tbuckley/cabot-search huggingface dataset:
Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of of the Hsp-90 inhibitor, KOS-1022 (17-DMAG), in patients with refractory hematological malignancies
Authors: J. Lancet, I. Gojo, M. Baer, M. Burton, M. Klein, C. Nowadly, M. Gorre, Z. Zhong, R. G. Johnson, A. L. Hannah
Journal: Journal of Clinical Oncology (2006)

2081 Background: Disruption of Hsp90-client protein heterocomplexes leads to degradation of a variety of oncoproteins. KOS-1022, an Hsp90 inhibitor and water-soluble geldanamycin derivative, is in trials in patients with solid tumors. Compared to a prior geldanamycin derivative (17-AAG), KOS-1022 is ∼3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies on the same schedule). Primary study objectives: establish safety and MTD of KOS-1022 in patients with advanced hematologic malignancies; characterize PK and PD. Methods: Escalating doses of KOS-1022 are given IV over 1 h twice weekly for 2 out of 3 weeks. Plasma KOS-1022 concentrations (1 st and 4 th infusion, Cycle 1) are quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts undergo flow cytometry to quantify Hsp70/90, pAKT/total AKT, markers of apoptosis and proliferation. Response in AML pts used IWG criteria. Results: 13 pts have been enrolled at doses of 8 (n=4), 16 (n=6), 24 (n=1) and 32 mg/m 2 (n=2). All were AML (except 1 CML). Most (n=11) patients had 2–3 prior induction regimens. DLT was seen in 2 pts at 32 mg/m 2 (acute myocardial infarction and elevation of troponin). Both patients had significant co-morbidity, including (1) prior myocardial infarction and (2) progressive AML with a similar troponin elevation during induction chemotherapy prior to study. Common drug-related toxicities (all Grade 1–2): fatigue, nausea, diarrhea and arthralgias. From 8 to 32 mg/m 2 , approximately linear PK was observed. Mean terminal half-lives varied from 13.0–31.2 hours. Day 1 clearance for 8, 16 and 32 mg/m 2 was 5.6, 9.7 and 10.8 L/hr/m 2 ; mean Vz (L/m 2 ) for these groups were 238, 433 and 489. Although pre-infusion drug was quantifiable on Day 11 in most patients, Day 11/Day 1 AUC 0–25h ratio was 0.96. Activity in AML: 2 CRi and 1 SD x 9 cycles were observed. Comparing BMAs taken at Day 8 and Day 15 to baseline: decreased Hsp90 (41% to 13%), increased Hsp70 (8% to 84%) with decreased pAKT (Ser), pAKT (Thr) and total AKT in CD34+ cells. Conclusions: KOS-1022 appears to be well tolerated, with preliminary signs of clinical and biologic activity in refractory leukemia. MTD has not been defined. Plasma PK is linear over this dose range. [Table: see text]
A retrospective analysis of nonmetastatic primary mucosal melanoma of the vagina: Clinical practice evaluation in different French institutes.
Authors: C. Vaysse, P. Pautier, T. Filleron, V. Maisongrosse, V. Lavoué, J. Rodier, C. Brunaud, A. Guizard, K. Peignaux-Casasnovas, M. Delannes
Journal: Journal of Clinical Oncology (2010)

e15500 Background: Mucosal melanoma of the vagina (MMV) is a very rare entity. Optimal treatment is still controversial. We report clinical presentation, treatment modalities and outcome profiles of 31 patients with MMV. Methods: This is the first large retrospective study of 31 patients with a nonmetastatic mucosal melanoma of the vagina treated in curative intent between 1990 and 2007 within 9 institutes. Data analyzed included age, tumor stage, type of treatment, type of recurrence and status at the end of the follow-up. Results: Median age was 65 years. Tumor stage distribution according to the TNM classification was: T1 (73.1%), T2 (15.4%) and T3/4 (11.5%). Nodal status at diagnosis was available for 20 patients, most of them were N0 (n=15). Twenty-nine patients had surgical resection (nonconservative surgery: n = 16 including 2 pelvic exenterations, atypical resection : n = 12 and lymph node expertise n = 13). Eight patients received adjuvant treatment (radiation therapy n = 4; chemotherapy n = 5; brachytherapy n = 3; immunotherapy n = 2). Median follow-up was 37 months. C-Kit status was evaluated by immunohistochemistry for 7 patients : all were positive (> or = 10% labelled cells). The median survival and the 3 years relapse-free survival (RFS) were 10.3 months and 7.7% respectively. Most of first events were loco-regional relapses (n=16). Three-year cumulative incidence was 54% and 38.3% for loco-regional recurrence and distant metastasis. At diagnosis, high tumors stage (T2,3,4) was associated with poor RFS compared to T1 (p = 0.04). Median survival and 3-year overall survival rates were 34.6 months and 46.9% respectively. Conclusions: In this retrospective study, we confirmed the pejorative prognosis of MMV. The high rate of local recurrences emphasizes the need of local optimal treatment, which could be combined in selected patients with adjuvant therapy with tyrosine-kinase inhibitors blocking c-Kit. No significant financial relationships to disclose.
Combination of gemcite and cisplatin chemotherapy in unresectables gall bladder cancer
Authors: P. Gupta, P. Chitalkar, A. Sen, S. Sarkar, S. Mukhopadhyay, N. Sultania, A. Mukhopadhyay
Journal: Journal of Clinical Oncology (2007)

15166 Background: Adenocarcinoma of the gall bladder accounts for approximately 4% of all malignant neoplasm of the gastro- intestinal tract. Though surgical resection is the treatment of choice, majority of the cases are unresectable. Different chemotherapeutic agents including 5Flurouracil, Mytomycin C, Cisplatin, Methotrexate, Etoposide and Doxorubicin have been tried single or in combination. Partial response lasting from weeks to several months have been observed only in about 10% - 20 % of the cases and the median survival for patients with gall bladder cancer is approximately 4 months. Gemcitabine has shown strong anti tumour activity in a variety of solid tumours. Cisplatin has synergistic activity with Gemcitabine. The aim of our study was to determine the response rate of Gemcitabine and Cisplatin combination in unresectable gall bladder cancer and to see the tolerability in Indian-Asian pollution. Methods: During period from November 2002 to December 2006 we selected 84 consecutive patients with histologicaly proven unresectable measurable, gall bladder cancer. The inclusion criteria were performance status more than 60% (Kornofsky) and normal liver (bilirubin &lt; 2) and kidney function ( creatinine &lt;2) function . All patient received Gemcitabine (1000mg/m 2 intravenously over 30 minute) on day 1 and day 8 and Cisplatin total (100mg/m 2 divided D1 to D3) every 21days. Response assessment was done by CT Scan after 3 cycles of chemotherapy. All 84 patients are eligible for efficacy and toxicity analysis. Results: There were 15 (17.8%) complete responders, 27 (32%) partial responders, 22 (26.1%) with stable disease and 20 (23.8%) shows disease progression. The median time to progression was 22 weeks (range 12- 30 weeks). The median duration of response was 16 weeks (range 5.6 - 60 weeks). The median over all survival was 24 weeks (range 11–32 weeks) with 1year survival rate of 20.2%. WHO grade III or IV anaemia was seen in 23 (18.63%) patients respectively. Sixteen (13.44%) patients experienced grade III or IV neutropenia while grade III or IV thompocytopenia was seen in 8 patients (6.72%). Conclusions: The present study showed the Gemcitabin &amp; Cisplatine combination was very useful in advanced unresectable gall bladder cancer. It was well tolerated by the patients. No significant financial relationships to disclose.
Rare presentation of in situ mantle cell lymphoma.
Authors: C. M. Hamm, R. Herriot
Journal: Journal of Clinical Oncology (2010)

e18566 Background: Mantle cell lymphoma (MCL) is an aggressive, rare (<10%) B cell neoplasm that is triggered by a tl(11;14)(q13;32) leading to an upregulation of cyclin D1. This cancer is generally considered to be incurable with a median survival of approximately four years. the malignant lymphoma cells most often present in four different patterns: diffuse, nodular, expanded mantle zone or the blastic variant. Two prior case reports have reported in situ MCL. In these cases, patients were treated aggressively with differing outcomes. One relapsed one year after presentation with generalized disease including bone marrow involvement, the other remained in remission. Methods: Case report. Results: This patient presented with asymptomatic right inguinal adenopathy Excisional biopsy of one of the nodes revealed a few scattered small aggregates of small lymphocytes having CD5 positivity. They also stained positive for CD20, CD79a, bcl2 and cyclin d1. The benign germinal centres were negative for the lateral marker. His final stage was Stage IA. A review of the scant literature available at the time revealed that these patients were treated aggressively. The patient was interested in aggressive treatment, and received 6 cycles of CHOP-rituximab, and continues with rituximab maintenance. Conclusions: Patient remains in clinical remission 8 months following chemotherapy. Mantle cell is a heterogenous disease and newer information suggests that 1/3 of patients will not progress with expectant follow up in the first year. We suggest that the insitu disease will behave similarly. Expectant treatment with close follow up should be considered. No significant financial relationships to disclose.
Surveillance for the management of small renal masses: Utilization and outcomes in a population-based cohort.
Authors: William C. Huang, Laura C. Pinheiro, Paul Russo, William Thomas Lowrance, Elena B. Elkin
Journal: Journal of Clinical Oncology (2013)

343 Background: Small renal masses (SRM) are comprised of a heterogeneous group of tumors with some having malignant potential. Although surgery is the standard treatment for SRMs, emerging data suggests that surgery in the elderly or morbidly ill patients may be unnecessary and may adversely impact non-oncologic outcomes. We analyzed a population-based cohort of patients to identify predictors of surveillance and assess the impact of surveillance on overall survival, kidney cancer-specific survival and cardiovascular (CV) events, compared with surgery. Methods: From surveillance, epidemiology, and end results (SEER) cancer registry data linked with Medicare claims, we performed a retrospective cohort study of patients 66 years of age or older who received surgery or surveillance for SRM (&lt; 4 cm) diagnosed between 2000 to 2007. Propensity score methods were used to control for potential confounders in multivariable analysis. Results: Of 8,317 patients, 5,706 (70%) underwent surgery and 2,611 (31%) underwent surveillance. The use of surveillance increased from 25% in 2000 to 37% in 2007 (p &lt; 0.001). During a median follow-up of 58 months, 2,053 (25%) patients had at least one CV event and 2,078 (25%) patients died, including 277 (3%) who died of kidney cancer. Compared with surgery, surveillance was associated with a significantly lower risk of death from any cause (hazard ratio [HR], 0.84; CI, 0.75-0.94) and of suffering a CV event (HR, 0.79; CI 0.70-0.89), controlling for patient and disease characteristics. Kidney cancer-specific survival did not differ by treatment approach (HR, 0.89; CI, 0.66-1.21). Conclusions: There is increasing utilization of surveillance as an initial treatment strategy for patients with SRMs. For older patients with SRM, surveillance does not appear to adversely affect kidney cancer-specific survival, while surgery may be associated with CV complications and an increased risk of death from any cause. Surveillance should be considered an option for patients with SRM who are not otherwise acceptable candidates for surgical treatment.
Residual cancer found on re-excision for close and positive margins after breast conservation for early-stage breast cancer: A single-institution review.
Authors: Dahlia Michelle Rice, Karen Beatrice Salud Ching, Sahil Gambhir, Edward Woo
Journal: Journal of Clinical Oncology (2014)

55 Background: The SSO/ASTRO guidelines for margins on breast-conservation therapy (BCT) were recently published, recommending re-excision for positive margins only defined as ink on invasive cancer. The aim of our study is to retrospectively analyze our institution’s re-excision rate and the rate of finding residual cancer in the re-excision specimen when re-excisions were performed for positive and/or close margins. We want to confirm that our institution’s data for re-excision rates and residual cancer rates are comparable to national data from where the SSO/ASTRO guidelines were derived. Methods: A 3-year (2010 to 2012) retrospective review of data from our institution’s prospectively collected breast cancer database was performed for all stage 0, I, and II breast cancer patients who underwent BCT with subsequent re-excision or completion mastectomy for close or positive margins. Close margins were divided into two groups of &lt; 1 mm or 1 to 2 mm margins, and positive margins were defined as tumor cells present on ink of specimen. Results: A total of 688 patients were analyzed. Our population was found to consist mostly of Caucasian females who were postmenopausal and married. 68% (468/688) of patients were found to have invasive ductal carcinoma (IDC), of which 27.8% (130/468) underwent re-excision for positive and/or close margins. Rates of residual cancer found in margins that are positive, &lt; 1 mm, and 1-2 mm were 54.8% (17/31), 56% (14/25), and 6.3% (1/16) respectively. For DCIS, 38.9% (65/167) underwent re-excision. Rates of residual cancer found in margins that are positive, &lt; 1 mm, and 1 to 2 mm were 38.9% (7/18), 28.6 % (4/14), and 20% (2/10) respectively. Conclusions: Our results reveal that in our institution, re-excision rates are comparable to published data. However, in patients with both positive and &lt; 1 mm margins, the rates of finding residual cancer in the re-excision specimen was higher than the national average. Therefore, in our institution, further analysis is necessary prior to adopting the current recommended guidelines by SSO/ASTRO to prevent adverse impact in local recurrence rate.
Predictive factors of response in patients with metastatic melanoma treated with chemo-immunotherapy
Authors: E. Ortega, R. Andres, J. I. Mayordomo, E. Polo, R. Lara, R. Lastra, J. Lambea, P. Escudero, D. Isla, A. Tres
Journal: Journal of Clinical Oncology (2004)

7566 Background: Phase II studies of chemoinmunotherapy have showed activity in metastatic melanoma but most treatments have a very high toxicity. This study attempted to identity characteristics that correlated with response to chemo-inmunotherapy in patients with metastatic melanoma. Methods: We retrospectively evaluated the pre-treatment and in-treatment characteristics of 20 consecutive patients with metastatic melanoma treated with cisplatin(80mg/m2, day1), dacarbacine (800 mg/m2,day 1), interleukin-2 (9MU/m2 days 2–5) and interferon-alpha (6 MU/m2 days 1–5), cycles/21 days, 6 cycles. Results: Overall response was 42.9 %. Pre-treatment parameters such as patient demographics and level of leukocytes and lymphocytes in peripheral blood did not correlate with response. However patients with normal level of lactate dehydrogenase (<450 UI/L) had a response rate 66.7 % versus 20 % in patients with LDH>450 UI/L (χ 2 pearson, p= 0.04). After three cycles of treatment overall response in patients with lymphocyte count below 2000 /mm3 was 22.2 % versus 75 % in patients with lymphocyte count above 2000/mm3 (χ 2 pearson, p= 0.03). Conclusions: Basal level of LDH and lymphocyte count after treatment of chemo-immunotherapy are correlated with response in patients with melanoma metastatic. No significant financial relationships to disclose.
A 2-stage controlled phase 1/2 study of STA-4783 in combination with paclitaxel in patients with advanced metastatic melanoma
Authors: J. Powderly, K. Khan, J. Richards, W. Urba, M. McLeod, T. Dahl, M. L. Sherman, S. O’Day
Journal: Journal of Clinical Oncology (2005)

7561 Background: STA-4783 (S), a novel inducer of heat shock protein 70 (hsp70) is a bis-thiobenzoylhydrazide compound. S leads to upregulation of hsp70 in tumor cell lines. Xenograft modeling with solid tumor cell lines demonstrated dramatic antitumor activity in combination with paclitaxel (P). Mechanistic studies suggest that the P enhancement is immune-mediated, creating, in effect, a chemically-induced biochemotherapy. The combination of S and P has been studied in a Phase 1 trial with the drugs coadministered i.v. over 3 h every 3 weeks. Doses ranged from (S/P, mg/m2) 44/135 to 525/175. Based on dose-related HSP70 induction (evidence of biological activity) and demonstrated tolerability, we began a Phase 2 study of the combination in patients with metastatic melanoma. Methods: The study consists of an initial safety assessment of the weekly dose schedule for 3 weeks every 4 weeks at S 106 mg/m2 and P 80 mg/m2. S was then escalated to 213 mg/m2 in combination. The higher tolerated dose level was expanded to a total of 20 patients (Stage 1). The criterion for continuation to Stage 2 was >= 50% non-progression rate (NPR) at 2 months. Stage 2 is a randomized 2-arm study comparing the drug combination to P alone. A total of 78 patients are to be randomized 2:1 (combination:control). The primary endpoint is time to progression; secondary endpoints are response rate, survival, and quality of life. Pharmacodynamic parameters include pre- and post-dose measurements of NK cell activity in blood and, when possible, tumor biopsies. Results: A total of 7 patients were treated in the initial safety assessment, 3 at the lower dose level and 4 at the higher. In the absence of dose-limiting toxicities in either group, the higher dose level was chosen as the dose of interest and additional patients were enrolled to complete Stage 1. Adverse events seen were as expected for P chemotherapy administration. In preliminary evaluation of 20 patients, 11 were stable at 2 months, for 55% NPR. The randomized Stage 2 portion will proceed, pending confirmation of the stage 1 data. Conclusions: The addition of S to P was well-tolerated on the weekly schedule. Enrollment in the randomized portion will assess the activity of S + P vs. P alone. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Synta Synta Synta Synta
Meta-analysis of the randomized comparisons between low-molecular weight heparin (LMWH) with oral anticoagulants (OA) for the long-term treatment of symptomatic venous thromboembolism (VTE): no difference in cancer-related mortality
Authors: G. Ferretti, E. Bria, P. Carlini, A. Felici, D. Giannarelli, M. Ciccarese, F. L. Cecere, N. Salesi, B. Di Cocco, F. Cognetti
Journal: Journal of Clinical Oncology (2005)

8145 Background: Long-term low-molecular-weight heparin (LMWH) has the advantage that this regimen is administered once-daily and does not require any anticoagulant monitoring. By contrast, because of the marked intra- and inter-patient variability associated with warfarin sodium or acenocoumarol dosage, oral anticoagulant therapy (OA) requires frequent anticoagulant monitoring, typically using the INR (range INR 2–3) to optimize effectiveness and safety. In high risk patients, such as cancer patients, long-term LMWH therapy seems to be as effective as oral anticoagulant therapy, but safer. Furthermore, it has been suggested that LMWH therapy may prolong survival in patients with cancer. The objective of this review was to evaluate the effect of long-term treatment of VTE with LMWH compared with OA on VTE recurrence, bleeds, total and cancer mortality. Methods: Computerized searches of MedLine, ASCO and ASH meeting abstracts were performed. Relative risk (RR), 95% confidence interval (CI) and heterogeneity were derived. Results: Nine studies that fulfilled our predefined criteria were identified. When all studies were combined, a statistically significant reduction in the risk of VTE (2298 patients, RR 0.61, CI 0.45–0.82, p=0.001) and bleeding (2445 patients, RR 0.72, CI 0.54–0.95, p=0.02) in favor of LMWH treatment was registered. No difference in total mortality (2445 patients, RR 0.96, CI 0.82–1.13, p=0.64) or in cancer-related mortality (944 patients, RR 0.96, CI 0.80–1.15, p=0.67) was found between LMWH and the OA therapy. No significant heterogeneity was observed. Conclusions: Cancer mortality does not seem to be favorably influenced by the use of LMWH compared with OA. The results of this meta-analysis indicate that a 3–6 months course of LMWH is more effective (with regard to VTE) and safe (with regard to bleeding) than a corresponding period of OA treatment and should be considered as a valuable alternative option for patients in whom OA treatment appears contraindicated or problematic. No significant financial relationships to disclose.
Prognostic index for chronic and smoldering types adult T-cell leukemia/lymphoma.
Authors: Hiroo Katsuya, Mototsugu Shimokawa, Kenji Ishitsuka, Kazuhiro Kawai, Masahiro Amano, Atae Utsunomiya, Ryosuke Hino, Shuichi Hanada, Tatsuro Jo, Kunihiro Tsukasaki, Yukiyoshi Moriuchi, Eisaburo Sueoka, Shinichiro Yoshida, Hitoshi Suzushima, Masaharu Miyahara, Kiyoshi Yamashita, Tetsuya Eto, Takeharu Yamanaka, Junji Suzumiya, Kazuo Tamura
Journal: Journal of Clinical Oncology (2015)

8522 Background: Adult T-cell leukemia/lymphoma (ATL) has been divided into 4 clinical subtypes: acute, lymphoma, chronic and smoldering. The prognosis in patients with chronic and smoldering type ATL is better than the others, but they have not been treated uniformly because of diverse clinical courses even in the same clinical type. The aim of this study is to develop a novel prognostic index (PI) for chronic and smoldering type ATL. Methods: We conducted a nationwide retrospective survey of ATL patients in Japan newly diagnosed between 2000 and 2009. Among chronic and smoldering types, fully eligible 248 individuals were used for this analysis; this is a largest study in chronic and smoldering ATL. We randomly selected subjects equally into training and validation samples, and developed a PI. Results: In univariate analysis, gender, performance status, log10[soluble interleukin-2 receptor (sIL-2R)] as well as the number of neutrophil and lymphadenopathy showed P values less than .05 in the training sample. A multivariate analysis was performed in factors above, and log10(sIL-2R) was only identified as an independent prognostic factor in the training sample. Using a regression coefficient of this variable, a prognostic model was formulated to identify different levels of risk: Indolent ATL-PI (iATL-PI) = 1.51 x log10[sIL-2R(U/ml)]. The values calculated by iATL-PI were divided into 3 groups using a quartile point. In the validation sample, median survival times (MSTs) were 1.6, 5.5 years and not reached for patients at high, intermediate, and low risk, respectively (P< .0001). To make the scoring system simpler and clinically practicable, we then simplified the original iATL-PI according to trichotomizing sIL-2R at 1,000 and 6,000 U/mL using a quartile point. Patients of more than 6,000 of sIL-2R were categorized into high risk group, less than and equal to 1,000 into low risk group, and the others into intermediate risk group. MSTs were 1.6, 5.5 years and not reached at high, intermediate, and low risk, respectively (P< .0001). Conclusions: The iATL-PI makes it possible to discriminate patients with chronic and smoldering type ATL into three distinct risk groups, and it will be a novel promising tool for risk adopted therapeutic approach.