tbuckley/cabot-search huggingface dataset:
The enzymology of the selective CYP17 lyase inhibitor, VT-464, and its effects in castration-resistant prostate cancer (CRPC) models.
Authors: William R. Moore, Sankar N. Maity, Joel Robert Eisner, Edward P. Garvey, William J. Hoekstra, Mark Anton Titus, Christopher Logothetis, John C. Araujo, Eleni Efstathiou, Robert J. Schotzinger
Journal: Journal of Clinical Oncology (2014)

158 Background: CRPC typically responds to anti-androgen therapy but resistance is common. CYP17 inhibitors that block lyase (L) and not hydroxylase (H), do not require prednisone, and may delay tumor resistance are needed. VT-464 is an oral, non-steroidal inhibitor of CYP17 L in clinical development for CRPC. The present studies characterized: 1) the kinetic mechanism of VT-464 inhibition of h-CYP17 L and H, and 2) VT-464 effects compared to abiraterone acetate (AA) in CRPC models. Methods: CYP17 Enzyme Assays: r-h-CYP17 inhibition studies were conducted using substrates pregnenolone (for H) or 17-a-hydroxypregnenolone (for L). Product rates (17-a-hydroxypregnenolone (H) and DHEA (L)) were assessed by LC/MS/MS. Data were fit to inhibition models using SigmaPlot 11.2. In vitro CRPC studies: VT-464 and AA effects on AR transcription (luciferase) and PSA and NKX3.1 gene expression (QRT-PCR) were compared in C4-2B cells. Mouse xenograft model: Effects of oral VT-464 or AA on tumor growth and tumoral steroids (T, DHT, P) were compared in the MDA-PCa-133 castrate mouse model. Results: VT-464 was a reversible uncompetitive inhibitor of CYP17 L (Ki = 84 nM, K’i=200 nM) and a competitive inhibitor of H (Ki = 620 nM). VT-464 CYP17 L/H selectivity was 7.4 at low [S] but selectivity increased with increasing [S]. VT-464 L/H selectivity was 60-x greater than AA. In C4-2B cells VT-464 and AA inhibited AR transactivation but VT-464 suppressed PSA and NKX3.1 more potently than AA. In the xenograft model, VT-464 decreased tumor volume as effectively as AA. VT-464 more potently decreased T and DHT, while AA increased P. Conclusions: VT-464 demonstrated much greater CYP17 L selectivity than AA and equivalent or superior activity in several CRPC models. Less tumor resistance may arise from treatment with the CYP17 lyase-selective inhibitor VT-464 than with AA, since it more effectively blocked androgen biosynthesis, did not cause an accumulation of progesterone, and should not require co-administration of prednisone.
The evolution of supportive care quality measures portfolio and conformance.
Authors: Ryan D. Nipp, Michael J. Kelley, Christina D. Williams, Arif Kamal
Journal: Journal of Clinical Oncology (2012)

259 Background: A growing set of quality measures is being implemented to evaluate all components of cancer care ranging from diagnosis through the end-of-life (EOL). With an increasing emphasis from ASCO and others on the regular delivery of supportive care principles throughout the cancer trajectory, we investigated our longitudinal Quality Oncology Practice Initiative (QOPI) data to understand the trends in supportive and EOL measures. Methods: We performed twice-yearly QOPI data collections from 2007 through Spring 2012 using chart review of the Durham Veterans Administration (VA) outpatient oncology clinic, staffed by VA and Duke faculty as well as Duke fellows. QOPI measures were categorized as non-treatment related supportive care (SC) (NTSC), treatment-related SC (TSC), diagnostic (D), or therapeutic (T). Descriptive statistics and chi square were used to compare longitudinal conformance. Results: The majority of QOPI measures assess processes of chemotherapy treatment (49.1% T and 11.1% TSC) or diagnostic modalities (21.1% D). Measures targeting NTSC are few (18.6%), but increased from two SC measures in 2007 to eight in Spring 2012, including the addition of two EOL measures. Over the five years, average conformance to NTSC, TSC, D, and T measures was 71.4%, 86.1%, 89.3%, and 75.4%, respectively (p&lt;0.001). Within the NTSC measures, emotional well-being, and constipation assessment were least documented (41.0%, and 46.3% respectively). In Spring 2012, SC measure conformance (76.0%) remained significantly lower than D measure conformance (91.5%) (p&lt;0.001). Potential explanations include heterogenous and non-standardized ways to document non-treatment measures despite an increasing emphasis within cancer care on supportive and palliative care. Conclusions: Most QOPI quality measures assess diagnosis or treatment processes of cancer care. Aggregate conformance to the NTSC measures was lower than other categories over five years. This disparity persists in the latest 2012 collection, and novel SC measures have been added. The differential conformance demonstrates the necessity of quality improvement efforts that stay commiserate with the increasing portfolio of SC measures.
Long-term consequences of treatment on paid work after diagnosis of breast cancer.
Authors: R. Jagsi, S. T. Hawley, P. Abrahamse, J. J. Griggs, A. S. Hamilton, S. J. Katz
Journal: Journal of Clinical Oncology (2011)

9007 Background: Missed paid work during breast cancer treatment is common but less is known about long term consequences of treatment on paid work among survivors. Methods: We surveyed a diverse, population-based sample of 2245 women with non-metastatic breast cancer reported to Detroit and Los Angeles SEER registries from 6/05-2/07 and merged these data to SEER. Patients were initially surveyed 9 months after diagnosis and again 4 years later (expected n=1520). We examined patterns and correlates of paid work for a preliminary sample of 482 patients from LA aged<65 whose cancer did not recur. Results: 346 patients (73%) reported working prior to diagnosis; 114 (34%) of whom were not working four years later (“work loss”). Work loss was much more common for women who received chemotherapy for initial treatment (51% vs 32%, p=0.001), as well as those who were older, Latina, less educated, had comorbidities, or received mastectomy; tumor behavior (in situ vs invasive), marital status, and radiation receipt were not associated with work loss. On multivariate analysis controlling for age, marital status, tumor behavior, comorbidity, race, mastectomy receipt, and radiation receipt, chemotherapy receipt at the time of diagnosis was independently associated with work loss (OR 2.6, p=0.006). The excess long term work loss observed for women who received chemotherapy began soon after diagnosis: Compared to women who did not get chemotherapy, women who did were much more likely to report stopping work 2 years ago or more (35% vs 14%, p<.001) and much more likely to have stopped work during the entire initial course of therapy (50% vs 13%, p<.001). Most women who were not working for pay at time of re-interview wanted to work: 55% reported that it was important for them to work and 32% were actively looking for work. Conclusions: Preliminary findings suggest that paid work loss related to breast cancer treatment may be long-lasting. Many women who stopped working during chemotherapy are unemployed several years after diagnosis but still desire to work for pay. Patients, clinicians, and policy-makers must recognize that long-term paid work loss is a possible serious adverse consequence of chemotherapy receipt.
The effect of inhibition of the insulin-like growth factor receptor with nordihydroguaiaretic acid on PSA progression: Results of a phase II study.
Authors: T. W. Friedlander, V. K. Weinberg, C. Formaker, J. Mi, A. M. Lin, A. L. Harzstark, L. Fong, E. J. Small, C. J. Ryan
Journal: Journal of Clinical Oncology (2010)

4670 Background: Insulin-like growth factor (IGF) mediated signaling is a newly recognized clinical target in prostate cancer, and it is hypothesized that blockade of the IGF-receptor (IGF-1R) will impair downstream signaling and slow tumor growth. In this study the efficacy of nordihydroguaiaretic acid (NDGA), a small molecule inhibitor of the IGF-1R, was prospectively evaluated in patients with hormone-sensitive prostate cancer (HSPC). Methods: Eligible patients had non-metastatic HSPC with a rising prostate specific antigen (PSA) and a normal testosterone level. NDGA 2000mg was given orally daily and treatment continued until PSA progression or toxicity. Sample size was calculated to look for an improvement in response from 15% to 35% with a total of 28 patients planned. Response was defined as a decline from baseline PSA of ≥50%. Accrual occurred in 2 stages with an overall power of 81% and level of significance of 5%. Results: Accrual has been halted to allow for follow-up of a pre-planned interim analysis for efficacy among the first 12 patients enrolled. Median baseline PSA was 5.1 ng/mL (range 1.5 to 9.1), median baseline PSA doubling time (PSADT) was 8.2 months (range 6.7 to 15.4), and median baseline testosterone was 353 ng/dL (range 202 to 521). Median time on treatment was 6 months (range 1 to 11) for 8 patients now off study; 4 patients continue to receive therapy and have been on study from 5 to 17 months. Eight patients experienced non-sustained declines in PSA ranging from 2% to 16% of baseline. PSADT lengthened in 6 patients when compared to pretreatment PSADT (range 2.5 to 16.2 months). PSA progression occurred in 5 patients, 1 patient was taken off study for recurrent grade 2 weakness, and 2 patients withdrew consent. All grade 3 events occurred in 1 patient and included nausea/vomiting, cognitive disturbance, syncope due to dehydration, and elevated liver function tests. Testosterone, dihydrotestosterone, and androstenedione levels were not significantly changed. Conclusions: NDGA therapy lengthens median PSADT but does not induce significant PSA declines. Further study may require a placebo-control to determine if changes in PSADT are drug related. No significant financial relationships to disclose.
Concurrent chemotherapy and radiotherapy for the treatment of cervix uterine cancer at experience in a general hospital
Authors: L. Mas, C. V. Montoya, J. Serrepe, J. Florian, J. Moreno
Journal: Journal of Clinical Oncology (2005)

5182 Background: Cervix uterine carcinoma is the first cause of cancer in women in Peru, concurrent chemotherapy and radiotherapy are the standar treatment for this condition, we developed a combination of gemcitabine plus cisplatin and concurrent radiotherapy to evaluated the activity and safety of this treatment in a General Hospital in Peru. Methods: This is a Fase II open, prospective non randomized clinical trial, to evaluated the activity and safety of the combination of Gemcitabine(G) 125 mg/m2 and Cisplatin(C) 40 mg/m2 weekly for five weeks and concurrent Radiotherapy administrated at 180 cGy/day for 5 day/week for 5 weeks. Results: Since Jan/2003 until Dec/2003, 23 women with biopse proved Cervical Uterine Carcinoma was admited at the study, the median age: 60 years (range: 45 - 74 y) Clinical stage II-B: 14 and III-B: 9, median tumor size: 7.3 cm. Total cycles administred: 138. Complete clinical response 22/23 (96%) and 1 partial response (4%), Patological complete response: 18/22 (81.8%). The toxicity profile Nausea and vomiting grade 3/4: 3/138, Diarrea grade 3/4: 15/138, febrile neutropenia: 2/138. Conclusions: the combination of GC and concurrent radiotherapy is an active and safety regimen, we do not have any dead related to the treatment. No significant financial relationships to disclose.
Motor control exercise for chronic non-specific low-back pain (PEDro synthesis)
Authors: Cameron C New, Jasan Dannaway, Heather New, Charles H New
Journal: British Journal of Sports Medicine (2017)

Saragiotto BT, Maher CG, Yamato TP, et al . Motor control exercise for chronic non-specific low-back pain. Cochrane Database Syst Rev 2016; 1 : CD012004.

By definition, the origin of pain is unclear in patients with non-specific low-back pain (NSLBP), but possible sources of pain include the intervertebral discs, facet and sacroiliac joints. Globally, low back pain is by far the most prevalent musculoskeletal disorder (9.4%), and it accounts for almost half (49.6%) of the total disability burden when considering musculoskeletal disorders.1 A lack of coordination of the muscles that support the spine is one of the proposed mechanisms for the onset and/or persistence of NSLBP. Motor control exercises (MCEs), targeting activation and co-ordination training of deep trunk muscles are used in the management of NSLBP.

To evaluate the effectiveness of MCEs to improve pain, disability, function, quality of life and return to work in patients with chronic NSLBP.

Eight electronic databases and two trial registers …
Molecular biomarkers and imatinib efficacy in metastatic gastrointestinal stromal tumors (an experience of the Russian Cancer Research Center)
Authors: M. Lichinitser, D. Filonenko, A. Mescheryakov, E. Stepanova, O. Anurova, B. Medvedeva
Journal: Journal of Clinical Oncology (2008)

21500 Background: The aim of the study was an evaluation of efficacy of imatinib as first-line therapy in patients with unresectable or metastatic gastrointestinal stromal tumor. We also evaluated an expression of molecular biomarkers of apoptosis, angiogenesis and proliferation in primary tumors to define new factors predicting the efficacy of treatment. Methods: 51 patients (pts) with CD117 expression in tumor were included into the study. Mean age was 60 years (range 20–76). Most of pts had hepatic metastases and/or peritoneal metastases. Median duration of imatinib treatment was 13.5 months (range 1–67+). Expression of molecular markers (Ki67, p53, Bcl-2, Bax, VEGF, PDGFR beta) was evaluated by immunohistochemistry on tumor paraffin blocks. Results: The efficacy of treatment was evaluated in 47 of 51 pts. Imatinib was effective in 93.6% cases (26 pts achieved partial remission, 1 - complete response, 17 - prolong stabilization). Response duration for complete and partial remission was (from starting of imatinib treatment) was 14+ months (range 6–67+), for stabilization of the disease - 18+ months (range 6–35+). The expression rate of molecular biomarkers in primary tumors was as follows: Ki-67 - 27.7%, Bcl-2 - 74.5%, Bax - 32.7%, p53 - 30.4%, VEGF - 51.4%, PDGFR beta - 100% (1+-3+). High Ki-67 index (more then 30%) and PDGFR beta overexpression (3+) correlated with time to progression (TTP). Pts with low Ki-67 index in tumor had progression in 55.8% cases (median TTP was 23 months) and with high Ki-67 index - in 76.9% (median was 9 months), p=0.013. 82.4% pts with PDGFR beta overexpression and 50% with low PDGFR beta expression (1+) had progression during observation (median TTP was 11 and 29 months), p=0.01. 14 pts, which did not have a progression for more than 2 years on imatinib, had low rate of VEGF expression (35.7%), Ki-67 (14.2%), Bax (14.3%), PDGFR beta (21.4%). Among pts who had progression within 6 months high rate of expression of VEGF was 55.6%, Ki-67 - 55.6%, Bax - 44.4%, PDGFR beta - 66.7%. Conclusions: Imatinib is highly effective in metastatic gastrointestinal stromal tumors. High Ki-67 index (more than 30%) and PDGFR beta (3+) hyperexpression can be unfavorable predictive factors of imatinib treatment. The study is continuing. No significant financial relationships to disclose.
Use of Echocardiography in the Diagnosis of Cardiac AL Amyloidosis - An Analysis of "Presumed" and "Endomyocardial Biopsy-Proven" Disease.
Authors: Christine I. Chen, Diego Delgado, Laveena Munshi, Adriana Luk, Andrew Winter, Heather Ross, A.Keith Stewart, Joseph Mikhael, Suzanne Trudel, Donna Reece
Journal: Blood (2005)
Golgi protein 73 (gp73) is a useful tumor marker in patients with colon cancer.
Authors: G. Ozal, H. Akbulut, N. Akgun, G. Cipe, F. Icli
Journal: Journal of Clinical Oncology (2011)

e14089 Background: Golgi protein 73 (gp73) is a 400 kD trans-membrane protein expressed in hepatocytes when induced by cytokines or exposed to viruses. Gp73 is also expressed in various tumor cells including colon cancer. In this study, we aimed to evaluate the value of the serum gp73 as a tumor marker in patients with colon cancer. Methods: A total of 126 patients with liver only metastases, with non-liver metastases, without distant metastasis (both preoperative and postoperative period), and a group of colon cancer patients in remission at least 3 years and not relapsed within at least 6 months after obtaining blood samples and a healthy group with similar age and gender were included in the study. The serum gp73 levels were measured by ELISA and compared with serum CEA and CA 19.9 levels. Results: Serum gp73 was higher than the lower detection limit of the test in the majority of the test subjects. The diagnostic performance of gp73 was better than both CEA and CA19.9 for colon cancer metastases (AUC= 0.974±0.003 [95%CI: 0.912-1.037] for gp73; AUC=0.859±0.089 [95%CI: 0.684-1.034] for CEA; and AUC=0.782±0.106 [95%CI: 0.574-0.990] for CA19.9) (p<0.05). The diagnostic performance of gp73 as a tumor marker was especially more prominent in the subgroup of liver only metastases. For the non-liver metastases, the performance of CEA was similar to gp73. At the cut-off level of 15 ng/mL, the sensitivity of gp73 was 80% and specificity 100%. The sensitivity and specificity of CEA were 72% and 100% at the level of 5 ng/mL and of CA 19.9 69% and 100% at the level of 45 U/mL. Conclusions: The serum gp73 seems to be a useful tumor marker in patients with colon cancer.
Impact of smoking history on patient outcome following hepatic metastasectomy for colorectal cancer.
Authors: Yehua Shen, Ibrahim Halil Sahin, Manal Hassan, Bryan K. Kee, Barry W. Feig, Lee M. Ellis, Thomas A. Aloia, Eddie K. Abdalla, Steven A. Curley, Jean-Nicolas Vauthey, Chris R. Garrett
Journal: Journal of Clinical Oncology (2013)

517 Background: Although it is clear that smoking increases perioperative risks associated with liver resection, there are also oncologic concerns associated with smoking. For example, nicotine induces CRC cell proliferation in vitro. We undertook a single institution retrospective analysis of pts outcome based on prior smoking history. Methods: Under an IRB-approved protocol, pts who underwent hepatic metastasectomy for treatment for CRC liver metastasis with curative intent at a single institution, from 2005 to 2009, were retrospectively evaluated for smoking history, time to progression (TTP), and overall survival (OS). Pts were analyzed as never smokers (A), ex-smokers (B), or current smokers and those who discontinued at the time of cancer diagnosis (C). Results: 350 pts outcomes were analyzed; their data is demonstrated in the table below. There were no difference in TTP or OS between group A and B (p = 0.346, p = 0.453 respectively). Pts in group A had a superior TTP and OS when compared to group C (p =0.002, p = 0.021 respectively). Patients in group B had a superior TTP when compared to group C (p =0.044), while a difference of OS was not found between the two groups (p =0.153). Conclusions: Smoking history is a negative prognostic factor for TTP in patients undergoing hepatic metastasecomy for CRC. Further studies are necessary to validate these preliminary findings. Active smokers who are candidates for hepatic metastasectomy for CRC should undergo nicotine cessation counseling and treatment. [Table: see text]
Human equilibrative nucleoside transporter 1 (hENT1) in gemcitabine and FOLFOX (oxaliplatin, 5-fluorouracil, and leucovorin)-treated patients with metastatic pancreatic cancer: The randomized phase II PAN1 study.
Authors: Yu Jo Chua, Christos Stelios Karapetis, Val Gebski, Rachel O'Connell, Stephen Begbie, Louise M. Nott, Michelle F. Cronk, Craig Underhill, Ehtesham A. Abdi, Thomas Van Hagen, Nicole Wong, Merryn Hall, Danielle Angela Ferraro, Katrin Marie Sjoquist, Cheryl Santos, John Robert Mackey, David Goldstein
Journal: Journal of Clinical Oncology (2014)

228 Background: GEM-based treatment is a standard treatment for metastatic pancreas cancer. Monotherapy efficacy is only modest, and outcomes are improved by combination treatment or the non-GEM FOLFIRINOX triplet. There is a need for biomarkers to select between these divergent options. hENT1 is a potential predictive marker of benefit from GEM, but conflicting results have been observed in studies that have evaluated resected and metastatic pancreatic cancer. This principal objective of this study was to evaluate hENT1 prospectively as a predictive marker in GEM and non-GEM treated patients. Methods: Patients with previously untreated metastatic pancreatic adenocarcinoma and tumour tissue available for hENT1 testing were randomized between GEM (1,000 mg/m 2 D1, 8, 15 Q4w) or FOLFOX (oxaliplatin 85 mg/m 2 , 5-fluorouracil (5FU) 400 mg/m 2 , leucovorin 400 mg/m 2 D1 and 5FU 2,400 mg/m 2 over 46 hours D1-3) until disease progression or unacceptable toxicity. Tumor samples were tested prospectively for hENT1 by immunohistochemistry. The primary endpoint was progression-free survival (PFS). Results: The study was open from July 2011 to February 2013, but closed after 16 of the planned 80 patients were enrolled. 1 patient who died before treatment was excluded from the outcome analysis. 7/16 patients were hENT1 high (43.8%, 95%CI 23.1-66.8%). In the GEM arm (n=7), the 4 who were hENT1 high had longer PFS and overall survivals (OS) than those who were hENT1 low (median PFS 5.7 vs. 1.8 months; median OS 13.9 vs. 3.5 months), whereas outcomes were similar with FOLFOX for both hENT1 groups. There were no unexpected adverse events. Conclusions: This prospective study showed a longer survival in those patients with high hENT1 treated with GEM. There was no difference in survival according to hENT1 expression in patients treated with FOLFOX. Given the small sample size this may be due to chance, but supports the need for further research into the predictive value of hENT1. Clinical trial information: ACTRN12610001047088.[Table: see text]
Radiotherapy (RT) for brain metastases (BM) near the end of life (EOL): Palliation or poor-quality care?
Authors: Joan Joonsun Ryoo, Michael Batech, Chengyi Zheng, Raymond W Kim, Michael K Gould, A. Robert Kagan, Winston Wei Lien
Journal: Journal of Clinical Oncology (2015)

58 Background: Patterns of care and EOL RT among BM patients (pts) are not well-described. Methods: Tumor registry of an integrated health care system identified 5,133 pts diagnosed with non-small-cell lung cancer (NSCLC) in 2007-2011. BM were determined by imaging. Clinical variables obtained by chart abstraction were tested as predictors of death within 14 and 30 days (d) of RT. Results: On NSCLC presentation, 10% had BM; 7% developed BM thereafter. Of 900 BM pts, 15% were not referred for brain RT due to pt preference or clinical judgments; median time to death was 21 d (range 0-578). Median survival for 5% not recommended RT was 48 d (range 13-764). Though survival was shorter when prescribed 5 vs 10 fractions (78 vs 179 d, p&lt;0.01), suggesting providers’ sense of prognosis, 15.6% of pts died ≤14 d and 23.3% ≤30 d of RT. Inpt consultation and planned fractions were higher at external RT facilities, and RT more likely not to be completed (p&lt;0.01). Independent predictors of EOL RT were older age, poor performance status, increasing metastatic sites, and RT consultation during hospital admission. Conclusions: BM incidence in this NSCLC cohort was 17%, with 85% referred for brain RT. A concerning number of pts received RT near the EOL. While RT recommendation, timing, and fractionation – especially on inpt evaluation – should be better tailored to life expectancy, benchmarks for quality measurement are needed. [Table: see text]