tbuckley/cabot-search huggingface dataset:
Epstein-Barr virus (EBV)-specific immunotherapy in nasopharygneal carcinoma (NPC)
Authors: L. J. Wirth, M. Fogg, F. Wang, J. Lorch, R. I. Haddad, M. R. Posner
Journal: Journal of Clinical Oncology (2009)

6025 Background: Immunotherapy for EBV-associated NPC is intriguing, as viral proteins serve as foreign tumor antigens for cytotoxic T cells (CTLs). EBV-specific CTLs are effective in PTLD, but translating this success to NPC is challenging. We conducted a feasibility study to establish the manufacture and administration of autologous EBV-specific CTLs and explore correlates of response. Methods: Eligibility criteria include incurable EBV+ NPC, ECOG PS ≤ 1, adequate end-organ function, and no chemotherapy within 2 weeks (wks). CTLs were generated using autologous EBV-transformed B cells to generate autologous EBV-specific CTLs. CTLs were administered in 2 infusions, 2 wks apart (2 X 10 7 and 1 X 10 8 cells/m 2 , respectively, for the 1 st 3 patients, then 1 X 10 8 cells/m 2 X 2 for remaining patients). Response was determined at 8 wks. Results: Ten patients were enrolled. CTLs were successfully generated in 9. Two patients came off study during CTL manufacture, due to decline in PS (n = 1) and tumor invasion into the brain (n = 1). One patient has a product available when clinically appropriate. There were no infusion-related events. Seven patients received CTLs. One had stable disease (SD) and remains progression-free at 64 wks, 4 had progressive disease and 2 await restaging. Five patients had EBV viral loads (VL) pre- and post-CTLs. VL remained undetectable in 1, decreased from 5300 to 1300 copies/ml in 1, increased from undetectable to 153 copies/ml in 1, and in 2 increased from 46,524 to 269,072 and 7,621 to 59,336 copies/ml, respectively. A CD3+/CD8+ phenotype predominated in the CTLs. LMP2- and EBNA-1 CTL specificity was evaluated by IFN-γ ELISPOTs. There were 2 responders to EBNA-1 (range: 100 to 150 sfc/10 6 cells), and 7 responders to LMP2 (range: 120 to 433 sfc/10 6 cells). Conclusions: EBV-specific CTLs can be generated from patients with NPC. CTLs are well-tolerated and may have some efficacy, as seen in 1 patient with SD. LMP2-specific CTLs were frequent, whereas EBNA-1-specificity was less common. While the sample size is small, the presence of LMP2 activity alone may not account for response. Factors critical to EBV-specific immunotherapy in NPC remain unclear. A phase II study to establish efficacy of this approach in less heavily pretreated NPC is underway. No significant financial relationships to disclose.
A phase I trial of the farnesyltransferase and geranylgeranyltransferase-I inhibitor L-778,123 (L-778) and radiotherapy for locally advanced pancreatic cancer
Authors: N. E. Martin, T. B. Brunner, E. J. Bernhard, K. D. Kiel, T. F. Delaney, W. F. Regine, B. W. Morrison, W. K. Tanaka, W. G. McKenna, S. M. Hahn
Journal: Journal of Clinical Oncology (2004)

4098 Background: Preclinical and clinical studies have demonstrated that inhibition of prenylation can radiosensitize cell lines with RASmutations or Ras activation and produce clinical response in patients with cancer. Treatment with the dual farnesyltransferase and geranylgeranyltransferase-I inhibitor L-778 in combination with radiotherapy has shown tolerability and clinical effects in patients with NSCLC and cancers of the head and neck. Methods: The aim of this study was to determine the maximally tolerated dose of L-778 for patients with locally advanced pancreatic cancer. L-778 was given by continuous I.V. infusion with concomitant radiotherapy to 59.4 Gy in standard fractions. Two L-778 dose levels were tested: 280 mg/m2/day over weeks 1, 2, 4, and 5 for dose level 1 and 560 mg/m2/day over weeks 1, 2, 4, 5, and 7 for dose level 2. Results: There were no dose-limiting toxicities (DLTs) observed in eight patients treated on dose level 1. Two of four patients on dose level 2 experienced DLTs consisting in one case of grade 3 diarrhea and in the other grade 3 GI hemorrhage associated with grade 3 thrombocytopenia and neutropenia. Other common toxicities were mild neutropenia, dehydration, hyperglycemia, and nausea/vomiting. Four patients did not complete therapy due to disease progression. One patient on dose level 1 showed a partial response of six months duration. Five patients had stable disease and two patients had progressive disease. K-RAS mutations were found in tumors from three of the four patients evaluated. Farnesylation of the surrogate marker HDJ2 in peripheral blood mononuclear cells was reversibly inhibited during L-778 treatment. In a patient-derived cell line with a K-RASmutation, radiosensitization and reversal of Akt and MAPK activation was noted in the presence of L-778. Conclusions: The combination of L-778 and radiotherapy at dose level 1 showed acceptable toxicity in patients with locally advanced pancreatic cancer. Radiosensitization accompanied by reduced Ras effector activation was seen in a patient-derived pancreatic cancer cell line. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Merck & Co., Inc. Merck & Co., Inc.
Comparison of Lesions Induced in the Syrian Golden Hamster by Diethylnitrosamine, Dimethylhydrazine, and Dibutylnitrosamine: Influence of Subsequent Butylated Hydroxyanisole Treatment&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: Malcolm A. Moore, Witaya Thamavit, Nobuyuki Ito
 7
Journal: JNCI Journal of the National Cancer Institute (1987)

The target organ specificity of the carcinogens diethylnitrosamine [(DENA) CAS: 55-18-5], dimethylhydrazine [(DMH) CAS: 57-14-7], and dibutylnitrosamine [(DBN) CAS: 924-16-3] was examined in Syrian golden hamsters. Groups of male animals were given 8 weekly injections of one of these carcinogens and then were maintained on a basal diet or a diet supplemented with 1% butylated hydroxyanisole [(BHA) CAS: 25013-16-5], or they were given the respective carcinogens in the drinking water until they were sacrificed at week 34. While DENA specifically induced tracheal polyps and hepatocellular foci and nodules, DMH administration was associated with development of both hepatocellular and hemangiocellular liver lesions as well as forestomach papillomas and adenocarcinomas of the large intestine. DBN induced lesions in the urinary bladder, forestomach, and trachea, in addition to a few preneoplastic foci in the liver and lungs. In all organs studied, preneoplastic and neoplastic populations were essentially similar to those observed in other experimental animals, with colon and tracheal lesions demonstrating alteration in polysaccharide metabolism. While inhibiting the development of hepatocellular lesions, especially in the group initiated with DENA, and while itself inducing extensive papillomatous forestomach hyperplasia, BHA administration did not exert a significant modifying influence on tumorigenesis in other organs. The present results demonstrate the efficacy of Syrian golden hamster studies for investigation of comparative neoplasia. Of particular interest in this respect were differences in the degree of phenotypic instability demonstrated by glutathione S-transferase placental form-positive foci induced by the 3 carcinogens, which indicated a possible qualitative variation in "initiation."
Prognostic implication of NF-κB and BCL3 activation in metastatic colorectal cancer
Authors: S. D. Puvvada, B. H. O’Neil, A. Deal, K. Greene, H. Chu, A. S. Baldwin, W. K. Funkhouser
Journal: Journal of Clinical Oncology (2008)

11090 Background: NF-κB is an anti-apoptotic transcription factor that can mediate treatment resistance. The goal of this study was to explore the prognostic impact of the activation status of NF-κB (determined by IHC) on survival in a group of patients with metastatic colorectal cancer (CRC). Differences in NF-κB expression between primary tumors (PT) and metastatic deposits to liver (LM) and/or lymph nodes (LN) were also explored. Methods: Retrospective study of 23 CRC patients who underwent surgical resection at UNC. Clinical data was collected under IRB approval. A tissue microarray (TMA) was created from triplicate cores of normal mucosa (NM), PT, LN and LM and scored by two blinded pathologists. Activation of NF-κB was defined by nuclear expression (NE) of subunits p50 and p65 along with a novel regulator of NF-κB, BCL3. An expression score was generated by multiplying average intensity (0–3+) by percent of nuclei positive. Generalized estimating equations were used to note differences in intensity scores among NM & non-normal tissues. Cox regression models were used to assess relationship to overall survival. Results: NF-κB P65 subunit NE was significantly higher in PT and LM than NM (p=0.002, p=0.02 respectively), but no different between PT and LN or LM. NF-κB P50 subunit NE was significantly higher for all tumor sites than for NM (PT and LN p<0.0001, LM p=0.01), but again no different between PT and LN or LM. BCL3-NE did not differ significantly between normal mucosa and tumor sites. NE in PT for each of these markers was strongly associated with survival: the increase in the hazard of death for each 50 point increase in NE was 45% for p65 (p=0.02), 50% for p50 (p=0.03), and 59% for BCL3 (p=0.01). Conclusions: NE of NF-κB is strongly associated with survival in this study suggesting NF-κB as a prognostic factor in this disease. NF-κB NE in PT appears to be as good as or better than metastatic sites at predicting prognosis, and p50 and p65 subunits produce similar results. BCL3 is a regulator of NF-κB activity that has not been studied in CRC to date. Our study suggests that BCL3 NE may also have prognostic importance in colorectal cancer and should be further explored as a therapeutic target. No significant financial relationships to disclose.
Rituximab maintenance for 2 years in patients with untreated high tumor burden follicular lymphoma after response to immunochemotherapy.
Authors: G. A. Salles, J. F. Seymour, P. Feugier, F. Offner, A. Lopez-Guillermo, R. Bouabdallah, L. M. Pedersen, P. Brice, D. Belada, L. Xerri
Journal: Journal of Clinical Oncology (2010)

8004 Background: The GELA sponsored intergroup PRIMA Phase III study investigated 2 years of rituximab (R) maintenance in follicular lymphoma (FL) patients responding to first-line immunochemotherapy consisting of either 8 cycles of R-CVP, or 6 cycles of R-CHOP or R-FCM (plus 2 additional rituximab infusions). Methods: 1,217 patients were enrolled from 223 centres (25 countries) between Dec 2004 and Apr 2007. Pre-induction characteristics: median age 56 years (range 22–87); 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 56% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin >3mg/L; 21% FLIPI 0-1: 36% FLIPI 2; 43% FLIPI 3-5. Most patients (75%) received R-CHOP induction (22% R-CVP, 3% R-FCM). 1,018 eligible patients responding to induction therapy were randomized (stratified by regimen and response to induction) to observation or R-maintenance, 375 mg/m2 i.v. every 8 weeks for 2 years. Results: The primary endpoint of PFS was met at the planned interim analysis (ITT: 513 observation, 505 rituximab maintenance). Median follow-up was 25 months from randomization (31 months from study entry). There was a significant (stratified log-rank, P<.0001) improvement in the primary endpoint PFS, for R-maintenance (hazard ratio [HR]=0.50; 95% CI [0.39-0.64]; 2-year PFS 82%; 95% CI [78-86%] vs 66% [61-70%] for observation). An independent response review committee confirmed the significant improvement in PFS in the R-maintenance arm (HR=0.53 [0.41-0.68]). Time to next anti-lymphoma treatment, as well as response rate at the end of maintenance or observation, were significantly improved in the R-maintenance arm. The most common AEs were infections (22% observation, 37% R-maintenance). Grade 3-4 AEs were reported in 16% (observation) and 22% (R-maintenance) of patients (neutropenia 1% vs 4%; infections 1% vs 4%, respectively). Conclusions: The PRIMA study demonstrates that 2 years of R-maintenance therapy after induction immunochemotherapy in previously untreated FL significantly improves PFS with little additional toxicity. The PRIMA study provides evidence for a new standard of care for FL patients in need of treatment. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche Genentech, Roche Roche
Erlotinib in non-small cell lung cancer (NSCLC): Interim safety analysis of the TRUST study
Authors: U. Gatzemeier, A. Ardizzoni, K. Horwood, J. van Meerbeeck, P. Magyar, M. Gottfried, O. Arrieta, M. Krzakowski, F. Franke, N. van Zandwijk
Journal: Journal of Clinical Oncology (2007)

7645 Background: In patients (pts) with relapsed NSCLC, erlotinib 150 mg/d significantly prolonged survival, delayed symptom progression, and improved quality of life versus placebo (Shepherd et al, N Engl J Med 2005;353:123–32). TRUST is an open label, non- randomized trial initiated to provide erlotinib access to pts with advanced NSCLC. Methods: Eligible pts had stage IIIb/IV NSCLC, and had failed or were unsuitable for chemotherapy. Erlotinib (150 mg/d p.o.) was given until disease progression or unacceptable toxicity. Pts were monitored monthly. Results: In November 2006, data were available for 5,015 pts (ITT population) from 51 countries. Median age was 63y (range 19–95). Pt characteristics (%) were: male/female 62/38; Caucasian/Oriental/other 76/19/5; non-smoker/ex- or current-smoker 28/71 (no data 1); ECOG PS 0/1/2/3 21/53/20/6; adenocarcinoma/squamous cell/other 53/25/21; stage IIIb/IV 22/78; erlotinib 1st/2nd/3rd-line/other 14/48/37/1. Safety data were available for 4,423 pts, 55% of whom had at least one adverse event (AE). Only 5% had one or more erlotinib- related serious AEs, the most common being gastrointestinal (GI) disorders (86 pts; 63 grade [gr] 3/4). 6% of pts discontinued treatment due to erlotinib-related AEs: GI disorders in 96 pts (54 gr 3/4), skin disorders in 92 (50 gr 3/4). Unexpected erlotinib-related AEs occurred in 10% of pts (4% gr 1, 3% gr 2, 3% gr 3/4). As expected, rash was observed in 70% of pts, with the majority (84%) being of gr 1/2. 80% pts received &gt;4 weeks of erlotinib. Among 4,405 pts, only 14% had dose reductions, mainly due to rash (83%) and diarrhea (21%). Similar safety results were seen for 2nd-line pts only. Efficacy for all and 2nd-line pts will be presented. Conclusions: These results, achieved through routine clinical use of erlotinib in unselected pts with advanced NSCLC, confirm the favorable tolerability profile seen with erlotinib in selected patients in the clinical trial setting. [Table: see text]
Carfilzomib (CFZ) in combination with DEX and other agents (Dox, Thal, DDP, vorinostat) for far advanced and refractory multiple myeloma (FARMM).
Authors: Y. Alsayed, B. P. Nair, M. Kauffman, N. Petty, S. Waheed, F. Van Rhee, J. Szymonifka, B. Barlogie
Journal: Journal of Clinical Oncology (2010)

e18504 Background: CFZ has activity in FARMM. We are reporting on 17 patients with FARMM treated on a compassionate basis with FDA and IRB approval. Methods: Median values are: prior therapy 3.9yr, salvage regimens 4, prior transplants 3; platelets 45,000/uL, hemoglobin 9.6g/dL, neutrophils 1,100/uL. 88% had CA's, 6/8 GEP high-risk. 17 patients started cycle-1 (28d) CFZ at 20mg/m2 on d 1, 2 and 27mg/m2 on d 8, 9, 15, 16 plus DEX 4mg with each CFZ dose. 13 patients started cycle-2 with CFZ 36mg/m2 plus DEX 4- 20mg; 9 patients started a third cycle of CFZ 36mg/m2 plus DEX with added Thal 100mg/d and doxorubicin (DOX) 3mg/m2/d × 16d CI; 4 patients received a fourth cycle as in cycle 3 with added C-DDP at 2mg/m2/d × 16d CI; and 2 patients finished a fifth cycle with further addition of vorinostat 200mg/d. Results: Responses included 1 CR (cycle 1), 3 PR (2 in cycle 2, 1 in cycle 4) and 4 improvements (IMP) (cycle 1, 1; cycle 2, 1; 2 beyond cycle 4). Current OS/EFS status is 13/3, including 9/7 in 9 starting third and 4/4 in 4 who began fourth cycle. CFZ-attributable toxicities were minor, flu-like symptoms in 3/17; there was no aggravation of pancytopenia pre-existing peripheral neuropathy. Conclusions: CFZ is well tolerated in doses up to 36mg/m2 in patients with FARMM and can be safely combined with low to moderate doses of other agents including THAL, DOX, C-DDP, and VOR. CFZ does not appear to aggravate pre-existing bone marrow or kidney dysfunction or peripheral neuropathy. CFZ appears to have activity in patients with FARMM and high frequencies of CA and GEP high-risk, despite very extensive prior therapy with all approved and several experimental agents. No significant financial relationships to disclose.
Combination therapy with docetaxel (D) and celecoxib (C) in patients (pts) with hormone resistant prostate cancer (HRPC)
Authors: B. Kasimis, V. Chang, J. Cogswell, N. Sambamoorthi, M. Gonzalez, S. Srinivas, F. Zhong, E. Morales, L. Duque, M. Blumenfrucht
Journal: Journal of Clinical Oncology (2006)

14519 Background: Cox-2 expression is an independent predictor of survival and is over expressed in 89.3% of pts with HRPC. Cox-2 expression has angiogenic and cytoprotective effects. Its suppression could lead to angiogenesis inhibition and increase chemotherapy sensitivity. D in low doses and C are angiogenesis inhibitors. The main objectives were to study the effects on PSA, time to progression (TTP), toxicity and survival. Methods: In a two stage, phase II trial designed for 66 pts, 30 pts with HRPC and evidence of biochemical and radiographic progression were treated with D 30 mg/m 2 IV/wk for 3 wks and C 400 mg po bid for 4 wks of each cycle. Response evaluation after every two cycles was made. RECIST criteria and PSA reduction by &gt;50% for biochemical response were used. Independent safety monitoring for renal (R) and cardiovascular (CV) toxicity were made. Results: Thirty (30) evaluable pts received minimum of 2 cycles, median (M) 4.5 (range 2–8). The M age was 74 yr (55–94), ECOG PS 1 (0–2), Hb 11.8 g/dl (8.6–14.6), and PSA 92.5 ng/dl (15.3–4192). Metastases were present in 24 pts (80%) by bone scan and 25 pts (83.3%) by CT scan. Twelve (12) pts (40%) had PSA response of &gt;50% and 4 pts (13.3%) had PSA normalization. By CAT scan, 3 pts (10%) had CR, 5 pts (16.7%) had PR, and 12 pts (40%) had SD. By bone scan 1 pt (4.8%) had a major response. The M TTP by PSA was 3.65 mos (0.87–12.0). With 27% pts still alive, the M survival was 10.9 mos (3.0– 30.7+), with 95% CI for the mean (9.3–15.2). One pt (3.3%) withdrew due to abdominal discomfort, 2 pts (6.6%) had grade III diarrhea and 1 pt (3.3%) had grade III nail toxicity. Conclusions: 66.7% pts had soft tissue response (CR+PR+SD), and 13.3% pts had PSA normalization. Safety analysis for R and CV toxicity demonstrated excellent safety of this regimen. Considering the unfavorable prognostic indicators of this population the MST of 10.9 mos indicates the activity of this combination. [Table: see text]
The accuracy of transrectal ultrasound before chemoradiation in predicting survival and after chemoradiation in predicting pathological stage in patients with rectal cancer
Authors: J. Fitzgerald, S. Goldstein, G. Isenberg, L. Gladstone, E. Mitchell, P. Anne, D. Loren, A. Saddiqu
Journal: Journal of Clinical Oncology (2005)

3679 Background: Endorectal ultrasound is frequently used to select patients with rectal cancer for neoadjuvant therapy. The ultrasound results can be difficult to interpret after chemoradiation. The purpose of this study is to determine the accuracy of transrectal ultrasound before pre-operative chemoradiation in predicting survival and after pre-operative chemoradiation in predicting the pathological stage of patients with rectal cancer. Methods: Patients with clinical stage II or III rectal cancer 0 to 15 cm from the anal verge had transrectal ultrasound before and after receiving a standardized regime of external beam radiation, 5-Fluorouracil and CPT 11. Patients then underwent surgical resection, followed by additional treatments with 5-Fluorouracil and Leucovorin. Ultrasound results before chemoradiation were compared to survival. Ultrasound results after chemoradiation were compared to surgical pathology. Results: 37 patients who were enrolled in the study with clinical stage II or III rectal cancer underwent both pre and post chemoradiation transrectal ultrasound examinations. On pre-chemoradiation ultrasound, 2 patients were found to be stage I, 24 patients were stage II, 11 patients were stage III. Patients were followed from 1 to 6 years. At 3 years follow-up, both stage I patients were alive, 92% (22/24) of patients with stage II cancers were alive (1 died, 1 lost to follow-up), 73% (8/11) of stage III patients were alive (1 died, 2 lost to follow-up). Post chemoradiation ultrasound correctly predicted pathology in 24% (9/37) patients. Tumor status was correctly predicted in 41% (15/27), with 51% (19/37) being overstaged. Nodal status was correctly predicted in 70% (26/37) of patients, with 24% (9/37) of patients understaged. Conclusions: Transrectal ultrasound is a valuable tool to select patients for neoadjuvant therapy. After chemoradiation therapy, ultrasound is of limited value in predicting pathological stage. No significant financial relationships to disclose.
Phase II randomized study of compound Chinese herbal extract LC09 for external treatment of hand-foot syndrome induced by anticancer therapy.
Authors: L. Jia
Journal: Journal of Clinical Oncology (2010)

TPS322 Background: Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) induced by anticancer therapy can impact quality of life (QoL) and may lead to dose modification or treatment interruption, even when the therapy may prove beneficial. The earlier-phase data of compound Chinese herbal medicine LC07 on treating capecitabine-induced HFS in metastatic breast cancer has shown significant effective. LC09 is an advanced Chinese herbal extract based on LC07. The objective of this clinical trial is to evaluate the efficacy and safety of LC09 external treatment on HFS/HFSR. The research is funded by the Ministry of Science and Technology of China (No. 2008BAI53B023), and designed by the China-Japan Friendship Hospital. Trial start date is 20 Aug 2009, and the completion date is 20 Dec 2011 (estimated). Methods: Entry Criteria:Diagnosis of cancer, with HFS/HFSR grade ≥ 1 (NCI-CTCAE version 3.0) after anticancer therapy, including chemotherapy and molecular targeted therapy. Age: 18 to 85. Able to participate in study procedures and QoL evaluations. No history of hand and foot skin diseases. No concurrent other treatment for HFS/HFSR. Expected Enrollment: 204 pts. Outline: This is a phase II, double-blind, randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. Patients soak their hands and feet in the Chinese herbal extract LC09 lotion (Arm I) or placebo lotion (Arm II) for 20 minutes, twice daily for 7 days. Anticancer treatment continues until the end of therapy in the absence of disease progression or unacceptable toxicity. Physical examination, NCI grade of HFS/HFSR, NRS scale of pain and Skindex-16 (a dermatologic QoL patient reported questionnaire) are assessed at baseline, and at 1 week. Patients also complete a daily diary to document side effects and medication compliance. After completion of study therapy, patients are followed at 3 weeks. No significant financial relationships to disclose.