tbuckley/cabot-search huggingface dataset:
Specificity in endogenous intoxication development in patients with different stages of gynecologic cancer.
Authors: Polina S. Kachesova, Irina A. Goroshinskaya, Ludmila A. Nemashkalova, Elena V. Shalashnaya, Anna Petrovna Menshenina, Elena Aleksandrovna Kalabanova, Sergey N. Kabanov, Irina A. Zhuzhelenko, Oleg Ivanovich Kit
Journal: Journal of Clinical Oncology (2018)

e24093 Background: Disease progression in cancer patients (pts) leads to the development of endogenous intoxication. The aim of the work was to study biochemical changes reflecting endotoxicosis syndrome in pts with cervical (CC) and ovarian cancer (OC) in early and late stages. Methods: The content of medium weight molecules (MM) measured at two peaks (254 and 280 nm), total and effective albumin concentrations (TCA and ECA), the albumin-binding capacity (ABC = ECA/TCA•100%) and intoxication factor IF = (MM254/ECA•1000) were studied in the blood of 27 CC pts stage I-IIB and 25 pts stage IVB, and 10 OC pts stage I-IIB and 18 pts stage IV in comparison with a group of healthy women. Median age of women was 48±3.5 years old. Results: In CC pts I-IIB st, the content of MM did not exceed the normal values, in pts IVB st MM280 increased by 27% (p < 0.05). MM content in OC pts I-IIBst was increased by 25-75% (p < 0.001), progression of OC was accompanied by the increase of MM280 by 49% (p < 0.001). The mean TAC in pts declined on average by 11% (p < 0.05) vs the healthy group, however in the most pts TAC was within the reference range (35-55 g/l). ECA and ABC in all CC pts were lower than the norm by 37-40% (p < 0.001) and 31-36% (p < 0.001) respectively. In OC pts in early stage the ECA and ABC decreased by 20% and 15% (p < 0.01) vs norm, in pts with IV stage were 25% and 22% (p < 0.01) lower than the values in group of I-IIB stage. IF in pts in the early stage exceeded by 1.4-1.5 times (p < 0.001) compared to the norm, at the progression - by 1.6-2.1 times (p < 0.001). In the OC pts IV st IF was 30% (p < 0.05) higher in comparison with CC pts IVB st. Conclusions: Thus, changes in the biochemical indicators showed the presence of endogenous intoxication in gynecological pts in early stage of the disease. In OC pts, first of all, an increase in the level of toxic ligands in the blood was observed, and then the detoxification function of albumin reduced. In CC pts the development of endotoxicosis was due to a change in the binding capacity of albumin. The obtained results can be taken into account when choosing the methods of supplemental therapy, such as dialysis, in CC and OC pts.
Sirtuins and NAD <sup>+</sup> in the Development and Treatment of Metabolic and Cardiovascular Diseases
Authors: Alice E. Kane, David A. Sinclair
Journal: Circulation Research (2018)

The sirtuin family of nicotinamide adenine dinucleotide–dependent deacylases (SIRT1–7) are thought to be responsible, in large part, for the cardiometabolic benefits of lean diets and exercise and when upregulated can delay key aspects of aging. SIRT1, for example, protects against a decline in vascular endothelial function, metabolic syndrome, ischemia-reperfusion injury, obesity, and cardiomyopathy, and SIRT3 is protective against dyslipidemia and ischemia-reperfusion injury. With increasing age, however, nicotinamide adenine dinucleotide levels and sirtuin activity steadily decrease, and the decline is further exacerbated by obesity and sedentary lifestyles. Activation of sirtuins or nicotinamide adenine dinucleotide repletion induces angiogenesis, insulin sensitivity, and other health benefits in a wide range of age-related cardiovascular and metabolic disease models. Human clinical trials testing agents that activate SIRT1 or boost nicotinamide adenine dinucleotide levels are in progress and show promise in their ability to improve the health of cardiovascular and metabolic disease patients.
Human papillomavirus (HPV)-associated malignancies as subsequent malignant neoplasms (SMN) in survivors of childhood cancer: A report from the Childhood Cancer Survivor Study (CCSS).
Authors: Tara O. Henderson, Paul C. Nathan, John Whitton, Wendy M. Leisenring, Joseph Philip Neglia, Brynn Fowler, Michael A. Arnold, Rebecca M. Howell, Leslie L. Robison, Gregory T. Armstrong, Kenneth Alexander
Journal: Journal of Clinical Oncology (2017)

10566 Background: It is not known whether childhood cancer survivors (CCS) develop human papillomavirus (HPV)-associated malignancies more frequently than the general population. Methods: We assessed the cumulative incidence of SMN in sites typically associated with HPV (HPV-SMN) and evaluated standardized incidence ratios (SIR) and absolute excess risks (AER) using age-, sex- and calendar-year specific rates from the Surveillance, Epidemiology and End Results (SEER) program. Multivariate Cox regression models identified associations between key risk factors and HPV-SMN development. Results: Among 27,620 CCS, 36 developed an HPV-SMN at a median age of 27 years (range: 8-42) and a median of 15 years (range: 5-29) after their primary cancer. The 30-year cumulative incidence of an HPV-SMN was 0.20% (95% confidence interval [CI]: 0.13%-0.28%). HPV-SMN locations included oral cavity/pharynx (N = 26, 72%), rectum (N = 4, 11%), cervix/uteri (N = 3, 8%), and vulva (N = 3, 8%). The incidence of HPV-SMN was almost 3-fold higher among CCS than the general population (SIR = 2.8, 95% CI 2.0-4.1) with an AER of 6.0/100,000 person-years. Rates were elevated in those exposed (SIR = 3.3, CI 2.1-5.2) and not exposed to radiotherapy (RT; SIR = 2.6, CI 1.4-4.8). Risk of oral cavity/pharynx SMN was elevated in both those exposed (SIR = 7.3, CI 3.9-13.6) and not exposed (SIR = 4.2, CI 2.2-8.1) to head or neck RT, whereas, risk in GU locations was elevated in those exposed (SIR = 4.1, CI 1.9-9.2) but not in those not exposed to pelvic RT (SIR = 0.8, CI 0.3-2.1). Male sex (HR = 2.9, CI 1.3-6.1), exposure to head/neck/pelvic RT (HR = 2.6, CI 1.2-6.1), and platinum chemotherapy (HR = 6.1, CI: 2.6-13.9) increased the risk. Among 15 deceased HPV-SMN cases, 10 (67%) died of their HPV-SMN. Conclusions: While the overall incidence is low, CCS are at increased risk of developing malignancies in locations commonly associated with HPV infection in the general population. Further research examining the role of HPV in the etiology of these SMNs is warranted. As HPV-SMNs are potentially preventable, promotion of HPV vaccination efforts should be considered in this population.
Prophylactic antibiotics to prevent pneumonia in patients treated with chemoradiotherapy (CRT) for locally advanced head and neck carcinoma (LAHNC).
Authors: Janneke Ham, Chantal Driessen, Mathijs P Hendriks, W. Edward Fiets, Bas Kreike, Ann Hoeben, Marije Slingerland, Claudia van Opstal, Bart-Jan Kullberg, Petronella Peer, Johannes Kaanders, Winette TA van der Graaf, Carla M.L. Van Herpen
Journal: Journal of Clinical Oncology (2016)

6079 Background: Platinum-based CRT is the treatment of choice for LAHNC, but induces a high rate of acute toxicity, including dysphagia and aspiration pneumonia. Aspiration pneumonia often requires hospitalization and negatively influences quality of life (QoL). We hypothesized that prophylactic antibiotics during CRT in LAHNC patients (pts) can prevent pneumonia and hospital admissions. Methods: A multicenter randomized trial was performed. The standard treatment group (STG) received standard care; the intervention group (IG) received prophylactic amoxicillin/clavulanic acid from day 29 until 14 days after completion of CRT. LAHNC pts treated with CRT were registered before start and randomized between day 21-28, unless they received antibiotics 14 days before planned randomization. The primary objective was to measure a reduction in the rate of pneumonias. A confirmed pneumonia was defined as a previously non-existing infiltrate on chest X-ray or ≥ 3 of the following features: sustained fever, rales or rhonchi on chest auscultation, sputum with substantial leukocytes or sputum culture showing a pathogen. A suspected pneumonia was defined as 2 of these features. Results: A total of 106 pts were registered, of which 94 pts were randomized: 48 pts were allocated to the STG and 46 pts to the IG. Pts were equally randomized by minimization for smoking, COPD status, HPV status in oropharyngeal cancer, degree of weight loss, primary tumor site, participating centre and tube feeding at time of randomization. A confirmed or suspected pneumonia during CRT and follow up till 3.5 months was observed in 20 (41.7%) of 48 pts in the STG, and 20 (43.5%) of 46 pts in the IG, respectively (P = 0.56). Hospitalization for any cause (i.e., fever, dehydration, mucositis or pneumonia), was necessary in 17 of 48 pts (35.4%) in the STG versus 9 of 46 pts (19.6%) in the IG (P = .08). Conclusions: Prophylactic antibiotics during CRT for LAHNC did not reduce the rate of pneumonias. However, there is a trend towards a reduced rate of hospitalizations, which potentially may lead to a better QoL and reduction in costs. Currently, further microbiological and cost-effectiveness analyses are being performed. Clinical trial information: NCT01598402.
The GENTleMEN study: Genetic testing for men with metastatic prostate cancer in Washington state and beyond.
Authors: Heather H. Cheng, Deborah Bowen, Nola Klemfuss, Colin M Sievers, Sarah H. Kang, Alicia Zhou, Colin Pritchard, Peter Nelson, Robert B. Montgomery
Journal: Journal of Clinical Oncology (2018)

TPS5098 Background: Germline DNA repair gene mutations are present in ~10% of patients with metastatic prostate cancer (mPC) irrespective of age at diagnosis or family history, and have potential profound implications for treatment, clinical trial selection and family counseling. However, patient/provider lack of awareness, limited access to genetic counseling services, variable insurance coverage and high out-of-pocket costs are known barriers. To remove these barriers and to assess feasibility and acceptability, we are conducting a research study, Genetic Testing for Men with Metastatic Prostate Cancer (GENTleMEN) that offers germline genetic testing to all men in Washington State with mPC. Methods: GENTleMEN is a prospective, observational study. Informed consent is provided via internet access (www.gentlemenstudy.org). Participants complete a HIPAA-compliant, RedCap (web-based) questionnaire including demographics, self-reported family cancer history and validated instruments including GAD7, PHQ9, Cancer Distress, Risk Perception, Decision Conflict, Knowledge of and Concern with Genetic Testing (~40 min). Supporting medical data are uploaded by the participant or, with permission, by the study team. Germline genetic testing is performed on a saliva sample via the CLIA-certified Color Genomics 30-gene targeted panel of cancer predisposition genes (www.color.com) through mail, and results are returned by email and/or phone. Men who test positive for pathogenic or likely pathogenic germline variants are required to receive results by phone from a genetic counselor and are strongly encouraged to share results with their medical providers and families. The study offers follow-up support and access to clinical trials, research and registry participation. Conclusions: Germline genetic testing is expected to become increasingly pertinent to the care of men with mPC and their families. The GENTleMEN study is investigating a novel mechanism to supplement existing genetics services and remove barriers to germline genetic testing. (NCT number pending)
Frequency of post-treatment surveillance and survival in localized prostate cancer: AFT-30 a national study.
Authors: Ronald C. Chen, Zahed Mohammed, Jessica R. Schumacher, Amanda B. Francescatti, Amanda Cuddy, George J. Chang, Benjamin D. Kozower, Caprice Christian Greenberg, Anne McCarthy, Stephen B. Edge, David P Winchester, Ramsankar Basak
Journal: Journal of Clinical Oncology (2018)

6503 Background: The optimal frequency of post-treatment PSA surveillance is undefined, and different existing guidelines based on expert opinions recommend frequencies ranging from 1x/year to 4x/year. Whether more frequent surveillance improves survival is unknown. Methods: Using the backbone of the National Cancer Data Base (NCDB), medical records of 10,477 randomly sampled patients diagnosed with localized prostate cancer from 2005-2010 were abstracted from 1007 sites throughout the US to provide additional data for this study. 53% of the cohort received primary radiotherapy; 47% received radical prostatectomy. Primary exposure is number of post-treatment PSA tests in the first 2 years, and primary outcome is overall survival. Results: There were 4,088 low-risk, 3,241 intermediate, and 3,148 high-risk patients. Median age at diagnosis was 64 years, and median follow-up was 8 years. At last follow-up, 17% (low-risk), 33% (intermediate), and 50% (high-risk) patients had died. Median numbers (IQR) of PSA tests in the first 2 post-treatment years were: 4 (2-5)(low-risk), 4 (2-5)(intermediate), and 4 (2-5)(high-risk). Cox multivariable models showed no significant association between frequency of PSA surveillance and overall survival in any risk group (Table). Conclusions: More frequent PSA surveillance after definitive treatment for localized prostate cancer is not associated with improved survival. This is the first large-scale study to provide data to inform guidelines and patient/physician decisions. Based on these results, surveillance guidelines recommending PSA tests every 3-6 months likely represent overutilization of care. Cox multivariable analysis for overall survival. Low risk HR (p-value) Intermediate risk HR (p-value) High risk HR (p-value) PSA frequency (REF: lowest third) Middle third 1.15 (0.50) 1.11 (0.49) 1.04 (0.73) Highest third 1.14 (0.55) 1.13 (0.43) 1.01 (0.94) Model adjusted for age, race, treatment, comorbidity score, facility type, census track education and income.
Detection of microsatellite instability (MSI) in colorectal cancer samples with a novel set of highly sensitive markers by means of the Idylla MSI Test prototype.
Authors: Bram De Craene, Jan Van de Velde, Evelien Rondelez, Liesbeth Vandenbroeck, Kelly Peeters, Thierry Vanhoey, Natasja Elsen, Genevieve Vandercruyssen, Linea Melchior, Gro Linno Willemoe, Amy Jones, Liu Hongxiang, Rui Henrique, Manuel Teixeira, Hui Zhao, Diether Lambrechts, Klaas Decanniere, Erwin Sablon, Geert G. Maertens
Journal: Journal of Clinical Oncology (2018)

e15639 Background: Detection of microsatellite instability (MSI) is currently recommended for all patients with colorectal cancer (CRC). Current clinical reference methods are immunohistochemical staining of mismatch repair proteins and/or PCR analysis of frequently mutated short tandem repeat regions of DNA. The Idylla™ MSI Test prototype is being developed using a new set of short homopolymers capable of faster detection with greater specificity and selectivity compared to current methods. Methods: Prototype Idylla™ MSI Test cartridges were developed up to a finalized design. Repeat length of a novel set of 7 biomarkers was determined on 348 formalin-fixed and paraffin-embedded (FFPE) CRC samples using these prototype tests which allow a complete automated workflow including sample preparation, DNA amplification followed by melting curve analysis and automated interpretation. Patient samples of several clinical sites and different ethnic groups were included to assess robustness of marker selection. All samples were additionally screened with a reference methodology for MSI detection (Promega MSI analysis system). Results: One hundred twenty-seven (36.5%) and 116 (33.3%) samples were classified as MSI-high (MSI-H), and 209 (60.1%) and 220 (57.3%) samples were classified as microsatellite stable (MSS) by Idylla™ and Promega respectively, while 12 samples (3.4%) could not be classified by either methodology. Concordance analysis revealed an overall agreement of 96.1% (93.4%-97.7% 95% CI). Fourteen cases were MSI-H by Idylla™ but MSS (11) or invalid (3) by Promega; with a median of 3/7 positive markers on Idylla™. Conclusions: This study validated the novel MSI biomarkers to discriminate MSI-H from MSS status on a large and diverse set of CRC samples. It also demonstrated the possibility of a fully automated analysis for MSI testing. The prototype Idylla™ MSI Test is compatible with the fully integrated Idylla™ platform providing accurate and reliable results within 150 minutes from just one FFPE tumour section (no reference sample required).
Stiffness memory of indirectly 3D-printed elastomer nanohybrid regulates chondrogenesis and osteogenesis of human mesenchymal stem cells
Authors: Linxiao Wu, Adrián Magaz, Tao Wang, Chaozong Liu, Arnold Darbyshire, Marilena Loizidou, Mark Emberton, Martin Birchall, Wenhui Song
Journal: Biomaterials (2018)

The cellular microenvironment is dynamic, remodeling tissues lifelong. The biomechanical properties of the extracellular matrix (ECM) influence the function and differentiation of stem cells. While conventional artificial matrices or scaffolds for tissue engineering are primarily static models presenting well-defined stiffness, they lack the responsive changes required in dynamic physiological settings. Engineering scaffolds with varying elastic moduli is possible, but often lead to stiffening and chemical crosslinking of the molecular structure with limited control over the scaffold architecture. A family of indirectly 3D printed elastomeric nanohybrid scaffolds with thermoresponsive mechanical properties that soften by reverse self-assembling at body temperature have been developed recently. The initial stiffness and subsequent stiffness relaxation of the scaffolds regulated proliferation and differentiation of human bone-marrow derived mesenchymal stem cells (hBM-MSCs) towards the chondrogenic and osteogenic lineages over 4 weeks, as measured by immunohistochemistry, histology, ELISA and qPCR. hBM-MSCs showed enhanced chondrogenic differentiation on softer scaffolds and osteogenic differentiation on stiffer ones, with similar relative expression to that of human femoral head tissue. Overall, stiffness relaxation favored osteogenic activity over chondrogenesis in vitro.
Feasibility of office hysteroscopy in evaluation of women with postmenopausal bleeding and association with improved pathological diagnosis.
Authors: Nicole Suzanne Nevadunsky, Jacquelyn Shaw, Kfeir Kuba, Gary L. Goldberg, Anne R. Van Arsdale
Journal: Journal of Clinical Oncology (2016)

e17119 Background: Endometrial sampling is critical in the evaluation of postmenopausal women for cancers of the uterine corpus. Hysteroscopy in the operating room is associated with monetary and time expense to the patient and health care system. The purpose of this study was to compare histopathological diagnoses of endometrial biopsies obtained by office hysteroscopy (OH) versus endometrial pipelle (EP). Methods: Records of all women with ICD-9 diagnosis (627.1) for postmenopausal bleeding who had OH attempted in the last 5 years at a single medical institution were evaluated. Demographic data collected included age, BMI, medical comorbidities, and histopathologic diagnosis. “Inadequate tissue” for pathologic evaluation was defined as stated in the pathology report or absence of endometrial tissue on biopsy specimen. Statistical analysis was performed using chi-square and Fisher’s exact testing with SPSS software. Results: 85 office OHs were attempted. 50 had prior attempted EPs. 98% of OHs and 94% of EPs were successfully performed. However, adequate pathology was obtained in 93% of OHs verses 38% of EPs, p < 0.01. Median age was 61 years (range 48-85) and median BMI was 32 kg/m2(range 19-71). 5% had a BMI < 25. The prevalence of diabetes mellitus, hypertension, hyperlipidemia, and cardiovascular disease were 32%, 74%, 44%, and 21% respectively. There was a significant difference in pathologic diagnoses between OH and EP, p < 0.01. Six patients were diagnosed with endometrial hyperplasia, and 3 with endometrial cancers by OH that were not identified by EP. Conclusions: OH is a feasible procedure that may enhance clinicians’ ability to diagnose both benign, pre-malignant and malignant causes of post-menopausal bleeding. Further research is needed to understand the association of cost and quality of life with OH versus hysteroscopy in the operating room.
Implementation of algorithm to guide CSF flow cytometry testing in hematological malignancies.
Authors: Bernard Tawfik, Navid Sadeghi, L. Steven Brown
Journal: Journal of Clinical Oncology (2018)

e18792 Background: In patients with hematologic malignancies, Multiparameter Flow Cytometry (FCM) offers greater sensitivity than cytology in detecting malignant cells in the initial Cerebrospinal Fluid (CSF) specimen. However, FCM testing of subsequent samples has decreased utility. We previously developed a testing algorithm to reduce the number of low yield FCM tests without significant impact on clinically meaningful results and now implement and evaluate the effect of that algorithm in our practice. Methods: As part of two routine educational lectures, all nine providers in one clinic were educated on past FCM utilization rates per sample and the developed algorithm was presented. The algorithm consisted of testing 1) Cytology and FCM on all initial samples, 2) Cytology on all subsequent samples, and 3) FCM on subsequent samples only if previous FCM was positive. Educational flowcharts of the algorithm were posted in the physician work room. Proportion test and confidence intervals assumes a binomial distribution with significance level ? 0.05. Results: In the 22 weeks after the algorithm was implemented, 48 of 49 (98%) patients and 126 of 129 (98%) samples tested followed the algorithm. The one patient whose testing did not follow the algorithm had known CNS disease. The FCM utilization rate per sample decreased from 47.8% (95% CI, 44.9-50.7%) pre-education to 31.2% (95% CI, 23.0-39.3%) (p ? 0.05) post-education. This resulted in a decrease of 22 FCM tests with a savings of $8,437 over the 22 week period examined. Conclusions: In CSF evaluation of hematological malignancies, an evidence based algorithm can be successfully implemented using educational lectures and visual reminders reducing unnecessary utilization of FCM and resulting in cost savings.