tbuckley/cabot-search huggingface dataset:
MMP-9 expression as a predictor of tumor response in patients with locally advanced rectal cancer undergoing preoperative chemoradiotherapy
Authors: D. Unsal, A. Uner, N. Akyurek, O. P. Erpolat, A. Dursun, Y. Pak
Journal: Journal of Clinical Oncology (2005)

9606 Background: To analyze whether the expression of matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) predict tumor response to preoperative chemoradiotherapy (CRT) in patients with locally advanced colorectal cancer. Methods: Forty-four patients were included. T stages: T2:2 (with N1–2), T3:38 and T4:4. Mean age 54 years, male/female ratio: 28/16. The mean RT dose was 50 Gy, 5-FU was administered on the first 4 and last 3 days of RT, at 425 mg/m2 following 50 mg folinic acid. MMP-2, MMP-9, TIMP-1 and TIMP-2 expressions were analyzed by immunohistochemistry at the preradiation biopsy and in the resected specimens. Surgery was performed 6–8 weeks later with a curative intent. The primary endpoint was clinical and histopathological tumor response rates with a secondary endpoint of the effect of CRT on the expression rates. Histopathological response was evaluated with a three-point scoring method. Results: Preoperative treatment resulted in downstaging in 20 patients (45%) and no clinical response in 24 patients (55%). Pathologic tumor response was complete in 11 patients (25%), partial in 23 patients (52%) and no regression in 10 patients (55%). MMP-9+ was observed in 20 tumors (45%) and was associated with both clinical nodal stage (p=0.035), and pathological and clinical response (p<0.0001 for each comparison). The positivity of the other markers were associated with neither any stage nor any response. The overall pathologic response rate was 55% in MMP-9+ patients vs 95% in those who were MMP-9- (p=0.001). None of the 11 pathologic complete remission patients was MMP-9+. The only significant predictor of overall pathologic response was found to be MMP-9 status (p=0.0148). MMP-9+ patients’ ratio was found to be increased by CRT (p=0.035). Conclusion: MMP-9 expression is found to be a predictor of poor tumor response to preoperative CRT in locally advanced rectal carcinoma. Other markers studied were found to have no effect on response rates. Thus, inhibition of MMP-9 may serve as a useful preventive or therapeutic adjunct to CRT in rectal cancer. Further studies are required to determine its prognostic role on survival. No significant financial relationships to disclose.
Improving the flow and scheduling of patients in the Systemic Treatment Program at the Odette Cancer Centre: Decreasing patients wait-times
Authors: I. Tyono, M. E. Trudeau, Y. Matyas, S. Palmer, K. Beattie, M. Leung, C. DeAngelis, F. Charbonneau, M. Gannon
Journal: Journal of Clinical Oncology (2008)

20565 Background: The efficiency of a systemic treatment (chemo) unit is dependent on many factors: the number (#) of chemos ordered, # treatment positions, # nurses, # pharmacists, type of treatment mixed and delivered and arrivals of patients at pre-booked times. Booking for chemo is often done manually. Long waits were noted at the Odette Cancer Centre, where 60% of patients have clinic visits pre- chemo (same day chemo). Patients can spend 78–90% of their time waiting for chemo to be delivered. Methods: A process map of chemo delivery was undertaken to better understand the patient timeline. Bottlenecks were identified and a set of solutions and quality indicators implemented. In order to study an alternate day chemo treatment model and more efficient scheduling algorithm, an analyst (MG) conducted a field study in the chemo unit and oncology pharmacy to study dynamics of patient flow and performance of the system, to collect data on resource utilization and develop a model of clinic operations. Data was collected on volumes, staffing, chemo preparation and nursing time resulting in a computer simulation model and analysis. Results: The closely linked, linear nature of the same day chemo process was the root cause of most delays which could be avoided through restricting same day chemo treatments, appropriate patient scheduling and availability of blood results. Chemo regimens were classified according to pharmacy prep time, nurse time and in-chair time, as long-long-long (15%), short-long-long (35%), short-short-long (22%), and short-short-short (28%). This case mix model was employed for simulation analysis. Simulation experiments investigated the impact of maintaining or increasing the number of treatment positions on position loading and case turnover as well as patients wait-times. Conclusions: The simulation model assumes temporal decoupling of chemo and clinic visits and provides more efficient utilization of chemo positions, nursing and pharmacy time as well as significantly decreased in-system waits for chemo patients. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Hoffman-La Roche Hoffman-La Roche Hoffman-La Roche
Activity of gemcitabine plus docetaxel in leiomyosarcoma (LMS) and other histologies: Report of an expanded phase II trial
Authors: M. L. Hensley, S. Anderson, R. Soslow, C. Antonescu, T. Upham, E. Riedel, C. Aghajanian, R. G. Maki
Journal: Journal of Clinical Oncology (2004)

9010 BACKGROUND: We previously reported the activity of gemcitabine plus docetaxel in LMS. Our phase II trial was expanded to include non-LMS histologies. We report the longer-term progression-free (PFS) and overall survival (OS) for LMS, and response rates (RR) for 52 patients with LMS and non-LMS sarcomas. METHODS: From 6/99–4/03, 52 patients with unresectable LMS (n=42) or other sarcoma (n=10) who had failed 0–2 prior chemotherapy regimens were enrolled on a phase II study of gemcitabine 900 mg/m2 IV days 1 and 8, plus docetaxel 100 mg/m2 IV day 8 with GCSF SQ days 9–15, delivered every 21 days for a maximum of 8 on-study cycles. Patients with prior pelvic radiation received 25% lower doses of both agents. Gemcitabine was delivered over 30 or 90 minutes in cycles 1 and 2, and by 90-minute infusion in all subsequent cycles. Patients were followed until death. RESULTS: Among 52 pts (mean age 54, range 23–77), the mean number of cycles delivered on study was 4.6 (range 1–11). Overall objective RR was 35% (95% confidence interval [95%CI] 22–48%). RR in LMS was 40%, and RR in non-LMS was 10%. Grade 3–4 toxicities were observed in 15% of pts, consisting mostly of myelosuppression. 7% of pts had pulmonary toxicity. PFS among LMS patients at 6 months is 34% (95%CI 20–49%), and OS at 2 years is 47% (95%CI 31–63%). Among the 18 patients with objective responses, median duration of response was 7 months (range 4.1–45 months). CONCLUSION: Gemcitabine plus docetaxel is active in LMS. In non-LMS histologies small numbers preclude firm conclusion about this regimen's activity. A significant minority of LMS patients have relatively prolonged PFS with this regimen. A multi-center study is underway to examine gemcitabine vs. gemcitabine with docetaxel in patients with metastatic soft-tissue sarcoma. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Lilly; Aventis; Pfizer; Daiichi
Apoptosis inducing factor is decreased in metastatic colon cancer in ex-vivo models of colon carcinogenesis by tissue microarray
Authors: S. Huerta, R. H. Amirkhan, A. A. Siddiqui, E. H. Livingston, S. Huerta-Yepez
Journal: Journal of Clinical Oncology (2007)

14539 Background: In vitro studies suggest that apoptosis inducing factor (AIF) expression is decreased in metastatic cells relative to those derived from primary tumors. This study was undertaken to determine AIF expression patterns in patients with stage I/II vs. stage III/IV colorectal cancers. Methods: Colon cancer specimens were prospectively collected (11/05–6/06) from 12 patients from 3 different sites: tumor, adjacent to tumor, and tissue 2 cm from the tumor. Paraffin-embedded specimens were examined by tissue microarray with AIF-specific antibodies. Total AIF expression as well as cytoplasmic and nuclear expression was assessed by an investigator blinded to the tissue site and patient stage. Staining was assessed as: 1=absent, 2=mild, 3=moderate, 4=high and 5=very high. The clinical characteristics and tumor stage of all patients were analyzed. Results: All patients were male. Eight patients had non-metastatic disease at the time of laparotomy, four had metastasis to: lymph nodes (n=3) and liver (n=1). Stage I/II patients (n=8) were of similar age compared to stage III/IV patients (n=4) [61.3±4.2 vs. 54.4±6.0 y.o.; p=0.6] had similar tumor size (3.81±0.7 vs. 4.08±1.4 cm; p=0.4). There was no difference in the level of expression of AIF in normal tissue collected 2-cm away from the tumor site in stage I/II vs. stage III/IV colon cancers in the cytoplasm (3.81±0.17 vs. 3.30±0.38; p=0.4), nucleus (3.19±0.43 vs. 2.49±0.46; p=0.8) or overall (4.06±0.27 vs. 3.37±0.8). A significant decrease in AIF expression was observed in stage III/IV tumors compared to stage I/II tumors in tissue collected adjacent to the tumor in the cytoplasm (3.12±0.22 vs. 4.46±0.25; p=0.03), the nucleus (2.10±0.44 vs. 3.63±0.32; p=0.03) and overall (3.12±0.22 vs. 4.46±0.25; p=0.03). There was a trend towards a decrease in AIF expression between stage III/IV vs. I/II tumors in tissue collected directly from the tumor in the cytoplasm (2.55±0.24 vs. 3.56±0.26; p=0.12), the nucleus (1.39±0.25 vs. 2.73±0.63; p=0.14) and overall (2.79±0.38 vs. 3.90±0.37; p=0.22). Conclusion: AIF expression is decreased in metastatic colon cancer. The main differences occur in the normal mucosa adjacent to the tumor. No significant financial relationships to disclose.
CD14 promoter polymorphism and atopic phenotypes in Czech young patients with IgE-mediated allergy
Authors: Dana Bučková, Lydie Izakovičová Hollá, Marcel Schüller, Vladimír Znojil
Journal: Allergy (2004)

Atopy is a generally considered to be caused by interaction of
genetic and environmental factors. The gene encoding CD14 is a
positional candidate gene for atopy, as it is localized on
chromosome 5q31.1, a region that has been linked to asthma and
atopic responses. The present study was conducted to determine
the association of -1145A/G polymorphism with atopic phenotypes
in the Czech population.
High Resolution Screening of Copy-Number Alterations in Chronic Lymphocytic Leukemia Using Affymetrix 250K SNP-Arrays Reveals a Higher Complexity of Genomic Alterations in Patients with Unmutated IGHV Genes
Authors: Rebeqa Gunnarsson, Anders Isaksson, Hanna Göransson, Larry Mansouri, Mattias Jansson, Nicola Cahill, Karin Ekström Smedby, Jesper Jurlander, Gunnar Juliusson, Richard Rosenquist
Journal: Blood (2008)
A phase II trial of denileukin diftitox to treat refractory advanced-stage ovarian cancer
Authors: B. G. Barnett, J. Ruter, M. J. Brumlik, I. Kryczek, P. J. Cheng, W. Zou, T. J. Curiel
Journal: Journal of Clinical Oncology (2006)

2506 Background: Denileukin diftitox is a fusion toxin consisting of interleukin-2 genetically fused to diphtheria toxin. It is approved to treat cutaneous T cell lymphoma. Our recent Phase I trial demonstrated that denileukin diftitox depletes human regulatory T cells (Tregs), and is associated with improved measures of T cell immunity and clinical improvements in ovarian cancer. This Phase II trial tests whether denileukin diftitox has clinical activity in the treatment of relapsed epithelial ovarian cancer. Methods: Patients with Stage III or IV ovarian cancer who have failed first-line therapy with optimal surgical debulking and platinum-based chemotherapy were eligible. Denileukin diftitox was given at 12 mcg/kg once monthly. In the Phase II design, patients received no chemotherapy for at least two weeks and no immune or radiation therapy for at least four weeks prior to enrollment. Infusion pretreatment includes antihistamines, acetaminophen and anti-emetics, but no corticosteroid. Results: Six patients (F1,2,4–7) have been treated to date. F1 experienced CA-125 stabilization and approximately 20% reduction in her pelvic mass after two cycles, but was then withdrawn for hypoalbuminemia. F2 experienced CA-125 stabilization after two cycles and remains stable through four cycles. F4 experienced a 20% drop in CA-125 after two cycles, but then progressed. F5 progressed after one cycle. Treatment was recently initiated for F6–7. Existing immune data to date confirm that denileukin diftitox treatment in the Phase II trial is associated with reductions in phenotypic CD4 + CD25 hi blood Tregs and increased CD3 + IFN-γ + T cells consistent with our Phase I results. Studies of Treg function, T cell cytokine production and CD4 + CD25 + T cell FOXP3 content using saved clinical material will be undertaken when full laboratory operations resume. The trial continues to accrue patients. Conclusions: These data suggest that denileukin diftitox depletes Tregs in ovarian cancer. The link between Treg depletion and any observed immune changes or clinical effects is under active investigation, and remains to be determined. No significant financial relationships to disclose.
Evolutionary Origins of Rhizarian Parasites
Authors: Roberto Sierra, Silvia J. Cañas-Duarte, Fabien Burki, Arne Schwelm, Johan Fogelqvist, Christina Dixelius, Laura N. González-García, Gillian H. Gile, Claudio H. Slamovits, Christophe Klopp, Silvia Restrepo, Isabelle Arzul, Jan Pawlowski
Journal: Molecular Biology and Evolution (2015)

The SAR group (Stramenopila, Alveolata, Rhizaria) is one of the largest clades in the tree of eukaryotes and includes a great number of parasitic lineages. Rhizarian parasites are obligate and have devastating effects on commercially important plants and animals but despite this fact, our knowledge of their biology and evolution is limited. Here, we present rhizarian transcriptomes from all major parasitic lineages in order to elucidate their evolutionary relationships using a phylogenomic approach. Our results suggest that Ascetosporea, parasites of marine invertebrates, are sister to the novel clade Apofilosa. The phytomyxean plant parasites branch sister to the vampyrellid algal ectoparasites in the novel clade Phytorhiza. They also show that Ascetosporea + Apofilosa + Retaria + Filosa + Phytorhiza form a monophyletic clade, although the branching pattern within this clade is difficult to resolve and appears to be model-dependent. Our study does not support the monophyly of the rhizarian parasitic lineages (Endomyxa), suggesting independent origins for rhizarian animal and plant parasites.
Semi-physiological pharmacokinetic/pharmacodynamic (PKPD) model for trabectedin-induced neutropenia
Authors: J. Hing, J. Perez Ruixo, K. Stuyckens, P. Zannikos, A. Soto-Matos, L. Lopez-Lazaro, M. A. Izquierdo, C. Pico, A. Yver, A. Chow
Journal: Journal of Clinical Oncology (2006)

9575 Background: Neutropenia was the trabectedin (T) dose limiting toxicity in phase I studies. The objective of the present study was to develop a semi-physiological PKPD model that describes the time course of the absolute neutrophil counts (ANC) in cancer subjects receiving trabectedin. Methods: A total of 704 subjects receiving intravenous T as monotherapy (dose range: 0.024 - 1.8 mg/m 2 ) as a 1, 3 or 24 hr infusion every 21 days; 1 or 3 hr infusion on day 1, 8, 15 every 28 days; or a 1 hr infusion daily for 5 consecutive days every 21 days were used to develop (N=405, ANC=7253) and validate (N=299, ANC=4977) the model. The model comprised of a trabectedin-sensitive progenitor cell compartment, linked to the peripheral blood compartment, through three transition compartments representing the maturation chain in the bone marrow. To capture the rebound effect due to endogenous growth factors, the model included a feedback mechanism. The model estimated three system-related parameters: ANC at baseline (ANC 0 ), mean transit time in bone marrow (MTT), and a feedback parameter. T concentrations at the effect compartment were assumed to reduce the proliferation rate and/or to increase the killing rate of the progenitor cells according to a sigmoid-E Max function. Model evaluation was examined using goodness of fit plots, relative error measurements, and posterior predictive checks. Computer simulations were undertaken to evaluate the neutropenia schedule dependency. Results: The mean (between subject variability, %) of the ANC 0 , MTT, T potency were estimated to be 4.4 × 10 9 /L (39%), 3.99 days (40%), and 15.6 μg/L (58%), respectively. The feedback parameter, E Max and Hill coefficient were estimated to be 0.198, 154 and 1.48. Model validation procedure evidenced accurate prediction of the incidence of grade 3/4 neutropenia. Simulations indicated that T dose and interdose interval, but not infusion duration, are the main determinants of the neutropenia severity. The model predicted time course of the ANC confirmed that neutropenia is reversible, short-lasting, and non-cumulative. Conclusions: The extent and time course of neutropenia following five different dosing regimens of T were well predicted by the semi-physiological PKPD model. [Table: see text]
Induction of remission in patients with acute myeloid leukemia without prolonged myelosuppression using diphtheria toxin-interleukin 3 fusion protein
Authors: A. E. Frankel, M. A. Weir, P. D. Hall, M. Holguin, C. Cable, D. A. Rizzieri, D. E. Hogge
Journal: Journal of Clinical Oncology (2007)

7068 The recombinant diphtheria toxin fusion protein, DT388IL3, composed of the catalytic and translocation domains of diphtheria toxin (DT388) fused to human interleukin-3 (IL3) showed selective cytotoxicity to acute myeloid leukemia (AML) stem cells both in vitro and in vivo and was prepared for a phase I clinical study (Urieto, Protein Exp Purif 33, 123, 2004). FDA approval (BB IND#11314) and IRB approvals were obtained. Seventy-five AML patients were screened and thirty-one patients treated. The median age of treated patients was 62 years (range, 25- 81 years). There were sixteen males and fifteen females. Disease was de novo in three, first relapse in ten, second relapse in eight, and refractory in ten patients. Four patients had a history of MDS, and one had a history of secondary AML. One patient each had previously received an autologous or allogeneic stem cell transplant. Cytogenetics were unfavorable in ten, intermediate in nineteen, and not done in two. Seven patients were treated with 4 μg/kg, eight patients were treated with 5.3 μg/kg, thirteen patients treated with 7.1 μg/kg, and three patients treated with 9.4 μg/kg DT388IL3. Drug-related toxicities were mild to moderate and transient including fever, chills, hypotension, hypoxemia, and hypoalbuminemia. Consistent with an absence of toxicity to normal hematopoietic progenitors, responses occurred in the absence of prolonged myelosuppression. Among thirty evaluable patients, we have observed one CR of 8 months duration, two partial remissions (PRs) lasting one and three months and three minimal responses with clearance of peripheral blasts and marrow blast cytoreductions of 89%, 90% and 93% lasting one to two months. Dose escalation is proceeding. No significant financial relationships to disclose.
A phase II study of paclitaxel and vinorelbine (Pac-Vin) in hormone-refractory metastatic prostate cancer (HRPC): A final update
Authors: S. Sewak, S. Kosmider, V. Ganju, A. Woollett, B. Le, E. Yeo, M. Henry, R. Bell
Journal: Journal of Clinical Oncology (2007)

15505 Background: Phase 2 trials of Paclitaxel + corticosteroid or Vinorelbine + corticosteroid have shown 20–40% PSA responses. Preclinical models have shown synergy between Paclitaxel and Vinorelbine. A phase I trial showed this to be a tolerable combination. Methods: The aim of this study was to determine the efficacy and safety of Paclitaxel and Vinorelbine. 30 castrate pts with progressive, metastatic prostate cancer were enrolled. Previous radiotherapy, strontium therapy, 1 line of chemotherapy, and concurrent bisphosphonate therapy were allowed. Pts were treated with Paclitaxel 40 mg/m2 (1 hr), and Vinorelbine 20 mg/m2 iv on day-1 &amp; day- 8 of a 21-day cycle. All pts received standard premedication for Paclitaxel including dexamethasone. Results: Baseline pt characteristics were: median ECOG PS of 1 (range 0–2), median age 70.5, mean PSA 413 ng/mL, mean Hb 11.9 g/dL. For 10 pts with measureable disease the partial response rate was 20%, with 70% of pts achieving stable disease (SD). Of 30 assessable pts, 20% had a 50% or greater decline in PSA, and 63% SD, maintained for at least 4 weeks. Median overall survival was 9.7 months. Median progression free survival was 5.1 months. All pts completed quality of life (QOL) questionnaires. Patient’s pain, fatigue, appetite, constipation, and mood improved after 3 cycles of therapy, however, statistical significance was not reached. Grade 3&amp;4 toxicities were: neutropenia 8%, febrile neutropenia 4%, infection 2%, anemia 3%, lethargy 1%, and somnolescence 1%. 1 pt died as a result of neutropenic sepsis. Conclusions: In this poor prognostic cohort of pts (where 17% of pts had received 1 prior chemotherapy regimen) the combination of Paclitaxel and Vinorelbine is a tolerable regimen, which has demonstrated a 20% PSA response. The majority of pts achieved PSA stability. There was similar rate of objective response to this regimen and importantly it stabilized disease in a majority of pts. Furthermore, QOL parameters such as pain were improved. This regimen is one that requires further testing in a poor prognostic cohort of HRPC pts. No significant financial relationships to disclose.
P0713 : The impact of ledipasvir (LDV)/sofosbuvir (SOF) combination on health-related quality of life (HRQL) and patient-reported outcomes (PROS) in cirrhotic patients with chronic hepatitis C (CH-C): The sirius study
Authors: Z. Younossi, M. Stepanova, S. Pol, J.-P. Bronowicki, P. Carrieri, M. Bourlière
Journal: Journal of Hepatology (2015)
KRAS mutations and relation to prognosis in patients operated for localized pancreatic cancer and other periampullary cancers
Authors: N. A. Schultz, A. Roslind, I. J. Christensen, M. Gaustadnes, J. S. Johansen, M. Kruhøffer, T. Horn, M. Wøjdemann
Journal: Journal of Clinical Oncology (2009)

e15618 Background: Prognostic biomarkers in patients with pancreatic cancer might direct patients to optimal treatment. We studied the prognostic value of KRAS mutations in patients operated for pancreatic and other periampullary cancers. Methods: Retrospective study of 328 patients who were operated with a Whipples procedure at a single HBP-center during the period August 1976 to May 2008. For the present pilot study cancer tissue blocks were collected from 58 patients (31 men, 27 women, median age 64, range 33–81 years, ASA 1–3). All had localized pancreatic (n=26), ampullary (n=26) or duodenal cancer (n=6) and were operated during the period June 2001 to May 2008. 32 patients died (3 within the first month after operation and were excluded). Median follow-up time was 41 months (range 7–90). KRAS mutations in exon 1 and 2 were determined by LightScanner analysis (Idaho Technology). Results: KRAS mutations were found in 32 (55%) of the patients; 16 (62%) patients with pancreatic cancer, 13 (50%) with ampullary cancer and in 3 (50%) with duodenal cancer. KRAS status was neither associated with type of cancer (p=0.68), TNM stage (T stage p=0.64, N stage p=0.31). The median survival time for all patients was 22 months (KRAS mutation: 21, 95% CI: 10–40; Wildtype: not reached yet). Univariate Cox analysis showed that T stage (TNM) (1: HR=0.09, 95% CI: 0.02–0.48 p=0.004; 2: HR=0.18, 0.06- 0.51, p=0.0013; 3: HR=0.26, 0.09–0.71, p=0.0089) was a prognostic factor of OS. KRAS status (HR=0.70, 0.33–1.49, p=0.36) and N stage (TNM) (HR=0.53, 0.25–1.11, p=0.09) were not significant factors of OS, but there is a strong tendency for both factors. Conclusions: KRAS mutations are frequent in patients with localized pancreatic, ampullary and duodenal cancers. Preliminary analysis of 58 patients out of our cohort of 328 patients indicate that KRAS mutations may be a marker of overall survival and time to progression. No significant financial relationships to disclose.