tbuckley/cabot-search huggingface dataset:
A feasibility study of intravenous (IV) paclitaxel, intraperitoneal (IP) carboplatin, and intraperitoneal paclitaxel (TCipTip therapy) in patients with epithelial ovarian carcinoma.
Authors: S. Nagao, H. Nakagami, S. Tsukahara, R. Ohishi, N. Iwasa, K. Hasegawa, K. Fujiwara
Journal: Journal of Clinical Oncology (2010)

e13118 Background: The objective of the current study was to determine the feasibility of TCipTip therapy in patients with epithelial ovarian carcinoma, fallopian tube carcinoma, or peritoneal carcinoma. Methods: The patients with histologically confirmed, stage IC-IV epithelial ovarian carcinoma were treated by TCipTip therapy. IV paclitaxel was administered at 135 mg/m2 followed by IP carboplatin administration based on the AUC=6 on day1, and IP paclitaxel was administered at 60 mg/m2 on day 8. To ensure the safety, our institutional review board recommended the administration of 45 mg/m2 of IP paclitaxel to the initial 3 patients. The toxicity grade was determined by CTCAE version 3. Results: Eighteen patients were entered in this study. These patients included 16 epithelial ovarian carcinoma (stage Ic, 8; stage IIc, 1; stage IIIc, 6; stage IV, 1), 1 stage IIc fallopian tube carcinoma and 1 stage IV primary peritoneal carcinoma. There were 10 serous adenocarcinoma, 5 endometrioid adenocarcinoma, 1 mucinous adenocarcinoma, 1 clear cell adenocarcinoma, and 1 mixed carcinoma (clear cell and endometrioid adenocarcinoma). The initial 3 patients who received 45 mg/m2 of IP paclitaxel did not encountered grade 3/4 hematological nor nonhematological toxicities at first cycle. Incidences of grade 3/4 hematological toxicities were 73% for neutrocytopenia, 9% for thrombocytopenia, and 24% for anemia. Observed grade 3/4 nonhematological toxicities were 4 for allergy, 1 for ileus. One patient encountered IP-related toxicity (grade 2 abdominal pain); however, she did not discontinue the chemotherapy. Six patients completed more than 6 cycles and 6 patients discontinued the chemotherapy before 6th cycle, 6 patients are now ongoing. The reasons of interruption were 3 for anaphylaxis to paclitaxel, 1 for anaphylaxis to carboplatin, 1 for disease progression, 1 for pleural embolism, 1 for patient refusal. Conclusions: The toxicities by TCipTip therapy were not severe, and this therapy is feasible for patients with epithelial ovarian carcinoma. No significant financial relationships to disclose.
Graded potency of chimeric antigen receptor (CAR)-engineered T cells for cancer immunotherapy.
Authors: Michel Sadelain, Maud Condomines, Zeguo Zhao, Renier J. Brentjens, Isabelle Riviere
Journal: Journal of Clinical Oncology (2014)

3022 Background: Second generation chimeric antigen receptors (CARs) are recombinant receptors for antigen that retarget and reprogram T cell function. We and others have recently demonstrated that CAR-modified, CD19-targeted T cells can induce complete remissions in patients with relapsed or refractory B cell malignancies, especially acute lymphoblastic leukemia. While CARs endowed with either CD28 or 4-1BB costimulatory endodomains have shown significant therapeutic potential, we previously reported that combined CD28 and 4-1BB signals direct even greater tumor eradication. We have now thoroughly compared these graded levels of therapeutic potency and examined their mechanism of action. Methods: Using a xenogeneic B-ALL leukemia model, we titrated CD19-targeted human T cells engineered to receive CD28 and/or 4-1BB signals and compared their therapeutic potency. Purified T cell subsets were analyzed by genome wide expression to correlate costimulatory patterns and therapeutic outcomes. Results: We show here that combining a second generation CD28-based CAR, in which CD28 signaling is provided through the CAR’s cytoplasmic domain,with 4-1BBL, which auto-costimulates T cells through their endogenous 4-1BB receptor, generates very highly efficacious T cells. We rigorously quantified the tumor eradication potential of T cell populations provided with CD28, 4-1BB or CD28+4-1BB costimulation. The most potent T cell populations were found to evade regulation by endogenous CTLA-4 and induce expression of the type I response pathway, which directly impacted on T cell expansion and function. Conclusions: We show here that T cell populations with graded therapeutic potency can be engineered through different CAR designs and costimulatory combinations. Our study further unravels a novel synergy between CD28 and 4-1BB signaling that is distinct from enhanced T cell proliferation or persistence, and results in increased therapeutic potency through the activation of the type I interferon response pathway. These findings open new perspectives for T cell engineering strategies intended to modulate the tumor microenvironment and augment tumor eradication.
A model assessing how variable timing of outcome assessments impacts progression-free survival (PFS)
Authors: G. A. Gignac, M. J. Morris, G. Heller, H. I. Scher
Journal: Journal of Clinical Oncology (2007)

5130 Background: PFS has been proposed as an endpoint in prostate cancer because tumor regression cannot be assessed easily and the significance of post-therapy changes in PSA is uncertain. There is significant variability in the frequency by which outcomes are assessed across clinical trials. We sought to create a model that would define the degree of error in estimating PFS from this variability. Methods: A simulation experiment was performed. An exponential distribution was used to generate 100 progression times for 3 hypothetical risk cohorts: rapid (median PFS of 18 wks), intermediate (36 wks) and slow progressors (72 wks). We examined how reported PFS would change depending on 3 assessment schedules: every (q) 6, 8 and 12 wks for 48 wks each, then q6 months for 2 years. The logrank statistic was used to compare PFS between schedules. If different schedules have no impact the expected type 1 error rate should be 5% (where a difference in PFS time is detected when none existed). Each simulation was repeated 1000 times. Results: Nine pairwise comparisons were performed and Kaplan-Meier PFS estimates created for the 3 assessment schedules and 3 risk cohorts (see table 1 ). In the highest risk cohort, PFS of 18 wks, 38% of the time the logrank test showed a falsely prolonged PFS for pts assessed on the q12 vs 6 wks schedule. This type 1 error rate (by simulation) was reduced to 20% and 11%, when the schedules were q8 vs 12 wks and q6 vs 8 wks, respectively, but remained above the 5% expected rate for type 1 error. For lower risk pts, PFS of 72 wks, the disparity in PFS times was diminished. Conclusions: Progression free survival is significantly skewed by the schedule of assessing treatment effects in clinical trials. This argues for uniformity in the timing of outcome assessments across trials and between arms in randomized trials. Grant support: 5T32CA09207 [Table: see text] No significant financial relationships to disclose.
Outcomes in double-negative (HER2/PR negative) LABC phenotype treated with cisplatin-based primary chemotherapy: Impact of intensified regimen
Authors: M. T. Ionta, F. Atzori, M. C. Deidda, M. Murgia, B. Frau, A. Coinu, M. Barca, F. Eltrudis, L. Minerba, B. Massidda
Journal: Journal of Clinical Oncology (2007)

11024 Background: It is widely assumed that HER2-negative and hormone receptors negative tumors (Triple-Negative as TN) are associated with poor outcome and would benefit from intensified chemotherapy and/or from specific EGFR-targeted therapies.Nevertheless, the lack of PR expression in presence of ER-pos tumors, (Double-Negative as DN) could reflect an aberrant growth factor signaling, identifying a more aggressive phenotype than ER-pos/PR-pos tumors that could contribute to the tamoxifen resistance and that could benefit from tailored specific treatment such as TN pts. Aim of our retrospective study was to evaluate,the clinical outcome among a group of LABC pts, according to the treatment’s schedule (standard vs intensified) and TN or DN phenotype. Methods: Between June 1996 and November 2001, 72 consecutive LABC pts, (77 % T4abc; 23 % T4d) median age 51 (29–70), ER/PR-neg 37,5%; ERpos/PR-neg 33%, were treated with primary PEV regimen (cisplatin 50 mg/m2; epirubicin 100 mg/m2; vinorelbine 25 mg/m2):q 3wks x 4 cycles in the first 24 pts (Standard); q 2 wks x 6 cycles in the subsequent 48 pts (Intensified), followed by adjuvant RT,CMF and TAM ± LH-RH ; 50 pts of 72 were IHC assessable for both HER2 and HR: 39 pts (78%) were identified as HER2-neg; 25 (64%) of 39 were HER2-neg/PR-neg irrespective of ER status, (any ER), of whom 12 were ER-neg (TN )and 13 were ER-pos ( DN ). Results: At a median follow up of 88 months (58–123) DFS was 20% and 80%; 20% and 100%; 20% and 62,5% in standard group and in intensified group respectively; OS was 40% and 80%; 40% and 100%; 40% and 62,5% in standard group and in intensified group respectively. Conclusions: Our findings suggest that DN as well as TN pts benefit from intensified primary chemotherapy. Therefore, tailored treatments are warranted for DN as well as TN pts. In addition, our data indicate that association of HER2-neg with PR-neg independently of ER expression (any ER) could be correlated with a more aggressive phenotype. [Table: see text] No significant financial relationships to disclose.
Non-oncogenic deletion mutants of adenoviral E1A enhance paclitaxel induced apoptosis of ovarian cancer cells
Authors: C. Kurzeder, C. Hanselmann, N. DeGregorio, G. Sauer, B. Opalka, R. Kreienberg, H. Deissler
Journal: Journal of Clinical Oncology (2007)

14102 Background: The phenotypical characteristics and spread of ovarian cancer cells, suggest intraperitoneal gene therapy of this disease. Phase I trials have been conducted to investigate the potential clinical benefits of adenoviral E1A-based gene therapy. Further gene therapeutic approaches which aim to enhance the efficacy of E1A-induced apoptosis in a multimodal approach including conventional chemotherapy are planned. However, besides tumor-suppressive effects, E1A is also known to transform rodent cells in conjunction with other factors, e.g. an activated ras oncogene. In an effort to eliminate elements favouring malignant conversion, the potential therapeutic effect of the E1AdelCR2 deletion mutant on ovarian cancer cells was studied. Methods: To avoid any selection bias, a doxycyclin-regulated system was used to express E1A wildtype protein and the mutant E1AdelCR2 lacking the p105 RB -binding motif. The effects of the E1A proteins on proliferation and induction of apoptosis in ovarian carcinoma cell lines was studied with a WST-1 assay and fluorcytometric analysis of FITC labelled AnnexinV. Results: As confirmed by Western blot analyses, expression of the mutant proteins was almost completely suppressed in the presence of doxycyclin. Substantial reduction in proliferation was achieved by expression of both wildtype E1A and E1AdelCR2. Expression of E1AdelCR2 was sufficient by itself to induce apoptosis in 8,7% of ovarian carcinoma cells as shown by an increase of the fraction of Annexin binding OVMZ-8 cells. A strong synergistic effect with an increase of the fraction of apoptotoc cells by 16.7% was found when the cells were treated with paclitaxel. Conclusion: Deletion of the CR2 sequence should increase the safety of therapeutic applications of E1A without affecting tumor suppression. A doxycyclin-regulated expression system was established allowing the elucidation of the mechanisms underlying the therapeutic effects of E1A in ovarian cancer cells in the future by means of expression profiling and quantification of activated components of signal transduction pathways. No significant financial relationships to disclose.
Cytokines and TLR agonists influence the expression of retention integrins CD49a, CD49b and CD103 by T cells
Authors: Marit M Melssen, Ciara Hutchison, Ileana S Mauldin, Timothy N Bullock, Craig L Slingluff
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts T cell infiltration in the tumor microenvironment (TME) is positively correlated with survival. Infiltration is not a stable state, but a dynamic process of homing, infiltration, retention and survival. Every step in this process is crucial for the eventual tumor reactive activity
Nasopharyngeal carcinoma at the National Institute of Oncology
Authors: E. Hassan, S. Afqir, N. Ismaili, H. M’rabti, S. Boutayeb, I. Elghissassi
Journal: Journal of Clinical Oncology (2009)

e17055 Background: To evaluate the disease characteristics and outcome of patients with nasopharyngeal carcinoma treated at the National Institute of Oncology (NIO) Rabat, Morocco. Methods: Between 1999 and 2001, 468 patients with a diagnosis of nasopharyngeal carcinoma were treated at the NIO. The median age was 42 years (range 10 to 83). The male/female ratio was 2.5/1. Of the 468 patients, 88 (19%), and 380 (81%) had T1-T2, and T3- T4 (TNM International Union Against Cancer staging system, 1997), respectively. Ninety percent presented with nodal metastasis. 163 patients (35%) had lymph nodes &gt;6 cm, and 229 (49%) had bilateral nodes at presentation. Histologically, 405 patients (86%) had undifferentiated carcinoma. Seventy-six percent received neoadjuvant multiagent chemotherapy containing cisplatin, followed by radiotherapy (RT). Results: After a median follow-up of 26 months, the disease-free survival (DFS) and overall survival (OS) rate for the entire group was 27% and 41%, respectively. Kaplan-Meier curves were used for evaluation of prognostic factors and were compared using the log-rank test. Nodal status had a significant impact on OS (p &lt; 0.001). Complete responders to chemotherapy had superior DFS and OS. Conclusions: Combined modality management using chemotherapy and RT resulted in satisfactory locoregional control and OS in patients with nasopharyngeal carcinoma. Nodal involvement and response to chemotherapy were important prognostic factors. No significant financial relationships to disclose.
Intraoperative radiotherapy (IORT) as a boost in patients with early breast cance
Authors: U. Kraus-Tiefenbacher, A. Scheda, L. Bauer, F. Melchert, F. Wenz
Journal: Journal of Clinical Oncology (2004)

695 Background: External beam radiotherapy (EBRT) after breast-conserving surgery (BCS) with 45–50 Gy is the gold-standard in patients with limited stages of breast cancer. Most recurrences appear close to the tumorbed. Therefore this area is often provided by a boost in routine practice but no standard technique exists. The boost is applicated either by EBRT-techniques, by brachytherapy or by intraoperative radiotherapy (IORT). Since february 2002 IORT is delivered in breast cancer patients by a mobile miniature x-ray source (Intrabeam™). Methods: From 2/2002 -10/2003 70 patients with breast carcinomas were treated by IORT after BCS. 45 patients received IORT as a tumorbed-boost, followed by EBRT. Median age was 63 years (43.1–86.5). Median tumor size was 14 mm (6–45). Pathology results showed ductal-invasive histology in 18, lobular-invasive in 13, mixed in 10, tubular-invasive in 2 patients and medullar and mucinous histology in 1 patient respectively. Treatment time took 20 minutes (18.6–48.8). In most cases a spherical applicator with a 4.5 cm diameter was chosen (3.0–5.0). A single high-dose (20 Gy) can be applicated on the applicators surface, reaching the wrapped breast tissue up to a tissue depth of 1.5 cm. After wound-healing all IORT-patients were treated by EBRT with 46 Gy. Results: After treatment no skin necrosis were observed. 3 patients had woundhealing problems, 2 an erythema °II on their first day after surgery. After a maximum follow-up of 22 months, patients showed good cosmetic results.1 patient had to have secondary mastectomy because of a previously not known mulitfocality, a second patient developed cervical lymph node metastases 2 months after BCS. In both casese EBRT was omitted. Another patient presented 10 months after EBRT with a multifocal relapse in her previously treated breast with skin metastases. She died 4 months after the secondary mastectomy. Conclusions: IORT with the Intrabeam system is a comfortable method to deliver a single boost to the tumorbed. After BCS, the tissue can be ideally adapted to the applicators surface and be treated by low-distance x-rays. By IORT the miss of the target, as it often appears in EBRT of the breast, can be avoided. No significant financial relationships to disclose.
Gemcitabine plus continuous infusion of 5-FU for heavily pretreated advanced colorectal cancer patients. Phase I/II study
Authors: V. Pachon, P. Garcia-Alfonso, L. Iglesias, I. Siso, G. Abad, P. Khosravi, V. Diaz, G. Perez-Manga
Journal: Journal of Clinical Oncology (2005)

3735 Background: Colorectal cancer (CRC) patients previously treated with more than one regimen but still with good performance status are a frequent clinical reality. It is necessary to investigate effective therapies with low toxicity for them. Since gemcitabine (G) and 5FU are active drugs in this setting, we are performing a phase I/II trial in CRC multitreated patients with a bi-weekly schedule of G plus continuous infusion of 5FU during 21 days. Methods: Patients (p) with stage IV CRC, previously treated with oxaliplatin and CPT-11 for metastasic disease, ECOG ≤ 2, adequate bone marrow, renal and hepatic function. Schedule: 5FU 200 mg/m2 continuous intravenous infusion during 21 days every 28 days. Dose escalation: level 1: G 800 mg/m2; level 2: 1000 mg/m2; level 3: 1250 mg/m2 on Day 1 and 15. Results: 18 p were included, male:14 (76.5%), median age 63 (range 44–74) and ECOG 0–1 82.4%, ECOG 2: 17.6%. Previous treatment: surgery of primary disease +/- metastasectomy 76.5%, median number chemotherapy regimes: 2 (range 2–5); median number of metastatic sites: 2 (range 1–3). Median number of cycles: 6 (range 2–23). No grade 3/4 toxicity was observed in levels 1–2. In L3, Grade 3 was observed in 3/17 p: liver, neutropenia and diarrhea. Overall toxicity in L3 was G1 nausea in 1 p, G2 diarrhea in 1 p; G2 constipation 1 p, G1 hand-foot syndrome in 2 p, G1 anemia in 1 p; G2 anemia in 1 p; G1 hepatic toxicity in 3 p and 1 p with G1 mucositis. In only 3/17 p dose reduction was necessary. Objective responses were not seen but 12/17 p (70.5%) were evaluated as stable disease. Five/17 (29.5%) progressed during treatment. Clinical improvement as measured by symptoms was achieved in 10/17 p (58.8%). Median TTP was 112 days (range 44–396); with a median follow-up of 324 days (range 58–680). Twelve/18 p have already died with a median overall survival of 296 days (range 58–569). Conclusions: MTD was not reached during Phase 1, however the schedule administered in L3 is recommended, as it presents an adequate and manageable toxicity profile in this heavily pretreated group. Preliminary data show that this is an effective alternative in this setting of patients with no other standard active therapy. No significant financial relationships to disclose.
Correlation of history of tobacco consumption and type of k-ras mutation in patients (pts) with pancreatic adenocarcinoma (PC)
Authors: D. P. Kelsen, E. M. O'Reilly, F. D. Huitzil Melendez, J. Zheng, M. Capanu, A. Duffy, B. Gansukh, G. Jacobs, P. B. Chapman, G. K. Abou-Alfa
Journal: Journal of Clinical Oncology (2008)

15557 Background: Approximately 90% of PC harbor mutations in k-ras codon 12. Smoking (Sm) is the most important risk factor for development of PC. Ras genes are critical targets for chemical carcinogens and a relationship between tobacco carcinogens and codon 12 k- ras mutations has been suggested. In lung adenocarcinoma, k-ras mutations have been identified preferentially in patients with a positive Sm history. In PC, a correlation of Sm history with specific k-ras mutations remains to be defined. Our aim was to evaluate whether a correlation between Sm history and k-ras mutation in pts with PC exists. We specifically looked at the correlation between Sm history and aspartic acid (D), valine (V), arginine (R), and serine (S) k-ras mutations. Methods: We retrospectively obtained the Sm history in a cohort of pts enrolled on a prospective pilot trial of k-ras vaccination in resected PC. Genomic DNA samples were analyzed for codon 12 k-ras mutations using multiplex competitive oligonucleotide probe ligation. Pts were categorized as non-smokers or smokers (> 15 pack-years). The statistical significance of associations between k-ras mutation status and Sm history was tested using the Fisher exact test. A p-value less than 0.05 was considered significant. Results: Of 55 pts screened for mutant k-ras after surgical resection of PC, 46 had a detectable k-ras mutation. 19 patients smoked > 15 pack-years. No significant association between Sm and overall presence of k- ras mutation was identified. Six patients (17%) had S mutant k-ras and all were non-smokers. Two of these patients had a strong family history of cancer, one was a fireman, one ran a manufacturing company assembling industrial machinery, one chewed tobacco and two had no obvious risk factors. Conclusions: In this small group of patients, we observed no significant relationship between Sm history and k-ras mutation status (D, V, R or S) in resected pancreas cancer. There has been no correlation between k-ras mutation status and smoking reported in the literature. The prognostic relevance of smoking and ras mutation status in pancreas remains unclear, although a therapeutic implication may exist. No significant financial relationships to disclose.
Abstract 14580: Vascular Hypoxia Augments Thrombogenic Potential of Atherosclerotic Plaque; Interactive Contribution of HIF-1{alpha} and NF-{kappa}B
Authors: Yunosuke Matsuura, Atsushi Yamashita, Takashi Iwakiri, Chihiro Sugita, Nozomi Okuyama, Kazuo Kitamura, Yujiro Asada
Journal: Circulation (2012)

Introduction: The presence of vascular hypoxia had been demonstrated in atherosclerotic lesion. However, little is known about the relationship between vascular hypoxia and arterial thrombogenesis....
Phase (Ph) 3 Study of Patritumab (P) Plus Erlotinib (E) in Egfr Wild-Type Subjects with Advanced Non–Small Cell Lung Cancer (Nsclc)
Authors: L. Paz-Ares, J. von Pawel, B. Moritz, J. Mendell, X. Jin, C. Copigneaux, R. Beckman
Journal: Annals of Oncology (2014)