tbuckley/cabot-search huggingface dataset:
A Large-Cohort, Longitudinal Study Determines Precancer Disease Routes across Different Cancer Types
Authors: Jessica X. Hu, Marie Helleberg, Anders B. Jensen, Søren Brunak, Jens Lundgren
Journal: Cancer Research (2018)

Abstract Although many diseases are associated with cancer, the full spectrum of temporal disease correlations across cancer types has not yet been characterized. A population-wide study of longitudinal disease trajectories is needed to interrogate the general medical histories of patients with cancer. Here we performed a retrospective study covering a 20-year period, using 6.9 million patients from the Danish National Patient Registry linked to 0.7 million patients with cancer from the Danish Cancer Registry. Statistical analysis identified all significant disease associations occurring prior to cancer diagnoses. These associations were used to build frequently occurring, longitudinal disease trajectories. Across 17 cancer types, a total of 648 significant diagnoses correlated directly with a cancer, while 168 diagnosis trajectories of time-ordered steps were identified for seven cancer types. The most common diseases across cancer types involved cardiovascular, obesity, and genitourinary diseases. A comprehensive, publicly available web tool of interactive illustrations for all cancer disease associations is provided. By exploring the precancer landscape using this large dataset, we identify disease associations that can be used to derive mechanistic hypotheses for future cancer research. Significance: This study offers an innovative approach to examine prediagnostic disease and cancer development in a large national population-based setting and provides a publicly available tool to foster additional cancer surveillance research.
High-Phosphate Diet Induces Exercise Intolerance and Impairs Fatty Acid Metabolism in Mice
Authors: Poghni Peri-Okonny, Kedryn K. Baskin, Gary Iwamoto, Jere H. Mitchell, Scott A. Smith, Han Kyul Kim, Luke I. Szweda, Rhonda Bassel-Duby, Teppei Fujikawa, Carlos M. Castorena, James Richardson, John M. Shelton, Colby Ayers, Jarett D. Berry, Venkat S. Malladi, Ming-Chang Hu, Orson W. Moe, Philipp E. Scherer, Wanpen Vongpatanasin
Journal: Circulation (2019)

Background: Inorganic phosphate (Pi) is used extensively as a preservative and a flavor enhancer in the Western diet. Physical inactivity, a common feature of Western societies, is associated with increased cardiovascular morbidity and mortality. It is unknown whether dietary Pi excess contributes to exercise intolerance and physical inactivity. Methods: To determine an association between Pi excess and physical activity in humans, we assessed the relationship between serum Pi and actigraphy-determined physical activity level, as well as left ventricular function by cardiac magnetic resonance imaging, in DHS-2 (Dallas Heart Study phase 2) participants after adjusting for relevant variables. To determine direct effects of dietary Pi on exercise capacity, oxygen uptake, serum nonesterified fatty acid, and glucose were measured during exercise treadmill test in C57/BL6 mice fed either a high-Pi (2%) or normal-Pi (0.6%) diet for 12 weeks. To determine the direct effect of Pi on muscle metabolism and expression of genes involved in fatty acid metabolism, additional studies in differentiated C2C12 myotubes were conducted after subjecting to media containing 1 to 3 mmol/L Pi (pH 7.0) to simulate in vivo phosphate conditions. Results: In participants of the DHS-2 (n=1603), higher serum Pi was independently associated with reduced time spent in moderate to vigorous physical activity ( P =0.01) and increased sedentary time ( P =0.004). There was no association between serum Pi and left ventricular ejection fraction or volumes. In animal studies, compared with the control diet, consumption of high-Pi diet for 12 weeks did not alter body weight or left ventricular function but reduced maximal oxygen uptake, treadmill duration, spontaneous locomotor activity, fat oxidation, and fatty acid levels and led to downregulation of genes involved in fatty acid synthesis, release, and oxidation, including Fabp4 , Hsl , Fasn , and Pparγ , in muscle. Similar results were recapitulated in vitro by incubating C2C12 myotubes with high-Pi media. Conclusions: Our data demonstrate a detrimental effect of dietary Pi excess on skeletal muscle fatty acid metabolism and exercise capacity that is independent of obesity and cardiac contractile function. Dietary Pi may represent a novel and modifiable target to reduce physical inactivity associated with the Western diet.
Pomalidomide + Bortezomib + Low-Dose Dexamethasone Vs Bortezomib + Low-Dose Dexamethasone As Second-Line Treatment in Patients with Lenalidomide-Pretreated Multiple Myeloma: A Subgroup Analysis of the Phase 3 Optimismm Trial
Authors: Meletios A Dimopoulos, Katja Weisel, Philippe Moreau, Larry Anderson, Darrell J White, Jesus F San-Miguel, Pieter Sonneveld, Monika Engelhardt, Matthew W Jenner, Alessandro Corso, Jan Dürig, Michel Pavic, Morten Salomo, Xin Yu, Tuong Vi Nguyen, Amine Bensmaine, Teresa Peluso, Mohamed Zaki, Paul Richardson
Journal: Blood (2018)
Factors Associated with Progression of Japanese Open-Angle Glaucoma with Lower Normal Intraocular Pressure
Authors: Rei Sakata, Takeshi Yoshitomi, Aiko Iwase, Chota Matsumoto, Tomomi Higashide, Motohiro Shirakashi, Makoto Aihara, Kazuhisa Sugiyama, Makoto Araie
Journal: Ophthalmology (2018)
Updated Safety and Activity of the Investigational Bruton Tyrosine Kinase Inhibitor Zanubrutinib (BGB-3111) in Patients with Mantle Cell Lymphoma
Authors: Constantine S. Tam, Michael Wang, David Simpson, Stephen Opat, Gavin Cull, Javier Munoz, Tycel J. Phillips, Won-Seog Kim, James Hilger, Jane Huang, William Novotny, Judith Trotman
Journal: Blood (2018)
Abstract 12592: Targeted Delivery of AntimiR-23a Using Ultrasound and Microbubbles Suppresses Cardiac Hypertrophy and Improves Cardiac Function in vivo
Authors: Jonathan A Kopechek, Charles F McTiernan, Xucai Chen, Rafey Feroze, Bin Qin, Jissy Cyriac, Linda Lavery, Daniel Whitehurst, Flordeliza S Villanueva
Journal: Circulation (2016)

Background: MicroRNAs ( miRs ) are dysregulated in various cardiovascular diseases. An antimiR against miR-23a suppressed hypertension-induced cardiac hypertrophy in preclinical models, but clinical translation is limited by a lack of cardiac-targeted delivery systems. Ultrasound-targeted microbubble (MB) destruction (UTMD) is a novel therapeutic delivery platform that utilizes MBs as nucleic acid carriers and offers a non-invasive image-guided approach to target delivery of molecular therapeutics to the heart. We hypothesized that cardiac delivery of an antimiR against miR-23a using UTMD suppresses cardiac hypertrophy and improves cardiac function in hypertensive mice. Methods: Cationic lipid MBs were loaded with negative control antimiR ( NC ) or antimiR-23a. C57BL/6 mice were implanted with phenylephrine-loaded osmotic minipumps (100 mg/kg/d) and received UTMD treatments (1.3 MHz, MI setting=1.0) with 300 pmol antimiR 0, 3, and 7 days later. A third group (no phenylephrine, No-PE) of age matched mice received no treatments. At 2 weeks, miR-23a levels were measured using RT-PCR. Left ventricular (LV) mass and function were serially assessed with echocardiography. Results: UTMD treatment with antimiR-23a knocked down cardiac miR-23a by 41 ± 8% compared to UTMD treatment with NC (n=8-9/group, p&lt;0.01). As expected, phenylephrine increased LV mass relative to No-PE mice. However, compared to treatment with UTMD + NC, LV mass in mice with UTMD + antimiR-23a was 16 ± 2% lower after 1 week (p &lt; 0.05), and remained lower during the study (p=0.06) (Figure 1). By 2 weeks, fractional shortening had decreased in UTMD + NC but was preserved in UTMD + antimiR-23a (45.2% vs. 37.7%, p &lt; 0.05). Conclusions: To our knowledge, this is the first study to demonstrate suppression of cardiac hypertrophy and preservation of cardiac function with UTMD-targeted delivery of a miRNA inhibitor. Our data suggest that UTMD could be used to deliver other miRNA therapeutics for cardiac therapy.
Phase II study of gemcitabine (GEM) plus sirolimus (SIR) in previously treated patients with advanced soft tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) study.
Authors: Xavier Garcia del Muro, Antonio Lopez-Pousa, Javier Martinez-Trufero, Javier Martin Broto, Ricardo Cubedo, Javier Lavernia, Andrés Redondo, Jose A. Lopez-Martin, Nuria Mulet-Margalef, Xavier Sanjuan, Oscar M. Tirado
Journal: Journal of Clinical Oncology (2014)

10594 Background: Combination of chemotherapy and targeted agents could be a strategy to improve efficacy. In preclinical sarcoma models, combination of GEM with SIR enhances apoptosis in vitro and increases anti-tumor efficacy in vivo. A phase I study by our group showed that the combination of both drugs is feasible. Methods: Patients (pts) with advanced STS, previously treated with doxorubicin, no prior GEM, ECOG PS 0-2, and adequate hematological, renal and hepatic function, were included in this phase II study, receiving GEM 800mg/m2 iv at 10mg/m2/minute on days 1 and 8 every 3 weeks plus oral SIR at 5mg daily and, after an amendment because of toxicity, SIR was reduced to 3 mg for the remaining patients. Tumor samples from pts were examined for pS6 expression by immunohistochemistry. The primary endpoint was progression-free rate (PFR) at 3 months. A one-sample binomial design was used (PFR P0=20%, P1=40%, α=0.15, β=0.20), requiring at least 9 of 25 pts free of progression at 3 months to be considered positive. Results: From May 12 to May 13, 28 pts were enrolled at 8 centers. 1 patient was ineligible because of histology. Median age was 53 (22-71). PS: 0-11, 1-14; 2-2 pts. Histologic types were: LMS 5, UPS 5, Lipo 3, SS 3, MPNST 2, EES 2, other 7 pts. All pts were pretreated with anthracyclines. 12 pts received 5 mg and 15 pts received 3 mg of SIR. The median number of cycles administered was 2 (1-6). PFR at 3 and 6 months was 44% and 20% respectively, with 12 pts being free of progression at 3 months. Median progression-free survival was 1.85 months (95% CI, 0.7-2.9) and median overall survival was 9.1 months (95% CI, 6.1-12.2). No objective responses were observed. Most common grade 3-4 toxicities were neutropenia (44%) with 2 episodes of neutropenic fever, infection (15%), thrombopenia, hepatotoxicity and pneumonitis (11% each). Other toxicities of varying grades included asthenia, emesis, diarrhea and mucositis. No association between pS6 staining and outcome was found. Conclusions: The study achieves its primary endpoint. Nevertheless, the combination of GEM and SIR appears to have modest clinical activity and significant toxicity in pts with advanced STS. Clinical trial information: NCT01684449.
Abstract 20774: Discharge Heart Rate and Outcomes in Hospitalized Patients With Heart Failure and Preserved Ejection Fraction (HFpEF) and Stable Admission-to-Discharge Heart Failure
Authors: Prakash Deedwania, Phillip H Lam, Gurusher Panjrath, Daniel J Dooley, Cherinne Arundel, Gerasimos Filippatos, Javed Butler, Charity Morgan, Marc Blackman, Ross Fletcher, Michel White, Wen-Chih Wu, Stefan D Anker, Gregg C Fonarow, Ali Ahmed
Journal: Circulation (2016)

Background: A lower heart rate (HR) has been shown to be associated with improved outcomes in patients with stable chronic HF. However, this association has not been well studied in hospitalized pa...
Sorafenib discontinuation due to toxicity: A literature-based meta-analysis and meta-regression analysis of 18 randomized controlled trials in solid and hematologic malignancies.
Authors: Johanna Wassermann, Olivier Huillard, Benoit Rousseau, Julien Peron, Manuel Jorge Rodrigues, Jean-Philippe Spano, Mohamed Bouattour
Journal: Journal of Clinical Oncology (2014)

e13545 Background: Prevalence of toxicities is different among pivotal trials of sorafenib. We aim to investigate factors associated with toxicity in randomized placebo controlled trials (RCT) with sorafenib in solid and hematologic malignancies. Methods: Comprehensive search for published RCT, two independent reviews of each study, and data extraction were performed following PRISMA guidelines. A random-effects model was used to calculate the pooled odds ratio (OR) for drug discontinuation due to toxicity (sorafenib vs placebo arms) and 95% IC. Subgroup, sensibility and meta-regression analyses were also conducted. Results: Eighteen RCT composed of 5,812 patients contributed to the analysis. Sorafenib was evaluated in monotherapy (n=6) or in combination with chemotherapy (n=10) or targeted therapy (n=2) in hematologic (n=1) or solid malignancies (n=17). Patients treated with sorafenib experienced significantly more drug discontinuation for toxicity than those treated with placebo (OR 2.38; 95% CI, 1.61 to 3.54; p<0.0001). No significant difference in term of drug discontinuation due to toxicity was observed according to tumor site or clinical trial start year. In univariate meta-regression, factors associated with the risk of drug discontinuation due to toxicity were overall survival (OR 2.36 per 1 year increase; 95% CI, 1.27 to 4.39; p=0.018), progression free survival (OR 3.20 per 6 months increase; 95% CI, 1.27 to 8.05; p=0.025) and performans status 0 in more than half of the patients (OR 2.56; 95% CI, 1.12-5.84; p=0.043). In contrast, treatment duration was not associated with drug discontinuation due to toxicity (OR 1.06 per month increase; 95% CI, 0.79 to 1.42; p=0.718). In multivariate meta-regression overall survival was the only factor significantly associated with drug discontinuation due to toxicity. Conclusions: Sorafenib discontinuation due to toxicity was more common in RCT with prolonged overall survival, independently of drug duration. Our findings support the hypothesis that patients and/or investigators in RCT may be more likely to discontinue treatment for toxicity in patients with better prognosis.
G-CSF related bone pain (BP) and Bv8/PK2 expression: Is there a link in breast cancer (BC) patients (pts) treated with FEC100 adjuvant chemotherapy (CT)?
Authors: Luigi Rossi, Federica Tomao, Giuseppe Lo Russo, Roberta Lattanzi, ANSELMO PAPA, Pierluigi Benedetti Panici, Silverio Tomao, Lucia Negri
Journal: Journal of Clinical Oncology (2014)

e20672 Background: G-CSF is the main regulator of granulopoiesis and neutrophil mobilization from bone marrow. Approximately 20% of cancer pts experience BP with administration of prophylactic G-CSFs. Bv8 mammalian homologue (prokineticin PK2) has been identified and linked to several biological effects as angiogenesis, cancer progression, haematopoiesis and nociception. Bv8 expression is dramatically enhanced by G-CSF, both in vitro and in vivo. Mechanisms involved in such up-regulation remain unknown. Methods: 20 BC pts were submitted to adjuvant FEC100. G-CSF was given as primary prophylaxis. 12 pts received Lenograstim (L: 5 doses, beginning 96 hours after CT) while 8 pts received Pegfilgrastim (P: 1 dose 24 hours after CT). Real-Time PCR and Elisa test were used to analyze Bv8/PK2 expression both in pts receiving L and P. Blood samples for Bv8/PK2 analysis were taken in different steps and days, in order to evaluate Bv8/PK2 expression according to CT time and G-CSF administration. Incidence of neutropenia (N), febrile-N and BP (NRS) were evaluated in all CT cycles. 6 healthy women were recruited as controls to evaluate their Bv8/PK2 basal level. Results: An impressive increase of Bv8/PK2 expression was observed both in L and P group. N occurred in 41.6% of pts treated with L (G3: 8.3%; G4: 16.7%) and in 75% of pts with P (G3: 12.5%; G4: 62.5%; 1 FN). In pts receiving L an incidence of BP occurred in 59.3% (NRS 7-8: 41%) with a mean duration of 6 days; in P group incidence was 37.5% (NRS 7-8: 37.5%), BP lasting 4 days. In all pts BP started within 24-48 hours after G-CSF administration, concurrently with Bv8/PK2 overexpression. Conclusions: Our preliminary results suggest an emerging role of Bv8/prokineticin system in occurrence of G-CSF related BP in primary prevention of CT induced N. Therefore, inhibition of Bv8/PK2 activity should constitute a promising therapeutic strategy to prevent inflammatory pain and perhaps other cancer characteristics (neoangiogenesis). Additional studies are required to further define relationship between G-CSF and Bv8/PK2 in different pathophysiological conditions.
Role of the PI3K Pathway in the Pathogenesis of Marginal Zone Lymphoma
Authors: Ariel Sindel, Ian McConnell, Jolene Windle, Roy Sabo, Alden Chesney, Guanhua Lai, Adolfo Mauro, Taha Al-Juhaishi, Mohamed Rahmani, Jamal Zweit, Steven Grant, Steven Grossman, Victor Youssef Yazbeck
Journal: Blood (2018)
Laparoscopic resection followed by decompression with a drainage tube for obstructive colorectal cancer.
Authors: Yoshinori Kagawa, Kohei Murata, Atsushi Naito, Kenji Kawai, Yutaka Takeda, Atsushi Takeno, Toru Masuzawa, Yoshiaki Ohmura, Yoshiteru Katsura, Kohei Murakami, Takuya Sakamoto, Ryota Mori, Yohei Nose, Keisuke Toya, Yoshiro Yukawa, Kouki Takase, Takeshi Kato
Journal: Journal of Clinical Oncology (2018)

844 Background: Obstructive colorectal cancer is an oncological emergency that requires emergency treatment. In Japan, laparoscopic resection after decompression with metallic-stent placement is becoming mainstream as a bridge to surgery (BTS). However, there are reports of worse prognoses due to stent placement, and the European Gastroenterology Society of Endoscopy guidelines do not recommend BTS. In our department, since 2011 the first choice of the treatment has been laparoscopic resection after decompression with a trans-anal or trans-nasal drainage tube. STo investigate the safety and short- and long-term results of laparoscopic resection after decompression with a drainage tube. Methods: Eighty-one cases of obstructive colorectal cancer that underwent surgery at our hospital from 2011 to 2016 were investigated with regards to the short- and long-term outcomes of treatment strategies for obstructive colorectal cancer. Results: The median age was 72 years old (39-94). The ratio of male to female was 46:29. The success rate of decompression was 86.7% (66 cases). Stages II, III and IV were involved in 25, 28 and 28 cases, respectively. The causes of the emergency operations were an inability to insert both the ileus tube and the stent (9.3%, 7 cases), and perforation (2.7%, 2 cases) when the trans-anal ileus tube was inserted. In the cases in which decompression was possible, the laparoscopic operation rate was 89.4% (56 cases) and the primary resection rate was 90.9% (59 cases). The median surgical time was 194 minutes (27-325), the median blood loss was 10 g (0-660 g),The median postoperative hospital stay was 14 days (5-147 days). The rate of anastomotic leak was 4.5%. There were no deaths within 30 and 90 days after surgery. The relapse free survival rate in Stage II and III were 72% and 67.9%, respectively. The median months of overall survival in Stage II, III and IV were 60.4, 56.3 and 18.7, respectively. Conclusions: A treatment strategy with laparoscopic resection followed by decompression with a drainage tube was performed feasibly and safely. At this time, the effects of a stent on oncological prognosis is unclear, and this strategy could be an effective treatment for obstructive colorectal cancer.
Role of positron emission tomography/computed tomography findings for indications of adjuvant chemotherapy in early lung cancer.
Authors: Shinsuke Sasada
Journal: Journal of Clinical Oncology (2014)

e18500 Background: This study aimed to determine the significance of the maximum standardized uptake value (SUVmax) on F-18-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) images to postoperative adjuvant chemotherapy for early lung adenocarcinoma. Methods: We inestigated recurrence-free interval (RFI) and overall survival (OS) based on SUVmax values derived from preoperative FDG-PET/CT images of 174 consecutive patients with pathological T1b-2aN0M0 lung adenocarcinoma performed the complete resection. Results: Ninety patients received adjuvant chemotherapy and 84 did not. Adjuvant chemotherapy conferred benefits upon RFI and OS compared with observation (RFI, p = 0.007 and OS, p = 0.004). Multivariate Cox regression analyses revealed SUVmax as an independent prognostic factor for RFI. The RFI and OS were significantly longer for patients who received adjuvant chemotherapy compared with those who did not in the group with SUVmax ≥ 2.6 (p < 0.001 and p < 0.001, respectively). However, RFI and OS did not significantly differ between such patients in the group with SUVmax < 2.6 (p = 0.421 and p = 0.452, respectively). Conclusions: Preoperative SUVmax derived from FDG-PET/CT images reflected the effect of postoperative adjuvant chemotherapy in patients with pathological T1b-2aN0M0 lung adenocarcinoma. Indications for postoperative adjuvant chemotherapy among patients with early lung adenocarcinoma might be more precisely determined using SUVmax derived from FDG-PET/CT images together with tumor size.
Outcome data for patients with colorectal cancer treated with adjuvant chemotherapy at our institution.
Authors: Madhu Kumar Emani, Dat C. Pham, John Ho Vu
Journal: Journal of Clinical Oncology (2014)

e14640 Background: Outcome data for patients with colorectal cancer treated with adjuvant chemotherapy have not been analyzed at our institution. Our regimen (FLOX1) is a variation of FOLFOX and is given as bolus instead of continuous infusion. Patients without access to infusional FOLFOX regimen received FLOX1 regimen. FLOX1 consisted of bolus 5-FU 500 mg/m2 IV and leucovorin (LV) 20 mg/m2 IV both on days 1,8, and 15, and oxaliplatin 85 mg/m2 IV on days 1 and 15 every 28-day cycle for six cycles. Our regimen is similar to the FLOX bolus regimen (bolus 5-FU 500 mg/m2 and LV 500 mg/m2 on days 1,8,15,22,29, and 36 and oxaliplatin 85 mg/m2 on days 1,15 and 29 of the cycle) used in the NSABP C-07 study. When compared to FOLFOX, the FLOX regimen was comparable in terms of disease-free survival (DFS). Methods: We retrospectively reviewed data from 256 patients treated with FLOX1 for stage II or III colon cancer after a curative resection. Patients were included in the study only if they had stage II or III colon cancer, underwent a surgical resection, received FLOX1 chemotherapy and had records that documented follow-up for at least 3 years since the first cycle of chemotherapy. We looked at the three-year DFS and compared the DFS of our study to the DFS of the NSABP C-07 study. Results: Of the 256 patients screened, 26 were included in the study. Of these 26 patients, 12% had stage II and 88% had stage III disease. All the patients completed six cycles of FLOX1. Fifteen patients were alive and disease-free after three years. The three-year DFS was 58% compared to 76% in the NSABP C-07 study. Our study population had 88% node positive disease compared to 71% in the NSABP C-07 study. Conclusions: The three-year DFS for FLOX1 was not as high as compared to FLOX. However, our patients had more node-positive disease which may have accounted for the inferior three-year DFS. Also it was a retrospective study with small sample size. The schedule of FLOX1 may be more convenient. Further randomized studies are needed to determine whether FLOX1 is as effective as FLOX for adjuvant treatment of colon cancer.
MDS Diagnosis: Many Patients May Not Require Bone Marrow Examination
Authors: Howard S. Oster, Simon Crouch, Alexandra Smith, Ge Yu, Bander Abu Shrkihe, Shoham Baruch, Albert Kolomansky, Jonathan Ben-Ezra, Shachar Naor, Pierre Fenaux, Argiris Symeonidis, Reinhard Stauder, Jaroslav Cermak, Guillermo Sanz, Eva Hellström-Lindberg, Luca Malcovati, Saskia Langemeijer, Ulrich Germing, Mette Skov Holm, Krzysztof Madry, Agnes Guerci-Bresler, Dominic Culligan, Laurence Sanhes, Juliet Mills, Ioannis Kotsianidis, Corine van Marrewijk, David Bowen, Theo de Witte, Moshe Mittelman
Journal: Blood (2018)