования. Рассмотрена тактика ведения больных целиакией.
Abstract 13090: Beneficial Effects of Left Ventricular Assist Device Compared to Medical Therapy in Ambulatory Non-inotropic Dependent Heart Failure Patients in INTERMACS Profiles 4 vs 5-7: Results From the ROADMAP Study
Authors: Douglas A Horstmanshof, Keyur B Shah, Joseph G Rogers, James W Long, Randall C Starling, Nader Moazami, Brian Bruckner, Vigneshwar Kasirajan, Donald C Haas, Rohinton Morris, Carmelo A Milano, Josef Stehlik, Craig H Selzman, Jerome M Thomas, David W Drucker, David E Lanfear, Robert J Brewer, Juan M Aranda, Charles T Klodell, Joyce Chuang, David J Farrar, Jerry D Estep
Journal: Circulation (2015)

Introduction: The role of left ventricular assist devices (LVAD) in advanced heart failure (HF) patients (pts) not dependent on intravenous inotropes is unclear. We hypothesize that the benefits of LVAD vs optimal medical management (OMM) are more pronounced in INTERMACS profile 4 (IM4) than profiles 5-7 (IM5-7). Methods: ROADMAP is a prospective, 41-center, non-randomized study of 200 pts. The objective was to evaluate the effectiveness and relative risks of HeartMate II LVAD support vs OMM in ambulatory NYHA Class IIIB/IV pts who met FDA indications for LVAD destination therapy but were non-inotrope dependent. The primary composite endpoint was survival with improvement in 6MWD ≥ 75m at 1 yr. Results: There were more LVAD pts in IM4 than IM5-7 (Table). Among IM4 pts, LVAD was 4.6X more likely than OMM to meet the primary endpoint, and 1 yr event-free survival as treated on original therapy was significantly greater for LVAD pts (Figure). The most frequent adverse event (AE) was bleeding for LVAD pts and worsening HF for OMM. For IM4 and IM5-7, LVAD pts had a higher composite of AEs compared to OMM, but freedom from rehospitalizations was similar for IM4. In OMM pts, 33% of IM4 and 15% of IM5-7 received delayed LVADs within 1 yr. Health related quality of life (HRQoL), severity of depression (PHQ-9), and NYHA class improved more at 1 yr with LVADs than OMM. Conclusions: Survival with improved functional status was better with LVADs compared to OMM in IM4 pts. HRQoL and depression improved more in all IM profiles with LVADs in spite of AEs being more frequent with LVADs. Results support the use of the HMII LVAD in functionally limited non-inotrope dependent HF patients, particularly those in IM4 profile.
Abstract P380: Validity and Reliability of Pulse Wave Velocity Measurement in a Seated Posture
Authors: Robert J Kowalsky, Lee Stoner, Sophy Perdomo, John Michael Taormina, Melissa Jones, Daniel Credeur, Bethany Barone Gibbs
Journal: Circulation (2019)

Introduction: Accumulating evidence suggests that prolonged sitting may have adverse effects on vascular health. Pulse wave velocity (PWV) is a simple measurement of vascular stiffness that would be advantageous to measure in a seated posture. However, the reliability and validity of PWV measured in a seated posture are unknown. Objective: To assess day-to-day reliability and validity of seated peripheral PWV. Methods: This randomized cross-over study (N=20, 50% male, mean (SD) age = 25.9 (7.7)) consisted of two experimental visits, conducted a maximum of 14 days apart. Outcome measures were carotid-radial PWV (crPWV), carotid-ankle PWV (caPWV), and carotid-femoral PWV (cfPWV; supine position only) by tonometry using the Complior Analyse System. Measurements were completed in both a supine and seated posture (counterbalanced), preceded by a 10-minute rest, and following a 12-hr abstention from food, caffeine, nicotine, alcohol, and exercise. Intra-class correlations (ICCs) assessed day-to-day reliability with ≥0.75 as the criterion for good reliability. Validity was determined by comparing (Pearson’s correlation) peripheral PWV measures in the seated compared to supine posture as well as to central PWV measures (supine cfPWV). Results: ICCs for crPWV were 0.64 (supine) and 0.77 (seated) and for caPWV were 0.36 (supine) and 0.76 (seated). Supine vs. seated peripheral PWV measures were highly correlated for crPWV but not correlated for caPWV ( Figure ). Comparison of supine cfPWV to seated peripheral PWV were r=0.483 ( p =0.031) for crPWV and r=0.386 ( p =0.103) for caPWV. Conclusion: While measures of seated crPWV and caPWV were both reliable and small-to-moderately correlated with related vascular measures, only seated crPWV was valid compared to the standard supine measure. Future studies evaluating the impact of prolonged sitting and breaking up prolonged sitting could consider measuring crPWV in a seated posture.
ARV-110: An oral androgen receptor PROTAC degrader for prostate cancer.
Authors: Taavi Neklesa, Lawrence B Snyder, Ryan R Willard, Nicholas Vitale, Jennifer Pizzano, Deborah A Gordon, Mark Bookbinder, Jennifer Macaluso, Hanqing Dong, Caterina Ferraro, Gan Wang, Jing Wang, Craig M Crews, John Houston, Andrew P Crew, Ian Taylor
Journal: Journal of Clinical Oncology (2019)

259 Background: The Androgen Receptor (AR) remains the principal driver of castration-resistant prostate cancer during the transition from a localized to metastatic disease. Most patients initially respond to inhibitors of the AR pathway, but the response is often relatively short-lived. The majority of patients progressing on enzalutamide or abiraterone exhibit genetic alterations in the AR locus, either in the form of amplifications or point mutations in the AR gene. Given these mechanisms of resistance, our goal is to eliminate the AR protein using the PROteolysis TArgeting Chimera (PROTAC) technology. Methods: Here we report an orally bioavailable small molecule AR PROTAC degrader, ARV-110, that promotes ubiquitination and degradation of AR. This molecule has been characterized in in vitro degradation and functional assays, and DMPK, toxicology and preclinical efficacy studies. Results: ARV-110 robustly degrades AR in all cell lines tested, with an observed half-maximal degradation concentration (DC 50 ) of ~1 nM. ARV-110 treatment leads to highly selective AR degradation, as demonstrated by proteomic studies. In VCaP cells, PROTAC-mediated AR degradation suppresses the expression of the AR-target gene PSA, inhibits AR-dependent cell proliferation, and induces apoptosis at low nanomolar concentrations. Further, ARV-110 degrades clinically relevant mutant AR proteins and retains activity in a high androgen environment. In mouse xenograft studies, greater than 90% AR degradation is observed at a 1 mg/kg PO QD dose. Significant inhibition of tumor growth and AR signaling has been achieved in LNCaP, VCaP and prostate cancer patient derived xenograft (PDX) models. Notably, ARV-110 demonstrates in vivo efficacy and reduction of AR-target gene expression in a long term, castrate, enzalutamide-resistant VCaP tumor model. Conclusions: In summary, we report preclinical data on an orally bioavailable AR PROTAC degrader, ARV-110, that demonstrates efficacy in multiple prostate cancer models. ARV-110 has completed IND-enabling studies and FIH studies are planned for 1Q2019.
Ipilimumab plus nivolumab (Ipi/Nivo) as salvage therapy in patients with immunotherapy (IO)-refractory metastatic renal cell carcinoma (mRCC).
Authors: Anita Gul, Neil J. Shah, Charlene Mantia, Hans J. Hammers, Moshe Chaim Ornstein, David F. McDermott, Michael B. Atkins, Brian I. Rini
Journal: Journal of Clinical Oncology (2019)

669 Background: Ipi/Nivo is now FDA approved for the first line treatment of patients (pts) with intermediate and poor risk mRCC but activity in IO refractory mRCC patients is still not well reported. Here we seek to report activity of Ipi/Nivo in IO refractory mRCC pts. Methods: In this retrospective review, we identified a total of 30 pts with mRCC from 4 academic medical centers across the USA who received salvage Ipi/Nivo after disease progression on IO therapy. Pts with only predominant clear cell histology were captured. Ipi/Nivo was administered as per CHECKMATE 214. Investigator-assessed response rate were noted. Immune related adverse events (irAE) were captured in accordance with CTCAE v5.0. Results: The baseline demographics included median age of 60 years (21-82), ECOG PS 0-2, and 73% (22) male and 27% (8) female. IMDC risk categories at the time of salvage Ipi/Nivo initiation were 23% (7), 60% (18) and 3% (1) with favorable, intermediate and poor risk, respectively. The median number of prior systemic therapies was 3 (1-6). Prior IO therapies included nivolumab monotherapy (14), avelumab plus axitinib (3), high dose interleukin-2 (3), pembrolizumab monotherapy (2) and Ipi/Nivo, nivolumab plus hypoxia inducible factor (HIF) inhibitor, atezolizumab plus interferon, atezolizumab monotherapy, pembrolizumab plus bevacizumab, pembrolizumab plus axitinib, varlilumab plus atezolizumab and an oral adenosine inhibitor (1 each). The median time on prior IO therapy was 7 months (1-50), best response was 3% (1) CR, 40% (12) PR, 23% (7) SD and 33% (10) PD. 73% (22) had restaging scans to assess response to ipi/nivo of which 17% (5), 3% (3) and 47% (14) showed PR, SD and, PD respectively. 37% (11) developed any grade irAEs and 6% (2) had grade ≥3 irAE including one patient with splenic rupture and one with rash and pneumonitis. Conclusions: Ipi/Nivo is feasible and safe in IO-refractory mRCC population with preliminary evidence of anti-tumor activity. Updated response data will be presented.
Neurologic Deficits in Patients With Newly Diagnosed Celiac Disease Are Frequent and Linked With Autoimmunity to Transglutaminase 6
Authors: Marios Hadjivassiliou, Iain D. Croall, Panagiotis Zis, Ptolemaios G. Sarrigiannis, David S. Sanders, Pascale Aeschlimann, Richard A. Grünewald, Paul A. Armitage, Daniel Connolly, Daniel Aeschlimann, Nigel Hoggard
Journal: Clinical Gastroenterology and Hepatology (2019)
Chinese expert consensus on the treatment of modern combat-related spinal injuries
Authors: Zhao-wen Zong, Hao Qin, Si-xu Chen, Jia-zhi Yang, Lei Yang, Lin Zhang, Wen-qiong Du, Xin Zhong, Ren-jie Zhou, Dan Tan, Hao Wu
Journal: Military Medical Research (2019)

The battlefield treatments of spinal and spinal cord injury vary from civilian settings. However, there is no unified battlefield treatment guidelines for spine trauma in PLA. An expert consensus is reached, based on spine trauma epidemiology and the concepts of battlefield treatment combined with the existing levels of military medical care in modern warfare. Since the specialized treatment for spine trauma are no significant difference between civilian settings and modern war, the first aid, emergency treatment and early treatment of spine trauma are introduced separately in three levels in this consensus. In Level I facilities, the fast and accurate evaluation of spine trauma followed by fixation and stabilization are recommended during the first-aid stage. Re-evaluation, further treatment for possible hemorrhagic shock, dyspnea and infection are recommended at Level II facilities. At Level III facilities, it is recommended to strengthen the intensive care and the prevention of urinary system and lung infection for the wounded with severe spinal injury, however, spinal surgery is not recommended in a battlefield hospital. The grading standard for evidence evaluation and recommendation was used to reach this expert consensus.
Reducing the global burden of preterm births
Authors: Bellington Vwalika, Joan T Price, Alan Rosenbaum, Jeffrey S A Stringer
Journal: The Lancet Global Health (2019)

In their systematic review and meta-analysis, Saifon Chawanpaiboon and colleagues1 provide global, regional, and country-level estimates for the frequency of preterm birth (defined as occurring before 37 weeks of completed gestation). Their report improves upon an established method that has been used for similar analyses and, as such, is particularly useful when analysing trends over time. However, as the authors point out, data from several developing countries are either absent altogether or do not have sufficient quality to provide reliable estimates.
Modulation of lipid rafts (LR), p-glycoprotein (P-gp) and proinflammatory cytokines (PIC) with HMG-Co A reductase inhibitor simvastatin (SV) in chronic myelogenous leukemia (CML) patients with imatinib mesylate (IM) resistance.
Authors: Eugene McPherson
Journal: Journal of Clinical Oncology (2015)

e18032 Background: Primarily monocyte-derived cytokines and soluble interleukin-2-receptor (sIL2R) form of a group of PIC which are significantly elevated in patients with CML-cp or CML-bc. C-reactive protein correlates to IL-6. IM is a tyrosine kinase inhibitor that blocks ATP binding site of kinase domain of Bcr/abl in CML. IM treatment with complete cytogenetic response but can acquire drug resistance via P-gp upregulation and lipid microdomains rich in sphingolipids and cholesterol of LR within plasma membranes important for regulating cell signaling and functions. Modulation of P-gp and disruption of LR/HDL-C upregulation readily overcame IM resistance. Methods: We present several cases of CML: CML-cp, CML-bc with evidence of resistance. After one year of IM therapy an 86 YOF with CML-cp developed Bcr/abl signaling c/w elevated PIC, sIL2R, CRP, acute coronary syndrome and low HDL-C (29.3 mg/dL). Results: Modulation of PIC and upregulation and increasing HDL-C by 50% with SV, IM dose adjustments and serial measurements of Bcr/abl ratio after two years, real time Bcr,abl ratio was ~ 5 log reduction, sIL2R normalized from 31,709.55 pg/ml to 5,345 pg/ml (Normal 1770-9753 pg/ml). CRP decreased by 30% and down to 6.23 mg/dL. Conclusions: IM an intracellular drug demonstrating high activity against Bcr,abl gene positive CML-cp or CML-bc patients may develop resistance by loss of cellular proliferation, upregulated P-gp and Bcr/abl protein with TK activity regulated signals of LR. Modulation of P-gp and disruption of LR/HDL-C upregulation with SV may synergistically allow intracellular levels of IM restoration of cytotoxicity and overcome resistance.
A pilot approach of pharmacokinetically guided 5-fluorouracil (5-FU) dosing for personalized gastric cancer treatment.
Authors: Eduardo Castanon Alvarez, Azucena Aldaz, Amaia EgÃÂ¼es, Patricia Martin, Juan Pablo Fusco, Leire Zubiri, Lucia Ceniceros, Ana Chopitea, Jose Luis HernÃÂ¡ndez-Lizoain, Javier Rodriguez
Journal: Journal of Clinical Oncology (2015)

e13587 Background: Infusional 5FU schedules remain the backbone of conventional regimens for gastric cancer (GC) patients (pts). 5-FU pharmacokinetic variability when posology is calculated by the body surface area (BSA) method has encouraged dose adjustment based on pharmacokinetics/pharmacodynamics (PK/PD) parameters to achieve a better therapeutic index (TI) for this drug. Significant correlations between systemic exposure, area under the curve (AUC) at steady state and clinical outcome have been reported in other gastrointestinal tumors. The purpose of this work is to analyze preliminary data from a medical assistance program based on 5FU dose adjustment through PK/PD parameters in pts with GC instead of BSA method. Primary end point is to rule out the feasibility of a prospective strategy to monitor 5-FU blood concentrations and adjust individual doses based on systemic exposure. Secondary endpoint is to provide preliminary evidence of clinical utility. Methods: Prospectively data from GC pts included in a PK/PD-dose adjustment program were analyzed. 38 stage II-IV GC pts, treated with 5FU-based regimens were identified. Two plasma samples were taken per patient in at least 2 cycles, equally spaced on time depending of 5FU infusion length according to chemotherapy scheme. 5FU concentrations were analyzed by High-Performance Liquid Chromatography (HPLC). PL/PD parameters were estimated by Bayesian methodology with Multiple Dose software. A target AUC of 20-30 mg*hr/L n was considered since it has been correlated with optimal TI. Results: 31 pts were evaluable after two cycles. After the first cycle, 25.8% (n = 8) had an AUC < 20 mg*hr/L and 18 pts (58%) were within the target AUC of 20-30 mg*hr/L and 5 pts had an AUC above 30 mg*hr/L . After 5FU PK-dose adjustment, , 24 pts (77.4%) were within the target AUC values. A radiological partial response was found in 9/16 pts who achieved the target AUC. The most frequent grade III/IV toxicity was neutropenia (31.9%). Conclusions: A PK/PD-based dose adjustment of 5-FU is feasible in GC pts, with > 75% achieving the target therapeutic levels after two cycles. Recruitment is ongoing to describe correlations between AUC, toxicity profile and clinical outcome.
A retrospective observational study assessing bone metastases (mets) detection and management of patients (pts) with castration-resistant prostate cancer (CRPC) in Canada.
Authors: Fred Saad, Anil Kapoor, Armen G. Aprikian, Richard Casey, Michele Caveen, Maureen Reiner, Brad Gillesby, Antonio Finelli
Journal: Journal of Clinical Oncology (2019)

161 Background: Canadian Urological Association guidelines outline the scheduling of imaging modalities based on prostate-specific antigen doubling time (PSADT) to screen for mets in pts with nonmetastatic (M0) CRPC and to manage pts with metastatic (M1) CRPC. Data describing guideline adoption and real-world timing of bone scans and treatment patterns in Canadian CRPC pts are limited. Methods: A retrospective chart review conducted at 13 Canadian urology practices included pts with CRPC (PSA ≥2 ng/mL despite androgen deprivation therapy) sequentially identified in reverse chronological order starting July 30, 2015. Pts had no mets at CRPC diagnosis (index date). Data were abstracted from the index date to the chart review date. Coprimary objectives were to describe CRPC management in terms of timing of the 1st and repeat bone scans in M0 and treatment patterns when pts became metastatic. Secondary objectives described nonbone imaging. Results: 232 pts enrolled. Over the observation period 109 remained nonmetastatic (M0 cohort); 123 developed mets (M1 cohort). Median index PSADT was ~1.5x greater for the M0 cohort than the M1 cohort. 68 pts (71.6%) in M0 and 117 pts (95.1%) in M1 had ≥1 bone scan. Median (95% CI) months from CRPC diagnosis to 1st bone scan was 7.5 (5.6–9.6) for pts in M1 and 15.7 (10.0–23.0) for pts in M0. Median (95% CI) months from identification of mets to start of treatment for the M1 cohort was 3.2 (2.3–5.7). The most common therapies were abiraterone (55%) and enzalutamide (42%), with respective median (95% CI) durations of 12.7 (8.7–23.3) and 15.7 months (10.4–NE). 25% of pts received a bone-targeted agent. Conclusions: In CRPC, time to first bone scan was shorter for pts who subsequently developed mets or had rapid PSADT. Abiraterone and enzalutamide were the most common therapies in pts with mets. [Table: see text]
Does poor understanding of sorafenib (S) toxicity(tox)/tolerance (tol) in the high risk population Hispanic (H), African Americans (AA) contribute in inferior survival in hepatocellular cancer HCC?
Authors: Emily Eyoung Baiyee Ebot, Kevan L. Hartshorn
Journal: Journal of Clinical Oncology (2015)

e15164 Background: Based on SEER data HCC incidence increased in the interval 2006–2010. Among persons aged 50–64 years, AA had the highest incidence rate, followed by H. The standard systemic treatment for advanced HCC is S based on data reported by the SHARP which had a very low AA and H population (pop). In AAs HCC presents at more advanced stages and has a poor mortality. Prior studies have reported a racial disparity in interventions for HCC as a factor contributing to the inferior outcomes. Better understanding of the tox profile and tol of S at different doses in this high-risk pop is a vital step towards improving survival. Methods: Retrospective chart review of all patients with advanced HCC diagnosed and treated at Boston Medical Center from 1/2008 to 12/2013. Data analyzed included race, performance status, Child Pugh score, initial dose (iDose) of S, maximum S dose tolerated, period on S, need for dose reduction, one year survival (1yrS) and side effects documented by oncologists. Results: 166 charts ICD coded as hepatobiliary cancer were reviewed. 130 patients (pts) had HCC and 36 were excluded because of lack of data, no follow up and a non-HCC liver cancer diagnosis. 27 pts of were treated with S as initial therapy with 59% 1yrsS. In pts treated with chemoembolization before S the 1yrS was 72%. AA were least likely to start S (13%), compared to 28% H, 21% C and 26% As. Pertinent results in table below. Conclusions: In this retrospective review of HCC outcomes and S toxicity profile in an inner city hospital treating a diverse pop we find better mortality rates than reported in prior studies. Better understanding of the S tox profile and dosing in this high-risk pop would definitely contribute to improve outcomes. H AA C As Race% 16 26 40 14 iDose 800 mg%* 50 66 55 66 Mn POS (mo) 15.8 3.2 8.2 2.4 1yrS%* 66 60 63 33** DR% 33 66 55 25 % (6)*** 50 80 63 20 HFS% 33 25 30 16 D% 12 25 47 23 F% 33 41 65 50 * % Pts S as initial therapy; ** 2Pts lost to follow up; *** Pts on S for > 5months (mo). Abbreviations: DR, Pts requiring dose reduction/discontinuation; HFS, Pts with Hand foot syndrome; D, Pts with Diarrhea; F, Pts with Fatigue; Mn, mean.