tbuckley/cabot-search huggingface dataset:
A phase II trial of combination chemotherapy with irinotecan and amrubicin in pretreated patients with non-small cell lung cancer (NSCLC): Results of Okayama Lung Cancer Study Group Trial 0402
Authors: S. Kuyama, Y. Segawa, N. Nogami, K. Kiura, N. Takigawa, T. Shibayama, S. Hosokawa, K. Aoe, M. Tabata, M. Tanimoto
Journal: Journal of Clinical Oncology (2009)

e19029 Background: We previously conducted a phase I trial of combination chemotherapy with irinotecan and amrubicin for NSCLC and found acceptable toxicity profiles with a favorable efficacy in patients with pretreated NSCLC. The aim of this phase II trial was to further evaluate its efficacy and toxicity in this population with a long-term follow-up. Methods: Primary endpoint was objective response. Patients with NSCLC previously treated with one or two chemotherapy regimens were enrolled in this trial. Irinotecan and amrubicin were both administered on days 1 and 8, every 3 weeks at doses of 100 and 40 mg/m2, respectively. Response and toxicity were assessed according to the RECIST guideline and NCI-CTC for AE v3.0. Results: Thirty-one pretreated NSCLC patients were enrolled between 2004 and 2006. A median number of courses administered was 3 (range: 1 to 6). All patients and courses were assessable for efficacy and safety. Demographics of the patients were as follows: M/F:21/10, Ad/others:21/10, ECOG-PS 0/1:12/19, and smoker/non-smoker:21/10. Platinum-based regimens were commonly used as the prior chemotherapy. Objective response was obtained in 9 of the 31 patients with a response rate of 29.0% (95%CI: 12.1–46.0%). Grade 4 leukopenia and neutropenia were observed in 6 (19%) and 14 (45%) patients, respectively, whereas thrombocytopenia were generally mild. Grade 3 febrile neutropenia was observed in 7 patients (23%), of whom two patients further developed Grade 4 and 5 septic shock each. Other grade 3 or greater non-hematological toxicities included diarrhea, vomiting, pneumonitis, liver dysfunction in 4, 1, 1 and 2 patients, respectively. With a median follow-up time of 24.2 months, median survival time and median progression-free survival time were 14.2 and 4.0 months, respectively. Conclusions: This combination seemed highly effective for pretreated NSCLC with an acceptable toxicity. No significant financial relationships to disclose.
Phase II trial of erlotinib with temozolomide and concurrent radiation therapy in patients with newly-diagnosed glioblastoma multiforme
Authors: C. J. Brewer, J. H. Suh, G. H. J. Stevens, G. H. Barnett, S. Toms, M. A. Vogelbaum, R. Weil, D. M. Peereboom
Journal: Journal of Clinical Oncology (2005)

1567 Background: Approximately 40 - 50% of GBM tumors overexpress EGFR, which activates tyrosine kinase to promote GBM cell infiltration in vitro. Radioresistance of some GBMs has been correlated with EGFR overexpression. Erlotinib is a specific and potent EGFR tyrosine kinase inhibitor (TKI) with activity against refractory GBM. Furthermore, the occurrence of erlotinib-induced rash of ≥ grade 2 has been correlated with improved survival in non-small cell lung cancer. A phase 2 trial of erlotinib with concurrent RT-temozolomide (RT-tmz) was therefore initiated with pharmacodynamic dosing of erlotinib. Methods: Eligible patients (pts) have newly diagnosed GBM; age ≥ 18; KPS ≥ 60; no cytochrome P-450 enzyme-inducing anticonvulsants; no prior temozolomide (tmz), TKI or cranial RT. Pts receive RT 60 Gy in 30 fractions with concurrent tmz (75 mg/m2/day × 7 days/week). Four weeks after RT-tmz pts receive tmz 150 mg/m2/day × 5 days, every 28 days for 12 cycles. Pts receive erlotinib daily from day 1 of RT until disease progression. Erlotinib dosing starts at 50mg/day with escalation every 2 weeks by 50mg/day until the occurrence of grade 2 rash or 150 mg/day. All tumors have FISH assay for EGFR amplification. Results: To date 11 patients have enrolled with a median follow up of 11 weeks (range 9–22); 2 did not start therapy and 4 remain on study. The median age is 47 (18–65); KPS 90 (70–100). Two pts had gross total resection. Seven pts are EGFR negative. Maximum dose of erlotinib reached before grade (G) 2 rash: 50 mg/d (1 pt), 100 mg/d (1 pt), and 150 mg/day (2pts). Three pts reached 150 with G0 or 1 rash and 2 pts are still on escalating doses of erlotinib. Of 9 pts evaluable for response, best response has been stable disease (3 pts) of 10.5, 7 and 3.5+ months duration; progression (3), and too early (3). No pt has had G4 toxicity. G3 toxicity has included neutropenia (1 pt) and lymphopenia (2). Additional events unrelated to therapy have included wound infection, spontaneous pneumothorax, and rectus sheath hematoma. Conclusions: The combination of erlotinib with RT-tmz is feasible and overall has been well tolerated. Dose escalation to a pharmacodynamic endpoint is feasible in GBM. Accrual continues. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech Genentech
Growth suppression of human pancreatic cells by a novel PKCβ inhibitor, enzastaurin
Authors: H. Cheng, J. G. Yan, Y. Jiang
Journal: Journal of Clinical Oncology (2007)

14141 Background: Human pancreatic cancer is a devastating disease. Standard therapy, gemcitabine, is not able to alter the natural history of the disease. Targeting intracellular signaling molecules has proven to be a powerful approach in cancer therapy. Protein kinase C (PKC) family has been implicated in many human cancers including pancreatic cancer. Methods: In this pre-clinical study, we evaluated the effect of a novel small molecule inhibitor, enzastaurin, for PKCβ on human pancreatic cancer cells. We utilized MTT assay to assess cell proliferation and viability. To evaluate cell transforming activity, soft agar colony forming assay was used. Results: We showed that with addition of 20μM enzastaurin into the culture, the proliferative growth of two pancreatic cancer cell lines, Panc1 and L3.6p1, was significantly attenuated, as measured by the MTT assay. In addition, the combination of enzastaurin and a low dose of gemcitabine (25 nM) resulted in a synergistic cytotoxic effect in L3.6p1 cells. Further, the in vitro tumorogenicity assay demonstrated that the L3.6p1 cells treated with enzastaurin (20μM) formed much smaller colonies than the control parental cells in 0.4% soft-agar. Consistent with the in vitro cell proliferation results, the combination of enzastaurin and the low concentration of gemcitabine (25nM) further reduced the numbers and sizes of colonies in the soft-agar. Conclusions: Collectively, our data indicate that enzastaurin can effectively suppress the proliferation and in vitro transforming activity of the pancreatic cells, and more effectively when applied in combination with the low dose of gemcitabine. No significant financial relationships to disclose.
“focus on…” session: T-cell
Authors: J Jørgensen, F Sørensen, K Bendix, J Nielsen, A Funder, M Karkkainen, T Tainola, F Pedersen, A Sørensen, A Ku ¨hle, F D'amore, T Watanabe, T Kinoshita, K Itoh, K Yoshimura, H Kaba, M Ogura, Y Kagami, M Yamaguchi, M Kurosawa, K Tsukasaki, M Kasai, K Tobinai, K Mukai, S Nakamura, K Ohshima, T Hotta, M Shimoyama
Journal: Annals of Oncology (2008)
Role of FOXC1 in regulation of basal-like/triple-negative breast cancer
Authors: P. S. Ray, J. Wang, Y. Qu, M. Shin-Sim, J. Shamonki, B. Liu, D. S. Hoon, A. E. Giuliano, X. Cui
Journal: Journal of Clinical Oncology (2009)

11016 Background: Class identification studies have proposed 3 prognostically relevant molecular subtypes of breast cancer: luminal, HER2 and basal-like. The latter is associated with poor prognosis but its molecular basis is not clear. We hypothesized a direct correlation between FOXC1 expression and basal-like breast cancer. Methods: Expression of FOXC1, CK5, CK14, EGFR, c-Kit, αB-crystallin, ITGB4 and FOXC2 in basal-like breast cancer was examined using publicly available microarray datasets. A molecular signature of 40 genes sharing co-ordinate up or down regulation with FOXC1 was identified on one microarray (49 patients) and validated on 5 other microarrays (1,232 patients). The clinical significance of FOXC1 gene expression and the FOXC1 gene signature was evaluated using censored survival data. FOXC1 protein expression was assessed by immunohistochemistry (IHC) of a 96-sample breast cancer tissue microarray. Normal breast epithelial, luminal and basal breast cancer cells transfected with FOXC1 vectors were evaluated for cell proliferation, migration and invasion. Results: FOXC1 was found to be consistently and exclusively upregulated in basal-like triple negative breast cancer and was associated with poor overall survival (p&lt;0.0001). The FOXC1 gene signature accurately predicted the basal-like phenotype. IHC analysis of FOXC1 protein expression in human breast cancers confirmed its potential to be used as a clinical biomarker of basal-like breast cancer. Normal breast epithelial cells and luminal breast cancer cells with low or no FOXC1 expression underwent epithelial-to-mesenchymal transition and displayed increased cellular proliferation, migration, invasion, and expression of basal cell markers when FOXC1 was overexpressed. In contrast, knockdown of FOXC1 by shRNA in basal-like breast cancer cells conferred luminal phenotype. Breast cancer progression-linked signaling pathways like NF-κB and p38MAPK were significantly stimulated in basal-like breast cancer as well as by in vitro FOXC1 overexpression. Conclusions: FOXC1 is a dominant determinant of the basal-like phenotype of breast cancer. We propose FOXC1 to be the single best molecular marker of and a potential therapeutic target for basal-like / triple negative breast cancer. No significant financial relationships to disclose.
Metastatic colorectal cancer (mCRC) patterns of care: Implications for clinical trial design
Authors: C. S. Denlinger, M. A. Collins, Y. Wong, S. Litwin, N. J. Meropol
Journal: Journal of Clinical Oncology (2007)

4079 Background: New approaches have expanded options for patients (pts) with mCRC. To characterize current practice paradigms that might bear on clinical trial design, we analyzed decision-making and treatment patterns in pts treated at a Comprehensive Cancer Center since the introduction of cetuximab (CET), and bevacizumab (BV). Methods: A retrospective review of all pts diagnosed with mCRC between 3/1/04 and 8/28/06 treated at Fox Chase Cancer Center. Results: 160 pts were treated, with 157 pts receiving at least one therapy regimen by 10 attending oncologists. There were 350 changes in therapy with 246 (70%) including continuation of at least one prior drug (92 BV, 111 fluoropyrimidines, 43 other). The most common reasons for treatment change were toxicity (33%), progressive disease (PD) (29%), treatment breaks (15%), and metastasectomy (11%) ( Table ). PD was a more common cause for treatment discontinuation in later phases of treatment (18% initial regimen vs. 36% subsequent regimens, p=0.0002). 24% of pts treated with oxaliplatin (OX) discontinued due to neuropathy. Hypersensitivity caused discontinuation in 5% of pts with OX and 7% of pts with CET. Resection of metastases was undertaken in 38% of pts. 43% of these pts received neoadjuvant therapy, and 56% received adjuvant therapy. 30% of pts have died, 29% remain on active treatment, 28% are on a treatment break, 3% are on hospice, and 11% are lost to follow-up. Conclusions: PD is no longer the primary reason for change of therapy in pts with mCRC. Metastasectomy is common and OX neuropathy is often treatment-limiting. These findings have important implications for endpoint selection and design of clinical trials in mCRC. Future clinical trials in mCRC must recognize treatment complexities and capture key components of decision-making that may result in prolonged survival. Furthermore, treatment breaks represent a potential window for the evaluation of new drugs. [Table: see text] No significant financial relationships to disclose.
Final report: Combination of MPC-6827 with temozolomide for the treatment of patients with metastatic melanoma.
Authors: W. Hwu, W. L. Akerley, J. Stephenson, M. K. Yu, B. A. Evans, G. Mather, E. A. Swabb, O. Hamid
Journal: Journal of Clinical Oncology (2010)

8531 Background: MPC-6827 (Azixa) is a microtubule destabilizing agent. This study was designed to establish the safety and tolerability of MPC-6827 when combined with temozolomide. Methods: Patients were treated weekly with a 2-hour intravenous infusion of MPC-6827 for either 6 of 8 or 3 of 4 consecutive weeks per cycle. Temozolomide was administered orally either at 75 mg/m2 daily during the first 6 weeks of an 8-week cycle or at 85 mg/m2 daily during the first 3 weeks of a 4-week cycle. Three pre-selected doses of MPC-6827 were tested: 2.1, 2.7, and 3.3 mg/m2in a standard “3 + 3” design. Patients enrolled in the 2.7 and 3.3 mg/m2 dose levels were studied at 4-week cycles. Acute dose-limiting toxicities (DLTs) were assessed during the first cycle. Pharmacokinetic evaluations were performed. Results: All patients have completed study. As of January 7, 2010,22 patients (age range, 35-81; 17 male) with stage IV (3 M1b, 19 M1c) melanoma were enrolled. Twenty-one patients (95 %) had an ECOG score 0-1. Ten (45%) patients had brain metastases. Twenty patients received prior systemic therapy (median 2, range 1-5); 8 patients (36%) received prior temozolomide or dacarbazine. Two patients (9%) experienced a ≥ grade 3 MPC-6827-related SAE, one asymptomatic elevation in Troponin I level and one cerebral hemorrhage (a DLT). The MPC-6827 half-life (t½) ranged from 2.9-10.6 hours. Two patients achieved a confirmed partial response (durations of 8 and 4 months) by modified RECIST. Another 10 patients achieved stable disease (duration range: 1.5-7 months). The median PFS was 2.8 months (95% CI: [1.7, 5.5 months]). Conclusions: The combination ofMPC-6827 and temozolomide in patients with metastatic melanoma is safe and well tolerated. Durable disease controls are observed in patients with refractory metastases. The median PFS compares favorably to studies using temozolomide as first-line treatment in chemotherapy-naïve melanoma patients with or without brain metastasis. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Myriad Pharmaceuticals, Inc. Myriad Pharmaceuticals, Inc. Myriad Pharmaceuticals, Inc.
Actionable locoregional failures (LRFs) after therapy of localized esophageal carcinoma (LEC): Surveillance strategies and their benefits.
Authors: Elena Elimova, Xuemei Wang, Wei Qiao, Kazuki Sudo, Roopma Wadhwa, Hironori Shiozaki, Venkatram Planjery, Nikolaos Charalampakis, Heath Devin Skinner, Jeffrey H. Lee, Brian Weston, Manoop S. Bhutani, Ritsuko Komaki, David C. Rice, Stephen Swisher, Mariela A. Blum, Dipen M. Maru, Wayne Lewis Hofstetter, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2015)

21 Background: The goal of surveillance after local therapy (trimodality or bimodality) is to salvage patients with actionable LRF, however, the benefits of current surveillance strategies are not well documented. We report on a large cohort of LEC patients with actionable LRF. Methods: Between 2000 and 2013, 127 patients with actionable LRF were assessed. Histologic/cytologic confirmation of LRF was the gold standard. All surveillance tools (imaging and endoscopy) were assessed. Results: The majority of the patients were men (89%), had adenocarcinoma (79%), had their LRF identified through surveillance (85%) and most had no new symptoms (72%). For the 41 LRFs after trimodality, the sensitivity of PET/CT alone was 93% but the specificity was 67%. In trimodality patients with a positive PET/CT for LRF, only 44% had LRF confirmed by endoscopy and 56% LRFs confirm by additional testing (e.g., FNA, etc). Alternatively, in bimodality patients, endoscopy confirmed LRF in 81% (n=85; 1 patient not evaluable). Trimodality patients were at higher risk of subsequent (e.g., distant) relapse after LRF was documented than were bimodality patients (p=0.03); 78% of the relapses were distant. In bimodality patients, 99% of relapses (LRF and/or distant) occurred within 36 months of therapy while in trimodality patients, 90% of relapses occurred within 36 months of surgery. Conclusions: Our data suggest that PET/CT is more likely to detect LRFs than endoscopy in trimodality patients. However, in bimodality patients, endoscopy is more valuable than PET/CT for documenting LRFs. At least 3 years of surveillance are needed for all LEC patients. However, even after the salvage, distant relapses are common. From U. T. M. D. Anderson Cancer Center (UTMDACC), Houston, Texas, USA. (Supported in part by UTMDACC, and CA 138671 and CA172741 from the NCI).
A population-based validation of the AJCC melanoma staging system
Authors: D. Guerry, J. D. Botbyl, P. A. Gimotty
Journal: Journal of Clinical Oncology (2004)

7500 Background: A major revision of the AJCC stages for melanoma was implemented in 2002 after validation in populations from cancer centers and cooperative groups. Methods: In this study, the National Cancer Institute's Surveillance, Epidemiology and End Results (SEER) cancer registry was used to validate the new AJCC staging system. 36,190 patients with primary invasive cutaneous melanoma diagnosed between 1988 and 2000 were identified. Survival rates computed from stage-specific Kaplan Meier curves (time to melanoma-specific death) were compared to the rates from 14,670 patients in the original validation study (Balch, et. al. JCO 19:3635–48, 2001). Cox proportional hazard models were used to identify significant prognostic factors. Results: 68% of SEER melanomas were ≤ 1.00 mm and 5% were > 4.00 mm compared respectively to 39% and 10% in the original study (p<0.001). As in the original study, Stage I, II and III melanomas with ulceration had lower survival rates, equivalent to the next higher stage. The 10-year survival rates and standard errors (SE) are presented below for stages with ≥ 900 SEER patients and from the original study. SEER rates were significantly higher than those in the original study in 15 of the 16-stage categories and notably so in T1a patients. For lesions ≤1.00, 1.01–2.00 and 2.01–4.00 mm, level, ulceration, age, sex, and site were statistically significant prognostic factors. SEER associations between survival and the prognostic factors were stronger than those in the original study, except for ulceration in lesions 2.01–4.00 mm. Conclusions: While this population-based study validates the new AJCC stages, it emphasizes that risk estimates are population specific. No significant financial relationships to disclose.
Analyses of circulating tumor cell (CTC) dynamics and treatment response in prostate cancer using the CTC-chip microfluidic device
Authors: R. J. Lee, S. L. Stott, S. Nagrath, L. E. Ulkus, D. M. Dahl, M. R. Smith, M. Toner, S. Maheswaran, D. A. Haber
Journal: Journal of Clinical Oncology (2009)

5149 Background: The CTC-Chip reliably detects CTCs in patients with localized and metastatic prostate cancer. In localized disease, CTCs may be indicative of tumor invasiveness. In the metastatic setting, CTCs may be useful in monitoring response to therapy. Molecular analyses of CTCs through this minimally invasive technique may provide insights into disease behavior, whereas sampling of metastatic deposits in bone (the predominant site of prostate metastasis) is not feasible. Methods: Peripheral blood was collected from patients undergoing treatment. CTCs were captured on the CTC-Chip. Quantities were determined using cytokeratin- and PSA-based staining and enumeration. In some cases, molecular analyses for the TMPRSS2:ERG chromosomal translocation were performed using FISH in intact cells or nuclei, or RT-PCR in extracted RNA. Subgroups of patients (n) included: localized disease undergoing prostatectomy (25), and metastatic disease undergoing either androgen deprivation therapy (ADT) (12) or docetaxel chemotherapy (5). Results: PSA-stained CTCs were captured in all patients. In localized disease, CTC quantities fell to undetectable levels 7–14 days after surgery; some patients exhibited an immediate decline while others had a delayed decline (&gt;24 hours). In patients with metastatic disease undergoing either ADT or chemotherapy, CTC quantities generally corresponded with changes in serum PSA and radiographic assessments. Approximately 50% of patients exhibited the TMPRSS2:ERG translocation. Conclusions: These studies are the first to use the highly sensitive CTC-Chip technology to assess dynamic changes in CTCs in patients undergoing prostatectomy, ADT, or chemotherapy. Ongoing larger studies will assess whether patterns of CTC changes predict recurrence or treatment response. Molecular characterization of CTCs may provide new insights into prostate cancer biology, clinical behavior, and therapeutic targets. [Table: see text]
Thromboembolism and outcomes in patients with gynecologic malignancies
Authors: R. Gogoi, A. Brusati, M. Liu, J. P. Curtin, S. V. Blank, B. Pothuri
Journal: Journal of Clinical Oncology (2008)

20548 Background: To evaluate survival in gynecologic oncology patients (pts) with thromboembolism (TE) and to evaluate whether method of TE treatment, warfarin or low-molecular weight heparin (LMWH), affected outcome. Methods: A chart review was performed identifying all pts with gynecologic malignancies and TE (deep venous thrombosis and/or pulmonary embolism) between 2002 and 2006 at our institution. Controls were all pts over this time period with gynecologic malignancies and complete data available. Pts were excluded if they had a TE diagnosis more than one year prior to their cancer diagnosis, had thrombophilia or were on anticoagulation for other indications. Unpaired t- test, Chi square and log rank tests were used in the statistical analysis. Results: Our subjects included 102 cases (of 105 identified) and 222 controls (of 588 identified) who met inclusion criteria. Among the 102 pts with TE, the site of disease was as follows: ovary, 52 (54%); uterus, 33 (32%); cervix, 11 (11%), vulva/ vagina, 4 (4%); and dual primary, 2 (2 %). There were no significant differences in histological subtypes, percentage of smokers, mean age or body mass index between the cases and controls. Pts with TE presented at a later stage of disease than controls (p<0.01). Among cases, there was a median survival of 18 months from the TE diagnosis. Survival analysis showed an overall worse survival from time of cancer diagnosis in pts with TE compared to controls (median 42 vs. 100 months; p<0.0001). There was no significant difference in survival among pts with TE based on disease site (p=0.5). A significant difference in survival from time of TE diagnosis was noted favoring warfarin treatment (n=59) compared to LMWH (n=28) (median 24 vs. 8 months; p<0.0001). Conclusions: TE diagnosis in pts with gynecologic malignancies constitutes a poor prognostic indicator. Pts with TE present at a later stage and have a worse overall survival relative to controls. In our pts, treatment of TE with LMWH was not associated with improved outcome relative to TE treatment with warfarin. No significant financial relationships to disclose.