tbuckley/cabot-search huggingface dataset:
Olanzapine (OLN) versus aprepitant (APR) in patients receiving high-emetogenic chemotherapy: Final results of randomized phase II trial.
Authors: Alexey Rumyantsev, Elena Glazkova, Rukhshona Nasyrova, Ekaterina Ignatova, Lia Chitia, Anna Popova, Dzhennet Chekini, Yaroslava Kochetkova, Sergei Kit, Kheda Elsnukaeva, Sophia Menshikova, Olga Sekhina, Ilya Pokataev, Alexandra Tyulyandina, Marina Stenina, Mona A. Frolova, Anatoly Bulanov, Mikhail Fedyanin, Alexey Tryakin, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2019)

11504 Background: Management of chemotherapy-induced nausea and vomiting (CINV) remains challenging. OLN might provide several benefits over APR which is current standard of care – particularly in terms of nausea control and cost effectiveness. However, sedation associated with recommended doses of olanzapine precludes its wide use in oncology practice. Methods: This was randomized phase II single center study aimed to compare OLN and APR in CINV prophylaxis. Key inclusion criteria were: chemo- and radio-therapy naïve patients, planned administration of high-emetogenic chemotherapy (cisplatin, carboplatin AUC≥4, doxorubicin etc). Patients were randomized 1:1 ratio in the following arms: olanzapine 5 QD day 0-4 or aprepitant 125 mg day 1, 80 mg day 2,3. All patients received ondansetron 16 mg day 1 and dexamethasone 8 mg day 1-3. Primary endpoint was complete nausea control (no nausea and no rescue medication) 0-120 hours after chemotherapy. Complete response (no emesis and no rescue medication) was a key secondary end point. Nausea was assessed using MASCC Antiemesis Tool. Sample size: 94 patients to increase nausea control rate from 40 to 70% (α = 0.05; β = 0.80; 10% of estimated data loss). Results: We included in the analysis 93 patients who could be evaluated. The groups were well balanced, median age was 49 years, vast majority of patients (95.6%) were females. The proportion of patients with complete nausea control in OLN and APR groups was 44.2% and 24.0% respectively (RR 2.5; 95% CI 1.04-6.08; p = 0.039). Complete response was achieved in 74.4% and 54.0% patients respectively (RR 2.48; 95% CI 1.026-5.99; p = 0.041). No differences in rates of undesired sedations were detected. Conclusions: Our data suggests superiority of OLN regimen in terms of nausea control. This regimen deserves further investigation. Clinical trial information: NCT03478605.
Metabolic profile and neoadjuvant chemotherapy sensitivity in high-grade bone sarcoma.
Authors: Pascaline Boudou-Rouquette, Ithar Gataa, Anne Jouinot, Sixtine De Percin, Audrey Bellesoeur, Jerome Alexandre, Valérie Dumaine, Antoine Babinet, David Biau, Virginie Audard, Frederique Larousserie, Philippe Anract, Camille Tlemsani, Francois Goldwasser
Journal: Journal of Clinical Oncology (2019)

e22506 Background: Neoadjuvant chemotherapy with intercalated surgery is the standard of care for resectable high-grade bone sarcoma (BS) but identification of biomarkers for chemosensitivity prediction is still needed. Methods: We recruited 121 pts with new primary localized or metastatic BS, measured fasting blood glucose and insulin, body mass index (BMI). The HOMA-IR (Homeostasis Model Assessment) score ((Glucose (mmol/l) x Insulin) / 22.5), which has been proven to reliably detect insulin resistance was calculated, and patients with HOMA-IR &gt; 2.6 were considered as insulin resistant (IR). We collected characteristics usually associated with insulin resistance (IR): age, obesity, diabetes, dyslipidemia and hypertension. Results: Out of 121 pts, 48 (40%) were IR: HOMA-IR &gt; 2.6. Thirty IR patients (62%) had no cardiovascular risk factor. In univariate analysis, IR was associated with obesity (BMI &gt; 30 kg/m 2 )(23% vs 3%, p = 0.0013), but not with age (median 38.4 vs 43.3 years, p = 0.15). IR was more prevalent in Ewing sarcoma (12/21; 57%) and chondrosarcoma (7/13; 54%) followed by osteosarcoma (25/61; 41%) and other rare bone sarcomas (4/26; 15.3%)(p = 0.037). After preoperative chemotherapy and surgery of Ewing tumor and osteosarcoma, pathologic tumor necrosis was higher in IR pts (85.8 vs 69.3%, p = 0.012). Using multivariate linear regression models, IR was independently associated with pathologic tumor necrosis (p = 0.042) but not with obesity (p = 0.55). Conclusions: Our results suggest that tumor-induced metabolic profile may help to discriminate best candidates for preoperative chemotherapy in high-grade bone sarcomas. Further studies are needed to confirm and explain these results.
A single-center retrospective study of patients treated with trabectedin (TRB) with long-term follow up.
Authors: Brett A. Schroeder, Chad He, Yuzheng Zhang, Michael Wagner, Robin Lewis Jones, Lee D. Cranmer, Seth Pollack
Journal: Journal of Clinical Oncology (2019)

11061 Background: TRB is FDA approved drug for the treatment of liposarcoma (Lipo) and leiomyosarcoma (LMS). The aim of this study was to evaluate potential biomarkers associated with prolonged benefit in patients treated with TRB at our center prior to 2016. Methods: We performed a retrospective search of UW/FHCRC CASIS database to identify patients treated with TRB prior to 2016. Demographic variables and clinical variables (such as histology and treatment) were retrieved. Statistics were performed with R 3.4.1 software. Pairwise Pearson’s correlation was calculated for the # of prior chemotherapy regimens with # of TRB cycles. The Kaplan-Meir method was used to evaluate overall survival (OS). Log-rank test was conducted to compare groups in terms of OS. Results: 145 sarcoma patients treated with TRB were identified with a mean follow up of 5 years (generally on NCT01427582 or NCT01343277). Patients averaged 1.9 prior chemotherapy regimens prior to TRB (range 0-7 regimens) and received an average of 5.6 TRB doses (range 1-25 doses). Subtypes are listed on table. The # of prior regimens was negatively correlated with the # of TRB cycles that patients received (pairwise correlation coefficient = -1.77; p=0.034), suggesting that multiple prior treatment lines either made TRB less tolerable or made sarcoma less sensitive to TRB. The median OS for this heavily treated metastatic population was 0.5 years. However, patients who were able to stay on TRB for more than 5 cycles had a significantly higher OS (p=0.001). While only 23% of patients who received less than 5 cycles of TRB were alive at 5 years (95% CI: 0.15, 0.32), 53% of those who received 5 or more cycles of (95% CI: 0.39, 0.65) were alive at 5 years. Conclusions: TRB may be more effective when administered as an earlier line of therapy. Patients who are able to stay on TRB for a longer duration had a significant improvement in OS. Detailed subset analysis will be presented as will initial findings of our biomarker work. These retrospective data warrant further evaluation. Clinical trial information: NCT01427582 or NCT01343277. [Table: see text]
Voluntary Wheel Running Has Beneficial Effects in a Rat Model of CKD-Mineral Bone Disorder (CKD-MBD)
Authors: Keith G. Avin, Matthew R. Allen, Neal X. Chen, Shruthi Srinivasan, Kalisha D. O’Neill, Ashley D. Troutman, Garrison Mast, Elizabeth A. Swallow, Mary Beth Brown, Joseph M. Wallace, Teresa A. Zimmers, Stuart J. Warden, Sharon M. Moe
Journal: Journal of the American Society of Nephrology (2019)

Significance Statement Impaired musculoskeletal health in individuals with CKD reduces their ability to participate in activities and quality of life, and increases the risk of illness, injury, and death. Exercise studies in animals or people with CKD have produced inconsistent results about the potential benefits on the musculoskeletal system and few studies have examined the systemic effects of exercise in CKD. The authors show that 10 weeks of voluntary wheel running in rats with CKD improved multiple systems, including mineral metabolism, left ventricular mass, physical function, and bone health. The results suggest physical activity may help patients with CKD, but further studies are needed to establish the most efficacious modalities and optimal dose. Background Reduced bone and muscle health in individuals with CKD contributes to their higher rates of morbidity and mortality. Methods We tested the hypothesis that voluntary wheel running would improve musculoskeletal health in a CKD rat model. Rats with spontaneous progressive cystic kidney disease (Cy/+ IU ) and normal littermates (NL) were given access to a voluntary running wheel or standard cage conditions for 10 weeks starting at 25 weeks of age when the rats with kidney disease had reached stage 2–3 of CKD. We then measured the effects of wheel running on serum biochemistry, tissue weight, voluntary grip strength, maximal aerobic capacity (VO 2max ), body composition and bone micro-CT and mechanics. Results Wheel running improved serum biochemistry with decreased creatinine, phosphorous, and parathyroid hormone in the rats with CKD. It improved muscle strength, increased time-to-fatigue (for VO 2max ), reduced cortical porosity and improved bone microarchitecture. The CKD rats with voluntary wheel access also had reduced kidney cystic weight and reduced left ventricular mass index. Conclusions Voluntary wheel running resulted in multiple beneficial systemic effects in rats with CKD and improved their physical function. Studies examining exercise interventions in patients with CKD are warranted.
RNA silencing of RPL19 modulates the malignant phenotype of prostate cancer
Authors: Alix Bee, Brian Lane, Paul Smith, Carol Beesley, Youqiang Ke, Christopher Foster
Journal: Cancer Research (2008)

4417  Introduction and Methods: Ribosomal protein L19 (RPL-19) mRNA is differentially expressed in benign and malignant prostatic cell lines and tissues. In-situ hybridization confirmed it to be as accurate as Gleason score in predicting patient outcome and hence a powerful novel indicator of prostatic malignancy. As an integral member of the ribosomal protein complex, RPL-19 is potentially able to modulate the expression of other cellular proteins, thus contributing to the malignant phenotype. To investigate the role of RPL-19, siRNA was used to inhibit expression of the gene in PC3M prostatic cancer cells. The siRNA target was designed against exon 11 of RPL19 variant “c”, the RefSeq version of the gene (NM_000981) in prostatic epithelial cells. Exon 11 was chosen as a candidate for suppression since it is included in seven of eight potential RPL-19 splice variants. Transient and stable transfectants have been constructed and cloned.  Results: Quantitative PCR of siRPL-19 transfectants confirmed that expression in the malignant cells was reduced by approximately 70% to levels at or below those of benign prostatic PNT2 cells. Expression levels remained low in subsequent sub-cultures. Morphologically, transfected RPL-19 cells were significantly less adhesive than the parental cells, but remained viable. Western blot analysis was used to determine the effect of RPL-19 silencing on protein production. The role of RPL-19 knockdown in apoptosis was confirmed by Annexin-V flow cytometric assay following apoptotic challenge using campothecin, taxol and U/V light. Invasion assays were performed to identify the effect of RPL-19 inhibition on cell migration and invasion. Downstream genomic effects of inhibiting RPL-19 were defined using the two color Human Genome DNA Expression Microarray (Agilent Technologies), particular attention being paid to genes involved in cell adhesion and invasion.  Conclusion: Successful suppression of RPL-19 in prostate cancer has provided a novel insight into the role of ribosomal proteins in the malignant progression of prostatic epithelial cells, particularly in apoptosis, invasion and metastasis.
The prognostic impact from the difference of surgical procedure after ipsilateral breast cancer recurrence.
Authors: Atsushi Yoshida, Nobuyuki Arima, Katsuhiko Nakatsukasa, Yasuhiro Okumura, Takuji Iwase, Tadahiko Shien, Norikazu Masuda, Satoru Tanaka, Masahiko Tanabe, Takehiro Tanaka, Yoshifumi Komoike, Tetsuya Taguchi, Reiki Nishimura, Hideo Inaji, Hideko Yamauchi, Makoto Ishitobi
Journal: Journal of Clinical Oncology (2013)

1106 Background: Mastectomy is the current standard of surgical procedure for ipsilateral breast cancer recurrence (IBTR). However, there is little evidence about a prognostic impact of surgical procedure after IBTR, due to small number of incidence of IBTR. Methods: A total of 271 consecutive patients who had histologically confirmed IBTR without distant metastases and underwent definitive surgery for the IBTR between 1989 and 2008 were included from eight institutions as a scientific research from the Japanese Breast Cancer Society. Distant Disease free survival (DDFS) rates were calculated by the Kaplan-Meier method. Univariate analysis was performed using the log rank test and multivariate analysis by Cox's proportional hazard model. Results: Of the 271 patients, 149 patients (55%) underwent lumpectomy and 122 patients (45%) underwent mastectomy after IBTR. One hundred thirty four patients (49%) did not receive radiation therapy after initial lumpectomy (52% in lumpectomy patients and 47% in mastectomy patients). The median follow-up period from definitive surgery for IBTR was 55 months. Seventy-six patients (28.2%) relapsed after IBTR (23.7% of lumpectomy patients, 33.6% of mastectomy patients). In comparing groups by type of surgery, patient and tumor demographics in each group were significantly less positive HER2 status and smaller tumor size of IBTR, and more receiving adjuvant endocrine therapy and less adjuvant chemotherapy for IBTR in lumpectomy patients compared with mastectomy patients. On univariate analysis, lumpectomy group was significantly longer DDFS than mastectomy group (p=0.012), but this difference was not appeared on multivariate analysis (p=0.35). Furthermore, only using small IBTR (&lt;2cm) population, this difference was not appeared (p=0.71). On multivariate analysis, the time intervals from initial surgery to IBTR (&lt;5years) (HR, 1.93; 95%CI, 1.01-3.67; p=0.047) and lymphovascular invasion of the IBTR (HR, 2.31; 95%CI, 1.18-4.52; p=0.015) were independent predictive factor for poor DDFS. Conclusions: Our study suggests that the type of surgical procedure after IBTR does not affect DDFS. Further analyses are needed. (UMIN-CTR number UMIN000008136).
The evolutionary history of human colitis-associated colorectal cancer
Authors: Baker A-M., W Cross, K Curtius, Choi C-Hr., I Al-Bakir, D Temko, P Martinez, M Williams, H Davis, S Biswas, N A Wright, M Moorghen, S J Hayes, M Rodriguez-Justo, A Silver, L M Wang, M Jansen, A L Hart, S J Leedham, T A Graham
Journal: Cancer Research (2018)
Pegylated interferon alfa-2a for polycythemia vera or essential thrombocythemia resistant or intolerant to hydroxyurea
Authors: Abdulraheem Yacoub, John Mascarenhas, Heidi Kosiorek, Josef T. Prchal, Dmitry Berenzon, Maria R. Baer, Ellen Ritchie, Richard T. Silver, Craig Kessler, Elliott Winton, Maria Chiara Finazzi, Alessandro Rambaldi, Alessandro M. Vannucchi, David Leibowitz, Damiano Rondelli, Murat O. Arcasoy, Rosalind Catchatourian, Joseph Vadakara, Vittorio Rosti, Elizabeth Hexner, Marina Kremyanskaya, Lonette Sandy, Joseph Tripodi, Vesna Najfeld, Noushin Farnoud, Elli Papaemmanuil, Mohamed Salama, Rona Singer-Weinberg, Raajit Rampal, Judith D. Goldberg, Tiziano Barbui, Ruben Mesa, Amylou C. Dueck, Ronald Hoffman
Journal: Blood (2019)
Liquid versus tissue biopsy for detecting acquired resistance and tumor heterogeneity in gastrointestinal cancers
Authors: Aparna R. Parikh, Ignaty Leshchiner, Liudmila Elagina, Lipika Goyal, Chaya Levovitz, Giulia Siravegna, Dimitri Livitz, Kahn Rhrissorrakrai, Elizabeth E. Martin, Emily E. Van Seventer, Megan Hanna, Kara Slowik, Filippo Utro, Christopher J. Pinto, Alicia Wong, Brian P. Danysh, Ferran Fece de la Cruz, Isobel J. Fetter, Brandon Nadres, Heather A. Shahzade, Jill N. Allen, Lawrence S. Blaszkowsky, Jeffrey W. Clark, Bruce Giantonio, Janet E. Murphy, Ryan D. Nipp, Eric Roeland, David P. Ryan, Colin D. Weekes, Eunice L. Kwak, Jason E. Faris, Jennifer Y. Wo, François Aguet, Ipsita Dey-Guha, Mehlika Hazar-Rethinam, Dora Dias-Santagata, David T. Ting, Andrew X. Zhu, Theodore S. Hong, Todd R. Golub, A. John Iafrate, Viktor A. Adalsteinsson, Alberto Bardelli, Laxmi Parida, Dejan Juric, Gad Getz, Ryan B. Corcoran
Journal: Nature Medicine (2019)
Biodegradable, pH-Sensitive Hollow Mesoporous Organosilica Nanoparticle (HMON) with Controlled Release of Pirfenidone and Ultrasound-Target-Microbubble-Destruction (UTMD) for Pancreatic Cancer Treatment
Authors: Feng Gao, Jianrong Wu, Shiwei Niu, Ting Sun, Fan Li, Yun Bai, Lifang Jin, Lizhou Lin, Qiusheng Shi, Li-Min Zhu, Lianfang Du
Journal: Theranostics (2019)

The dense extracellular matrix (ECM) and hypovascular networks were often found in solid pancreatic tumors form an impenetrable barrier, leading to limited uptake of chemotherapeutics and thus undesirable treatment outcomes. Methods: A biodegradable nanoplatform based on hollow mesoporous organosilica nanoparticle (HMON) was designed as an effective delivery system for pirfenidone (PFD) to overcome the challenges in pancreatic tumor treatment. By varying pH producing a mildly acidic environment to emulate tumor cells, results in cleavage of the acetal bond between HMON nanoparticle and gating molecular, gemcitabine (Gem), enabling its controlled release. Results: The in vitro and in vivo immunocytochemistry evaluations demonstrated an excellent ECM regulation efficacy of the nanoplatform and therefore the improved penetration of drug into the cells. The technique employed was especially enhanced when mediated with ultrasound target microbubble destruction (UTMD). Evaluations culminated with pancreatic cancer bearing mice and demonstrated therapeutic efficacy, good biodegradability, and negligible systemic toxicity. Conclusion: the designed Gem gated biodegradable nanosystem is expected to provide an alternative way of improving antitumor efficacy by down-regulation of ECM levels and offers a passive-targeted therapy for pancreatic cancer treatment.
New Guidelines and SPRINT Results
Authors: Mark A. Supiano, Jeff D. Williamson
Journal: Circulation (2019)

he projected growth in the geriatric age population, its high cardiovascular disease risk, and its prevalence of hypertension that exceeds 60% have created a public health opportunity to carefully examine treatment recommendations for hypertension in older individuals.Based on new evidence related to brain health observed in SPRINT (Systolic Blood Pressure Intervention Trial), 1 this perspective from 2 of its investigators highlights the benefits of achieving a lower systolic blood pressure (SBP) goal that should be considered in managing hypertension in older adults.The evolution in the recommended SBP treatment goal for older individuals beginning with the publication of the seminal Systolic Hypertension in the Elderly Program study in 1991 is illustrated in the Figure .The most current (2017) American College of Cardiology/American Heart Association guideline states that an "SBP treatment goal of less than 130 mm Hg is recommended for noninstitutionalized ambulatory community-dwelling adults (≥65 years of age) with an average SBP of 130 mm Hg or higher." 2 This recommendation was based primarily on new evidence from the SPRINT study. 3Of relevance to geriatric hypertension, SPRINT enrolled 2656 participants ≥75 years of age. 4 In this older cohort, a 34% reduction in the cardiovascular disease outcome and 33% reduction in total mortality were identified with intensive SBP management to a goal of 120 mm Hg.These benefits were noted among the frailest older participants and were not accompanied by any serious, irreversible adverse events.It is notable that the rate of injurious falls did not differ by treatment group, even among participants ≥85 years of age.Moreover, the rates of withdrawal and loss to follow-up did not differ according to the treatment arm.SPRINT was also designed to address the hypothesis that the incidence of allcause dementia would be lower with intensive SBP treatment in its Memory and Cognition in Decreased Hypertension (MIND) component.Cognitive data collection continued beyond the termination of the active intervention at 3.26 years, and these data are now available from 8563 SPRINT participants followed up for an average of 5.11 years. 1 Although the 17% reduction in adjudicated all-cause probable dementia in the intensive relative to the standard group did not achieve statistical significance, there were significant reductions of the same magnitude in the occurrence of mild cognitive impairment (MCI; 19%; P=0.01) and in the composite outcome of MCI or dementia (15%; P=0.02).It is important to recognize that MCI is a distinct clinical condition that is an obligatory precursor to developing dementia.Estimates for the rate of progression from MCI to dementia range from 10% to 22% per year, depending on the study cohort's risk factors and the type of MCI, with its amnestic form being more likely to progress.Demonstrating a delay in developing MCI has important public health implications.Postponing the development of dementia by 2 years could result in a 20% decrease in the number
A risk prediction model for the development of subsequent primary melanoma in a population‐based cohort
Authors: A.E. Cust, C. Badcock, J. Smith, N.E. Thomas, L.E. Haydu, B.K. Armstrong, M.H. Law, J.F. Thompson, P.A. Kanetsky, C.B. Begg, Y. Shi, A. Kricker, I. Orlow, A. Sharma, S. Yoo, S.F. Leong, M. Berwick, D.W. Ollila, S. Lo
Journal: British Journal of Dermatology (2019)

Guidelines for follow‐up of patients with melanoma are based on limited evidence. To guide skin surveillance, we developed a risk prediction model for subsequent primary melanomas, using demographic, phenotypical, histopathological, sun exposure and genomic risk factors. Using Cox regression frailty models, we analysed data for 2613 primary melanomas from 1266 patients recruited to the population‐based Genes, Environment and Melanoma study in New South Wales, Australia, with a median of 14 years' follow‐up via the cancer registry. Discrimination and calibration were assessed. The median time to diagnosis of a subsequent primary melanoma decreased with each new primary melanoma. The final model included 12 risk factors. Harrell's C‐statistic was 0·73 [95% confidence interval (CI) 0·68–0·77], 0·65 (95% CI 0·62–0·68) and 0·65 (95% CI 0·61–0·69) for predicting second, third and fourth primary melanomas, respectively. The risk of a subsequent primary melanoma was 4·75 times higher (95% CI 3·87–5·82) for the highest vs. the lowest quintile of the risk score. The mean absolute risk of a subsequent primary melanoma within 5 years was 8·0 ± SD 4.1% after the first primary melanoma, and 46·8 ± 15·0% after the second, but varied substantially by risk score. The risk of developing a subsequent primary melanoma varies considerably between individuals and is particularly high for those with two or more primary melanomas. The risk prediction model and its associated nomograms enable estimation of the absolute risk of subsequent primary melanoma, on the basis of on an individual's risk factors, and can be used to tailor surveillance intensity, communicate risk and provide patient education. What's already known about this topic? Current guidelines for the frequency and length of follow‐up to detect new primary melanomas in patients with one or more previous primary melanomas are based on limited evidence. People with one or more primary melanomas have, on average, a higher risk of developing another primary invasive melanoma, compared with the general population, but an accurate way of estimating individual risk is needed. What does this study add? We provide a comprehensive risk prediction model for subsequent primary melanomas, using data from 1266 participants with melanoma (2613 primary melanomas), over a median 14 years' follow‐up. The model includes 12 risk factors comprising demographic, phenotypical, histopathological and genomic factors, and sun exposure. It enables estimation of the absolute risk of subsequent primary melanomas, and can be used to tailor surveillance intensity, communicate individual risk and provide patient education.