tbuckley/cabot-search huggingface dataset:
LMTK3 polymorphism in patients with metastatic colon cancer.
Authors: Fotios Loupakis, Wu Zhang, Armin Gerger, Dongyun Yang, Pierre Oliver Bohanes, Melissa Janae Labonte, Leonor Benhaim, Takeru Wakatsuki, Yan Ning, Peter M.D. Wilson, Rita El-Khoueiry, Anthony B. El-Khoueiry, Syma Iqbal, Afsaneh Barzi, Georgios Giamas, Justin Stebbing, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2012)

471 Background: LMTKs are a family of serine-threonine-tyrosine kinases. LMTK3 isoform is a potent regulator of estrogen receptor activity LMTK3 gene polymorphisms affect DFS and OS of breast cancer patients. Cumulative evidence implies that estrogen receptor signalling plays a role in colon carcinoma development and progression. We investigated whether the LMTK3 rs9989661 SNP is a prognostic factor in patients with advanced colon cancer. Methods: 318 patients with metastatic colon cancer treated at the USC/Norris Comprehensive Cancer Center or the LA County/USC Medical Center were included in this study. Genomic DNA was extracted from white blood cells of peripheral blood samples using the QiaAmp kit (Qiagen, Valencia, CA). The LMTK3 polymorphism was genotyped by PCR-RFLP. The association between the LMTK3 polymorphism and overall survival was examined using the log-rank test and multivariate Cox-model. Results: There were 141 females and 177 males, with a median age of 58 years (range 25-86). The cohort comprised 234 whites, 43 Asians, 15 Blacks, 24 Hispanics, and 2 Native Americans. The median survival was 13.7 months with a median follow-up of 2.3 years. The median overall survival was 16.6 vs. 12.8 months for patients with C/- vs. patients with T/T (HR=0.78; 95% CI: 0.56-1.08; p=0.055). At a multivariate analysis restricted to subjects with left-sided disease (n=126) the median OS for patients with C/- genotype was 23.8 months compared to 14.9 months of T/T patients (HR=0.51; 95%CI: 0.28-0.91; p=0.014). Conclusions: This study suggests that LMTK3 may be an independent prognostic factor for patients with metastatic colon cancer and raise the issue of possible disparities according to primary tumor location. Our group produced similar results also in the adjuvant setting. Functional correlative preclinical analyses and external clinical validation studies are currently ongoing.
Testosterone increases coronary artery plaque in older men but helps anaemia and bone density
Authors: Susan Mayor
Journal: BMJ (2017)

Testosterone treatment increased the amount of coronary artery non-calcified plaque rather than reducing this early sign of increased cardiovascular risk in older men with low testosterone levels, a randomised study has shown.1

But a separate observational study published at the same time found a lower risk of cardiovascular events in men receiving testosterone treatment,2 while further randomised trials showed improvements in anaemia3 and bone density,4 although no increase was seen in cognitive function.5

The first study, published in JAMA ,1 randomly assigned 170 men aged over 65 with low serum testosterone levels to …
Patterns of PET/CT scan use in patients with advanced non-small cell lung cancer (NSCLC)
Authors: G. Franz, L. Kronish, R. U. Osarogiagbon, L. Thompson, M. Jahanzeb
Journal: Journal of Clinical Oncology (2008)

19112 Background: PET/CT Scans are now widely used in the diagnosis and treatment of NSCLC, but it is costly, and its true advantages are continuing to be documented with respect to patient outcomes over other less expensive tests. There is no consistent algorithm for its use. Methods: We retrospectively reviewed our database of NSCLC patients to look at employment of this technology at UTCI over a 5 year period (between 2002 and 2007) for advanced NSCLC comparing two groups based upon the use of PET/CT for treatment planning and decision making. We included patients with stage III-IV NSCLC treated with various modalities, and we further stratified patients with respect to stage (IIIA, IIIB and stage IV) age, sex, ECOG performance status, race, and insurance status. Group A consisted of patients with PET/CT scans (N=20) and Group B consisted of patients without PET/CT scans (N=19). Patients in Group A were treated in the setting of a multidisciplinary thoracic oncology outpatient clinic. Results: PET/CT scan usage was clearly associated with the date of diagnosis with its usage increasing sharply over time. Seventeen out of twenty patients (85%) in group A were diagnosed between 2006 and 2007, and fourteen out of nineteen patients (73.7%) in group B were diagnosed between 2003 and 2005. In group A, (PET/CT group) 9/20 (45%) had stage IV disease, 6/20 (30%) had stage IIIB disease, and 5/20 (25%) had stage IIIA disease. In group B, (no PET/CT group) 13/19 (68.4%) had stage IV disease, 4/19 (21%) had stage IIIB disease, and 2/19 (10.5%) had stage IIIA disease. Conclusions: Review of our institution’s data base revealed a significant increase in the employment of PET/CT scans in patients with advanced NSCLC over the past 5 years. These findings were seen especially in patients with stage IV disease, despite a lack of evidence that use of this modality improves patient outcomes. We propose a larger retrospective review to obtain statistical data supporting this practice pattern. No significant financial relationships to disclose.
Prospective randomized controlled study on multiple preoperative treatments in stage IB2 to IIA cervical cancer.
Authors: H. Wen, X. H. Wu, J. LI, Z. T. Li, H. Wang, R. Y. Zang, G. H. Ke, M. Sun, W. T. Li, X. Huang, S. M. Cai
Journal: Journal of Clinical Oncology (2011)

e15508 Background: Patients with stage IB2 to IIA cervical cancer have a poor survival whatever primary standard treatment is chosen. We conducted a study to demonstrate whether preoperative treatments could improve their prognosis. Methods: During Jan 2006 through Dec 2009, 123 patients were enrolled and randomized to four groups. 31 patients in Group 1(G1 for abbreviation) underwent radical surgery alone as control. Brachytherapy with a total dosage of 15Gy to point A in two fractions were delivered to 31 patients in G2 before surgery. 30 patients in G3 received intravenous chemotherapy consisting of DDP 50mg/m2 and 5-Fu 750mg/m2 every two weeks for two courses before surgery. 31 patients in G4 were administered intra-arterial chemotherapy with the same regimen as G3 before surgery. All patients underwent radical hysterectomy and bilateral pelvic lymph node dissection +/- para-aortic lymphadenectomy regardless of response to preoperative therapy. Primary endpoints were PFS and OS. Largest tumor diameter on pathologic examination and pathologic risk factors (positive parametrium,positive lymph node,positive surgical margin,LVSI,large primary tumor(≥4cm) and deep stromal invasion) were also compared between groups. Analysis was done in per-protocol population. Results: Up to Dec 2010,114 of 123 (92.7%) patients were evaluable and followed for an average of 49.5 (3-57.5) months. Baseline characteristics(age,tumor volume at first visit,pathologic type and clinical stage)were similarly distributed in four groups. 26 recurrences and 19 deaths were observed. Two-year PFS were 71.2% for G1, 67.2% for G2, 84.2% for G3 and 85.0% for G4, respectively. Two-year OS were 82.5% for G1, 76.6% for G2, 95.8% for G3 and 88.6% for G4, respectively. No significant differences in PFS (p=0.26) or OS (p=0.30) were noted between groups. Each preoperative treatment reduced tumor volume significantly compared with the control (p=0.01). Except for large tumor size (p<0.01), no significant differences in pathologic risk factors were noted between groups. Conclusions: Preoperative treatments did not improve survival significantly although each of them could lead to significant reduction of tumor volume.
Casting-type calcification breast cancer: Assessment of response to cytotoxic insult in human tumor primary culture spheroids
Authors: R. A. Nagourney, B. Sommers, S. Evans, C. Kollin, Y. Z. Su, T. Evans, J. Islas, J. Kakkis, L. Tabar
Journal: Journal of Clinical Oncology (2005)

680 Mammographic casting-type calcifications (CTC) represent Grade 3 DCIS that are often associated with T1a/b invasive tumors. CTC’s have an unexpectedly poor prognosis, at odds with the expected outcome for this size category (Tabar L, Cancer, 2004; Zunzunegui RG, Arch Surg, 2003). CTC is associated with (+) lymph nodes, higher grade and early death. It has been suggested that these tumors are chemo- and radio-resistant with viable CTC tumors observed at surgery following neo-adjuvant therapies. To test this hypothesis, we applied an ex vivo analysis (EVA) of drug sensitivity, shown to correlate with response & survival (Nagourney R, J Clin Oncol 2000; Gyn Oncol 2003), to surgical biopsies of CTC. Two the first 3 specimens submitted provided adequate cells for analysis, 1 from a previously untreated patient and 1 from a patient after neo-adjuvant Doxorubicin/Cytoxan/Taxol. The histological appearance of the isolated micro-spheroids is one of large cells with abundant mucinous cytoplasm. Drug response profiles reveal striking degrees of resistance, with the ex vivo LC50 values for most agents tested exceeding the highest concentration ranges. Noteworthy was the high activity for Gefitinib, an agent that has generally shown modest activity in breast cancer specimens, as we have reported (Nagourney R, Proc AACR 2003). Compared to the overall breast tumor database, the CTC tumors are significantly more Gefitinib sensitive. These preliminary results suggest CTC tumors manifest resistance to conventional chemotherapy yet sensitivity to agents that target cellular survival capacity associated with EGFR pathway activation. If confirmed in ongoing analyses (to be reported), the poor prognosis of CTC cancers may reflect altered intracellular response and survival cascades that could provide novel avenues for the management of these high-risk patients. Supported by a research grant from the Vanguard Cancer Foundation. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Central Hospital, Malcolm Todd Cancer Institute, Rational Therapeutics Rational Therapeutics
A phase I dose-escalation trial of TH-302 with nab-paclitaxel and gemcitabine in patients with locally advanced or metastatic pancreatic adenocarcinoma.
Authors: Anthony J. Olszanski, Andrea Wang-Gillam, Eunice Lee Kwak, Kamal Nazzal, Fazal Mehdi, Mitesh J. Borad
Journal: Journal of Clinical Oncology (2015)

TPS505 Background: TH-302 is a hypoxia-activated, nitroimidazole-linked prodrug of bromo-isophosphoramide mustard (Br-IPM), which is released under hypoxic conditions. TH-302 is currently being studied in combination with gemcitabine (G) in a phase III trial in patients (pts) with advanced pancreatic adenocarcinoma (PDAC) (NCT01746979). Encouraging preclinical activity of TH-302 plus nab-paclitaxel (nab-P) and G provides a rationale for further study of this triplet (Sun JD et al, AACR Special Conference on Pancreatic Cancer 2014; abstract #B88). Methods: Clinical trial: NCT02047500. Open-label, phase I, dose-escalation trial of TH-302 plus nab-P and G in pts with previously untreated locally advanced or metastatic PDAC. Dose escalation: 3 + 3 design with one of 3 planned dose levels of TH-302 (170, 240 and 340 mg/m 2 ) on days 1, 8, and 15 of a 28-day cycle, plus nab-P 100–125 mg/m 2 followed by G 800–1,000 mg/m 2 . Expansion cohort (n≥15): TH-302 at the recommended phase II dose (RP2D) with nab-P 100–125 mg/m 2 followed by G 800–1,000 mg/m 2 . Treatment will be continued until disease progression or intolerable toxicity. Primary objectives: To evaluate safety and tolerability, define the maximum tolerated dose and determine the RP2D of TH-302 in combination with nab-P/G. The primary endpoint is no. of pts with dose-limiting toxicities during the first 28 days. Secondary objectives: To evaluate overall safety of the triplet regimen, metabolic response rate using EORTC criteria for 18 F-FDG PET, CA19–9 response rate (defined as &gt;50% decline from baseline), and RECIST response rate of TH-302 plus nab-P/G. The pharmacokinetic (PK) profile of TH-302 and Br-IPM in the plasma of pts will also be evaluated, as will the effect of TH-302 on the PK of nab-P, and vice versa. Exploratory analyses include the association of pharmacogenomic markers, such as CYP2C9, BRCA1 and BRCA2, with PK, safety and efficacy. The association of potential hypoxia biomarkers (CA IX, GLUT1, VEGF, osteopontin) with antitumor activity will also be explored. The trial is in progress; 7 of an estimated 48 planned pts have been recruited (trial start Jan 2014, estimate end Aug 2016). Clinical trial information: NCT02047500.
ON 01910.Na Suppresses Cyclin D1 Accumulation in trisomy 8 Myelodysplastic Syndromes Patients While Decreasing Bone Marrow CD34+ Blast Counts and Aneuploid Clone Size.
Authors: Elaine M Sloand, Matthew J. Olnes, Naomi Galili, Aarthi Shenoy, Loretta Pfannes, Francois Wilhelm, Barbara Weinstein, Phillip Scheinberg, Jerome E. Groopman, Azra Raza
Journal: Blood (2009)
“It’s a wink and a nod”: A qualitative evaluation of clinician-investigator perceptions of the benefits of early-phase (EP) clinical trials.
Authors: D. P. Dohan, N. Laven, L. Dunn, C. Daugherty, L. Trupin, J. Hult, M. Bondi, D. McCabe
Journal: Journal of Clinical Oncology (2011)

e13035 Background: EP trials assess toxicity and dosing yet are often perceived to benefit individual patients. This therapeutic misconception (TM) has often been attributed to patients’ beliefs and perceptions. This project further examines the origins of TM by describing clinician-investigators’ perceptions of the benefits of EP trials. Methods: Two PhD investigators (sociology and anthropology) conducted participant-observation at 39 practice meetings and conducted 10 in-depth interviews with clinician-investigators at an academic EP trials program over 18 months. Data were analyzed iteratively using Atlas.ti software and emergent themes were identified. Results: Clinician-investigators’ perceptions of the benefits of EP trials emerged as a theme. Analysis identified 4 such benefits. 1) Clinical: In interviews, clinician-investigators stated that some EP trials, especially of targeted agents, could lead to remission. Discussion of positive responses were common at practice meetings. 2) Emotional: In interviews, all but one clinician-investigator said discussing EP trials helped foster hopefulness when treating patients with poor or terminal prognoses. 3) Scientific: In most practice meetings and interviews, clinician-investigators discussed how conducting EP trials advanced medical science. 4) Professional: In some practice meetings and in one interview, clinician-investigators discussed how conducting EP trials can enhance clinician-investigators’ careers and provide financial support for the academic center and EP program. In interviews, clinician-investigators said they discussed clinical, emotional, and scientific benefits of EP trials with patients. They did not report discussing professional benefits with patients, but in practice meetings they occasionally debated whether this topic should be part of the informed consent process. Conclusions: Clinician-investigators perceive a variety of potential benefits of EP trials. These perceptions suggest TM is multifactorial, a finding consistent with other studies. Further normative and empirical work is needed to determine what safeguards may be needed to mitigate TM in EP trials.
Low-Burden TP53 Mutations Occur in Chronic Phase of Myeloproliferative Neoplasms Regardless of Hydroxyurea Administration, Disease Type, and JAK2 Status
Authors: Blanka Kubesova, Sarka Pavlova, Jitka Malcikova, Jitka Kabathova, Lenka Radova, Nikola Tom, Boris Tichy, Karla Plevova, Barbara Kantorova, Kristyna Fiedorova, Jarmila Kissova, Bettina Gisslinger, Heinz Gisslinger, Jiri Mayer, Robert Kralovics, Sarka Pospisilova, Michael Doubek
Journal: Blood (2016)
Evaluation of the role of UGT1A1 genotype testing in colorectal cancer patients administered irinotecan and the occurence of grade 3 and 4 neutropenia.
Authors: Sushma M. Patel, Jim Chan, Rita L. Hui, Michele M. Spence
Journal: Journal of Clinical Oncology (2012)

412 Background: Irinotecan is metabolized primarily in the liver by the carboxylesterase enzyme to the SN-38 active metabolite and is then inactivated through conjugation by the UGT1A1 enzyme, a polymorphic enzyme. Individuals genotyped with the homozygous allele have an increased risk for grade 3 and 4 neutropenia. Methods: A retrospective cohort analysis was conducted in the Kaiser Permanente California regions. The study period was November 1, 2005 to July 1, 2010 and included patients that were 18 years of age or older, newly initiated on irinotecan for colorectal cancer and had no previous irinotecan therapy within six months of the initiation dose. Patients were excluded if they were enrolled in clinical trials, on granulocyte-colony stimulating factor prophylaxis, and genotype tested for UGT1A1 and subsequently not treated with irinotecan. Patients tested with the UGT1A1 assay were grouped according to their genotype results: wild-type, heterozygous, or homozygous*28. The incidence of grade 3 and 4 neutropenia were compared among patients tested for UGT1A1 variant alleles by their genotype results. Results: A total of 305 (28%) patients were tested with the UGT1A1 assay with a mean age of 62 (+/- 12) years, and 52% of the population female. There were 161 (53%) wild-type, 123 (40%) heterozygous, and 21 (7%) homozygous patients. The median irinotecan dose was 150 mg/m 2 (124-180 mg/m 2 ) and median number of irinotecan cycles were 6 (3-12). The wild-type, heterozygous, homozygous*28 population had a 21% (33/161), 24% (29/123), and 48% (10/21) rate of grade 3 and 4 neutropenia. When the homozygous*28 group was compared to the heterozygous and wild-type genotype the adjusted Cox Proportional Hazard was 3.05 (95% CI, 1.55-5.99), p = 0.001. The Kaplan-Meier Log Rank Test yielded a p-value of 0.002. Conclusions: The adjusted risk for homozygous genotyped patients was three times higher compared to the wild-type and heterozygous group for grade 3 and 4 neutropenia. Additional investigational studies examining the benefits of UGT1A1 genotyping as a prognostic test and further effect of dosage adjustments in UGT1A1*28 homozygous initiated on irinotecan therapy are needed.
A comparison of the outcome of systemic therapy (Rx) of metastatic melanoma of unknown primary site (MUPS) and metastatic mucosal/cutaneous melanoma (MCM)
Authors: C. Wang, N. Papadopoulos, K. Kim, L. H. Camacho, P. Hwu, A. Y. Bedikian
Journal: Journal of Clinical Oncology (2005)

7545 Background: The management of MUPS remains controversial. Whether identification of the primary site would lead to better Rx outcome is unknown. The objective of this study is to compare 1) the outcome of systemic Rx in patients (pts) with MUPS with those with MCM, 2) the efficacy of chemotherapy (CVD-Cisplatin, Vinblastine, DTIC) vs. biochemotherapy (BCT-CVD + interferon α 2b + interleukin-2) for both groups of pts. Methods: We reviewed the records of 448 pts with MUPS and MCM enrolled in 6 phase II/III trials of CVD or BCT conducted from 1987 to 2001. All pts were treated with either CVD or BCT. Treatment cycles were repeated every 21 days and the tumor responses were assessed every 2 cycles. Results: 378 pts with MCM (96% cutaneous) and 70 pts with MUPS were identified. The longest follow-up was 16 years. Both groups had comparable age ranges, male to female ratios, performance status, number of visceral sites involved and proportion of M1c pts. 56% of pts with MCM and 61% of pts with MUPS received BCT. The overall responses (ORR) (49.5% vs. 30%, p=<0.001) and CR rates (14% vs. 3%, p<0.001) of BCT were significantly higher than those of CVD in MCM pts. Similar higher ORR was seen in pts with MUPS (55.8% vs. 33%, p=0.08) treated with BCT. The OS of pts with MCM was similar (p=0.54) to that of pts with MUPS. The OS of pts with MCM and MUPS treated with BCT was significantly superior to those of pts in the respective groups treated with CVD (p=0.0025 and p=0.0026 respectively). More importantly, the chance for long-term survival at 10 years was improved when the pts in either group were treated with BCT (13%) compared to CVD (4%). Conclusions: The outcome of treatments with CVD was the same in pts with MUPS and MCM. BCT induced greater ORR and OS than CVD in either group. BCT also resulted in durable responses with long-term survival in a significant percentage of pts. Altogether, our data support the use of BCT as a reasonable front-line therapy for both groups of pts once choroidal melanoma is excluded as a primary source. No significant financial relationships to disclose.
Safety and Efficacy of Venetoclax and Obinutuzumab in Patients with Previously Untreated Chronic Lymphocytic Leukemia (CLL) and Coexisting Medical Conditions: Final Results of the Run-in Phase of the Randomized CLL14 Trial (BO25323)
Authors: Kirsten Fischer, Othman Al-Sawaf, Anna-Maria Fink, Mark Dixon, Jasmin Bahlo, Simon Warburton, Thomas J. Kipps, Robert Weinkove, Sue Robinson, Martin H. Dreyling, Stephen Opat, Carolyn J. Owen, Javier López, Kathryn Humphrey, Rod A. Humerickhouse, Eugen Tausch, Barbara Eichhorst, Clemens-M. Wendtner, Anton W. Langerak, Jacques J.M. van Dongen, Matthias Ritgen, Sebastian Boettcher, Stephan Stilgenbauer, Valentin Goede, Mehrdad Mobasher, Michael Hallek
Journal: Blood (2016)
Predictors of chemotherapy-induced peripheral neuropathy among breast cancer patients treated with taxanes.
Authors: Nellowe Candelario, Supakanya Wongrakpanich, Mark S. Morginstin
Journal: Journal of Clinical Oncology (2015)

90 Background: Breast cancer is one of the most common types of cancer. Taxanes are used to treat both early and metastatic breast cancer. Chemotherapy-induced peripheral neuropathy (CIPN) is its most common dose-limiting side effect that is debilitating and that could alter the treatment outcomes. This study aims to assess the predictors in the development and severity of CIPN. Methods: A retrospective review of 229 breast cancer patients was done to identify if age, BMI, race, smoking history, alcohol use, diabetes, chronic kidney disease (CKD), estrogen (ER), progesterone receptor (PR) and HER2 status, type and dose of taxane were predictors in the development and severity of CIPN. Patients who had incomplete data and baseline neuropathy were excluded from the study. Severity of peripheral neuropathy was graded from 1 to 4. Pearson Chi-square and T-test were done to determine the presence of statistical difference in the development and severity of CIPN among the above predictors. Odds ratio was computed using logistic regression analysis. Results: Among the 229 patients in this study, 158 (69%) developed neuropathy, 90 (57%) of whom had grade 1 neuropathy. Majority of the subjects in this study were African American (75.1%). Age, BMI, race, smoking, alcohol use, CKD and diabetes did not show any statistical significance as predictors of development and severity of CIPN (p &gt; 0.05). Patients with ER+/PR- and ER+/PR+ had lower odds of developing neuropathy with OR 0.36 (p = 0.006) and 0.44 (p = 0.026) respectively. HER2 positivity was associated with higher chances of neuropathy (OR 2.11, p = 0.028). Paclitaxel was associated with higher chances of neuropathy compared to docetaxel (OR 2.89, p = 0.02). Dose of paclitaxel did not show any difference in the occurrence of CIPN. Those treated with paclitaxel had more severe neuropathy (p = 0.04). Conclusions: Positive ER and PR receptors have lower chances of developing CIPN. HER2 positivity is a predictor in the development of neuropathy. Paclitaxel is more neurotoxic than docetaxel. Age, race, BMI, smoking, alcohol use, diabetes and CKD were not predictors in the development and severity of CIPN.