tbuckley/cabot-search huggingface dataset:
Radiosensitization of MYC-overexpressing prostate cancer cells by statins.
Authors: T. Salih, K. Aziz, S. Thiyagarajan, M. Armour, B. Shanmugam, J. Zeng, S. J. Adam, D. W. Felsher, T. L. DeWeese, P. T. Tran
Journal: Journal of Clinical Oncology (2011)

26 Background: Studies have shown a link between HMG-CoA reductase inhibitors (statins) and decreased cancer risk in various cancers including prostate cancer. Recent clinical studies have shown improved outcome for men on statin therapy receiving definitive radiation therapy compared to radiation therapy alone for prostate cancer. The oncogene Ras can be inhibited by statin treatment and in turn also result in targeted downregulation of Myc. Inactivation of Myc has been shown to induce tumor regression in transgenic mouse models of different cancers. Methods: Utilizing both in vitro and in vivo models, we studied in MYC over-expressing prostate cancer cells statin induced cytotoxicity and radiosensitization. We studied the effect of statin treatment with and without radiation treatment on in vitro cell death and clonogenic survival and correlated effects to levels of MYC and phospho-MYC. We constructed mutant cell lines to specifically examine the MYC-dependent effects of statins on prostate cancer cell cytotoxicity and radiosensitization. We performed similar studies in vivo using subcutaneous tumor grafts. Results: Statin treatment alone of prostate cancer cells resulted in increased cell death and decreased clonegenic survival. Statin treatment further sensitized prostate cancer cells to ionizing radiation as shown through colony formation assays. These cellular effects were associated with decreased levels of active MYC as confirmed by western and phospho-western analysis. Statin-induced cell death and decreased MYC levels could be rescued with the HMG-CoA bypass product mevalonate. Finally, flank tumor graft experiments demonstrated the ability of statins and radiation to delay tumor growth in vivo. Conclusions: Our preliminary data have implicated MYC as a potential critical target for the cytotoxic effects of statins on prostate cancer cells. The prevalence of MYC overexpression in human prostate cancers is as high as 80%. Thus the ability of statins to radiosensitize MYC overexpressing prostate cancer cells may provide a mechanistic explanation to the improved outcomes for men taking statins while on radiation therapy and now may afford us a molecular biomarker to examine this phenomenon in the clinic. No significant financial relationships to disclose.
Renal failure deaths and their risk factors in India 2001–13: nationally representative estimates from the Million Death Study
Authors: Anna J Dare, Sze Hang Fu, Jayadeep Patra, Peter S Rodriguez, J S Thakur, Prabhat Jha
Journal: The Lancet Global Health (2016)

Renal failure represents a growing but mostly undocumented cause of premature mortality in low-income and middle-income countries. We investigated changes in adult renal failure mortality and its key risk factors in India using the nationally representative Million Death Study.In this cross-sectional analysis of population-based data, two trained physicians independently assigned underlying causes to 150 018 deaths at ages 15-69 years from a nationally-representative mortality survey in India for 2001-03 and 2010-13, using the International Classification of Diseases, 10th version (ICD-10). We applied the age-specific proportion of renal failure deaths for the 2010-13 period to the 2015 UN estimates of total deaths in India and calculated age-standardised death rates for renal failure by rural or urban residence, state, and age group. We used proportional mortality of renal deaths (cases) to injuries (controls) to calculate the odds of renal death in the presence of different comorbidities and stratified risks by decade of birth.In 2001-03, 2·1% of total deaths among 15-69 year olds were from renal failure (1266 [2·2%] of 58 871; unweighted). By 2010-13, the proportion of deaths from renal failure had risen to 2·9% (2943 [3·2%] of 91 147; unweighted) of total deaths and corresponding to 136 000 renal failure deaths (range 108 000-150 000) of 4 688 000 total deaths nationally in 2015. Age-standardised renal death rates were highest in the southern and eastern states, particularly among adults aged 45-69 years in 2010-13. Diabetes, hypertension, and cardiovascular disease were all significantly associated with increased renal failure deaths, with diabetes the strongest predictor-odds ratio (OR) vs control 9·2 (95% CI 6·7-12·7) in 2001-03, rising to 15·1 (12·6-18·1) in 2010-13. In the 2010-13 study population, the diabetes to non-diabetes OR was twice as large in adults born in the 1970s (25·5, 95% CI 17·6-37·1) as in those individuals born during or before the 1950s (11·7, 9·1-14·9).Renal failure is a growing cause of premature death in India. Poorly treated diabetes is the most probable reason for this increase. Strategies aimed at diabetes prevention, and early detection and treatment are urgently needed in India, as well as greater access to renal replacement therapy.US National Institutes of Health, International Development Research Centre, Centre for Global Health Research, University of Toronto.
Prolonged Survival despite High Disease Burden in Elderly (≥55) Patients with Hb SS or Hb Sβ0 Thalassemia
Authors: Damian Silbermins, Laura M. De Castro, Allison E Ashley-Koch, Jude C Jonassaint, Melanie E. Garrett, James R. Eckman, Eugene P. Orringer, Marilyn J. Telen
Journal: Blood (2008)
Adaptation to Climate Change: A Comparative Analysis of Modeling Methods for Heat-Related Mortality
Authors: Simon N. Gosling, David M. Hondula, Aditi Bunker, Dolores Ibarreta, Junguo Liu, Xinxin Zhang, Rainer Sauerborn
Journal: Environmental Health Perspectives (2017)

Background: Multiple methods are employed for modeling adaptation when projecting the impact of climate change on heat-related mortality. The sensitivity of impacts to each is unknown because they have never been systematically compared. In addition, little is known about the relative sensitivity of impacts to “adaptation uncertainty” (i.e., the inclusion/exclusion of adaptation modeling) relative to using multiple climate models and emissions scenarios. Objectives: This study had three aims: a) Compare the range in projected impacts that arises from using different adaptation modeling methods; b) compare the range in impacts that arises from adaptation uncertainty with ranges from using multiple climate models and emissions scenarios; c) recommend modeling method(s) to use in future impact assessments. Methods: We estimated impacts for 2070–2099 for 14 European cities, applying six different methods for modeling adaptation; we also estimated impacts with five climate models run under two emissions scenarios to explore the relative effects of climate modeling and emissions uncertainty. Results: The range of the difference (percent) in impacts between including and excluding adaptation, irrespective of climate modeling and emissions uncertainty, can be as low as 28% with one method and up to 103% with another (mean across 14 cities). In 13 of 14 cities, the ranges in projected impacts due to adaptation uncertainty are larger than those associated with climate modeling and emissions uncertainty. Conclusions: Researchers should carefully consider how to model adaptation because it is a source of uncertainty that can be greater than the uncertainty in emissions and climate modeling. We recommend absolute threshold shifts and reductions in slope. https://doi.org/10.1289/EHP634
Pulmonary metastasectomy in soft tissue sarcomas (STS): A single-institution experience.
Authors: M. Glogowski, L. Talarek, I. A. Lugowska, S. Falkowski, T. Switaj, M. Zmijewski, R. Wlodarczyk, H. Kosela, M. Turski, M. J. Krzakowski, P. Rutkowski
Journal: Journal of Clinical Oncology (2011)

10088 Background: Pulmonary metastasectomy (PM) is a well-accepted approach to treat resectable lung metastases from soft tissue sarcomas (STS). The aim of the study was to evaluate results of surgical resection of lung metastases (LM) from STS and determine prognostic factors for overall survival. Methods: Between 1996 and 2009, 159 consecutive pts (mean age 44.5 years) with STS after PM due to LM were identified. At the time of 1st diagnosis of LM there were 76 unilateral and 83 bilateral lesions. 144 pts had perioperative chemotherapy. Median follow-up time was 20.7 months (range 1.8-167). Overall survival (OS) was calculated from date of the first thoracotomy. We retrospectively analysed demographic data, treatment-related variables and outcomes in uni- and multivariate analyses to identify prognostic factors. Results: A total 294 pulmonary resection of LM from STS were underwent. Median disease-free interval (DFI) was 15.8 months (range 0-174). The 30-day mortality rate was 0.3%. Complete (R0) resection was achieved in 129 pts (81%). After first PM 93 pts (59%) relapsed with lung metastases alone and 37 of them (40%) have undergone further PM. 23 pts (14%) had more than 2 thoracotomies. 34 pts (21%) developed metastases at other sites. 5-year OS rate was 29%, median OS - 25.5 months (range 0.3-167). The results of the uni-/multivariate analysis are presented in the table. Conclusions: PM in STS is safe and potentially curative procedure. Patients with isolated lung recurrence after PM should be assessed for consecutive PM if complete resection is possible. Complete resection, relapse isolated to the lung, number of resected metastases less than 4 and primary site of STS in uterus are the most predictive factors of prolonged survival. Clinical parameters 5-year OS and log rank test Cox regression model Resection R1/2 vs R0 0 vs 34.6%%; p<0.001 HR 1,87; 95% CI: 1.1–3.2; p=0.021 Site of relapse: nonlung vs lung metastases 9.6% vs 18.6%; p=0.035 HR 2,24;95% CI: 1.4–3.5; p=0.001 Lung metastases 1-3 lesions vs 4+ 11% vs 40.7%; p<0.001 HR 1,63;95% CI: 1.03–2.56; p=0.036 Leiomyosarcoma of uterus vs other than in uterus 24.8% vs 61.5%; p=0.019 HR 2,76; 95% CI: 1.18–6.42; p=0.019 DFI 0-12 months vs 12+ 19% vs 35.9%; p=0.036 HR 1,03; 95% CI: 0.69–1.55; p=0.88
Could a salvage lymphadenectomy after chemotherapy have clinical impact on cancer survival in patients with metastatic urothelial carcinoma?
Authors: Takashi Saika, Kensuke Bekku, Ryo Kishimoto, Shin Ebara, Kohei Edamura, Kyohei Kurose, Yasutomo Nasu, Hiromi Kumon
Journal: Journal of Clinical Oncology (2012)

321 Background: A clinical impact of salvage lymphadenectomy after chemotherapy in urothelial carcinoma patients with metastatic lymphnodes swelling is controversial. We verified a clinical role of salvage lymphadenectomy with analyzing long-term outcome after salvage surgery in the patients treated with cisplatin/gemcitabine-based chemotherapy. Methods: From 2003 to 2011, 20 of 28 (71%) urothelial carcinoma patients with metastatic lymphnodes showed objective responses (CR in 2, PR in 18) after multiple courses of the chemotherapy. Thirteen of the PR patients underwent salvage lymphadenectomy after the chemotherapy (9 male and 4 female, median 64.0 years old). Seven of the patients underwent radical surgeries for primary lesions as well. Remaining 5 patients denied salvage surgery. Progression free survival and overall survival of the patients were analyzed retrospectively in comparison with those of patients without salvage surgery. Results: All 13 patients could achieve surgical CR. Pathological findings showed pathological CR in 9 patients. In median follow-up 26.9 months (range: 4.5-74.6), progression free survival and cause specific survival in patients with salvage lymphadenectomy showed better trends in comparison with those in 5 PR patients without the surgery (63.5% vs 20.0%, and 85.7% vs 40.0% at 2 years, p=0.0907 and 0.0229; log-rank test). Conclusions: Although this study was retrospective and nonrandomized, salvage lymphadenectomy in patients with residual tumor after GCP chemotherapy could have an impact on cancer survival. Surgical CR should be achieved in an affordable patient who is responder of GCP therapy.
Pathologic outcomes in patients with clinically low-risk prostate cancer deemed eligible for active surveillance.
Authors: A. Srivastava, S. Grover, P. Sooriakumaran, S. Rajan, Y. El-Douaihy, A. Tewari
Journal: Journal of Clinical Oncology (2011)

110 Background: Active surveillance (AS) is becoming increasingly popular as a treatment option for men with clinically localized low-risk prostate cancer. Gleason score ≤ 6 and clinical stage ≤ T2a are selection criteria for AS. However, Gleason upgrading or upstaging from the diagnostic biopsy to the surgical specimen is not uncommon. We thus sought to identify risk factors that could more accurately predict Gleason upgrading and/or upstaging in AS-eligible men. Methods: 786 patients from our prospective database of 2,412 men who underwent robotic-assisted radical prostatectomy by a single surgeon from January 2005 to August 2010 would have fulfilled standard AS criteria (Gleason sum ≤ 6, clinical stage ≤T2a disease, PSA &lt;10ng/ml, &lt;3 positive cores and ≤50% cancer present in a single core). This formed the basis of our study cohort. Clinicopathologic parameters, including number of cores at initial biopsy, biopsy cancer volume, preoperative PSA, number of cancer-positive cores, body mass index, and prostate volume were recorded prospectively. Data were evaluated using chi- square and multivariate logistic regression analyses. Receiver operator characteristic curves (ROC) were constructed to determine the optimal cutoff values. Results: 320 of 786 AS-eligible patients (40.7%) had Gleason upgrading at final pathology following radical prostatectomy. Upstaging was present in 591 patients (75.1%). 626 patients (79.6%) had Gleason upgrading and/or upstaging. On univariate analysis, BMI, PSA density, preoperative PSA, lower prostate volume and maximum percentage of cancer in biopsy cores were predictors of Gleason upgrading and/or upstaging. On multivariate analysis, all variables, except for BMI and PSA density, lost statistical significance. PSA density &gt; 0.1 ng/ml/cm 3 and BMI &gt;29 kg/m 2 are the optimal cutoff values based on ROC analysis. Conclusions: PSA density and BMI are significant predictors of Gleason upgrading and/or upstaging, and should be incorporated into contemporary selection criteria for AS protocols. No significant financial relationships to disclose.
Neoadjuvant hormone therapy for radical prostate radiotherapy: A case-matched study comparing bicalutamide to LHRH agonist therapy.
Authors: Jolyne O'Hare, Ursula McGivern, Cliona McDowell, Darren M. Mitchell, Gemma Corey, Joe M. O'Sullivan
Journal: Journal of Clinical Oncology (2012)

88 Background: To assess and compare the biochemical failure free survival (BFFS), PSA kinetics and absolute PSA responses in men receiving radical radiotherapy for localized prostate cancer (RT) receiving either neoadjuvant bicalutamide or neoadjuvant LHRH agonist therapy. Methods: A retrospective review of consecutive cases with prostate cancer treated with BC monotherapy prior to radical radiotherapy was individually case matched to men treated with neoadjuvant LHRHa monotherapy from April 2004 to December 2008. PSA kinetics and absolute pre-RT, post neo-adjuvant hormone PSA (PRPH-PSA) level and subsequent BFFS were analyzed. Results: 65 men treated with BC monotherapy were individually matched with 65 men treated with LHRHa. The median follow-up was 44 months and 54 months respectively. There were no significant differences in pre-treatment patient or tumour characteristics. Statistically significant differences were noted between groups in the PRPH-PSA with a geometric mean of 2.0ng/ml (range 0.1 – 11.2ng/ml) for BC patients and 1.0ng/ml (range 0.1 – 11.1ng/ml) for LHRHa patients (p&lt;0.001). The geometric mean PSA halving time during the neo-adjuvant period of 14.6weeks (range 2 – 160weeks) in the BC treated group was statistically significantly different when compared to the mean of 16.1 weeks (range 2.1-96.8 weeks) for LHRHa patients (p=0.056). There were however no differences in PSA velocity. A PRPH-PSA of &lt;1.0ng/ml and &lt;0.1ng/ml was seen in 16(24.6%) and 2 (3%) of the BC patients and 34(52.3%) and 3(4.6%) of LHRHa patients respectively. Phoenix biochemical failure was seen in 10(15.4%, 95%CI [8.6%, 26.1%]) and 8(12.3%, [6.4%, 22.5%) of BC and LHRHa patients respectively. Neither PRPH-PSA level nor PSA kinetics during the neo-adjuvant period predict for subsequent BFFS at this duration of follow-up. Conclusions: In this case-matched study, we found that although neo-adjuvant BC therapy did not result in equivalent PRPH-PSA suppression when compared to neo-adjuvant LHRHa alone, there was no difference in biochemical failure rates between the cohorts at an overall median follow-up of 44 months. Longer follow-up is required.
Selection, therapy, and outcome in an unselected population-based study of 604 patients with pancreatic cancer.
Authors: Jon Kroll Bjerregaard, Michael Bau Mortensen, Katrine R. Schønnemann, Per Pfeiffer
Journal: Journal of Clinical Oncology (2012)

238 Background: Knowledge of patients (pts) with pancreatic cancer (PC) is often inferred from randomized phase III trials or registry based studies. Information about selection, therapy, and outcome is however often limited by availability of data in registries or lack of generalizability due to strict inclusion criteria in phase III studies. We wanted to investigate therapy choices and survival in a complete population of pts with PC. Methods: During 2007-2009 all cases of PC in the Region of Southern Denmark (RSD) (pop: 1,200,000) was retrieved from the Danish Cancer Registry. Concurrently we established a registry at the regional PC cancer center, recording clinical variables. The two registries were merged and dis-concordant cases were all examined. Information about hematology, liver function, performance status and therapy was retrieved from patient charts. Patients with neuroendocrine or acinar cell carcinomas were excluded from outcome analysis. Results: 618 cases of PC were retrieved from the Danish Cancer Registry. After examining dis-concordant pairs and histology 64 cases were removed and 25 added resulting in a total of 579 eligible pts with PC. Based on therapy delivered pts were divided in four groups (Table 1). Sixty-five pts had an initial resection of their tumor, 191 pts were treated with either chemotherapy or chemo-radiotherapy (CT/CRT), 56 pts were evaluated for CT/CRT, but was in too poor performance status or progressed/died before therapy; finally 268 pts were never evaluated for CT/CRT and never received tumor directed therapy. Of the total population 3% participated in clinical trials. Conclusions: Survival of un-selected patients appears to be similar to trial patients, and has improved compared to other registry based studies. However the majority of pts with PC do not receive cancer directed therapy. Improving the outcome of PC pts as a whole requires research into the large group of untreated pts. [Table: see text]
A phase II trial of chemotherapy plus hormone therapy as initial treatment of unresectable/metastatic adenocarcinoma of the prostate.
Authors: Robert J. Amato, Jaroslaw Jac, Mika Stepankiw, Perla Ramirez
Journal: Journal of Clinical Oncology (2012)

247 Background: Chemotherapy for hormone-refractory prostate cancer reduces PSA levels and enhances overall survival (OS), suggesting that administration in earlier disease stages may be beneficial. If expansion of an androgen-independent clone is present during androgen deprivation mediates the transformation from an androgen-dependent to an androgen-independent phenotype, combination chemohormonal therapy could be effective initial treatment for locally advanced or metastatic prostate cancer. This study examined the efficacy and safety of chemohormal therapy approach. Methods: Patients received medical castration plus an anti-androgen and chemotherapy (nab-paclitaxel, leuprolide, bicalutamide). Patients were followed with PSA levels and radiographic assessments. Results: Forty-six men (median age) 64.7 years were treated. Fifty-eight percent underwent prior local therapy including prostatectomy (30%), prior radiation (15%), or both (13%). Median baseline PSA was 8.9 ng/ml, and 96% of patients had a Gleason score of ≥7%. At 2 years, 78% of patients experienced tumor regression with a median reduction in PSA level of &gt;90%. Median time to progression was 28.43 months measured by PSA and 34.52 months measured radiographically. Median OS was 62.4 months. The most frequent significant adverse events included grade 3 hypokalemia (17%) and lymphopenia (59%). Conclusions: Combination chemohormonal therapy for locally advanced and metastatic prostate cancer delayed disease progression and enhanced OS. Information presented will include curves and correlation detailing efficacy and adverse events of various sub-populations.
The introduction of bevacizumab for the treatment of metastatic colorectal cancer (CRC) in Ontario and its effect on hepatic metastectomy.
Authors: William Robert Leeper, Hector Hugo Li Chang, Stephen Welch, David K Driman, Douglas Quan
Journal: Journal of Clinical Oncology (2012)

303 Background: Where possible, the optimal treatment for CRC liver metastases is metastectomy. Perioperative chemotherapy may be associated with improved outcomes in this setting. The government of Ontario approved public funding of bevacizumab (Bev) for metastatic CRC in July 2008. For first-line treatment, funding of Bev has been limited to use in combination with FOLFIRI, an irinotecan-containing regimen. However, the best evidence in support of perioperative chemotherapy for CRC liver metastases involves the use of oxaliplatin, not irinotecan. We sought to analyze changes in prescribing patterns, histologic findings, and clinical outcomes since the funding approval for Bev in Ontario. Methods: A single centre, retrospective review was performed of all patients receiving metastectomy for CRLM between 2004 and 2010, and archival hematoxylin-eosin slides were reviewed. Results: A total of 121 patients underwent metastectomy for CRLM during the study period. Of these, 54 were treated with perioperative chemotherapy, 37 before and 16 after funding approval of Bev. A marked increase was seen in Bev and irinotecan-containing regimens since funding approval (p &lt; 0.01). Pathologic examination of the surgical specimens did not reveal any increase in steatosis or steatohepatitis. However, there was a trend towards more R0 resections (p = 0.3) in the post-bev era. A significant reduction in the occurrence of post-operative hepatic dysfunction was observed in the post-Bev era (p = 0.04). Overall survival (OS) and disease-free survival (DFS) were similar. Conclusions: Public funding of Bev-FOLFIRI for metastatic CRC has led to an increased and yet incomplete utilization of this regimen for CRLM. Pathologic and clinical data do not suggest harm and may show early signs of benefit. Further research is needed to determine the optimal utilization of bev in the setting of CRLM. [Table: see text]