tbuckley/cabot-search huggingface dataset:
Prognostic stratification of post-docetaxel metastatic castration resistant prostate cancer (mCRPC) from a phase III randomized trial.
Authors: Guru Sonpavde, Gregory Russell Pond, Stephen John Clarke, Janette L. Vardy, S. L. Wang, Jolanda Paolini, Mariajose Lechuga, M. Dror Michaelson, Matthew Raymond Smith, Isan Chen, Edna Chow Maneval
Journal: Journal of Clinical Oncology (2012)

4644 Background: A prognostic model for mCRPC post docetaxel is necessary to guide therapy. We retrospectively analyzed a phase III trial enrolling progressive mCRPC following docetaxel to construct a prognostic model. Additionally, we studied the impact of neutrophil-lymphocyte ratio (NLR), a potential marker for inflammatory and immune state. Methods: A phase III trial (SUN-1120) comparing prednisone combined with sunitinib (N=584) or placebo (N=289) for mCRPC following docetaxel-based chemotherapy was evaluated. The treatment arms were combined for analysis, since no statistical difference was observed in the primary endpoint of overall survival (OS). A logarithmic transformation was applied to non-normal factors. The Kaplan-Meier method was used for OS estimation. To identify an optimal prognostic model for survival, we used a Cox proportional hazards regression methods with forward stepwise selection, stratifying for ECOG PS, progression type (PSA or radiographic) and treatment group. A risk score was calculated and patients were categorized into risk groups to assess model performance. Results: Data from patients without missing data (n=806) were used to construct an optimal model. The factors used in the model that remained individually significant in multivariate analysis were: log-LDH (HR 2.77 [95% CI=2.23, 3.44], p&lt;0.001), hemoglobin (0.81 [0.76, 0.87], p&lt;0.001), log-NLR (1.63 [1.38, 1.92], p&lt;0.001), &gt;1 organ involved (1.53 [1.24, 1.88], p&lt;0.001), log-alkaline phosphatase (1.14 [1.01, 1.30], p=0.041) and log-PSA (1.07 [1.00, 1.13], p=0.036). No clear cutpoints were identified; thus, these prognostic factors were used to group patients into 3 equally sized risk categories. Low, medium and high risk patients (n=268-270 per group) had median (95% CI) OS estimates of 23.7 (21.4-not reached), 13.5 (11.6-15.8) and 7.3 (6.3-8.4) months, respectively. Conclusions: A prognostic risk model with readily available variables significantly discriminated between outcomes in post-docetaxel mCRPC and may provide valuable information in future studies. High NLR was associated with an independent poor prognostic impact, and warrants prospective validation.
Predictability of survival outcome by early tumor shrinkage (ETS) at 8 weeks with cutoff value of 20% in metastatic colorectal cancer (mCRC) patients treated with mFOLFOX6 plus bevacizumab (bev) or FOLFIRI plus bev as first-line chemotherapy (1st-CTx): Validation in the phase III WJOG4407G trial.
Authors: Kentaro Sakamaki, Yosuke Kito, Naoki Izawa, Takashi Tsuda, Satoshi Morita, Kentaro Yamazaki, Narikazu Boku, Kei Muro, Ichinosuke Hyodo
Journal: Journal of Clinical Oncology (2017)

729 Background: We reported that ETS at 8 weeks with cutoff value of 20% is the best candidate for predicting overall survival (OS) in mCRC patients who received 1st-CTx in the retrospective study (Kito, ESMO, 2015), where ETS was estimated by the tumor growth inhibition model (Claret, JCO, 2013). The objective of the study was to validate our proposed evaluation time and cutoff value for ETS in the phase III WJOG4407G trial which showed equivalent efficacy of mFOLFOX6+bev and FOLFIRI+bev as 1st-CTx for mCRC (Yamazaki, Ann Oncol, 2016). Methods: Tumor shrinkage ratio (TSR), which is the relative change in the sum of the longest diameters of target lesions according to the RECIST between before and during 1st-CTx, was calculated using actually measured tumor size data. Cutoff values of TSR for ETS and allowance ranges for measurement time of tumor size were evaluated. The association between ETS and OS was investigated by Cox regression model. In multivariate analyses, the general prognostic factors of mCRC, such as ECOG performance status (PS), prior history of adjuvant chemotherapy (AC), baseline tumor size (bTS), serum alkaline phosphatase (ALP) and white blood cell (WBC), were adjusted. Results: Of 402 enrolled patients, 305 patients had tumor size data measured within 8 +- 2 weeks. Patient characteristics were: mFOLFOX6+bev/FOLFIRI+bev 153/152; PS 0/1 244/61; AC Yes/No 49/256; median bTS 79 mm (range 10-512); median ALP 274 IU/L (110-1,200); median WBC 6400/mm 3 (3,030–12,000). In multivariate analyses, ETS at 8 weeks with cutoff value of 20% was most significantly associated with OS showing hazard ratio (HR) of 0.53 (95%CI: 0.38-0.74, p &lt; 0.001). Moreover, HR of ETS was 0.47 (95%CI: 0.33-0.67, p &lt; 0.001) in using the data during 8 +- 1 weeks (n = 257), while HR was 1.03 (95%CI: 0.41-2.62, p = 0.95) in using the data earlier or later than 8 +- 1 weeks (6 to 7 or 9 to 10 weeks) (n = 48). Conclusions: This analysis supported that ETS with cutoff value of 20% using data within 8 +- 1 weeks is optimal for predicting OS in mCRC patients who received 1st-CTx. Clinical trial information: UMIN000001396.
Omacetaxine mepesuccinate in chronic-phase chronic myeloid leukemia (CML) in patients resistant, intolerant, or both to two or more tyrosine-kinase inhibitors (TKIs).
Authors: Luke Paul Akard, Hagop Kantarjian, Franck E. Nicolini, Meir Wetzler, Jeffrey Howard Lipton, Michele Baccarani, Adam Craig, Nisha Nanda, Peter D. Brown, Jorge E. Cortes
Journal: Journal of Clinical Oncology (2012)

6596 Background: Omacetaxine mepesuccinate (“omacetaxine”) is a first-in-class, reversible, transient inhibitor of protein elongation that facilitates tumor cell death without depending on BCR-ABL signaling. Clinical activity was shown in two phase 2, open-label, multicenter studies of patients with treatment-resistant CML who had failed at least prior imatinib, many of whom were also resistant to or intolerant of dasatinib and/or nilotinib. Methods: A subset of data from the phase 2 studies included patients in chronic phase who were resistant/intolerant to ≥2 approved TKIs. Omacetaxine 1.25 mg/m 2 was given subcutaneously twice daily: ≤14 consecutive days/28-day cycle for induction, ≤7 days/cycle as maintenance. Patients had never achieved or lost response to ≥2 TKIs (R group), were intolerant of ≥2 TKIs (I), or resistant to 1 and intolerant of another (R/I) were evaluated. Results: Of 81 patients (median age, 58 years), 69 were R, 7 I, and 5 R/I. Major cytogenetic response occurred in 13 (19%) in the R group (median duration not reached), 2 (29%) I (median duration 7.4 months), and 1 (20%) R/I (duration 17.7 months). For all patients, cycles of exposure and study duration were 7 cycles and 9.1 months (R); 4 cycles, 7.3 months (I); and 2 cycles, 2.3 months (R/I). Median overall survival in months were 33.9 (R), not reached (I), and 25.0 (R/I). Of 66 (81%) patients with treatment-related grade 3/4 adverse events (AEs), the most common were thrombocytopenia in 44 R, 6 I, and 4 R/I patients and neutropenia in 32 R, 4 I, and 1 R/I. Fifteen patients had an AE leading to discontinuation (10 R, 2 I, 3 R/I), primarily disease progression. There were 9 deaths (the most common were disease progression, sepsis), 8 I, 1 R/I; 2 were considered related to treatment (both sepsis). Conclusions: This subset analysis of patients with chronic-phase CML and prior therapy with ≥2 TKIs shows that omacetaxine provides efficacy and tolerability across TKI-R, I, and R/I groups. Interpretation of the I and the R/I group data was limited by small sample sizes. Support: Teva Pharmaceutical Industries Ltd.
Time-related changes in yield and harms of screening breast MRI.
Authors: Holly Jane Pederson, Colin O'Rourke, Lauren D Bolden, Sobia Khan, Manisha Yadav, Joanne Lyons, Laura Shepardson, Alice Rim, Joseph P. Crowe, Stephen R. Grobmyer
Journal: Journal of Clinical Oncology (2013)

1508 Background: MRI has been accepted as a useful adjunct to screening mammography in high-risk women. Concerns remain over false positive findings, however, and little is known about harms and yield over time. Such information will help women decide about enhanced surveillance. Methods: Of 350 high risk patients offered MRI screening, 320 underwent 757 screens with a 1.5 Tesla magnet from 2008 to 2012 alternating (q 6 mo.) with digital mammography. Data collected included patient characteristics, mammographic density, estimated lifetime risk, and need for additional imaging and/or biopsy. Harms were defined as second look ultrasounds, US or MRI guided core biopsies, surgical biopsies or recommendation for short interval follow up. Estimates of harms over time were modeled by logistic regression. A significance level of 0.05 was used for all testing. Results: Compliance with MRI screening as recommended was 91% with the first MRI, and was not associated with age, race or level of risk. Harms were highest with the first MRI and decreased significantly with subsequent MRIs. Of 59 biopsies, 7 were malignant. Two were found in MRI 1, 3 in MRI 3 and 2 in MRI 4. Women with biopsies resulting from false positive findings were significantly younger (median age 44.5 as compared with 48; p=0.049) and were more likely to have extremely dense breast tissue (36% vs 17%; p=0.028.) Conclusions: This study of highly compliant high risk patients supports the use of MRI as an adjunct to mammography for early detection. The rate of harmful events decreased over time, yet cancer detection did not. This information is critical in counseling women who are considering annual screening breast MRI, particularly younger women and those with dense tissue. [Table: see text]
Survival in metastatic castration resistant prostate cancer (mCRPC) trial participants.
Authors: Carmel Jo Pezaro, Aurelius Gabriel Omlin, Deborah Mukherji, Diletta Bianchini, Shahneen Kaur Sandhu, Amy Mulick Cassidy, Gal Maier, David Olmos, Emilda Thompson, Gerhardt Attard, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2012)

e15136 Background: Median overall survival (mOS) in patients (pts) with metastatic prostate cancer progressing despite castrate levels of testosterone (mCRPC) was 13-16 months (m) in the pre-docetaxel era. These data, obtained from clinical trials, were used to construct currently available prognostic nomograms. We hypothesise that these models no longer reflect survival. Pts and physicians urgently require updated prognostic data on which to base management decisions. Methods: Pts with mCRPC treated on phase I-III trials at our institution were identified and data retrospectively collected. Predicted survival by Halabi and Smaletz nomograms were compared to calculated survival using Kaplan-Meier analysis. Cox model multivariate (MV) analysis used variables at referral, including performance status (PS), Gleason (GS), prostate specific antigen (PSA), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), hemoglobin (Hb), visceral disease and albumin. Results: 423 pts with CRPC treated between 2003 and 2011 were included. At diagnosis median age was 62 years (y; 41.8 – 82.7); 226 (53.4%) had metastatic disease. Median interval from diagnosis to CRPC was 2.7y (0.2 – 21.7). At referral 248 pts (58.6%) were chemotherapy-naïve. Halabi and Smaletz models predicted mOS in chemo-naïve pts of 21m and 18m respectively, however the observed mOS was 32m (95%CI 28 – 38). Survival from CRPC was 43m (CI 37 – 46) and 39m (CI 34 - 44) in pre- and post-chemo pts, respectively. Conclusions: Despite aggressive disease characteristics, our pts lived significantly longer than predicted by current nomograms. MV analysis confirmed the importance of several previously identified prognostic factors. Survival data from this large cohort of CRPC pts should encourage men considering clinical trial participation. Previously developed nomograms no longer accurately predict survival.
Management of colorectal hepatic metastases in the Veterans Affairs medical system: Opportunities for curative intent surgery.
Authors: Dalia A. Mobarek, Brendan C. Visser, Ashley Freeman, Deyne Bentt, Jemma Ayvazian, David Maron, Richard Amdur, Steven Krasnow
Journal: Journal of Clinical Oncology (2014)

e14541 Background: Surgical resection of isolated liver metastases in colon cancer offers the greatest chance of long-term survival. An initial 15-20% of patients are resectable with an additional 10-30% after conversion chemotherapy. We aimed to study surgical intervention rates and survival outcomes in the Veterans Affairs Medical System. Methods: A retrospective analysis of stage IV colon cancer and isolated liver metastases from 10/01/2004-12/31/2012 nationwide was performed using the VA Central Cancer Registry (VACCR) and patient level clinical data via Veterans Affairs Informatics and Computing Infrastructure (VINCI). Kaplan-Meier analysis was used to examine differences in time from diagnosis to death by surgery status. Cox regression was then used with age at diagnosis as a covariate. All analysis was done using SAS (version 9.3, Cary, NC), and p<.05 was considered significant. Results: We identified 1727 cases of stage IV colon cancer and isolated hepatic metastases. Hemicolectomy was carried out in only 53.1% (917), with a majority not receiving any metastatic site intervention 85.8% (787/917). Metastatectomy was carried out in 14.1% (130/917). A significantly higher death rate in the non-surgery group (76.1 vs 60.6%, p<.0001) was observed. In the Kaplan-Meier analysis, patients without surgery had a significant reduction in time to death (log-rank chi-square=205.94, p<.0001). In the no-surgery group, 50% of the patients died at 0.51 years after diagnosis (95% confidence interval 0.45-0.61). In the surgery group, death occurred at 1.48 years (1.38-1.65). When age was included as a covariate using Cox regression, any surgery remained significantly associated with time to death (HR = 2.19 [95% confidence interval 1.94-2.46], p<.0001). Thus, not having surgery raised the odds of dying by 119% after correcting for age at diagnosis. Conclusions: Overall mortality is high in this cohort, however all-cause mortality is notably lower in the metastatectomy compared to those without metastatectomy (46.1%, 60/130 vs. 54.1%, 496/917, respectively). Ongoing analysis of factors affecting metastatectomy decision is underway.
Oxygen saturation measured in vivo in bronchial tumors during bronchoscopy in patients with lung cancer using differential path length spectroscopy (DPS) correlates with survival, stage of the disease, and expression of HIF1a
Authors: J. G. Aerts, M. P. Bard, A. Amelink, D. Sterenborg, F. Bom, J. Van Meerbeeck, H. Hoogsteden, B. Lambrecht
Journal: Journal of Clinical Oncology (2006)

10084 Background: Tumor hypoxia is known to correlate with poor prognosis in solid cancers. In bronchial tumors direct determination of oxygen saturation is not possible and therefore indirect measures like hypoxia related proteins as HIF1a have been studied. We studied the prognostic significance on patient survival and tumor stage of microvascular oxygen saturation (StO 2 ) measured in vivo in bronchial tumors using optical spectroscopy and compared this to HIF1a expression in bronchial biopsies. Methods: DPS is a non-invasive real-time measurement of hypoxia related parameters such as microvascular blood oxygenation (StO 2 ) which can be used during bronchoscopy (Bard Am J Respir Crit Care Med 2005). Endobronchial tumors (12 squamous cell carcinomas, 5 adenocarcinomas, 15 large cell undifferentiated and 6 small cell carcinomas), were measured in 38 patients. In a subgroup of patients HIF1a expression was related to StO2 using linear regression analysis. Results: StO 2 of bronchial tumors was predictive for patient survival. Patients with an endobronchial tumor and a saturation lower than the median value of 52% had a significant shorter overall survival than patients with a better saturated tumor. The StO 2 was also related to the stage of the disease. StO 2 was significantly lower in case of advanced lung tumors (stage III &amp; IV, StO2= 44.7 ± 24.7%) in comparison with localized lung tumors (stage I&amp;II, StO2 = 73.3 ± 12.4) (p&lt;0.05). StO2 correlated to HIF1a expression levels (r = −0.65). Conclusions: StO 2 using DPS correlates with HIF1a expression, is related to tumor stage and is a prognositc factor. This opens a new field for study of therapeutic agents in lung cancer and may also be important in the staging of lung cancer. No significant financial relationships to disclose.
Urgent improvements needed to diagnose and manage Lynch syndrome
Authors: Kevin J Monahan, Deborah Alsina, Simon Bach, James Buchanan, John Burn, Sue Clark, Peter Dawson, Bianca De Souza, Farhat V N Din, Sunil Dolwani, Malcolm G Dunlop, James East, D Gareth Evans, Nicola Fearnhead, Ian M Frayling, Rob Glynne-Jones, James Hill, Richard Houlston, Mark Hull, Fiona Lalloo, Andrew Latchford, Suzy Lishman, Phil Quirke, Colin Rees, Matt Rutter, Peter Sasieni, Asha Senapati, Doug Speake, Huw Thomas, Ian Tomlinson
Journal: BMJ (2017)

Lynch syndrome is currently under-recognised, underdiagnosed, and undermanaged, so opportunities to reduce cancer mortality are often missed. The new guideline from the National Institute for Health and Care Excellence recommends universal testing for Lynch syndrome in all people newly diagnosed as having colorectal cancer.1 This should prevent several hundred colorectal cancers annually, but several issues hinder good care …
Prognostic and predictive impact of Ki-67 before and after neoadjuvant chemotherapy on PCR and survival: Results of the GeparTrio trial.
Authors: Gunter Von Minckwitz, Berit Mueller, Jens U. Blohmer, Manfred Kaufmann, Holger Eidtmann, WOLFGANG Eiermann, Bernd Gerber, Hans Tesch, Joern Hilfrich, Jens Bodo Huober, Tanja N. Fehm, Jana Barinoff, Christian Jackisch, Judith Prinzler, Thomas Ruediger, Erhard Erbstoesser, Sibylle Loibl, Carsten Denkert
Journal: Journal of Clinical Oncology (2012)

1023 Background: We previously reported as a result of the GeparTrio phase III trial that response-guided neoadjuvant chemotherapy (CT) with TACx8 or TAC/NX, compared to TACx6, can improve survival especially in hormone-receptor (HR)-positive tumors. As this benefit could not be predicted by pathological complete response (pCR), better surrogate response markers are warranted. Methods: 2072 patients with operable or locally advanced breast cancer were treated with 2 cycles TAC before interim response assessment. Responders were randomized to additional TACx4 or TACx6 and non-responders to TACx4 or NXx4. We centrally measured Ki-67 in1165 pre-CT core biopsies and in 676 post-CT surgical samples. Counting patients with a pCR as having 0% Ki-67, 757 pre-/ post-CT pairs were available. Ki-67 percentage levels were grouped to low (0-15%), moderate (15.01-35%), and high (35.01-100%) according to cut-point finding analysis in a training and validation cohort. Results: pCR rates were 4.2%, 12.9%, and 29.0% in tumors with low, moderate, and high pre-CT Ki-67 levels (p&lt;0.0001). Pre-CT Ki-67 levels significantly predicted disease-free survival (DFS) (log rank p&lt;0.0001) overall, in the HR+ (p&lt;0.0001), but not in the HR- (p=0.5) subgroup. Post-CT Ki-67 levels correlated with DFS (p&lt;0.0001). Patients with low post-CT Ki-67 levels showed comparable outcome to patients with pCR. Patients with increased Ki-67 levels from before to after CT showed an impaired outcome compared to patients with stable or decreased Ki-67 levels (p&lt;0.0001). However, post-CT Ki-67 levels appeared to have more prognostic relevance than Ki-67 changes. Low post-CT Ki-67 levels were not more frequent after response-guided treatments (response-guided vs conventional: p=0.153; TACx6 vs TACx8: p=0.335; TACx6 vs TAC/NX: p=0.420). Similar negative results were found for HR+ and HR- subgroups. Conclusions: Pre-CT Ki-67 levels are predictive for pCR and prognostic for DFS. Post-CT Ki-67 levels and changes between pre-and post-CT-Ki-67 levels are prognostic for DFS. As neither could predict different treatment effects on DFS, Ki67 cannot replace pCR as a surrogate marker for outcome after neo-adjuvant CT.
The effect of 8-OH-DPAT and dapoxetine on gene expression in the brain of male rats during ejaculation
Authors: Xijun Qin, Xiaojun Ma, Dongping Tu, Zuliang Luo, Jie Huang, Changming Mo
Journal: Acta Pharmaceutica Sinica B (2017)

The 5-HT1A receptor agonist 8-hydroxy-2-[di-n-propylamino] tetralin (8-OH-DPAT) promotes ejaculation of male rats, whereas dapoxetine delays this process. However, the gene expression profile of the brain at ejaculation following administrationof these two compounds has not been fully elucidated. In the present study, a transcriptomic BodyMap was generated by conducting mRNA-Seq on brain samples of male Sprague–Dawley rats. The study included four groups: pre-copulatory control (CK) group, ejaculation (EJ) group, 0.5 mg/kg 8-OH-DPAT-ejaculation group (DPAT), and 60 mg/kg dapoxetine-ejaculation (DAP) group. The resulting analysis generated an average of approximately 47 million sequence reads. Significant differences in the gene expression profiles of the aforementioned groups were observed in the EJ (257 genes), DPAT (349 genes) and the DAP (207 genes) compared with the control rats. The results indicate that the expression of Drd1 and Slc6a3 was significantly different after treatment with 8-OH-DPAT, whereas the expression of Drd4 was significantly different after treatment with dapoxetine. Other genes, such as Wnt9b, Cdkn1a and Fosb, exhibited significant differences in expression after the two treatments and are related to bladder cancer, renal cell carcinoma and sexual addiction. The present study reveals the basic pattern of gene expression that was activated at ejaculation in the presence of 8-OH-DPAT or dapoxetine, providing preliminary gene expression information during rat ejaculation.