tbuckley/cabot-search huggingface dataset:
Genetic differences based on miRNAs of colorectal adenocarcinoma according to age and the presence or absence of MMR defect.
Authors: Carmen Guillen-Ponce, ELISA Conde Moreno, Elia Aguado, Jl Soto, Cristina Alenda, Adela Castillejo, Victor M Barbera, Dolores Salas, Alfredo Carrato, Maria LAURA Garcia Bermejo
Journal: Journal of Clinical Oncology (2012)

495 Background: More than 1.2 million new cases of colon adenocarcinoma (CRC) are diagnosed annually. Specific germline mutations are responsible for hereditary CRC syndromes, while somatic mutations is thought to underlie most sporadic cases. Recently, miRNAs have been described as important regulators of malignant transformation. We aim to study the expression of miRNAs in CRC patients with Lynch syndrome and in patients with CRC without microsatellite instability (MSI-S) who have developed cancer at different ages. Methods: We included 60 cases of CRC patients: 20 with CRC associated with Lynch syndrome in carriers of germline MMR mutation (group 1), 20 with CRC MSI-S diagnosed before 45 years (group 2) and 20 with MSI-S diagnosed after age 50 (group 3). From all these cases we selected 7: 3 from group 1, 2 from group 2, another 2 from group 3, and a control with healthy colonic mucosa. Screening was carried out for expression of miRNAs (850 miRNAs) and hybridization arrays (Exiqon) using paraffin colic tissue. A comparative analysis was made of the expression obtained in the different groups. Results: Hybridization arrays analysis indicates that there are 248 miRNAs differentially expressed between healthy controls and patients with CRC. In addition, there are 165 miRNAs differentially expressed between different groups of patients with CRC according to age at diagnosis (≤ 45 years vs.&gt; 50 years). Moreover, the pattern of miRNAs in patients with germline mutation in Lynch syndrome is very different to that of patients diagnosed with CRC&gt; 50 years. There are 117 miRNAs differentially expressed between these cases. Just a group of 20 miRNAs have different expression among patients with CRC MSI-S ≤ 45 years for CRC patients with Lynch syndrome mutation in MLH1. Conclusions: Differences exist in the profile of CRC mRNAs expression according to the age, as well as between CRC MSI-S patients &gt; 50 years and CRC in Lynch syndrome. Different patterns of miRNAs in CRC indicate different molecular signature in different groups of CRC could became new CRC diagnostic markers and most importantly could point out new targets for therapeutic interventions in CRC.
Interrelated bowel symptoms to fecal incontinence among gynecologic cancer survivors.
Authors: G. Dunberger
Journal: Journal of Clinical Oncology (2010)

5102 Background: Fecal incontinence (FI) is a symptom reported by gynecological cancer survivors treated with pelvic radiotherapy. Methods: A population-based study of 869 women, who had been treated with pelvic radiotherapy for a gynecological cancer during 1991 to 2003 at two departments of gynecological oncology in Sweden, took place in 2006. A control group of 480 women from the Swedish Population Registry, matched for age and regional residence, was also included. In preparation, we made in-depth interviews with 26 women with gynecological cancer. Based on their narratives, we constructed a study-specific questionnaire including 351 questions and it was validated face-to-face. The questionnaire covered questions of physical symptoms originating in the pelvic region, demographics, psychological and quality of life factors. In relation to bowel symptoms, 60 questions were asked concerning FI, daily life and interrelated symptoms. Results: In total 616 cancer survivors (78%) and 344 (72%) control women participated. Mean follow-up since radiotherapy was 7.8 years. Forty-nine percent among cancer survivors reported FI at least occasionally and among them 23% reported fecal leakage without forewarning. Loose stools at least once a week was reported in 58% of the survivors with FI compared to 20% in survivors without FI. Defecation urgency at least once a week among survivors with compared to survivors without FI showed a prevalence of 48% and 11% respectively. The need to have immediate toilet access to avoid FI, with the cut-off level at least once a week, was reported by 26% of survivors with FI compared to 3% among survivors without FI, with a relative risk of 10.0 (95% CI; 4.8-19.9). Conclusions: Interrelated bowel symptoms, as loose stools and defecation urgency, are common among gynecological cancer survivors and may be contributing factors for FI. No significant financial relationships to disclose.
A phase I trial of TPI-287 as a single agent and its combination with temozolomide in relapsed neuroblastoma or medulloblastoma.
Authors: G. L. Saulnier Sholler, G. Bergendahl, S. Lenox, P. E. Zage, W. Roberts, J. M. Kraveka, D. Eslin, J. Kaplan, T. Higgins, W. Ferguson
Journal: Journal of Clinical Oncology (2010)

TPS329 Background: Neuroblastoma is the most common extracranial solid tumor and medulloblastoma is the most common brain tumor in children. The prognosis for infants with neuroblastoma is good, while only 30% of children diagnosed after 12-15 months of age survive despite aggressive multimodal therapies. Therapies for children with relapsed medulloblastoma are associated with severe long-term toxicities with <15% survival. Thus, development of new therapies, especially ones with favorable toxicity profiles, would improve the treatment of these diseases. A novel anti- microtubule agent, TPI 287, is synthetically manufactured from naturally occurring taxanes extracted from yew starting material. The synthesis involves modifications of the side chain to make the drug more lipophilic, and modification of the baccatin ring structure which circumvents multidrug resistance (MDR)-based resistance and allows for binding to mutant tubulin. Selection was also made on the basis of the very high potency of this drug against several neuroblastoma cell lines and xenograft models. The primary objective is to determine the safety, tolerability and maximum tolerated dose (MTD) of TPI 287. The secondary objectives are to examine the activity of TPI 287 as a single agent and in combination with temozolomide (TMZ) in these tumor types based on overall response rate (ORR), progression free survival (PFS), and median overall survival (OS) and to evaluate the pharmacokinetics (PK) of TPI 287. Methods: TPI 287 is an open label, multicenter, dose escalation standard 3+3 design in which cohorts of 3 patients will receive two cycles of intravenous (IV) TPI 287 at a starting dose of 90 mg/m2 on Days 1, 8 and 15 of a 28-day cycle. After 2 cycles, TMZ 100 mg/m2 on days 1-5 of each cycle is added. There are 4 dose level escalations with the MTD of single agent therapy defined as the dose level below which DLTs are seen in ≥ two of six patients dosed. The ORR will be measured by the presence of radiologically assessable disease by cross-sectional imaging and by MIBG scans. The following PK parameters will be determined: Cmax, AUC (0–24 hr), Plasma half-life (t1/2), Plasma clearance (Cl), Vd. No significant financial relationships to disclose.
Mouse models of pancreatic cancer induced by chronic pancreatitis and smoking.
Authors: M. Edderkaoui, Paul J. Grippo, Y. Ouhaddi, H. Benhaddou, S. Xu, K. Pinkerton, H. Tsukamoto, Beatrice Knudsen, A. S. Gukovskaya, Stephen Pandol
Journal: Journal of Clinical Oncology (2014)

229 Background: Chronic pancreatitis (CP) and smoking are two major risk factors for pancreatic cancer (PaCa). Here we developed mouse models of PaCa by exposing mice to CP and/or smoking. Methods: Wild type (WT) and Pdx1-Cre;LSL-Kras transgenic mice were subjected to 7-hourly cerulein injections (50µg/kg) twice a week for 3 weeks to induce CP. Another group of mice was exposed to tobacco smoke (80mg/m 3 ) in chambers for 5days/week during 6 weeks. A third group was exposed to both treatments. Mice were then sacrificed and pancreatic tissue analyzed. Pancreatic lesions, proliferation, fibrosis, inflammation, EMT and stem cell markers were analyzed by immunohistochemistry and Western. Results: CP significantly increased the number and stage of pancreatic neoplastic (PanIN) lesions with fibrosis, stellate cell activation and inflammation in transgenic mice. These changes were significantly less in WT mice. EMT markers (decrease in E-Cadherin and increase in vimentin protein levels) were stimulated by CP in both WT and transgenic mice. Similarly, smoking stimulated PanIN lesion formation, fibrosis and inflammation in transgenic mice, but to a lesser extent than CP model. Expression of EMT and stem cell markers was greater in the smoking model compared to CP. Combination of CP and smoking induced greater stimulation of PanIN lesion formation, fibrosis and inflammation compared to either treatment alone in transgenic mice. Conclusions: The results indicate that both CP and tobacco smoke promote PaCa progression in transgenic mice. The combination of CP and smoking has greater effects than either treatment alone. EMT and stem cell markers developed in WT as well as in transgenic mice with smoking suggesting that smoking has effects independent of Kras on cell transformation.
Does conversion chemotherapy really improve survival in patients with colorectal liver metastases?
Authors: Kozo Kataoka, Akiyoshi Kanazawa, Shigeyoshi Iwamoto, Yasuhiro Miyake, Takeshi Kato, Akio Nakajima, Akira Arimoto, Yukihiro Kono
Journal: Journal of Clinical Oncology (2013)

435 Background: Recently, liver resection becomes possible by intensive chemotherapy, i.e. conversion chemotherapy, in patients with initially unresectable colorectal liver metastases (CLM). But the criteria for non-resectability varies one team to another, and there are few reports about the clinical benefit of conversion chemotherapy followed by liver resection. Methods: Our criteria for resectability of CLM depends on the size of remnant liver volume (&gt;30%) and expected function after the removal of all metastases, regardress of number and size of CLM. From December 2007 to September 2011, 113 patients were diagnosed as CLM without extra-hepatic metastases and received chemotherapy. 47 patients were initially diagnosed as resectable and received hepatic resection after chemotherapy (resected group). 66 patients were initially diagnosed as unresectable, but 11 patients become resectable after chemotherapy (conversion group) and 55 patients remain unresectable in spite of chemotherapy (unresecetd group). We assessed the survival benefit between these 3 groups, retrospectively. Results: 110 patients received oxaliplatin-based regimen and 3 irrinotecan-based regimen. In coversion group, 8 patients received cetuximab containing regimen and 2 received bevacizumab containing regimen. 46 of 47 patients in resected group received R0 resection and 7 of 11 patients in conversion group. No serious postoperative complications were observed in resected and conversion group, but the incidence of a surgical site infection in conversion group was somewhat higher than in resected group. Median disease-free survival was significantly higher in the resected group than conversion group (16.73 months [95% CI: 7.80~25.47] and 3.83 months [95% CI: 0.35~7.31 months]) (P=0.031). And median overall survival (OS) was also higher in resected group, but not significant. In resected and conversion group, median OS was significantly higher than in unresected group. (52.20 vs 39.37 vs 20.57 months (p &lt;0.001)). Conclusions: The recurrence rate was higher in coversion group, but conversion chemotherapy followed by hepatic resection seems to be promising and feasible strategy in initially unresectable CLM patients.
Evidence for Vasculogenic Potential and Endothelial Differentiation of Bone-Marrow-Derived Very Small Embryonic-like Stem Cells
Authors: Coralie L Guerin, Xavier Loyer, Jose Vilar, Audrey Cras, Tristan Mirault, Pascale Gaussem, Jean Sebastien Silvestre, David M Smadja
Journal: Blood (2014)
The value of genetic polymorphisms to predict toxicity in metastatic colorectal patients with irinotecan-based regimens.
Authors: M. J. Lamas, G. Duran, E. Balboa, S. Candamio, B. Bernardez, A. Carracedo, R. Lopez, F. Barros
Journal: Journal of Clinical Oncology (2011)

e14065 Background: We are trying to identify factors that predict which patients are likely to high risk of toxicity by analyzing candidate genes in the irinotecan pathways in order to identify useful tools to improve mCRC patient management. Methods: Genomic DNA was genotyped for UGT1A1 (*28,*60 and *93) from all 101 patients, irinotecan was administered biweekly (180mg/m2) and clinical data were obtained by retrospective chart review. All toxicities were graded according to the National Cancer Institute Common Toxicity Criteria CTC v3.0. For each patient, we recorded the maximum observed toxicity grade and use of granulocyte colony-stimulating factor (G-CSF). The primary end-point is to find out if the pharmacogenetic test in the clinical practice may predict toxicity. Results: Frequencies of 6/6, 6/7, and 7/7 genotypes were 59 (58.4%), 32 (31.7%), and 9 (8.9%) of 101 patients, respectively. Grade 3/4 diarrhea occurred in twelve patients and required dose reduction in six patients and neutropenia reached grade 3/4 in 19 patients independently of genotype (only one patient with 7/7 genotype). The UGT1A1*93 showed a trend with grade 3/4 neutropenia but only in the heterozygote state (G/A), p=0.071, otherwise UGT1A*60 showed no association with neutropenia. 28 patients required the use of G-CSF, 18 out of them (64.3%) harboured 6/7 or 7/7 genotypes, p=0.003. Thirty-seven (36.6%) patients required dose reduction of irinotecan and/or 5-FU due to toxicity, mainly neutropenia and diarrhea: 32 (31.7%) patients received 75-80% of the dose and 5 patients required a deeper reduction (less of 75%). Dose reduction occurred in 18 of 36 patients with 6/7 or 7/7 genotypes (p=0.17). No significant association was detected between *28,*60 and *93 UGT1A variants and severe irinotecan-associated hematologic or GI toxicity. Conclusions: The impact of increased risk of toxicity attributed to the UGT1A1 * 28 may be overridden by regular use of irinotecan in clinical practice: dose reduction, use of colony stimulating factor, or instruct the patient for early management of toxic diarrhea.
Selection of medical oncology electronic medical record (EMR): A case study.
Authors: Josie McMurtrey, Paul Driver, Pam Reed, Thomas Thrower, Binay Kumar Shah
Journal: Journal of Clinical Oncology (2012)

327 Background: Selection of an ideal EMR is an important but a complicated process, especially because there are few established guidelines available. We describe a case study on the process of selection of medical oncology EMR from our experience at St. Joseph Regional Cancer Center, Lewiston ID. Methods: A multidisciplinary team was developed, including a medical oncologist to develop workflow diagrams capturing tasks completed for patient care. This allowed the team to identify requirements and functionality important to have within an EMR. Requirements rating as high, medium or low. The scoring methodology was based on a rating scale (0-5, where 0 does not meet the fundamental requirement and 5 fully meets the fundamental requirement; 0-2, where 0 does not meet the differentiator requirement and 2 fully meets the differentiator requirement) to capture if system met fundamental and differentiator requirements. The team developed a list of the ten most important needs within a system to focus on while viewing vendor demos. The top 10 requirements focused on lab result integration, other facility integration, alerts, billing flow of information, electronic prescriptions, local assessments, electronic consent forms, flexibility in chemo calculations, sign-offs of treatments throughout the patient flow process, and the ability to order cycles of treatment in a multi-visit treatment plan. Finally, use case scenarios were developed and vendors were given the opportunity to demo their product using workflow scenarios. Results: Out of 10 medical oncology systems in consideration, the evaluation included four 3rd party vendor systems and one EMR platform system. Four systems were chosen for evaluation based on rankings from the 2011 Oncology IS KLAS report. Complete evaluation of the systems and the scorings were based on vendor demo webinars and multidisciplinary input. This methodical approach allowed the team to gain a broad, balanced approach in narrowing the search down to the top three finalists. Conclusions: A systematic approach that includes an objective scoring system and research by interviewing other sites is useful in selection of a medical oncology EMR.
Rapid adoption of chemotherapy regimens for advanced colorectal cancer (CRC) in the community oncology setting
Authors: T. McKibbin, P. Kwan, J. Simon, J. Koeller
Journal: Journal of Clinical Oncology (2008)

6563 Background: A multitude of randomized controlled trials have evaluated chemotherapy and monoclonal antibody therapy for the treatment of advanced CRC. However, few studies characterize timelines of how these treatments have been incorporated into community practices. We sought to characterize the adoption of new regimens into general practice over time. Methods: A national, multi- center, retrospective chart review was conducted at 11 oncology clinics throughout the USA. Patients were eligible for inclusion if they started chemotherapy for advanced CRC from January 1, 2003 through December 31, 2006. Initial and subsequent chemotherapy utilization was analyzed. Results: Overall, 551 patients met inclusion criteria. Median age was 66 years (range 24–95) and 53% of patients were male. Rapid adoption of treatments was noted. Coinciding with the release of data from N9741 (ASCO 2003, abstr. 1009), a marked decrease in the utilization of IFL was noted during 2003. In the first 3 months of 2003, IFL was used in 55% of first-line patients compared to 21% during the last 3 months of 2003. In 2004, 9% of patients received IFL with only 1% in 2005, and none in 2006. There was a resultant increase in the oxaliplatin (initially FOLFOX4) usage (Table 1). In 2006, mFOLFOX6 was the most widely used regimen and the capecitabine increase appeared to be caused by new CapeOx data in 2005. Additionally, bevacizumab was rapidly incorporated into treatment with 51% of patients receiving it first-line within 6 months of FDA approval. Conclusions: The treatment of advanced CRC has undergone numerous changes in recent years, with a paradigm change from first-line irinotecan to oxaliplatin and from 5-FU to capecitabine. Clinicians in the community oncology setting have largely kept pace with current medical literature and have rapidly adopted new regimens and medications into their practice. Percent of Patients Receiving Selected Treatments First-Line 2003(n=116) 2004(n=180) 2005(n=166) 2006(n=89) Irinotecan 50 16 10 15 Oxaliplatin 23 55 60 67 Capecitabine 22 22 23 34 5-FU 75 74 74 65 Bevacizumab – 40 54 59 Top First-Line Regimens (% of Pts) 1 IFL (37%) FOLFOX4 (19%) FOLFOX4 (17%) mFOLFOX6 (34%) 2 Roswell Park (15%) Roswell Park (17%) mFOLFOX6 (17%) Capecitabine (17%) 3 FOLFOX4 (13%) CapeOx (12%) Capecitabine (14%) CapeOx (16%) Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca Oncology, Bristol-Myers Squibb, Genentech™ BioOncology, ImClone Systems Incorporated, sanofi-aventis Lilly Oncology, MGI Pharma, Pfizer Oncology Pfizer Oncology
Rechallenge with oxaliplatin and fluoropyrimidine (FOX) after prior therapy in metastatic colorectal carcinoma (mCRC).
Authors: A. R. Townsend, V. Broadbridge, C. Beeke, C. S. Karapetis, S. Bishnoi, K. Jain, C. Luke, R. Padbury, T. J. Price
Journal: Journal of Clinical Oncology (2011)

e14118 Background: Patients with mCRC who have received standard oxaliplatin, 5FU and irinotecan chemotherapy (+/- bevacizumab) and anti-EGFR (if KRAS WT) have no further standard treatment options. For patients with an adequate performance status, repeating a prior chemotherapy, in particular FOX, is an option, but there is very little evidence suggesting benefit, with only one trial reported (RR of 25% in 12 patients and no PFS or OS reported [Daniele Santini et al. Oncology. 2005;69:27-34.]). Methods: Patients treated in South Australian (SA) public hospitals who had been rechallenged with FOX were identified from the SA mCRC database. Patients developing mCRC within 12 mths of completion of oxaliplatin based adjuvant therapy were also eligible. Patient characteristics were analysed and tumour response was assessed using RECIST criteria by retrospective review of radiology. Results: 24 patients were identified, of these 20 were eligible for inclusion. Patient characteristics were as follows; male 12, median age 64 yrs, synchronous mCRC 12, liver only disease 12, rectum or sigmoid primary 16, KRAS status; WT 7, MUT 5, U/K 8. The number of prior lines of therapy received for mCRC was four = 2, three = 6, two = 7, one = 3, with 3 patients having received oxaliplatin as adjuvant therapy. 4 patients received prior bevacizumab, and 7 anti-EGFR Rx. 4 had prior liver resection. The median time from commencing last chemotherapy was 8.4 mths. 3 patients were not evaluable for radiological response, 1 (6%) had complete response, 2 (12%) partial response, with overall response rate 18%, 8 (47%) had stable disease, and 6 (35%) had progression at first scan. The median PFS was 3.7 mths, median OS 7.8 mths and 1 yr survival 37%. 12 % reported worsening of neuropathy and allergic reaction to oxaliplatin was noted in 1 patient and treatment continued with premedication. Conclusions: In this unselected population there is evidence of modest activity of rechallenge with FOX chemotherapy although radiological response is uncommon.
Quality of life in male patients with hormone-independent cancers: The role of testosterone.
Authors: P. Homel, S. B. Fleishman, M. F. Suhail, V. Rosenwald
Journal: Journal of Clinical Oncology (2011)

9125 Background: Prior studies of quality of life (QoL) in hypogonadal men examined prostate cancer (ca) patients undergoing androgen suppression. This cross-sectional study examines the relationship of hypogonadism to aspects of QoL in patients with hormone independent cancers (HIC). Methods: Serum, demographics, and medical histories were collected from 428 male HIC subjects at 3 cancer centers. Morning blood samples were analyzed for Total Testosterone (TT), Free T, Bio-available T (BAT) and Sex Hormone Binding Globulin. Functional Assessment of Cancer Therapy-Prostate (FACT-P) measured physical, social, emotional and functional domains plus sexual function. Exclusion criteria: <18 yrs, prostate cancer, testicular ca, male breast ca, known hypogonadism, HIV. Multiple regression with backwards selection was used to identify significant, non-redundant predictors of FACT-P subscales. P-value for retention of a predictor was 0.15. Results: Mean age of subjects was 62.1±13.2 years. Median TT was 310 ng/dl (IQR: 190-443, and 196 (48 %) were hypogonadal. BAT showed the strongest univariate relationship with subscales of the FACT-P, correlating significantly with Physical Well-being (PWB), r=0.32, p<0.001; Emotional Well Being (EWB), 0.14, p=0.004; Functional Well-Being (FWB), 0.28, p<0.001; and QoL related to Prostate Ca (QPCa), r=0.37, p<0.001. After controlling for other factors, BAT remained significantly correlated with PWB and QPCa (both p=0.04). There was also a trend between QPCa and hypogonadism (p=0.12). Conclusions: FACT-P subscales show significant correlations with testosterone level. Hypogonadism was not as highly correlated with sexual dysfunction as with fatigue. Hypogonadism was not an independent predictor of sexual dysfunction, which is multi-determined, linked clinically and statistically to other factors, e.g., diabetes, age, opioids. T replacement may improve QoL with amelioration of fatigue. Sexual dysfunction may require co-optimization of glycemia and analgesia. A more specific QoL measure of androgen suppression which is not associated with prostate cancer may better define the correlations.