tbuckley/cabot-search huggingface dataset:
Efficacy of first-line bevacizumab (Bev) combined with weekly paclitaxel (wPac) for HER2-negative metastatic breast cancer (MBC): Results of a Japanese phase II study (n=120).
Authors: Y. Ito, K. Aogi, N. Masuda, S. Ohno, T. Oda, H. Iwata, M. Kashiwaba, Y. Fujiwara, S. Kamigaki, T. Ueno, S. Takashima
Journal: Journal of Clinical Oncology (2011)

1119 Background: Three phase III trials have shown significantly improved progression-free survival (PFS) and response rate (RR) when Bev is combined with first-line chemotherapy for MBC. We conducted a phase II study to evaluate the E2100 Bev–wPac regimen in Japanese MBC patients (pts). Methods: Pts aged ≥20 years with HER2-negative measurable MBC and no prior chemotherapy for MBC received Bev 10 mg/kg d1 and 15 with wPac 90 mg/m2 d1, 8, and 15, q4w. Co-primary endpoints were PFS and safety. Secondary endpoints included RR (RECIST v1) and overall survival (OS). We also analyzed efficacy in clinically important subgroups. Results: All 120 planned eligible pts (median age 55 years) were enrolled between Apr 2007 and Jul 2008. Median follow-up is 11.0 months (range 1.4–24.0). Median PFS by independent review committee is 12.9 months (95% CI 11.1–18.2). The table shows PFS and RR subgroup analyses. Median OS is 35.8 months (95% CI 26.4–not reached; 56% of pts still alive). The 1-year OS rate is 89% (95% CI 83–95). Median exposure to Bev and wPac is 10.6 months (range 0.3–24.7). 50 pts (42%) have been treated for ≥1 year. The main reason for discontinuation is progression (45%). First onset of most adverse events was during the first 6 months of therapy. Grade 3 hypertension has been reported in 17% (no grade 4); grade >2 proteinuria is absent; grade 3 and 4 bleeding have occurred in 2% and 1%, respectively. There have been no treatment-related deaths. Conclusions: Bev–wPac therapy showed high activity, similar to that in E2100, in this large single-arm Japanese study. Median PFS in important subgroups, including difficult-to-treat populations such as triple-negative MBC (median 9.6 months), supports findings from the E2100 trial. Subgroup RR, % Median PFS, months All (n=117)* 74 12.9 Age, years <65 (n=97) ≥65 (n=20) 73 75 14.5 9.4 Triple negative Yes (n=38) No (n=79) 68 76 9.6 14.8 No. of metastatic sites <3 (n=61) ≥3 (n=56) 72 75 14.5 12.8 Visceral metastases Yes (n=88) No (n=29) 77 62 12.8 14.5 Disease-free interval, months <24 (n=27) ≥24 (n=64) 56 81 9.3 15.2 Prior taxane therapy Yes (n=22) No (n=95) 68 75 11.1 15.2 * 3 pts without efficacy evaluation excluded.
Sequential dose-intensive paclitaxel plus ifosfamide and carboplatin plus etoposide with autologous stem cell transplantation for germ cell tumor (GCT) patients (pts)
Authors: G. V. Kondagunta, J. Bacik, D. F. Bajorin, L. Reich, J. Sheinfeld, M. Bains, G. J. Bosl, R. J. Motzer
Journal: Journal of Clinical Oncology (2005)

4503 Background: Pts with an incomplete response (IR) to initial conventional dose therapy or relapsing primary mediastinal GCT have <10% 3-year survival with conventional-dose salvage regimens.(Cancer 67:1305) This study reports the efficacy and toxicity of dose-dense therapy with paclitaxel (T) /ifosfamide (I) and carboplatin(C)/etoposide (E) with peripheral blood-derived stem cell support (PBSC) in poor prognosis GCT. An earlier study of TICE in 37 pts was reported (JCO 18, 1173); this trial differed in dosing of C by target AUC using the Jellife formula to estimate GFR. Methods: 47 pts for this phase I/II trial had progressive GCT following chemotherapy and unfavorable prognostic features defined as: 1) extragonadal primary site; 2) IR to first-line therapy; or 3) relapse/IR to ifosfamide/cisplatin conventional-dose salvage. Chemotherapy with 2 cycles of TI (T 200 mg/m2 plus I 6 gm/m2 at 14 day intervals followed by leukapheresis), then 3 cycles of CE at 21 day intervals with re-infusion of PBSC. E was 1200 mg/m2 and C was dosed by target AUC using Jeliffe formula for GFR. Target AUC ranged from 21- 28 (mg/ml)-min in this phase I/II trial, and 31 patients were treated at a target AUC of 24 (mg/ml)-min. Results: 47 pts were treated; 23 (49%) achieved a CR to chemotherapy alone and an additional 3 (6%) pts achieved a CR to chemotherapy plus surgical resection of viable GCT. Therefore, 26 (55%) achieved a favorable response. 6 relapsed; and 20 of 26 CR pts (77%) remain continuously disease-free at a median follow-up of 33 months. Continuously disease-free by primary site were 3/9 mediastinal GCT, 15/32 testis GCT, 2/6 other extragonadal GCT. Myelosuppression was the predominant toxicity; there were no treatment-related deaths. Conclusion: TICE chemotherapy achieved a high proportion of durable CR and was relatively well tolerated for a high dose program. Two sequential trials have demonstrated efficacy and safety of TICE; the combined data show a CR achieved in 47 of 84 (56%) patients with metastatic GCT and an unfavorable prognosis to standard conventional dose salvage chemotherapy. Support: Craig D. Tifford Foundation No significant financial relationships to disclose.
Quality of life in children with osteosarcoma after limb salvage operation
Authors: M. Aono, I. Kudawara, K. Ohzono, Y. Aoki, A. Matsumine, M. Ieguchi
Journal: Journal of Clinical Oncology (2006)

19501 Background: There are several options for the surgical management of osteosarcoma (OS) especially in the skeletally immature patients. We evaluate the clinical results and quality of life (QOL) of OS patients with limb salvage operations. Methods: From 1996 to 2005, ten children with newly diagnosed previously untreated nonmetastatic (stage IIB) OS of extremities were reviewed. There were 5 females and 5 males. The median age was 12 years (range, 8 to 14). Tumor locations: proximal humerus in 2, proximal femur in 1, distal femur in 2, proximal tibia in 3, distal tibia in 1, and tibial shaft in 1. Patients received neoadjuvant and adjuvant chemotherapy, and local wide resection of tumor. Limb salvage procedures: intraoperative extracorporeal autogenous irradiated bone graft (IORBG) in 4 and prosthetic replacement in 6. The functional results were measured for the patients accordance with the Musculoskeletal Tumor Society rating score. Results: With a median follow up of 4 years (range, 1 to 9), 7 were continuously disease free, 2 died of disease and in one there was no evidence of disease. No local recurrence was seen. Mean functional rating scores of patients with IORBG and prosthetic replacement were 82% (range 77 to 90) and 82% (range 57 to 93), respectively. Functional results were not different between these study groups and relatively good. There was one infection in patients with prosthetic replacement. There were subchondral collapse in 2 (50%), fracture in 1 (25%) and infection in 1 (25%) with IORBG. Conclusions: Limb salvage operation with neoadjuvant chemotherapy is the optimum treatment. However there remain several problems of function after limb salvage operations, with improvement of survival of pediatric osteosarcoma patient. We should select the most suitable surgical procedure to achieve the good function of limbs as well as local control. No significant financial relationships to disclose.
Phase I study of the novel proteasome inhibitor NPI-0052 in patients with lymphoma and solid tumors
Authors: C. A. Aghajanian, P. Hamlin, M. S. Gordon, D. S. Hong, A. Naing, A. Younes, A. Hannah, M. A. Palladino, M. A. Spear, R. Kurzrock
Journal: Journal of Clinical Oncology (2008)

3574 Background: NPI-0052 is a novel proteasome inhibitor that produces prolonged inhibition of all three catalytic activities of the 20S proteasome. Preclinical data suggest NPI-0052 may demonstrate an improved therapeutic ratio, with activity as a single agent or in combination in hematologic (myeloma, lymphoma, leukemia) and solid tumor models. Clinical trials are being conducted in patients with myeloma, lymphomas, leukemias and solid tumors. Methods: In this first-in-human study cohorts of 3 or more patients with solid tumor or lymphoma were treated with NPI-0052 administered weekly, for 3 weeks in 4-week cycles using a 3+3 design dose escalation. The dose of NPI-0052 was escalated in 50–100% increments dependent on observed adverse events (AE). In addition to regular safety monitoring, proteasome inhibition (PI) (baseline, D1–2, D8, D15–17, D22 and D29) and PK (D1 and D15) were assayed in blood. A Recommended Phase 2 Dose (RP2D) cohort of up to 20 patients will be enrolled at the RP2D. Results: 23 patients have been treated over a 20-fold dose range (0.0125 mg/m2 to 0.25 mg/m2) for up to 11 cycles without reaching an MTD. The AE profile has been unremarkable at the highest dose level assessed. Sixteen patients (73%) had no > Grade 1 drug-related AE. Preliminary PK data indicate an T1/2 of approximately 3–4 minutes, with clearance at 8–21 mL/min and Vz of 44–99L. PI has been assayed in blood, indicating a dose:response relationship with inhibition of up to 64% observed. No responses have been confirmed, however, 6 patients have had stable disease for at least 2 cycles, including one with melanoma (4 months), one with colorectal carcinoma (3 months), one with hepatocellular carcinoma (6 months), two with adenoid cystic carcinoma (4 months each), and one with cervical carcinoma (11 months). This patient (cervical carcinoma) underwent four intra-patient dose escalations, with increased PI observed at the higher dose assessed. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects at doses below the MTD. Combination studies are being initiated in solid tumor diagnoses with other cytotoxic / targeted agents. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Nereus Nereus Nereus
Effect of nilotinib on cell proliferation and migration of ovarian cancer cells alone and in combination with standard chemotherapy.
Authors: M. T. Weigel, K. Rath, C. Schem, M. Bauer, I. Alkatout, W. Jonat, C. Mundhenke
Journal: Journal of Clinical Oncology (2010)

e15526 Background: Nilotinib, a multi-target tyrosine kinase inhibitor (TKI), was tested for the treatment of human ovarian cancer (target-receptors: c-Kit, abl, PDGFR α/β). Ovarian epithelial adenocarcinoma cells express several membrane-bound tyrosine kinase receptors, among others elevated levels of PDGFR. Methods: The effect of nilotinib on ovarian cancer cell lines (OVCAR 3 and OVCAR 8) was studied alone and in combination with carboplatin. Cells were incubated with nilotinib (100 nM- 4 μM) for monodrug therapy and nilotinib (2 μM) was combined with increasing carboplatin concentrations to evaluate the combinatory effect. To determine nilotinib's apoptotic potential, TUNEL assays were performed after 24 and 48 hours of drug incubation. Furthermore, the effect of nilotinib on migration of ovarian cancer cells was detected using planar migration assays which were analyzed after 24, 48 and 72 hours. Results: Nilotinib alone and in combination with carboplatin inhibits cell proliferation of ovarian cancer cell lines (IC50 OVCAR3: 3μM, IC50 OVCAR8: 2.5μM). The combination of nilotinib with carboplatin shows a synergistic effect on cell growth inhibition. The migration assays display a clear influence of nilotinib on the migratory behavior of ovarian cancer cells. The velocity of migration is significantly reduced in nilotinib treated OVCAR3 cells after 24, 48 and 72 hours (p < 0.01 at all time points). Similar results can be observed for OVCAR8 cells, most distinctive after 72 hours (p < 0.01). TUNEL-assays reveal an increased rate of apoptotic cells among ovarian cancer cells incubated with nilotinib, which further increases by adding carboplatin. Conclusions: Nilotinib inhibits cell proliferation, cell migration and induces apoptosis in ovarian cancer cell lines in clinically relevant concentrations. The combination with carboplatin reveals a synergistic effect. These in vitro data suggest that especially the combination of carboplatin with nilotinib could be of clinical importance for the treatment of ovarian cancer patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Pfizer
Chemotherapy induces microssatelite instability (MIS) in plasma free DNA (pfDNA), peripheral blood mononuclear fraction (PBMNF) cells, and urine free DNA (ufDNA) of breast cancer (BC) patients as well as in normal PBMNF cells in vitro in the absence of amifostine (A)
Authors: A. Del Giglio, J. F. Pinto, F. A. Fonseca, S. R. Marsicano, P. O. Delgado, P. G. Coelho, A. L. Sant’Anna, P. Maeda
Journal: Journal of Clinical Oncology (2009)

e11505 Background: We have previously shown that alkylating agent based chemotherapy regimens (AQT) could induce MIS in the PBMNF of BC patients in parallel to a decrease in the expression of the protein hMSH2 in these cells (Fonseca et al., 2005, Breast Cancer Res, 7, R28–32). Since plasma DNA derives mainly from tumor cells, we wanted to know if chemotherapy would also produce MIS in tumor DNA and if this phenomenon could be reproduced in vitro. Methods: 33 previously untreated female BC patients with a mean age of 51 years received AQT(16 ACT;3FAC;2 TAC;1FEC;10AC). Samples from 3 additional patients who received Fulvestrant only as neoadjuvant therapy were also included. Blood (pfDNA and PBMNNF) and urine (ufDNA) were evaluated at time 0,3 and 6 months with 6 MIS markers (BAT40,BAT26, MR2,TP53 PCR15.1, APC and ALU). Levels of fpDNA and fuDNA were measured by spectrophotometry. We incubated in vitro cultures of MCF- 7 cells and PBMNF cells with M at a dose of 0.7μg/ml for 30 minutes with and without A at 20% of the M dose and evaluated serially for 48 hours for MIS and hMH2 expression by immunohistochemistry. Results: We observed at least one MIS event in the PBMNF, fpDNA or fuDNA in 87%, 80% and 80% of the patients, respectively, mainly in BAT40 and BAT 26 markers. There was only 14.74% of concordance of MIS alterations between PBMNF and fpDNA and 8. 42% between fpDNA and fuDNA. Patients receiving Hormones also exhibited MIS. Interestingly, fpDNA levels increased significantly in patients with measurable disease who responded to therapy (47.4 ± 13.34 vs 14.37± 5.32; p = 0.021). In vitro, incubating MCF-7 cells and normal PBMNF cells with M ±A, we observed that we could induce MIS in both MCF-7 cells and normal PBMNF cells but A prevented MIS only in normal PBMNF cells. In normal PBMNF cells without A that sustained MIS there was a significantly decreased percentage of cells expressing hMSH2 ( 96% vs 57% p &lt; 0.001). Conclusions: We conclude that Chemotherapy as well as Fulvestran can induce MIS in normal and malignant cells and that in vitro these effects could be reproduced by treatment with M and prevented in normal cells by A. No significant financial relationships to disclose.
Radiological tissue changes and pathological response in localized high-grade soft tissue sarcomas (STS) as predictors of outcome after neoadjuvant treatment with chemoradiotherapy (CRT).
Authors: A. Lopez-Pousa, S. Bague, J. Llauger, J. Majo, J. Isern, M. Quintana, M. Fernandez, L. Robert, N. Sala, I. Sullivan
Journal: Journal of Clinical Oncology (2010)

10095 Background: Neoadjuvant CRT has demonstrated efficacy in the treatment of locally advanced STS. We analyzed the relation between radiological and pathological changes in the response and outcome after concurrent preoperative chemotherapy and radiation therapy (RT) in localized high-grade STS. Methods: Between 2001 and 2006, 22 patients with localized high-risk STS of extremities or superficial trunk received 3 cycles of neoadjuvant epirubicin + ifosfamide and concomitant RT, followed by surgery, within a prospective phase III trial. MRI were performed before and after the neoadjuvant treatment. Changes in tumor size, tissue characteristics (T1/T2), and contrast enhancement variations were recorded. Pathological changes were analyzed in the surgical specimen and correlated with radiological response patterns, and post-treatment changes (necrosis, hemorrhage, tumor viability, tumor cell distribution). Results: According to RECIST, 6 patients (27%) had a PR, 14 patients (63%) SD and 2 patients had a PD confirmed histologically, in terms of more than 50% of residual vial tumor cells. 3 patients had a RECIST SD, and pathologically, there was more than 50% of residual tumour in all surgical specimens. Other 5 (23%) patients had a RECIST SD with radiographic signs of tissue changes (T1 hiperintensity): pathologically, the residual tumour was less than 50% in all. Another 10 patients with PR/SD showed radiological changes (size and T1) and pathological response > 50%; 1 patient with a RECIST SD had radiological signs of tissue progression confirmed histologically with the presence of the 95% of vial tumor cells in the surgical specimen. Tumor size reduction has prognostic significance (p 0.04); Tumor necrosis and positive margins didn't have prognostic value. Radiological change to hiperintensity in T1 was the only statistically significant change for overall survival (p 0.002). Conclusions: Tumor size and some tissue response criteria on MRI may predict pathological tissue responses, helping RECIST criteria, in order to establish prognosis in high-grade STS treated with preoperative chemoradiotherapy. No significant financial relationships to disclose.
Palliative care resource (PCR) utilization associated with cancer pain management background
Authors: R. A. Madan, S. S. Hwang, V. T. Chang, Y. Alejandro, P. Osenenko, C. Zhao, S. Srinivas, K. Toomey, B. Kasimis
Journal: Journal of Clinical Oncology (2004)

8077 Background: Resources required for cancer pain management are not well documented. We monitored the use of PCR, including medications, consultations, imaging needs and hospitalizations in patients (pts) undergoing management of cancer pain by Hematology/Oncology palliative care program at a VA Medical Center. Methods: 99 inpts and 96 outpts with worst pain \(\underline{\mathrm{{>}}}\) 4/10 completed the Brief Pain Inventory at baseline and 1 week (wk). Pain management followed the Agency Health Care Policy Research Cancer Pain Management Guidelines. PCR were obtained prospectively. Results: The median (M) age was 69.2 yrs (range 44.3–87.6). Pts had metastatic cancer of the prostate (29.2%), lung (26.7%), head and neck (9.2%), colorectal (7.7%), pancreas (5.1%), and advanced lymphoma (5.1%) and multiple myeloma (4.6%). Pain pathophysiology included somatic (56.9%), neuropathic (32.8%) and visceral pain (10.3%) By wk 1, worst pain severity (mean 8.4 vs 6.1,p<0.0001), pain relief (40.8% vs 70.9%,p<0.0001) and pain interference scores (38.1 vs 19.9,p<0.0001) improved significantly. PCR by category included: (A) Medications: 71% of pts changed opioids. The M morphine equivalent daily dose (MEDD) was 20 mg orally (0–3,120mg) on day 1 and 90mg (0–3,200mg) at wk 1 (p<0.0001). Adjuvant analgesics included steroids (27%), anticonvulsants (16%) and NSAIDs (8%). Opioid-related side effect treatments included laxatives (72%), antiemetics (19%), anxiolytics (8%), psychostimulants (7%) and neuroleptics (3%). (B) Consultation referrals included radiation (26%), neurology (14%), psychiatry (9%), surgery (14%) and physical therapy (13%); 30 pts (15%) were started on radiation therapy. (C) Imaging studies included 234 plain films, 135 CT scans, 86 MRIs, 54 bone scans, 27 ultrasounds; pain specific imaging needs were identified. (D) Hospitalization: 58 pts (29.7%) were admitted for pain management and the M length of stay was 7 days (1–21). Conclusions: These identifiable costs for effective cancer pain management in a VA population provide a basis for cost effectiveness evaluation and comparison to the private sector (VAHSR&D PCC 98–068). No significant financial relationships to disclose.
Improved anti-tumor immunity and efficacy upon combination of the IDO1 inhibitor GDC-0919 with anti-PD-l1 blockade versus anti-PD-l1 alone in preclinical tumor models
Authors: Jessica Spahn, Jing Peng, Edward Lorenzana, David Kan, Thomas Hunsaker, Ehud Segal, Mario Mautino, Erik Brincks, Andrea Pirzkall, Sean Kelley, Sami Mahrus, Liling Liu, Stephanie Dale, Cristine Quiason, Elizabeth Jones, Yichin Liu, Sheerin Latham, Laurent Salphati, Kevin DeMent, Mark Merchant, Georgia Hatzivassiliou
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Indoleamine 2, 3-dioxygenase (IDO1) is a cytosolic enzyme catalyzing the oxidation of tryptophan to kynurenine. IDO1 plays an important role in modulating immune responses in cancer, where increasing evidence suggests that IDO1 expression by dendritic cells (DCs) and other antigen
Prognostic value of health-related quality of life on survival in patients diagnosed with hepatocarcinoma carcinoma
Authors: J. L. Steel, B. I. Carr, J. Goodman, M. A. Dew, D. A. Geller, T. C. Gamblin
Journal: Journal of Clinical Oncology (2008)

4643 Background: Accumulating evidence suggests that health related quality of life (HRQL) is prognostic of survival across several disease types, including cancer. The aims of the present study were to (1) assess the prognostic value of HRQL with a disease-specific instrument, and (2) explore linear and non-linear associations between HRQL and survival in patients diagnosed with unresectable hepatocellular carcinoma. Methods: A prospective study study of 166 patients diagnosed with hepatobiliary carcinoma and referred for treatment were administered the Functional Assessment of Cancer Therapy-Hepatobiliary (FACT-Hep) to assess HRQL. Survival was measured from diagnosis to death. Results: Using Cox regression and Kaplan Meier survival analyses, baseline overall HRQL (p=0.05) and the physical well-being scale (p=0.04) was found to significantly predict survival while controlling for sociodemographic (i.e., age) and disease- specific variables (i.e., etiology, tumor size, number of lesions, vascular invasion, alpha-fetoprotein, bilirubin, prothrombin time). A linear association between overall HRQL and survival was observed with patients reporting overall HRQL scores in the highest tertile having a mean survival of 19.4 months, the middle tertile with a mean survival of 17.6 months, and the lowest tertile having a mean survival of 17.2 months. A similar trend in mean survival was found for patients who reported physical well being in the highest tertile (15 months), middle tertile (11 months), and lowest tertile (5 months) of this subscale. The disease-specific module of the FACT-Hep was not found to significantly predict survival, however a robust trend was revealed (p=0.06). Conclusion: Overall HQRL and the physical well-being scale were found to be prognostic for patients with HCC. A linear relationship was found between HRQL and survival and a robust trend was found in regard to the association between the disease-specific module of the FACT-Hep and survival. With accumulating evidence regarding the prognostic value of HRQL, stratification of patients in clinical trials based on baseline HRQL may be recommended. HRQL may represent an important element in new prognostic systems for HCC. No significant financial relationships to disclose.