tbuckley/cabot-search huggingface dataset:
A pharmacogenetic study in rectal cancer patients treated with preoperative chemoradiotherapy based on capecitabine: Polymorphisms in thymidilyate synthase and DNA repair genes.
Authors: A. Sebio, D. Paez, L. Pare, J. Salazar, E. Del Rio, A. Barnadas, M. Baiget
Journal: Journal of Clinical Oncology (2011)

e14009 Background: Several studies have been performed to evaluate the usefulness of neoadjuvant treatment based on oxaliplatin and 5-fluorouracil in locally advanced rectal cancer. However, preoperative biomarkers of outcome are lacking. In this study we analyze polymorphisms in thymidylate synthase (TS), and several DNA repair genes to evaluate their usefulness as pharmacogenetic markers in a cohort of 56 rectal cancer patients treated with preoperative chemoradiotherapy based on capecitabine. Methods: DNA was extracted from peripheral blood nucleated cells of a total of 56 stage II and III rectal cancer patients. The germline polymorphisms studied were: TS (VNTR/5’UTR, 2R G>C SNP, 3R G>C SNP), ERCC1 (118 C>T) and XRCC1 (Arg399Gln). Patients were treated with radiotherapy (a total of 45 Gys over 5 weeks) plus capecitabine 825 mg/m2/12h/day for 5 days a week +/- oxaliplatin 50 mg/m2 once a week. Pathological response, pathological regression and progression-free survival (PFS) were evaluated according to each genotype. Results: The ERCC1 118 T/T genotype was associated with a higher pathological complete response (48% in T/T vs. 21% in C/T and 0% in C/C; p=0.014) and a higher probability of downstaging (96% in T/T vs. 79% in C/T and 56% in C/C; p=0.025). Median PFS was 54 months for ERCC1 T/T, 35 months for C/T and 21 months for C/C genotypes (p 0.007). The *3/*3 thymidylate syntase genotype was associated with a higher downstaging (94%) compared to *2/*3 (86%) and *2/*2 (50%) ( p< 0.010). Conclusions: ERCC1 118 C>T and thymidylate synthase polymorphisms might help to identify stage II/III rectal cancer patients with a better outcome after preoperative concomitant chemoradiotherapy based on capecitabine.
Weekly and twice-weekly bortezomib in AL amyloidosis: Results of a phase II study.
Authors: D. E. Reece, U. Hegenbart, V. Sanchorawala, G. Merlini, J. Blade, K. Liu, C. Enny, H. Van De Velde, A. Cakana, R. Comenzo
Journal: Journal of Clinical Oncology (2010)

8023 Background: Case series studies suggest bortezomib (VELCADE; btz) ± dexamethasone is active in relapsed AL. In the phase I portion of the prospective CAN2007 study, single-agent btz was well tolerated at doses of up to 1.6 mg/m2 weekly and 1.3 mg/m2 twice weekly. Here we report safety and activity at these doses in the phase II portion. Methods: Patients (pts) aged ≥18 y with relapsed AL received btz 1.6 mg/m2, days (d) 1, 8, 15, 22 of 35-d cycles (QW; N=18), or 1.3 mg/m2, d 1, 4, 8, 11 of 21-d cycles (BIW, N=34). Primary/secondary objectives were safety/hematologic response rate. Responses were assessed by standard consensus criteria. Results: In the QW/BIW groups, median age was 56.5/67 y, 44%/62% were male, median time since diagnosis was 27/28 mo, 67%/50% had prior ASCT, and 56%/38% had >2 organs involved, including 56%/79% renal, 56%/59% cardiac, 22%/12% hepatic, 50%/24% GI, and 11%/6% neurologic involvement. Median btz duration was 8/6 cycles in the QW/BIW groups. Hematologic response data are shown in the Table. Organ responses appeared associated with hematologic response. Renal responses were seen in 4/9 (44%) and 7/26 (27%) pts in the QW and BIW groups, respectively. Both QW pts with neurologic involvement had a response. No cardiac responses were seen, possibly due to eligibility restrictions (NYHA class 3/4 excluded); 3/30 (10%) pts had ≥2 mm decreases in mean left ventricular wall thickness. No pt had progression of cardiac involvement. Estimated 1-yr OS rates were 94% (QW) and 84% (BIW). In the QW/BIW groups, 50%/79% of pts reported grade ≥3 adverse events (AEs), including 11%/18% fatigue, 0/18% thrombocytopenia, and 0/12% vomiting; 44%/41% had serious AEs; 28%/38% discontinued and 22%/53% needed dose reductions due to AEs; peripheral neuropathy rates were 22%/35%, with no grade ≥3 events. Two BIW pts died due to treatment-related AE. Conclusions: Btz 1.6 mg/m2 QW and 1.3 mg/m2 BIW are both highly active in relapsed AL, providing high rates of durable hematologic responses. BIW dosing offered more rapid responses but toxicity appeared lower with QW btz. Hematologic response, % QW (n=16) BIW (n=33) CR+PR 69 67 CR 38 24 SD 25 30 PD 6 3 Median time to first/best response, mo 2.1/3.2 0.7/1.2 Response duration ≥1 yr, % 79 76 1-yr progression-free rate, % 72 75 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Janssen-Cilag Johnson & Johnson Janssen-Cilag, Millennium, Orthio Biotech Celgene, Janssen-Cilag, Johnson & Johnson, Millennium
Abstract 12822: Increased Expression and Serum Levels of Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 in Patients With Aortic Valve Stenosis
Authors: Tomotaka Yoshiyama, Kei Yunoki, Ryushi Komatsu, Kazuo Haze, Takahiko Naruko, Kenichi Sugioka, Masashi Nakagawa, Mayumi Inaba, Minoru Yoshiyama, Kagehiro Uchida, Tatsuya Sawamura, Makiko Ueda
Journal: Circulation (2014)

Background: The development of aortic valve stenosis (AS) involves multiple events, including inflammation and lipid deposition and oxidation. Circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) play an important role in the development and progression of atherosclerosis. The aims of this study were to investigate the serum levels of sLOX-1 in patients with AS and also examine the expression of LOX-1 immunohistochemically in aortic valve specimens from these patients. Methods: Serum sLOX-1 levels were measured in patients with AS (n=128), stable angina pectoris (SAP, n=343) and in 53 control subjects using a sandwich ELISA method. Frozen aortic valve samples were also obtained surgically from a cohort of 20 AS patients. In addition, frozen aortic valve specimens were obtained at autopsy from individuals who died of non-cardiovascular causes (n = 11, mean age 68 yr) as a reference. Immunostaining of the samples was performed using antibodies against smooth muscle cells, macrophages, T-lymphocytes, neutrophils, microvessels, and LOX-1. Results: Serum sLOX-1 levels were significantly higher in AS patients compared with SAP patients ( P &lt;0.0005) or control subjects ( P &lt;0.0001). There were no differences in serum sLOX-1 levels between AS patients with or without coronary artery disease. Immunohistochemical staining showed that the LOX-1-positive area, as a percentage of the total area, was significantly (P&lt;0.01) higher in AS patients compared with reference cases. Double immunostaining for LOX-1 and macrophages revealed that the vast majority of LOX-1-positive cells were macrophages. Conclusions: This study demonstrates for the first time that serum sLOX-1 levels are elevated in patients with AS, and AS lesions contain a significantly higher percentage of LOX-1-positive macrophages. These findings suggest that LOX-1, a marker of oxidative stress, may play an important role in the development of aortic valve stenosis.
Renal interstitial sclerosis in aging
Authors: F Inserra, L A Romano, E M de Cavanagh, L Ercole, L F Ferder, R A Gomez
Journal: Journal of the American Society of Nephrology (1996)

The effects of nifedipine and enalapril on age-associated renal interstitial fibrosis were investigated in 60 CF1 female mice. Mice received 20 mg enalapril (ENAL) per L (N = 20), or 40 mg nifedipine (NIF) per L (N = 20) in their drinking water. Control (CONT) mice received tap water ad libitum. The percentages of both interstitial peritubular sclerosis (IPS) in cortex and interstitial medullary sclerosis (IMS) were determined. Kidney tissue was studied using immunological techniques and optical (OM) and electron microscopy (EM) to analyze the expression of renin. alpha-SM-actin and vimentine expression were also evaluated. The results showed that blood pressure levels in ENAL or NIF animals were not different from those of CONT. Renin expression was observed in arcuate vessels (AV) in ENAL animals, whereas no renin staining in AV was found in either NIF or CONT animals. Renin immunoreactivity in the juxtaglomerular apparatus was more intense in ENAL mice, as compared with NIF or CONT animals. Laboratory testing showed the following values: proteinuria (mg/mL): CONT 6.1 +/- 0.6, NIF 11.2 +/- 2.3, and ENAL 1.0 +/- 0.6 (P < 0.05); creatinine: CONT 1.37 +/- 0.24, NIF 0.87 +/- 0.16, and ENAL 0.63 +/- 0.1 (P < 0.01). The percentages of interstitial sclerosis were: %IPS: CONT 18.12 +/- 1.1, NIF 17.40 +/- 0.9, and ENAL 3.42 +/- 1.3 (P < 0.01); %IMS: CONT 23.41 +/- 1.5, NIF 21.80 +/- 1.9, and ENAL 6.12 +/- 1.2 (P < 0.01). Percentages of alpha-SM-actin expression were: CONT 13.10 +/- 1.9, NIF 13.80 +/- 0.2, and ENAL 1.00 +/- 0.1 (P < 0.01). Vimentine staining showed no differences among the groups. It was concluded that enalapril reduces the peritubular and medullar interstitial fibrosis, whereas nifedipine has no effect.
Impact of sentinel lymph node (SLN) mapping (M) on nodal metastasis (mets) and recurrence in colon cancer (Cca) compared with conventional surgery (CS)
Authors: S. Saha, T. Beutler, A. G. Dan, R. Sehgal, A. Puthillath, D. Wiese, P. Ng, V. Peram, M. Arora, T. Singh
Journal: Journal of Clinical Oncology (2005)

3567 Background: CS and pathology understages 20% of patients (pts) with Cca. Adjuvant chemotherapy (CRx) is highly effective in pts with nodal mets. SLNM upstages up to 20% of Cca pts for nodal mets. Upstaged pts benefit from adjuvant CRx, reducing the chances of recurrence. A comparative analysis was done for nodal mets and recurrence in Cca pts undergoing SLNM vs. CS. Methods: Group (gp) A pts underwent SLNM with 1% Lymphazurin followed by standard oncologic resection. Gp B pts underwent CS. SLNs were examined by 4 sections for H&E and 1 for IHC. The nonSLNs in gp A and all LNs in gp B were examined by 1–2 section with H&E. The median follow-up was 54 months and the minimum follow-up was 27 months. Comparison was done for age, number of LNs, T-stage, nodal status and recurrence rates between gp A and B. Results: Gp A (SLNM) had 153 pts (median age =72 yrs); Gp B(CS) had 162 pts (median age =82 yrs). Mean number of LNs per pt in gp A was 15.5 vs. 11.8 in gp B (p=0.0001). T-stage distributions for gp A and gp B were as follows: 11.1% vs. 8%(T1), 22.2% vs. 14.2%(T2), 62.1% vs. 68.5%(T3) and 4.6% vs. 8.6%(T4) respectively. SLNM was successful in 100% of pts with an accuracy of 94.7% and a sensitivity of 89%. SLNM upstages 15% of pts with micromets which may have been missed by conventional pathological exam. For stage I (T1/T2, N0) pts, the recurrence in gp A was 2.5% vs. 12.5% in gp B (p=0.002). Overall, the recurrence rate in gp A was 7.1% vs. 24.6% in gp B (p=0.001). The distribution of nodal mets and recurrence between gp A and gp B are in Table 1. Conclusions: SLNM is highly feasible and accurate in determining nodal status. Compared with CS, SLNM upstages a significant number of pts whose disease may remain undetected by conventional exam. Upstaged pts received adjuvant CRx, leading to a significant decrease in recurrence and a possible increase in survival. Table 1 Distribution of nodal metastasis and recurrence rate between group A and group B A. Nodal metastasis between group A and B Group A (SLN) Group B (conv) Total No=153 Total No=162 p-value Node positive/total(%) Node positive/total (%) T1 2/17 (11.7%) 1/13 (7.7%) 0.72 T2 9/34 (26%) 3/23 (13%) 0.24 T3 64/95 (67.3%) 47/112 (42%) 0.0004 T4 4/7 (57.1%) 6/14 (42.8%) 0.55 Total 79/153 (51.6%) 57/162 (35.6%) 0.005 B. Recurrence rates by nodal status between group A and group B (7.1% vs 24.6%, p value=0.0001) Node Positive Node Negative Group A Group B p-value Group A Group B p-value (n=79) (n=57) (n=74) (n=105) T1 0 0 — 1 2 0.76 T2 0 0 — 0 2 — T3 8 19 0.001 1 13 0.009 T4 1 2 0.39 0 2 — Total 9(11.3%) 21(36.8%) 0.0004 2(2.7%) 19(18%) 0.0025 No significant financial relationships to disclose.
Phase II study of liposomal MUC1 vaccine in PSA failures post-radical prostatectomy (RP)
Authors: S. A. North, C. Yeung, K. Graham, D. Bodnar, P. Venner
Journal: Journal of Clinical Oncology (2004)

2523 Background: Men with biochemical failure post-prostatectomy have few therapeutic options other than androgen deprivation therapy (ADT). This therapy has significant morbidity, especially if used for long periods of time. Optimal timing of initiation of hormonal therapy in this patient population is unknown and rationally designed, targeted therapies in this group of men are appropriate. We present data from our trial of active specific immunotherapy in hormone naïve patients with PSA failure post RP Methods: Men with biochemical failure as evidenced by 3 rises in PSA post-prostatectomy were enrolled. Primary endpoints were efficacy (as measured by PSA response) and safety of a MUC1 liposomal vaccine (L-BLP25). Changes in PSA doubling time (PSADT) were also evaluated. Patients received a single intravenous dose of 300 mg/m2 cyclophosphamide (CTX) followed by 8 weekly subcutaneous vaccinations with L-BLP25 containing 1,000 μg antigen (induction). Subsequent vaccinations were given at 6-week intervals through week 49 (maintenance). PSA's were measured during induction and maintenance and PSADT was calculated for these intervals and compared to PSADT prior to enrolment Results: Sixteen patients were enrolled, with a median age of 60, all were ECOG 0 or 1, and median Gleason score was 7. All 16 patients received CTX and 15/16 completed the induction period. Ten pts completed the maintenance period. The most common adverse events were nausea (31%) and fatigue (25%) but none worse than grade 1. After induction, 8/15 evaluable patients had either stabilization or decrease in PSA (as per PSA Working Group definition). At the last on-study PSA measurement, one patient maintained a stable PSA, but all others had progressed. However, 6/15 patients had a >50% prolongation of PSADT compared to pre-study PSADT. Conclusions: L-BLP25 vaccine shows promise in prolonging PSADT in men with biochemical failure post-prostatectomy with little morbidity. As prolongation of PSADT may result in delayed time to clinical progression and therefore delay the time to which more aggressive therapy is needed, L-BLP25 should be further tested in this population of patients. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Biomira, Inc.
Variation in heat shock proteins within tropical and desert species of poeciliid fishes.
Authors: C E Norris, P J diIorio, R J Schultz, L E Hightower
Journal: Molecular Biology and Evolution (1995)

The 70-kilodalton heat shock protein (hsp70) family of molecular chaperones, which contains both stress-inducible and normally abundant constitutive members, is highly conserved across distantly related taxa. Analysis of this protein family in individuals from an outbred population of tropical topminnows, Poeciliopsis gracilis, showed that while constitutive hsp70 family members showed no variation in protein isoforms, inducibly synthesized hsp70 was polymorphic. Several species of Poeciliopsis adapted to desert environments exhibited lower levels of inducible hsp70 polymorphism than the tropical species, but constitutive forms were identical to those in P. gracilis, as they were in the confamilial species Gambusia affinis. These differences suggest that inducible and constitutive members of this family are under different evolutionary constraints and may indicate differences in their function within the cell. Also, northern desert species of Poeciliopsis synthesize a subset of the inducible hsp70 isoforms seen in tropical species. This distribution supports the theory that ancestral tropical fish migrated northward and colonized desert streams; the subsequent decrease in variation of inducible hsp70 may have been due to genetic drift or a consequence of adaptation to the desert environment. Higher levels of variability were found when the 30-kilodalton heat shock protein (hsp30) family was analyzed within different strains of two desert species of Poeciliopsis and also in wild-caught individuals of Gambusia affinis. In both cases the distribution of hsp30 isoform diversity was similar to that seen previously with allozyme polymorphisms.
Phase II study of metronomic chemotherapy (MC) with irinotecan (CPT-11) in patients with refractory metastatic colorectal cancer (MCRC).
Authors: V. Moiseyenko, V. Chubenko, S. Protsenko, T. Mikhalichenko, F. Moiseyenko, N. Brezhnev, A. Moiseyenko, A. Kornilov, E. Zueva, M. Gorchakova
Journal: Journal of Clinical Oncology (2010)

e14109 Background: Tumor angiogenesis is one of the factors contributing to the growth and metastasis. In addition, it is a possible mechanism for repopulation of cells between cycles of standard chemotherapy, which leads to low efficiency of drug treatment in terms of overall survival. Therefore, inhibition of angiogenesis is a promising option of therapy for patients with metastatic disease. Methods: We conducted a phase II study of metronomic CPT-11 2.8 mg/m2/daily C.I. for 24 hours. There was no limit on the number of prior therapies. CT scans were performed every 6 weeks. Patients were treated until tumor progression or development of unacceptable toxicity. Serum was collected for measurement of endothelial progenitor cells (CD45-, CD105+, CD34+, CD59+, CD80+, CD86+). Results: 20 patients (pts) with MCRC were enrolled (12 female, 8 male), 17 of them were evaluated. Median age was 57.5 years (range 32-73). 6 (32.5%) pts had ECOG 2 and more. 60% of pts had 3 or more and 40% at least 2 prior chemotherapy lines. Toxicities included allergic reaction (1 G3), nausea (5 G1), vomiting (1 G1), diarrhea (3 G1), fatigue (1 G1), fever (1 G1), alopecia (1 G1). There were no treatment related deaths. There were no CR or PR. 9 of 17 pts had SD (53%). Median progression-free survival (PFS) was 103 (range 90-107) and 110 days (range 50-239) for 2nd and 3d lines chemotherapy, accordingly. The level of endothelial progenitor cells decreased with metronomic CPT-11 after 6 week evaluation from 0,008% to 0.005% (p = 0.17). Conclusions: Low-dose metronomic C.I. of irinotecan is well tolerated and leads to long-term median PFS in patients with MCRC failed to standard therapy. No significant financial relationships to disclose.
Multinucleation and Mesenchymal-to-Epithelial Transition Alleviate Resistance to Combined Cabazitaxel and Antiandrogen Therapy in Advanced Prostate Cancer
Authors: Sarah K. Martin, Hong Pu, Justin C. Penticuff, Zheng Cao, Craig Horbinski, Natasha Kyprianou
Journal: Cancer Research (2015)

Abstract Patients with metastatic castration-resistant prostate cancer (CRPC) frequently develop therapeutic resistance to taxane chemotherapy and antiandrogens. Cabazitaxel is a second-line taxane chemotherapeutic agent that provides additional survival benefits to patients with advanced disease. In this study, we sought to identify the mechanism of action of combined cabazitaxel and androgen receptor (AR) targeting in preclinical models of advanced prostate cancer. We found that cabazitaxel induced mitotic spindle collapse and multinucleation by targeting the microtubule depolymerizing kinesins and inhibiting AR. In androgen-responsive tumors, treatment with the AR inhibitor, enzalutamide, overcame resistance to cabazitaxel. Combination treatment of human CRPC xenografts with cabazitaxel and enzalutamide reversed epithelial–mesenchymal transition (EMT) to mesenchymal–epithelial transition (MET) and led to multinucleation, while retaining nuclear AR. In a transgenic mouse model of androgen-responsive prostate cancer, cabazitaxel treatment induced MET, glandular redifferentiation, and AR nuclear localization that was inhibited by androgen deprivation. Collectively, our preclinical studies demonstrate that prostate tumor resistance to cabazitaxel can be overcome by antiandrogen-mediated EMT-MET cycling in androgen-sensitive tumors but not in CRPC. Moreover, AR splice variants may preclude patients with advanced disease from responding to cabazitaxel chemotherapy and antiandrogen combination therapy. This evidence enables a significant insight into therapeutic cross-resistance to taxane chemotherapy and androgen deprivation therapy in advanced prostate cancer. Cancer Res; 76(4); 912–26. ©2015 AACR.
Treatment failure upon gemcitabine intake: Is cytidine deaminase extensivity the ideal culprit?
Authors: L. Dahan, J. Ciccolini, C. Mercier, M. Duluc, P. Ries, E. Norguet, C. Oculi, A. Evrard, L. Ouafik, J. F. Seitz
Journal: Journal of Clinical Oncology (2010)

e14558 Background: Gemcitabine is a mainstay for treating various solid tumors, including pancreatic and lung cancers, as well as sarcomas. Gemcitabine metabolism in the body is dependent primarily upon a detoxification step in the liver driven by cytidine deaminase (CDA). Activity in CDA is highly variable among patients, with possible impact on drug disposition and subsequent clinical outcome. The aim of this work was to investigate whether extensivity in CDA could be at the origin of treatment failure with gemcitabine. Methods: Forty patients (19F, 21 M, mean age 61 years) mostly treated with gemcitabine alone (23 patients) or associated with oxaliplatin, capecitabine, erlotinib or a biotherapy (7 patients) for pancreatic or biliary cancers were retrospectively studied. CDA status was evaluated both upon a phenotypic (CDA residual activity in serum) and a genotypic (search for the 79A>C polymorphism) basis. Extensive Metabolizer (EM) phenotype was defined as a CDA activity above 6 U/mg (e.g., 50% above the mean value of a reference adult population). Results: Median CDA activity was 3.4 U/mg (range: 0.8-17.4). No genotype to phenotype relationship was evidenced. Eight out of 40 patients (20%) displayed CDA values associated with the EM phenotype (range: 6-17.4). A statistical difference (p < 0.001, Mann-Whitney Rank Sum Test) was observed in response between EM and non-EM patients. In the EM subset, 75% of the patients had progressive disease (PD), the remaining 25% patients displaying equally Objective Response and Stable Disease. Conversely, Progressive disease was observed in 15.5% patients with normal/low CDA activities, whereas 84.5% had controlled disease. Conclusions: Our data suggest that EM with CDA could be a predictive marker for treatment failure with gemcitabine. Complementary data from patients with sarcoma are currently evaluated and should be presented. Overall, our data suggest that CDA-based adaptive dosing strategies could improve clinical outcome with gemcitabine, one of the most prescribed anticancer drug worldwide. No significant financial relationships to disclose.
Cisplatin therapy for disseminated mixed mesodermal sarcoma of the uterus.
Authors: D M Gershenson, J J Kavanagh, L J Copeland, C L Edwards, C A Stringer, J T Wharton
Journal: Journal of Clinical Oncology (1987)

Eighteen patients with metastatic mixed mesodermal sarcoma of the uterus received cisplatin therapy at the University of Texas (UT) M.D. Anderson Hospital and Tumor Institute at Houston. The dose of cisplatin varied from 75 mg/m2 to 100 mg/m2. Previous therapy included surgery in 11 patients, radiotherapy in two patients, and surgery plus radiotherapy in four patients. One patient had no prior therapy. Seven patients had also received prior chemotherapy with doxorubicin. Of 12 patients with measurable disease, one (8%) had a complete response and four (33%) had a partial response for an overall response rate of 42%. The median progression-free survival of patients treated with cisplatin as first- and second-line therapy was 4.5 and 5.5 months, respectively. Cisplatin demonstrated moderate activity with mild toxicity in this group of patients with metastatic mixed mesodermal uterine sarcomas. Further studies including cisplatin-containing combination regimens seem to be warranted.