tbuckley/cabot-search huggingface dataset:
Clinical outcome of atypical uterine smooth muscle tumors
Authors: B. Pothuri, S. M. Kehoe, T. Wright, T. Herzog
Journal: Journal of Clinical Oncology (2006)

15028 Background: Smooth muscle tumors of uncertain malignant potential (STUMP) and atypical leiomyomas have increased mitotic activity, cellular atypia and necrosis but the degree is less than that used to define uterine leiomyosarcomas. Our objective is to evaluate the clinical outcome of patients with uterine masses histologically defined as smooth muscle tumors of uncertain malignant potential or atypical leiomyomas. Methods: A thorough search of our institution’s pathology database from 1990 to 2005 was performed. A retrospective chart review was performed to obtain initial and subsequent treatments, documented recurrences and clinical outcomes. Pathology reports and slides were reviewed and the presence of atypia, necrosis and number of mitosis was recorded. Statistical analysis was performed by Student’s T-test. Results: Eighteen patients with a histologic diagnosis of atypical leiomyoma were identified with 14 STUMP, 2 bizarre leiomyomas, 1 myxoid and 1 mitotically active leiomyoma. The mean age of these patients was 41.8 years (range: 25–77) and was significantly younger than those with leiomyosarcoma (mean age was 54 years, p &lt; 0.001). The histologic characteristics of the tumors included the presence of atypia at 50%, necrosis at 82% and mitoses at 94%. The rate of necrosis and number of mitosis was significantly less in the atypical group as compared to the leiomyosarcoma group (p values &lt; 0.05). However the rate of cellular atypia was not statistically different between the two groups. The median follow-up period was 25 months, range 1–138 months. One of the eighteen patients developed a pelvic and pulmonary recurrence at which time a low grade leiomyosarcoma was diagnosed. The recurrence occurred 32 months after the initial diagnosis of a mitotically active leiomyoma. Sixteen patients demonstrated no recurrence or metastatic disease at the time of follow-up. Conclusions: Atypical leiomyomas appear to be diagnosed in younger women which leads to challenging treatment issues involving fertility preservation. While these tumors generally behave in a benign fashion, they have histologic characteristics that may allow for progression or recurrence. Close follow-up is warranted for patients who are diagnosed with atypical leiomyomas and smooth muscle tumors of uncertain malignant potential. No significant financial relationships to disclose.
Promoter methylation status of hMLH1, hMSH2 and MGMT genes in colorectal cancer associated with adenoma-carcinoma sequence
Authors: Kyung Hwa Lee, Chang Woo Han, Sung Soon Kim, Ji Shin Lee, Jong Hee Nam, Jae Hyuk Lee
Journal: Cancer Research (2008)

2647   Background: Epigenetic silencing of DNA repair genes,  human mut-L homologue 1 (hMLH1) ,  human Mut S homologue 2 (hMSH2) , and  O-6-methylguanine-DNA methyltransferase (MGMT) , by promoter hypermethylation have been observed in various cancers. Promoter hypermethylation status of DNA mismatch repair genes has been poorly described in colorectal carcinoma (CRCs) associated with adenoma-carcinoma sequence. We assessed the methylation status of the three MMRs in paired sporadic colorectal adenomas and adenocarcinomas.  Methods: We evaluated  hMLH1, hMSH2,  and  MGMT  promoter methylation in nontumoral mucosa, adenoma, and carcinoma from 112 colorectal cancer patients who had coincident adenoma and adenocarcinoma. The methylation status of three gene promoters was determined by bisulfite modification and methylation specific PCR (MSP). The expression of hMLH1, hMSH2, MGMT was also examined by immunohistochemistry.  Result: 74 (66.1%) of 112 primary colorectal carcinomas (CRCs) exhibited methylation in the CpG island of the three gene promoters. Of the 112 adenomas, 2 (1.8%), 9 (8.0%), 38 (33.9%) were methylated for  hMLH1 ,  hMSH2 , and  MGMT . Methylation was seen in 2 (1.8%), 15 (13.4%), and 53 (47.3%) of carcinoma samples for each promoter.  hMSH2  and  MGMT  methylation was present in 6 (5.4%) and 12 (10.7%) of 112 samples of normal mucosa, but no methylation of  hMLH1  was found. Significant association of  MGMT  methylation status of adenomas and carcinomas within individual patients was observed using a nominal logistic regression model (odds ratio = 4.279 and 7. 486). Immunohistochemically, abnormal expression of  hMLH1 ,  hMSH2 , and  MGMT  protein was seen in 14 (4.9%), 11 (2.5%) and 53 (8.3%) of 112 cases of CRCs, with a significant correlation between aberrant  MGMT  methylation and loss of  MGMT  protein expression.Conclusion: These data suggest that CpG island methylation of  hMLH1, hMSH2,  and  MGMT  could be closely related to the carcinogenesis in CRCs showing conventional adenoma to carcinoma sequence. Therefore, detection of  hMLH1, hMSH2,  and  MGMT  methylation may have clinical applications in the management and follow-up of patients who may be at risk of developing colorectal carcinoma.
Barriers to communication in multidisciplinary breast cancer teams
Authors: F. M. Boyle, E. Robinson, P. Heinrich, S. M. Dunn
Journal: Journal of Clinical Oncology (2004)

6133 Background: Multidisciplinary teams have been recommended for patient care in breast cancer, with potential benefits including improvements in survival, quality of life and recruitment to clinical trials, and reductions in waiting times and service duplication. The literature highlights potential obstacles which may impede effective functioning of cancer teams, including inter-professional and interpersonal barriers and healthcare system characteristics. Methods: Members of multidisciplinary teams in 5 Australian states were surveyed, to assess the impact of potential barriers, including confidentiality; time pressures; individual responsibilities; “group think”; stress due to team membership; lack of support from other disciplines; uncertainty about responsibility for addressing psychosocial concerns; poor patient orientation; facilitation of meetings; inter-professional boundaries; facilities; administrative support; reimbursement; gender biases; hierarchies; terminology; delays due to interruptions; and disparate communication of prognosis. Results: 58 health professionals responded to the questionnaire. The most problematic issues for professionals in the Australian context were: Time pressures reducing the effectiveness of multidisciplinary meetings (65%); Insufficient administrative support (54%); Stress arising from teamwork (45%); Insufficient facilities for team meetings (43%); Lack of reimbursement for time spent in meetings (39%). Issues that were thought to be well-managed included: Patient confidentiality (78.9%); Gender biases not hindering effective communication (77%); Terminology across disciplines not posing a problem (74%); Individual responsibility for patient care not reduced through multidisciplinary teamwork (67%); Facilitation of meetings being appropriate (44%). Conclusions: The data highlights that health system barriers are generally perceived to be more important in hampering team performance than interpersonal or interprofessional issues, and will need to be addressed systematically to improve communication in Australian breast cancer teams. No significant financial relationships to disclose.
Disruption of KMT2D perturbs germinal center B cell development and promotes lymphomagenesis
Authors: Jiyuan Zhang, David Dominguez-Sola, Shafinaz Hussein, Ji-Eun Lee, Antony B Holmes, Mukesh Bansal, Sofija Vlasevska, Tongwei Mo, Hongyan Tang, Katia Basso, Kai Ge, Riccardo Dalla-Favera, Laura Pasqualucci
Journal: Nature Medicine (2015)
Enhanced MAF Oncogene Expression and Breast Cancer Bone Metastasis
Authors: Milica Pavlovic, Anna Arnal-Estapé, Federico Rojo, Anna Bellmunt, Maria Tarragona, Marc Guiu, Evarist Planet, Xabier Garcia-Albéniz, Mónica Morales, Jelena Urosevic, Sylwia Gawrzak, Ana Rovira, Aleix Prat, Lara Nonell, Ana Lluch, Joël Jean-Mairet, Robert Coleman, Joan Albanell, Roger R Gomis
Journal: JNCI Journal of the National Cancer Institute (2015)

Background:There are currently no biomarkers for early breast cancer patient populations at risk of bone metastasis. Identification of mediators of bone metastasis could be of clinical interest.
Ensuring multisectoral action on the determinants of reproductive, maternal, newborn, child, and adolescent health in the post-2015 era
Authors: Kumanan Rasanathan, Nazneen Damji, Tesmerelna Atsbeha, Marie-Noel Brune Drisse, Austen Davis, Carlos Dora, Azza Karam, Shyama Kuruvilla, Jacqueline Mahon, Maria Neira, Eugenio Villar Montesinos, Deborah von Zinkernagel, Douglas Webb
Journal: BMJ (2015)

<b>Kumanan Rasanathan and colleagues</b> explain how integrating action on determinants of women’s, children’s, and adolescents’ health beyond the health sector into core health strategies is crucial to achieving sustainable development goal targets to end preventable deaths and ensure healthy lives
A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)
Authors: M. G. Fakih, L. Pendyala, K. Toth, P. Creaven, N. Soehnlein, A. Litwin, D. Trump
Journal: Journal of Clinical Oncology (2006)

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m 2 and oxaliplatin 85mg/m 2 over 2 hours followed by 5-FU bolus 400mg/m 2 and 5-FU infusion 2400mg/m 2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4 th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1 st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.
Dyamic contrast enhanced MRI (DCE-MRI) pharmacodynamic (PD) study of sorafenib in metastatic renal cell carcinoma (RCC): Results of a randomized, phase II trial
Authors: O. M. hahn, C. Yeng, M. Medved, G. Karczmar, E. Kistner, B. Manchen, M. Mitchell, T. Karrison, M. Ratain, W. M. Stadler
Journal: Journal of Clinical Oncology (2007)

3545 Background: SOR is an antiangiogenic drug for metastatic RCC. We conducted a randomized, dose ranging trial to investigate if DCE-MRI is a PD marker for SOR. Methods: Patients (pts) were randomized to placebo, 200 or 400 mg bid SOR. DCE-MRI was performed at baseline and after 4 weeks (wks) of therapy at which time placebo pts were rerandomized to 200 or 400 mg bid of SOR. RECIST based response was determined by CT every 12 wks. DCE-MRI parameters, area under the contrast concentration vs. time curve for 90 seconds after contrast injection (IAUC 90 ) and K trans , were calculated for a tumor region-of-interest selected in a blinded manner. K trans was calculated with the Tofts model using a tumor local arterial input function from a multiple reference tissue method. Blood pressure (BP) was obtained from clinic charts. Primary endpoint: change in K trans or IAUC 90 over 4 wks with a planned 66 pts to detect 20% and 40% decrease in 200, 400 mg groups. Results: Due to SOR approval 57 pts were enrolled, 48 with two MRIs (5 early progression, 3 withdrew, 1 toxicity); 44 are evaluable for study endpoints. Analyses were conducted with log ratio of IAUC 90 and K trans at 4 wks relative to baseline. Mean IAUC 90 log ratio (± SD) in the placebo, 200 and 400 mg cohorts were 0.041 (± 0.197), -0.040 (± 0.132), -0.356 (± 0.411) respectively (p = 0.0003 for linear trend), corresponding to changes of +4%, -4% and -30%. K trans log ratios were 0.131 (± 0.315), -0.148 (± 0.382), -0.271 (± 0.499) respectively (p = 0.0077 for trend) corresponding to changes of +14%, -14% and -24%. In 27 pts with plasma SOR levels, change in IAUC 90 and K trans did not correlate with steady state levels on day 28. Using a Cox proportional hazards model, IAUC 90 and K trans change are not predictors of progression-free survival (median f/u 24 wks). The mean BP increased with SOR dose (0.8 ± 8.0, 8.3 ± 10.4, and 10.5 ± 11.1 for the placebo, 200, and 400 mg doses) but no correlation with IAUC 90 or K trans change was seen. Conclusions: DCE-MRI parameters IAUC90 and K trans have high variability and are PD markers for SOR, but the magnitude of effect in this prospective blinded study is less than previously reported. With this small study, no correlations with PK or clinical outcome are detectable. No significant financial relationships to disclose.
Neoadjuvant, biweekly, dose-dense chemotherapy with epirubicin (E) and cyclophosphamide (C) followed by docetaxel (T) in primary breast cancer (BC)
Authors: E. Cramer, C. Moers, V. Zarghooni, K. Bosse, P. Mallmann, M. Warm
Journal: Journal of Clinical Oncology (2006)

10656 Background: Primary chemotherapy is established in the treatment of local advanced BC. Two important advances are the chance to detect the clinical responders during the chemotherapy and an increasing rate of breast conserving surgery (BCS). According to the promissing results of dose-dense chemotherapy schedules in the adjuvant setting we tested the benefit of this approach in a primary chemotherapy protocol. Methods: This clinical trial (01/2003–11/2005) enrolled 93 females with advanced (cT2-cT4), non metastatic BC. The pts received four courses of E (90 mg/m 2 ) and C (600 mg/m 2 ) q2w, followed by four courses of T (100/75 mg/m 2 ) q2w. The severe hand-foot-skin reaction NCI-CTG grade 3 during the T courses of the first pts (G1: n = 19) lead to a dose reduction of T to 75 mg/m 2 for the following pts (G2: n = 73). During the first four cycles Pegfilgrastim was applied to prevent neutropenic complications. After every two cycles the actual tumor size was measured by clinical and sonographical examination. The clinical and pathological response, the toxicity and the rate of BCS were evaluated. Results: Pathological complete remission (pCR) of the invasive tumors was observed in 7/19 pts (G1) and 17/73 (G2), pathological partial remission (pPR) in 7/19 pts (G1) and 28/73 (G2), minimal response (pMR) in 3/19 pts (G1) and 14/73 (G2), a stable disease in 2/19 pts (G1) and 11/73 (G2). Two pts in group two showed a progressive disease (pPD). Three pts developed neutropenic fever and stopped the chemotherapy after the 5th and 6th cycle, respectively. One patient died after the 8th cycle in neutropenic sepsis. During this trial the main side effect of T was a hand-foot-skin reaction. Conclusions: This neoadjuvant dose-dense chemotherapy is a potent schedule for the treatment of primary BC. Using T with 75 mg/m 2 instead of 100 g/m 2 is generally better tolerated. The first group of pts treated with T 100 mg/m 2 exhibited a higher frequency of pCR (36.8%) compared to the pts treated with 75 mg/m 2 (pCR 23.3%), (p = 0.23). But the increased rate of severe side effects lead to an early dose reduction to 75 mg/m 2 in this clinical trial.These first promissing results will be improved in an enlarged number of pts. No significant financial relationships to disclose.
A phase III randomized trial of intermittent versus continuous androgen suppression for PSA progression after radical therapy (NCIC CTG PR.7/SWOG JPR.7/CTSU JPR.7/ UK Intercontinental Trial CRUKE/01/013).
Authors: J. M. Crook, C. J. O'Callaghan, K. Ding, G. Duncan, D. P. Dearnaley, C. S. Higano, E. M. Horwitz, E. Frymire, S. Malone, J. Chin, A. Nabid, P. R. Warde, T. B. Corbett, S. Angyalfi, S. L. Goldenberg, M. K. Gospodarowicz, F. Saad, J. P. Logue, P. F. Schellhammer, L. Klotz
Journal: Journal of Clinical Oncology (2011)

4514 Background: Intermittent androgen suppression (IAS) for PSA recurrence after radical radiotherapy (RT) may improve quality of life (QoL) and delay hormone resistance (HR) but has an unknown effect on survival. We compared overall survival (OS) for IAS vs. continuous androgen deprivation (CAD) in an open label, non-inferiority randomized trial. Methods: Eligible patients had rising PSA > 3.0 ng/ml >1 year post radical or salvage RT +/- up to 1 year of neo/adjuvant androgen deprivation therapy (ADT) for localized prostate cancer. Stratification factors were time since RT (>1-3 vs. >3 years), initial PSA (<15 vs. >15), and prior radical prostatectomy or ADT. IAS cycles were 8 months treatment with PSA-determined off-treatment periods. Primary endpoint was OS. Secondary: QoL, HR, cholesterol/HDL/LDL, length of non-treatment periods, testosterone and potency recovery. The study closed when the p-value for non-inferiority in a planned interim analysis was < a pre-specified stopping threshold. Results: 690 patients were randomized to IAS ; 696 to CAD. Median age was 74.2 years; follow up 6.9 years. Baseline factors were balanced. IAS patients completed 1-9 8-month cycles (median:2) and had reduced hot flashes but no differences in other AEs, including myocardial events or osteoporotic fractures. 35% of IAS cases had full testosterone recovery. Cross sectional QOL analysis shows a range of benefits for IAS at varying times. Using a 10 point change from baseline score as clinically meaningful, IAS patients had better QoL in physical function (p < 0.01), fatigue (p < 0.01), urinary problems (p = 0.01), hot flashes (p < 0.01), desire for sexual activity (p < 0.01) and erectile function (p < 0.01). 524 patients died (268 IAS vs. 256 CAD). Median OS was 8.8 vs. 9.1 years on IAS and CAD arms respectively (HR 1.02, 95%CI = 0.86-1.21; p for non-inferiority [HR IAS vs. CAD ≥ 1.25] = 0.009). IAS arm had more disease related (122 vs. 97) and fewer unrelated (134 vs. 146) deaths. Time to HR was statistically significantly improved on the IAS arm (HR 0.80, 95CI 0.67-0.98, p=0.024). Conclusions: IAS is non-inferior to CAD with respect to OS.
Activation of the Endogenous Renin-Angiotensin-Aldosterone System or Aldosterone Administration Increases Urinary Exosomal Sodium Channel Excretion
Authors: Ying Qi, Xiaojing Wang, Kristie L. Rose, W. Hayes MacDonald, Bing Zhang, Kevin L. Schey, James M. Luther
Journal: Journal of the American Society of Nephrology (2015)

Urinary exosomes secreted by multiple cell types in the kidney may participate in intercellular signaling and provide an enriched source of kidney-specific proteins for biomarker discovery. Factors that alter the exosomal protein content remain unknown. To determine whether endogenous and exogenous hormones modify urinary exosomal protein content, we analyzed samples from 14 mildly hypertensive patients in a crossover study during a high-sodium (HS, 160 mmol/d) diet and low-sodium (LS, 20 mmol/d) diet to activate the endogenous renin-angiotensin-aldosterone system. We further analyzed selected exosomal protein content in a separate cohort of healthy persons receiving intravenous aldosterone (0.7 μg/kg per hour for 10 hours) versus vehicle infusion. The LS diet increased plasma renin activity and aldosterone concentration, whereas aldosterone infusion increased only aldosterone concentration. Protein analysis of paired urine exosome samples by liquid chromatography-tandem mass spectrometry-based multidimensional protein identification technology detected 2775 unique proteins, of which 316 exhibited significantly altered abundance during LS diet. Sodium chloride cotransporter (NCC) and α- and γ-epithelial sodium channel (ENaC) subunits from the discovery set were verified using targeted multiple reaction monitoring mass spectrometry quantified with isotope-labeled peptide standards. Dietary sodium restriction or acute aldosterone infusion similarly increased urine exosomal γENaC[112-122] peptide concentrations nearly 20-fold, which correlated with plasma aldosterone concentration and urinary Na/K ratio. Urine exosomal NCC and αENaC concentrations were relatively unchanged during these interventions. We conclude that urinary exosome content is altered by renin-angiotensin-aldosterone system activation. Urinary measurement of exosomal γENaC[112-122] concentration may provide a useful biomarker of ENaC activation in future clinical studies.
Political attitudes in social environments
Authors: Andrew Gelman, Neil Gross
Journal: Behavioral and Brain Sciences (2015)

Abstract We agree with Duarte et al. that it is worthwhile to study professions' political alignments. But we have seen no evidence to support the idea that social science fields with more politically diverse workforces generally produce better research. We also think that when considering ideological balance, it is useful to place social psychology within a larger context of the prevailing ideologies of other influential groups within society, such as military officers, journalists, and business executives.
Angio-Associated Migratory Cell Protein and Smooth Muscle Cell Migration in Development of Restenosis and Atherosclerosis⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Paul Holvoet, Peter Sinnaeve
Journal: Journal of the American College of Cardiology (2008)