tbuckley/cabot-search huggingface dataset:
Circadian rest-activity rhythm as a predictor of survival in metastatic colorectal cancer.
Authors: David Spiegel, Pierre-Antoine Dugué, Pasquale F. Innominato, Abdoulaye Karaboué, Garance Dispersyn, Arti Parganiha, Sylvie Giacchetti, Thierry Moreau, C. N. J. Focan, Jim Waterhouse, Francis Levi
Journal: Journal of Clinical Oncology (2012)

e14006 Background: Experimental disruption of the Circadian Timing System (CTS) accelerates cancer progression. The relative amount of activity in-bed versus out-of-bed (I&lt;O) was identified as a quantitative CTS estimate that predicted survival in two cohorts of patients with metastatic colorectal cancer (CI, CII). Methods: The independent prognostic value of I&lt;O was investigated for Overall Survival (OS) and Progression-Free Survival (PFS) 1) in a new cohort of 142 patients (CIII) receiving circadian-based salvage treatment for metastatic colorectal cancer, and 2) in a pooled population of 436 patients from cohorts I-III. All patients had two-day rest-activity rhythm monitoring and then received a new treatment. Cohort-adjusted data were analyzed with log rank and multivariate Cox analyses. Results: Patients in CIII had poor prognosis disease compared to CI and CII, as assessed by prior chemotherapy (CIII, 69%; CI, 59.5%; CII, none), prior oxaliplatin (CIII, 55%; CII, none; CI, 2%) and/or irinotecan (CIII, 39.4%; CII, none; CI, 7%). The 273 male and 163 female patients in the pooled population had generally good performance status 0 (60.7%) or 1 (33.1%) and 51% had two or more metastatic sites. Following rest-activity rhythm determination, patients received a median of 8 chemotherapy courses. Median OS was 21.6 months [95% Confidence Limits, 17.8 to 25.5] in the patients with I&lt;O above the cutoff median value of 97.5% as compared to 11.9 months [10.4 to 13.3] in those with a lower I&lt;O (p from Log rank &lt; 0.001). The adjusted relative risk related to I&lt;O above cutoff was 0.587 [0.477 to 0.722] for earlier death (p&lt;0.001) and 0.661 [0.542 to 0.807] for earlier progression (p &lt;0.001). Conclusions: The circadian biomarker indicator I&lt;O is a robust and independent quantitative long-term predictor of both OS and PFS in patients with metastatic colorectal cancer. Cancer patients with low I&lt;O could potentially benefit from specific treatments for circadian disruption in order to enhance survival.
Proteomic analysis of primary colorectal cancer to generate response biomarkers for liver metastases.
Authors: Paul Anthony Sutton, Rob Jones, Cliff Rowe, Rosalind Jenkins, Hassan Zakria Malik, Dale Vimalachandran, Chris Goldring, Neil Kitteringham, Daniel H. Palmer
Journal: Journal of Clinical Oncology (2014)

e14535 Background: Understanding the biological phenotype of colorectal liver metastases would be invaluable in informing clinical decision making; however, deriving this information from the metastatic lesion is not feasible until after resection. By contrast, material from the primary tumour is routinely available. We aimed to establish the feasibility of using biological information from a primary colorectal tumour to inform and predict response to neoadjuvant chemotherapy for liver metastases. Methods: Fresh tissue from primary colorectal tumour and liver metastases, and from normal colonic mucosa and liver parenchyma were acquired at the time of resection in 17 patients and subjected to comparative proteomic analysis using isobaric tagging for relative quantification. Data were analysed with Protein Pilot (Ab Sciex, Framingham, USA); proteins with expression significantly different across the different tissue types were subjected to pathway analysis with Metacore software. Stratification of patients into those showing low or high response to chemotherapy allowed the identification of proteins that were differentially expressed and thus represented potential response biomarkers. Results: 5,768 discrete proteins were identified, with 1,814 present in all samples and therefore used for analysis. No proteins were significantly different between primary and metastatic tumours. 25 proteins were significantly (p<0.05) differentially expressed in the primary tumour compared with normal colon, whereas 53 were different between the liver metasases and normal colon. Five candidate proteins that predict favourable histopathological response to fluorouracil-based chemotherapy regimens were identified. Conclusions: Proteomic sequencing of matched metastatic colorectal cancer samples is feasible with high protein coverage. Analysis of dysregulated proteins revealed putative pathways that may be implicated in carcinoma progression and identify potential novel drug targets. The high degree of similarity between primary and secondary proteomes suggests that information from primary tissue is predictive of the metastatic phenotype. Further validation of candidate biomarkers is underway.
MicroRNA signature to predict sensitivity to anti-EGFR monoclonal antibodies in metastatic colorectal cancer (mCRC).
Authors: Federico Cappuzzo, Andrea Sacconi, Lorenza Landi, Francesca Biagioni, Vienna Ludovini, Gabriella Fontanini, Elisa Sensi, Cristiana Lupi, Jessica Salvini, Giovanni Blandino, Lucio Crinò
Journal: Journal of Clinical Oncology (2012)

3521 Background: MicroRNAs (MiRNAs) are post-transcriptional regulators that bind to complementary sequences on target messenger RNA transcripts, usually resulting in gene silencing. Microarray technology is a powerful high-throughput tool capable of monitoring the expression of thousands of small noncoding RNAs at once. In the present study we aimed to investigate whether MiRNA signature was predictive for sensitivity to anti-EGFR monoclonal antibodies in mCRC. Methods: A total of 183 mCRC from two independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab/panitumumab either alone (n=19) or in combination with chemotherapy (n=164) were included onto the study. MiRNA arrays were analysed using Agilent’s miRNA platform. Results: MiRNA array analyses identified the cluster miR-99a/Let7c/miR-125b located on 21p11.1 as associated with different outcome to anti-EGFR therapies. In the first cohort, individuals with high signature (n=25, 33.8%) had a significantly longer progression free survival (PFS, 6.1 versus 2.3 months, p=0.01, HR=0.42) and overall survival (OS, 29.8 versus 7.0 months, p=0.04, HR=0.39) than patients with low signature (n=25, 33.8%). Similar results were observed in the validation cohort. Patients with high signature (n=60, 32.8%) had a significantly longer PFS and longer OS than individuals with low signature (PFS 8.2 versus 4.2 months, p=0.04, HR=0.52; OS 12.8 versus 6.8 months, p=0.09, HR=0.65). To further assess the potential confounding effect of KRAS and BRAF mutations, we analyzed the outcome of patients with high and low signature in the 75 cases with KRAS or BRAF mutation and in 90 cases KRAS and BRAF wild-type. In the wild-type population, high signature patients (n=29, 32.2%) had a significantly longer PFS (8.8 versus 4 months, p=0.002, HR:0.46) and longer OS (17.7 versus 10 months, p=0.015, HR=0.62) than low signature individuals, with no difference in the KRAS or BRAF mutated patients. Conclusions: MiR-99a/Let7c/miR-125b signature is useful for improving selection of KRAS/BRAF wild-type mCRC patients candidate for anti-EGFR strategies.
Patient factors associated with survival in non-small cell lung cancer: An analysis of 846 patients from a single Institution.
Authors: Jing Zhao, Vijay Patel, Zhonglin Hao, Byron Dasher, Catherine Ferguson, William Davis, Carsten Schroeder, Bennett Greenspan, Paul Biddinger, Feng-Ming (Spring) Kong
Journal: Journal of Clinical Oncology (2015)

e18520 Background: Survival of a patient is determined by factors related to patient, tumor and treatment. For patient factors in non-small cell lung cancer (NSCLC), it is unclear whether there is a difference in survival between Caucasians and African Americans (AA). This study aimed to study the racial disparity in survival and other patient factors with overall survival (OS) in NSCLC patients. Methods: The study population included patients treated and with data recorded in our Tumor Registry from 2002 to 2013. Age, gender, race, marital status, stage, histology, tumor location, alcohol and smoking history, insurance information and treatments were tested using chi-square test. A Cox proportional hazards model was used to determine differences in OS (SPSS 18.0). Results: A total of 846 consecutive NSCLC patients were included for analysis. 58.8% were Caucasians and 41.2% AA. Under multivariate analysis, gender, marital status, histology, tumor location (upper/lower), alcohol use, stage, chemotherapy and surgery were significantly associated with OS. Median OS was not significantly different between Caucasians and AA (10.3 vs 7.2 months, HR = 0.925, P = 0.359). Median OS between Caucasians and AA patients were 70.1 vs. NR (not reached) (HR = 0.757, P = 0.314), 11.0 vs 15.2 (HR = 1.396, P = 0.057) and 3.5 vs 3.8 (HR = 1.054, P = 0.665), for stage I-II, III, and IV, respectively. In patient treated with chemotherapy alone, Caucasians had longer median survival than that of AA (8.0 vs 3.6 months, P = 0.002), but not significantly different in patients treated with surgery or radiotherapy alone. Interestingly, for stage III patients, Caucasians significantly benefited from concurrent chemoradiotherapy (n = 57, P = 0.031) but not AA (n = 46, P = 0.189). In stage II patients, Caucasian patients had better survival if they had surgery (n = 39, P = 0.040). Conclusions: This study suggests that there are significant racial disparities of survival in patients with NSCLC. Should these result are validated, future treatment needs to be individualized for these patients.
Adverse Effects of Statins—Reply
Authors: Paul D. Thompson
Journal: JAMA (2017)

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A decision-analytic model of idelalisib and rituximab combination therapy versus rituximab monotherapy in relapsed, unfit chronic lymphocytic leukemia.
Authors: Alexander Xenakis, Nathaniel Smith, Rachel Beckerman, Jagpreet Chhatwal, Stephanie A. Gregory, Javier Pinilla-Ibarz, Andrew Briggs
Journal: Journal of Clinical Oncology (2014)

7101 Background: There are few treatment options for relapsed, unfit CLL patients. Idelalisib (IDELA) is a first-in-class inhibitor of PI3Kδ with significant clinical efficacy in relapsed, unfit CLL patients. A recent phase III clinical trial (Study 116) reported that in comparison with rituximab monotherapy (R-MONO), IDELA plus rituximab therapy (IDELA+R) resulted in improved progression-free survival (PFS, HR=0.15) and overall survival (OS, HR=0.28) in relapsed, unfit CLL patients. Methods: A decision-analytic model simulated a cohort of relapsed, unfit CLL patients receiving treatment over a 1 to 5 year horizon. Patients received IDELA+R or R-MONO either until death or until transitioning to a progressive-disease (PD) state where they received salvage therapy until death. Survival data for IDELA+R and R-MONO was fit and extrapolated from Study 116. A claims analysis of a large dataset provided disease- and treatment-related adverse events (AEs) and medical resource utilization rates for the PD state. Utility was based on literature review. All outcomes were discounted at 3% per year. Results: Treatment with IDELA+R over R-MONO resulted in better health outcomes, increasing life-years (LYs) by 1.0 to 9.7 mos, increasing progression-free life-years (PFLYs) by 4.6 to 11.6 mos, and improving quality-adjusted life-years (QALYs) by 0.1 to 0.7, while decreasing AEs by 46% to 2% and reducing hospitalizations by 48% to 5% over a 1 to 5 year time horizon. Conclusions: IDELA+R was projected to yield better health outcomes in relapsed, unfit CLL patients compared to R-MONO, largely driven by and improved PFS and OS; reductions in AEs were specifically related to a delayed progression to the PD state. Health outcomes (per patient) Time horizon (years) IDELA+R R-MONO Δ(IDELA+R-R-MONO) LYs (months) 1 11.2 10.2 +1.0 3 29.9 24.2 +5.7 5 40.4 30.6 +9.7 PFLYs (months) 1 10.3 5.7 +4.6 3 17.4 6.0 +11.4 5 17.5 6.0 +11.6 QALYs 1 0.7 0.6 +0.1 3 1.8 1.3 +0.5 5 2.3 1.7 +0.7 Health outcomes (1,000 patient cohort) Time horizon (years) IDELA+R R-MONO Δ(IDELA+R-R-MONO) No. AEs incurred 1 99 182 -83 3 378 470 -92 5 592 602 -10 No. hospitalizations incurred 1 114 218 -104 3 366 571 -206 5 728 766 -37
Tamoxifen use and osteoporotic fracture risk in Asian female breast cancer patients: A nationwide population-based cohort study.
Authors: Huey-En Tzeng, Wen Li Hwang, Chun-Hao Tsai
Journal: Journal of Clinical Oncology (2015)

e11512 Background: Opposite bone mineral densitychange with tamoxifen treatment has been proven in pre-and post-menopausal breast cancer woman in the related literature. However, there remains controversy as to whether tamoxifen significantly reduces fracture rates in different age groups. Breast cancer occurs at 10-20 years younger in Asian women as compared with Western women. Therefore, we conducted a population-based case-control study to determine whether or not tamoxifen use is associated with osteoporotic fractures. Methods: We selected 75,488 women with breast cancer without prior fracture history from the Longitudinal Health Insurance Database for Catastrophic Illness Patients in 2000-2011. They were followed from the date for breast cancer diagnosed to the fracture occurred included hip, vertebral and wrist fracture. Because tamoxifen used was as a time-dependent variable, the Cox proportional hazard model with time-dependent exposure covariates was used to estimate the risk for fracture. Results: There were 50,257 and 25,231 patients with and without tamoxifen treatment. Tamoxifen users with lower risk for overall fracture were 0.52 and 0.61 in the crude and adjusted model (95% CI = 0.45-0.61 and 0.53-0.71, respectively). They had lower risks for hip (HR = 0.57, 95% CI = 0.47-0.69) and vertebral fractures (HR = 0.67, 95% CI = 0.53-0.85). The risk for fracture decreased when the dosage of tamoxifen increased. No matter in what age group, tamoxifen users had a lower risk for fracture than non-users. Conclusions: In this Asian population-based case-control study, tamoxifen use was associated with a reduction in osteoporotic fractures, especially hip fractures.
68Ga-PSMA PET/CT in Osteosarcoma in Fibrous Dysplasia
Authors: Arun Sasikumar, Ajith Joy, M.R. A. Pillai, Tony M. Alex, Geetha Narayanan
Journal: Clinical Nuclear Medicine (2017)

Fibrous dysplasia (FD) is a benign bone lesion with a rare but potential for malignant transformation. Neither 99mTc-MDP nor 18F-FDG PET/CT can differentiate between FD and areas of malignant transformation in FD. We described a case of osteosarcoma developing in FD with selective uptake of tracer in malignant transformation areas demonstrated on a 68Ga-PSMA PET/CT scan. Our case highlights the ability of 68Ga-PSMA PET/CT to map tumor neoangiogenesis in osteosarcoma arising in FD, which can have potential implications in prognostication, possibility of antiangiogenesis-based therapeutic options, and in response assessment following chemotherapy.
The mutational oncoprint of recurrent cytogenetic abnormalities in adult patients with de novo acute myeloid leukemia
Authors: A-K Eisfeld, K Mrózek, J Kohlschmidt, D Nicolet, S Orwick, C J Walker, K W Kroll, J S Blachly, A J Carroll, J E Kolitz, B L Powell, E S Wang, R M Stone, A de la Chapelle, J C Byrd, C D Bloomfield
Journal: Leukemia (2017)
Efficacy results of first-line chemotherapy re-challenge in sensitive small cell lung cancer (SCLC): A retrospective multicenter analysis.
Authors: Giovenzio Genestreti, Marcello Tiseo, Marco Angelo Burgio, Manuela Monti, Emanuela Scarpi, Federica Carloni, Alberto Verlicchi, Claudia Casanova, Claudio Dazzi, Dino Amadori
Journal: Journal of Clinical Oncology (2013)

e18561 Background: Response and duration to initial chemotherapy are important factors used to classify SCLC patients into two groups. The first group comprises sensitive disease that responds to initial chemotherapy and relapses after more than 3 months and for which disease control could be obtained by re-challenging with first-line chemotherapy. The second group comprises refractory disease that progresses at the end or within 3 months of finishing first-line chemotherapy and for whom second-line chemotherapy represents the gold-standard. Methods: We reviewed clinical data from 4 Oncology Departments on sensitive SCLC treated with a first-line chemotherapy re-challenge in order to evaluate its activity and efficacy. Results: Of 211 SCLC patients diagnosed from January 2007 to December 2011, 25 (12%; 20 males, 5 females) had sensitive disease of whom 13 (52%) limited disease (LD) and 12 (48%) extended disease (ED). Median interval between the last day of chemotherapy and the onset of disease progression was 205 days (95% CI 169 – 279; range: 90 – 665). Chemotherapy consisted of etoposide + carboplatin in 15 (60%) patients or cisplatin in 10 (40%). On average 3-4 (range: 1-6) chemotherapy courses were administered, producing 8 (32%) partial responses, 3 (12%) stable disease, 10 (40%) progressive disease and 4 (16%) non evaluable disease. Further-line chemotherapy, mainly topotecan, was administered in 13 (52%) patients. Median overall survival produced by all treatments was 19.6 months (95% CI 16.5 – 27.6). Conclusions: In our experience, sensitive SCLC treated with first-line platinum/etoposide re-challenge produced interesting results in terms of activity and efficacy. Prospective randomized trials are warranted to investigate whether this strategy produces better results than standard second-line chemotherapy.
Ruxolitinib in polycythemia vera: Follow-up from the RESPONSE trial.
Authors: Srdan Verstovsek, Alessandro M. Vannucchi, Martin Griesshammer, Tamás Masszi, Simon Durrant, Francesco Passamonti, Claire N. Harrison, Fabrizio Pane, Pierre Zachee, Masayuki Hino, Beatriz Moiraghi, Carole Brennan Miller, Vittorio Rosti, Ruben A. Mesa, Mark M. Jones, Huiling Zhen, Jingjin Li, Nathalie Francillard, Dany Habr, Jean-Jacques Kiladjian
Journal: Journal of Clinical Oncology (2015)

7087 Background: The RESPONSE trial is a multicenter, open-label phase 3 study evaluating the efficacy and safety of ruxolitinib (Rux) compared with best available therapy (BAT) in patients (pts) with polycythemia vera resistant to or intolerant of hydroxyurea. Results from the primary analysis, 48 wks from last pt first treatment (LPFT), were published (Vannucchi, NEJM 2015). Methods: This was a second preplanned analysis 80 wks after LPFT. The primary response was defined as achieving both hematocrit (HCT) control without phlebotomy (PBT) through wk 32 and a ≥ 35% reduction in spleen volume (SV) by imaging at wk 32. Durability of the primary response, HCT control, spleen volume reduction, and complete hematologic remission (CHR), as well as long-term safety, were evaluated. Results: At data cutoff, 91 (82.7%) pts randomized to Rux (Rux arm) were receiving treatment (median exposure, 111 wks), compared to 93 (84.5%) at the wk 48 analysis (median exposure, 81 wks). No pts remained on BAT, compared to 3 pts at the wk 48 analysis. Of the 23 (21%) pts in the Rux arm who achieved the primary response at wk 32, only 1 lost this response. For the 60% of pts in the Rux arm who achieved HCT control at wk 32, the probability of maintaining this response for 80 wks from time of initial response was 89%. Of the 98 pts on Rux at wk 32, 90% did not have a PBT from wk 32 to 80. A ≥ 35% SV reduction at wk 32 was achieved in 38% of Rux pts; all maintained their response. CHR at wk 32 was achieved in 24% of Rux pts; the probability of maintaining CHR for 80 wks was 69%. The Pruritus Symptoms Impact Scale was "very much improved" for 5 of 10 pts in the Rux arm at their end of study visit. The most common nonhematologic adverse events in the Rux arm were headache (21.8% at the wk 80 analysis [ie, entire follow-up] vs 20.9% at the wk 48 analysis), diarrhea (20.0% vs 19.1%), pruritus (20.0% vs 17.3%), and fatigue (17.3% vs 17.3%); most were grade 1 or 2. Grade 3 or 4 anemia and thrombocytopenia occurred in 1.8% and 5.5% of pts, respectively (no increase from wk 48 analysis). The rate of treatment discontinuation in the Rux arm due to adverse events remained low (4.5%). Conclusions: In RESPONSE, Rux responses were durable and treatment remained generally well tolerated, with 83% still receiving Rux at a median exposure of 111 wks. Clinical trial information: NCT01243944.
Women from certain BRCA1/2-mutation–negative hereditary breast ovarian cancer families and consideration of prophylactic saplingo-oophorectomy before menopause.
Authors: Rozumna-Martynyuk Nataliya, M. P. Farrell, Simon D. Hooper, Darragh S Gogarty, C. Nolan, Berkeley Eileen, R. M. Clarke, Tom Walsh, Bill Boyd, David J. Gallagher
Journal: Journal of Clinical Oncology (2014)

1560 Background: Prophylactic salpingo-oophorectomy (PSO) is recommended at 35-40 years for BRCA1 mutations carriers and 40-45 years for BRCA2 mutation carrier. The optimal timing of PSO is less certain for women from BRCA1/2 mutation negative hereditary breast ovarian cancer (HBOC) families. There is an increasing trend to defer this surgery until after menopause. We explored the safety of this approach if it were to be adopted in BRCA1/2 wild-type HBOC families. Methods: BRCA1/2 mutation negative families with at least one case of ovarian cancer were identified in an Irish cancer genetics clinic. Four generation family pedigrees were reviewed and clinical data recorded including cancer diagnosis, and age at diagnosis. Results: 680 women underwent BRCA1/2 diagnostic testing. Forty-four families with breast and ovarian cancer were BRCA1/2 mutation wild-type. 113 (age range: 28-77, median=47.9 years) of 936 women in these families developed breast cancer. There were 40 cases of ovarian cancer (age range: 27-79, median=53.9 years). Sixty-six percent of ovarian cancer occurred at </=60 years and 34% occurred at < /=50 years. Seven families had more than one case of ovarian cancer (OC)(table 1). In one family there were 7 cases. In 5 of these 7 families ovarian cancer was diagnosed at ages </= the average age of menopause (51 years). Conclusions: Pre-menopausal prophylactic salpingo-oophorectomy should be considered for women from BRCA1/2 mutation wild-type HBOC families. Family No No of women in the family OC cases, No OC diagnosis, age OC diagnosis, age OC diagnosis, age OC diagnosis, age OC diagnosis, age OC diagnosis, age 688 26 2 48 40 507 15 3 60 40 60 503 19 2 51 52 185 31 2 64 30 173 10 2 79 unknown 129 55 2 64 58 1 36 7 61 49 60 49 48 Unknown