tbuckley/cabot-search huggingface dataset:
Major prognostic factors of adult patients with advanced T-cell lymphoma/leukemia.
Authors: M Shimoyama, K Ota, M Kikuchi, K Yunoki, S Konda, K Takatsuki, M Ichimaru, S Tominaga, S Tsugane, K Minato
Journal: Journal of Clinical Oncology (1988)

Eighty-one adult patients with advanced T-cell lymphoma/leukemia including 54 with adult T-cell leukemia/lymphoma (ATL), who were treated between 1981 and 1983 with vincristine, cyclophosphamide, prednisolone, and doxorubicin (VEPA) or VEPA plus methotrexate (VEPA-M) in randomized fashion, were evaluated for pretreatment characteristics. The overall complete response (CR) and the 4-year survival rates were 39.5% and 19.4%, respectively, and 69% of 32 CR patients had relapses, indicating the need for development of new effective regimens for the disease. In a multiple logistic regression analysis, only three factors, leukemic manifestation, poor performance status (PS), and a high lactate dehydrogenase (LDH) level, were significantly associated with the poor response rate. In a Cox proportional hazards model analysis, shortened survival was again significantly associated with poor PS and a high LDH level, but not with a clinical diagnosis of ATL. The two factors, PS and LDH level, that were found to be significantly associated with both CR and survival rates, were used to construct a model containing six categories of patients at increasing risk for poor response and shortened survival. These categories divided the patients into three groups with respective CR and 4-year survival rates of 75% and 53% for low-risk, 45% and 15% for moderate-risk, and 15% and 0% for high-risk. The results indicate that PS and LDH levels were the most important in predicting the response and survival of an adult patient with advanced T-cell lymphoma/leukemia. The prognosis of patients with usual peripheral T-cell lymphoma, excluding ATL, was comparable with that of advanced B-cell lymphoma. These results have important implications for the design of new prospective therapeutic trials.
PGK1 a prospect marker for peritoneal dissemination in gastric cancer
Authors: D. Zieker, I. Koenigsrainer, F. Traub, K. Nieselt, C. Stirnkorb, S. Kupka, F. Fend, J. T. Hartmann, H. Northoff, B. L. Bruecher, A. Koenigsrainer
Journal: Journal of Clinical Oncology (2008)

22171 Background: In patients with primary gastric cancer peritoneal carcinomatosis is a frequent finding, and it is related with a moderate prognosis. The dissemination of cancer cells into the abdominal cavity in diffuse gastric adenocarcinoma seems to be a major mechanism for peritoneal carcinomatosis. The features that enable diffuse primary gastric tumours to develop peritoneal dissemination have been little investigated and are still incompletely understood. Methods: Therefore the gene expression profile in patients with diffuse primary gastric cancer with and without peritoneal carcinomatosis was compared. Using oligonucleotide microarrays, human specimens from consecutive gastric cancer patients with and without peritoneal carcinomatosis were investigated. Differentially expressed and selected genes of interest were additionally evaluated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: A significant overexpression of phosphoglycerate kinase 1 (PGK1), the chemokine CXCR4 and its ligand CXCL12 was detected in specimens from diffuse gastric cancer patients with peritoneal carcinomatosis. Increased expression of PGK1 is associated with an enhancement in the metastatic rate due to effects on CXCR4 and CXCL12 expression, which play an important role in the metastatic homing of malignant cells. Conclusion: The overexpression of PGK1 and its signalling targets CXCR4 and CXCL12 in peritoneal disseminated diffuse primary gastric carcinomas strongly indicate that this pathway may promote peritoneal dissemination. These genes may pose as prognostic markers and/or be potential therapeutic targets to prevent the migration of gastric carcinoma cells into the peritoneum. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Fortuene Funding of the University of Tuebingen
Population pharmacokinetic analysis of abiraterone acetate in healthy volunteers and chemotherapy-naive and chemotherapy-pretreated metastatic castration-resistant prostate cancer patients.
Authors: Kim Stuyckens, Fred Saad, Steven Xu, Charles J. Ryan, Matthew R. Smith, Thomas W. Griffin, Margaret K. Yu, An Vermeulen, Partha Nandy, Italo Poggesi
Journal: Journal of Clinical Oncology (2014)

58 Background: Abiraterone acetate (AA) is an effective therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). AA is metabolized to abiraterone, an androgen biosynthesis inhibitor. We performed population pharmacokinetic (PK) analyses to estimate PK parameters after a 1,000 mg/d oral dose of AA in patients with mCRPC with and without prior chemotherapy and after a one-time 1,000 mg dose in healthy volunteers, to determine consistency between groups. Methods: Studies included in analysis: COU-AA-302 (pre-chemotherapy mCRPC); COU-AA-301 and COU-AA-006 (post-docetaxel mCRPC); and COU-AA-008, COU-AA-009, and COU-AA-014 (healthy subjects). A total of 4,627 plasma concentrations from 360 subjects were analyzed using nonlinear mixed-effects modeling. Results: A two-compartment model with three-transit compartments following sequential zero-first order kinetics was used to characterize the systemic absorption of abiraterone. Absorption-related parameters were affected by food intake. Abiraterone PK was characterized by an extensive apparent clearance, which was lower in patients with mCRPC (1505 L/h) compared with healthy subjects (2240 L/h), and by large apparent central (5630 L) and peripheral volumes of distribution (17,400 L). PK of abiraterone was similar in chemotherapy-naïve and chemotherapy-pretreated patients and was characterized by a relatively high between- and within-subject variability (eg, between-subject coefficient of variation [CV%] for relative bioavailability in the clinical studies was 61.1% and the CV% for within-subject variability was 71.3%). No factors other than food intake and patient-healthy volunteer status impacted PK. Conclusions: Based on this population PK model, the recommended 1,000 mg/d dose of AA results in similar abiraterone exposure for patients with mCRPC regardless of prior chemotherapy status. The food effect on absorption-related parameters in this analysis confirms current dosing instructions for AA. Clinical trial information: NCT00638690, NCT00887198.
Susceptibility Alleles for Aberrant B-1 Cell Proliferation Involved in Spontaneously Occurring B-Cell Chronic Lymphocytic Leukemia in a Model of New Zealand White Mice
Authors: Yoshitomo Hamano, Sachiko Hirose, Akinori Ida, Masaaki Abe, Danqing Zhang, Sanki Kodera, Yi Jiang, Jun Shirai, Yuko Miura, Hiroyuki Nishimura, Toshikazu Shirai
Journal: Blood (1998)
Phase 1 study of IMC-3G3, an IgG1 monoclonal antibody targeting PDGFRα in patients with advanced solid malignancies
Authors: H. Youssoufian, R. J. Amato, C. J. Sweeney, E. G. Chiorean, F. Fox, T. Katz, E. K. Rowinsky
Journal: Journal of Clinical Oncology (2008)

14617 Background: Platelet derived growth factor receptor alpha (PDGFRα) plays a critical role in tumorigenesis and tumor progression. PDGFRα and its ligands are expressed by an array of tumors and supportive stroma, and the integrity of this axis results in the proliferation of tumors, supportive stroma and blood vessels. IMC-3G3 is a recombinant human IgG1 MAb targeted to PDGFRα and induces prominent anticancer effects in vitro and on human tumor xenografts in vivo. Methods: This Phase 1, multicenter study of IMC-3G3 administered intravenously in patients (pts) with advanced refractory or untreatable cancer plans to enroll 5 cohorts of 3–6 pts. The primary objectives were to determine the MTD and safety profile. Cohorts 1–3 received 4 weekly infusions of 4, 8, and 16 mg/kg IMC-3G3 per cycle and are reported here. Future cohorts (Cohorts 4 and 5) will receive IMC-3G3 every 2 weeks at doses of 15 and 20 mg/kg. Results: Thirteen pts have enrolled to date (11 male, 2 female; 9 prostate cancer, 1 bladder/transitional cell carcinoma, 1 endometrial cancer, 1 SCLC, and 1 carcinoid unspecified). Eight pts were treated > 10 weeks; 2 pts at 16 mg/kg are ongoing at 18 and 26 weeks, respectively. One pt at 4 mg/kg who experienced a PSA decrement of > 50% was treated for 39 weeks until discontinuing due to disease progression. No dose-limiting toxicities were observed at any dose level in cycle 1. The most frequently reported AE has been fatigue (2 of 12 pts). No Grade 3/4 IMC-3G3-related events were reported. Following the final infusion of cycle 1, as IMC-3G3 dose was escalated from 4 to 8 to 16 mg/kg; A) the mean t1/2 remained relatively constant (126–138 hrs), B) mean Cmax and AUCinf increased in a greater-than-dose-proportional manner, suggesting nonlinear IMC-3G3 pharmacokinetics (Cmax = 139, 297, and 1198 μg/mL; AUCinf = 23686, 48149, and 130302 hr*μg/mL for the 4, 8, and 16 mg/kg cohorts respectively), and C) mean clearance decreased (0.196–0.132 mL/hr/kg), suggesting saturation of IMC-3G3 elimination was being approached. Conclusions: Enrollment continues with evaluation of 15 and 20 mg/kg every 2-weeks based on supportive PK data and toxicity profiles. Preliminary safety, PK, and biological activity data support further IMC-3G3 disease-directed development. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration ImClone Systems ImClone Systems ImClone Systems
Surgical closure of nerve stump to prevent a phantom pain in major amputation
Authors: S. Dos Santos Aguiar, A. Cassone, J. C. Barbi-Goncalves, E. Sobral Vulcano
Journal: Journal of Clinical Oncology (2005)

8170 Background: Patients’ perceptions of the result of the limb amputation vary widely, yet the factors associated with this variability are not well understood. The phantom limb sensation after surgery are frequent barrier to rehabilitation. The neuroma formation after nerve section is one reason of .Our objective was to treat the nerve stump before a neuroma formation, put it into the bone medulary canal to prortect it to further trauma and deserve particular emphasis in the management of patients to rehabilitation. Methods: In this prospective study, 42 patients with bone sarcomas who had had a major extremity amputation a standardized questionnaire, amputation characteristics, and function. The surgical procedure consist in a closure of the nerve stump into the bone medulary canal and a closure of the muscle and skin as a usual.We correlated all patients completed a validated quality of life questionnaire and visual analog scale (ranging from 1 to 10) and at each evaluation thereafter. Results: 42 consecutive patients (13 women and 29 men) underwent 42 amputation procedures for the treatment of bone sarcoma in extremities. The mean age of the patients was 12,5years. The mean pain rating decreased (p < 0.04), and it remained substantially improved months postoperatively with a good period for rehabilitation.The major levels of amputation were six hip disarticulation, twenty five tigh amputation, six transtibial. Conclusions: The closure of the nerve stump into the bone medulary canal perceived good result of amputation in control of phantom pain and improve short period of rehabilitation. No significant financial relationships to disclose.
Elderly patients with aggressive non-Hodgkin's lymphoma: disease presentation, response to treatment, and survival--a Groupe d'Etude des Lymphomes de l'Adulte study on 453 patients older than 69 years.
Authors: Y Bastion, J Y Blay, M Divine, P Brice, D Bordessoule, C Sebban, M Blanc, H Tilly, P Lederlin, E Deconinck, B Salles, C Dumontet, J Brière, B Coiffier
Journal: Journal of Clinical Oncology (1997)

PURPOSE To clarify disease characteristics and optimal treatment for elderly patients with non-Hodgkin's lymphoma (NHL), we performed a randomized trial in 453 patients older than 69 years with aggressive lymphoma. PATIENTS AND METHODS Two hundred twenty patients received cyclophosphamide 750 mg/m2, teniposide (VM-26) 75 mg/m2, and prednisone 40 mg/m2/d for 5 days (CVP) and 233 patients received CVP plus pirarubicin (THP-doxorubicin) 50 mg/m2 (CTVP), each for six courses every 3 weeks. RESULTS The median age was 75 years. Most patients had clinically aggressive disease; 30% had one and 53% two or three adverse prognostic parameters as defined by the International Prognostic Index. More patients on the CTVP arm had an elevated lactic dehydrogenase (LDH) level, but the two groups were otherwise well balanced. CTVP treatment was more frequently associated with leukopenia, thrombocytopenia, and infectious complications. Death during chemotherapy occurred in 16% and 21% of patients on the CVP and CTVP arms, respectively (not significant). Forty percent of patients achieved a complete response (CR): 47% on CTVP and 32% on CVP (chi2 = 20.98, P = .0001). The median time to treatment failure (TTF) was 7 months for CTVP versus 5 months for CVP (log-rank test, P &lt; .05). The median survival time was 13 months in both groups; however, the 5-year survival rate was 26% with CTVP versus 19% with CVP (chi2 = 4.68, P &lt; .05). Lymphoma progression was the primary cause of death. CONCLUSION Elderly patients with aggressive lymphoma have an aggressive disease with adverse prognostic parameters at the time of diagnosis. Slightly longer survival was observed for patients treated with an anthracycline-containing regimen.
Effect of oxaliplatin-capecitabine first-line chemotherapy and tumor response on serum proteomic profiles in advanced colorectal cancer and identification of diagnostic biomarkers
Authors: H. H. Helgason, J. Y. Engwegen, A. Cats, H. Boot, H. G. Bonfrer, J. H. Beijnen, J. H. Schellens
Journal: Journal of Clinical Oncology (2006)

3603 Background: Colorectal cancer (CRC) is the third most common cause of cancer related death. Prognosis is highly dependent on stage at diagnosis making early diagnosis mandatory. Previously we identified serum biomarkers for CRC, by comparing serum from CRC patients and healthy controls, using SELDI-TOF mass spectrometry. Methods: We validated our identified biomarkers and assessed the effect of first-line oxaliplatin (130 mg/m 2 day 1, q21)-capecitabine (1000 mg/m 2 d1–14, q21) therapy by prospective standardized serum sampling at &lt; 2 weeks prior to start of chemotherapy and serially before each chemotherapy cycle in patients with advanced CRC. Samples were drawn according to standardized protocol, centrifuged within 1 hour and stored at -30°C. After thawing they were analyzed with SELDI-TOF MS on CM10 chips at pH 5. Healthy control subjects were matched according to age, gender and time of serum collection. For serial analysis the time points T: 0, 6, 12 and 18 - 24 weeks were used. All patients had given written consent, had WHO PS ≤ 2 and measurable disease, according to RECIST criteria, and/or were evaluable by CEA. Results: In total 42 patients (mean age: 57 years; range: 37 - 73; male 62%), were treated between 06/2003 and 09/2005. All patients were previously untreated except 8 patients who had received radiation or chemo-radiation for rectal carcinoma (all &gt; 6 months). Median follow up was 45 weeks and median number of courses was 5.5 (range: 1 -10). Response rate was 46%; PR in 19, SD in 12 and PD in 10 patients, respectively (1 not evaluable) and median overall survival was 10.5 months. We identified 6 peptides/proteins (m/z: 31948, 8078, 28101 (apolipoprotein A-I), 7970, 5912 and 12861 Da, respectively (in order of significance) discriminating between CRC and healthy controls (p &lt; 0.001). In a serial analysis of the patients a peptide, with m/z: 5.9-kDa (most likely fibrinogen split product) declined, during chemotherapy in some responsive patients, but apolipoprotein A-I appeared not to change. Conclusions: We confirmed our previous identification of apolipoprotein A-I (m/z: 28-kDa) as a potential biomarker for CRC and suggest a peptide with m/z: 5.9-kDa as a potential biomarker of response. No significant financial relationships to disclose.
Adaptation and Validation of the Plasma Inhibitory Activity (PIA) Assay to Detect Inhibition of Aurora, ABL and FLT3 Kinases by AT9283 In Children and Adolescents with Leukaemia
Authors: Jennifer E Podesta, Melanie J Griffin, Richard Sugar, Matthew S Squires, Alan Boddy, Spiros Linardopoulos, Andrew DJ Pearson, Andrew S Moore
Journal: Blood (2010)
Phase II clinical trial of paclitaxel loaded polymeric micelle (GPM) in patients (pts) with advanced pancreatic cancer (APC): Final results
Authors: N. A. Podoltsev, M. S. Rubin, J. A. Figueroa, M. Y. Lee, J. Kwon, J. Yu, R. O. Kerr, M. W. Saif
Journal: Journal of Clinical Oncology (2008)

4627 Background: APC is poorly responsive to chemotherapy. Cremophor-based paclitaxel (CBP) as well as docetaxel have been tested in APC, with occasional responses but considerable toxicity. GPM is a novel micellar formulation of paclitaxel in a low molecular weight biodegradable synthetic polymer. MTD for GPM in both preclinical and phase I studies are higher than that for CBP. In addition, at MTD GPM was more effective than CBP or gemcitabine against several tumor models, including 2 PC xenografts. Methods: Pts with measurable APC, ECOG PS ≤ 2, no prior chemotherapy and adequate organ function were treated with 3-hr GPM infusions q 3 wks. Initial pts were treated at 435 mg/m2 (n=11) which was reduced for subsequent pts to 350 or 300 mg/m2 (n=45). Response was evaluated by RECIST criteria; pts without disease progression for >6 wks were considered to have SD. Primary endpoint was time to tumor progression (TTP), time from first dose to documentation of progression or death, whichever occurred first. Results: 56 pts were enrolled: median age 64; M/F (40/16); 93% PS 0–1. At 300 or 350 mg/m2 dose, most common grade 3 toxicities were: neutropenia (40.0%), fatigue (17.8%), infection, dehydration, neuropathy (each 13.3%), and abdominal pain (11.1%). Median TTP for pts treated at 300 or 350 mg/m2 doses of GPM was 3.2 mths (95% CI, 2.6, 4.2; n=45). Median PFS for these pts was 2.8 mths (95% CI, 1.4, 4.0). Median overall survival (OS) for these pts was 6.5 mths (95% CI, 5.1, 7.9). Results for all 3 time-dependent parameters were similar for both of ITT or EE groups. Among pts treated at 300 or 350 mg/m2 doses of GPM, there was 1 CR and 2 PR with an ORR of 6.7%. Disease control rate (CR+PR+SD) was 60.0%. Conclusions: Treatment of APC with GPM at a dose of 300 mg/m2 q 3 wks was well tolerated and common toxicities were qualitatively similar to CBP. GPM monotherapy resulted in OS and other efficacy parameters preferable to that seen historically with gemcitabine. Future studies of GPM in combination with other agents for treatment of APC are warranted. Time to Development of Neuropathy ≥ Grade 2 Dose Level 435 mg/m2 Dose Level 300 or 350 mg/m2 Overall Pts # 11 45 56 Pts # with ≥ G2 neuropathy 4 (36.4%) 15 (33.3%) 19 (33.9%) Cumulative dose (mg/m2) to development of G2 neuropathy, median (95% CI) Range 435 431* - 790* 1,757 (1,056 - 3,002) 131* - 3,002 1,500 (1,020 - 3,002) 131* - 3,002 Time (months) to development of G2 neuropathy, median (95% CI) Range 0.0 - 2.5* 4.7 (2.8 - 6.5) 0.0* - 6.5 3.6 (2.8 - 6.5) 0.0* - 6.5 * Censored observation; G: grade Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Samyang Samyang
Defining the pathophysiology of the paclitaxel-acute pain syndrome
Authors: S. L. Wolf, C. L. Loprinzi, K. Maddocks-Christianson, R. D. Rao, P. B. Dyck, P. Mantyh, P. J. Dyck
Journal: Journal of Clinical Oncology (2007)

19613 Background: Paclitaxel therapy often results in a unique sub-acute pain syndrome, whose pathophysiology is unknown. While this syndrome is often termed as a ‘myalgia’ or ‘arthralgia’, it has not been demonstrated to be associated with any structural injury of muscles or joints. Identifying the pathophysiology mechanisms that result in the paclitaxel-acute pain syndrome might be a positive step in the development of effective prevention and/or treatment strategies. With the hypothesis that the paclitaxel-acute pain syndrome occurs as a result of nerve injury, an observational study to clarify the clinical characteristics of this syndrome was initiated. Methods: Oncology patients who were treated with at least one dose of paclitaxel and reported developing sub-acute pain were questioned using a detailed structured interview. Various aspects of the pain, including the time of onset, duration, location, severity, and exacerbating factors were evaluated. Data were tabulated descriptively. Results: Eighteen patients were interviewed. The onset of pain typically occurred 1–2 days after therapy and lasted for a median of 4–5 days. Pain was most commonly located in the back, hips, shoulders, thighs, legs and feet, with the most common descriptors used being ‘aching’ or ‘deep pain’. Commonly used adjectives to describe the pain were: ‘radiating’, ‘shooting’, ‘aching’, ‘stabbing’ and ‘pulsating’. Some patients described increased pain with weight bearing or walking. Fifteen of 18 patients specifically denied localization of pain to either joints or muscles. Conclusions: The nature of the pain, i.e. , generalized, deep aching pain, the notation of increased sensitivity with weight bearing (mechanical hyperalgesia) and the lack of localization to joints or muscles, support the hypothesis that the paclitaxel-acute pain syndrome results from a hyperalgesic dysfunction of nociceptive receptors, their fibers, or the spinothalamic system. These clinical conclusions are supported by the recent findings that markers of cellular injury can be identified in peripheral nerve tissues shortly following paclitaxel administration in an animal model (Peters CM, et al., Exp Neurol. 2007 Jan;203(1):42- 54). No significant financial relationships to disclose.