tbuckley/cabot-search huggingface dataset:
NT-3/TRK-C regulated proteins in the biology of medulloblastoma
Authors: M. Gruber-Olipitz, T. Strobel, F. Quehenberger, M. A. Grotzer, G. Lubec, I. Slavc
Journal: Journal of Clinical Oncology (2007)

12519 Background: Medulloblastoma (MB) is the most common malignant childhood brain tumor. Because of its high risk of leptomeningeal dissemination, standard postoperative treatment includes craniospinal irradiation and chemotherapy. Such treatment produces significant sequelae including neurocognitive dysfunction, endocrine and growth disturbances. These therapy-induced morbidities warrant a novel less toxic approach possibly targeting key molecules within specific pathways of medulloblastoma biology. Recent reports identified high neurotrophin receptor TrkC mRNA expression as a powerful independent predictor of a favorable survival outcome in MB patients. However, the role of activated TrkC receptors in the development and biology of MB remains unclear. Methods: To determine downstream effector proteins of TrkC signaling, the medulloblastoma cell line DAOY was stably transfected with a vector containing the full-length TrkC cDNA sequence or an empty vector control. Accounting for the complexity of ligand-induced changes in cellular pathways and effector proteins, we investigated proteomic changes at multiple time points for up to 48 hrs following neurotrophin-3 induced TrkC receptor activation. Results: We identified 18 proteins differentially expressed: Caldesmon; Cathepsin D; Metastasis inhibition factor nm23; Multidrug resistance-associated protein Mgr1-Ag; Vimentin; Vinculin; Superoxide dismutase (Mn); Glutathione S-transferase P; Stathmin, Lamin A/C, Valosin-containing protein, Annexin A1; ULIP protein; DJ-1 protein; Fascin; Mitofilin; Heterogeneous nuclear ribonucleoprotein H and K. Conclusion: The proteins affected play substantial roles in differentiation, migration, invasion, proliferation, apoptosis and drug resistance. Almost all of the proteins have been described as being essential in the pathogenesis of different solid tumors, but have not been related to MB pathogenesis so far. No significant financial relationships to disclose.
Rituximab Plus Lenalidomide Improves the Complete Remission Rate in Comparison with Rituximab Monotherapy in Untreated Follicular Lymphoma Patients in Need of Therapy. Primary Endpoint Analysis of the Randomized Phase-2 Trial SAKK 35/10
Authors: Eva Kimby, Giovanni Martinelli, Bjorn Ostenstad, Ulrich JM Mey, Daniel Rauch, Björn E Wahlin, Felicitas Hitz, Micaela Hernberg, Ann-Sofie Johansson, Peter de Nully Brown, Hans Hagberg, Andrés J.M. Ferreri, Andreas Lohri, Urban Novak, Thilo Zander, Hanne Bersvendsen, Mario Bargetzi, Walter Mingrone, Fatime Krasniqi, Stephan Dirnhofer, Hanne Hawle, Simona Berardi, Steffi Demmel, Stephanie Rondeau, Emanuele Zucca
Journal: Blood (2014)
A phase II neoadjuvant study of cisplatin/paclitaxel with or without RAD001 in patients with triple-negative (TN) locally advanced breast cancer (BC).
Authors: I. A. Mayer, I. M. Meszoely, M. Sanders, Y. Shyr, V. G. Abramson, J. A. Means-Powell, A. B. Chakravarthy, C. L. Arteaga, J. A. Pietenpol
Journal: Journal of Clinical Oncology (2010)

TPS119 Background: In a fraction of TN BC, p63 is coordinately expressed with p73, and may be antagonizing p73 transcriptional and tumor suppressive activity. Based on findings that mTOR inhibitors can activate p73 and can enhance chemosensitivity of cancer cells to cisplatin (known to activate p73) and paclitaxel (known to inhibit p63 expression), we hypothesized that combined use of RAD001 (mTOR inhibitor), cisplatin, and paclitaxel would have synergistic effects in TN BC. Methods: This is a phase II trial, where patients with measurable clinical stage II/ III TN BC are assigned (2:1) to Cisplatin 25 mg/m2 ± RAD001 30 mg weekly for 3 weeks, followed by cisplatin + paclitaxel 80 mg/m2 ± RAD001 weekly for 9 weeks until the time of definitive surgery. Since June 2009 ten patients have been accrued. Biopsy specimens are obtained prior to therapy, and at 3-5 days after day 1 of treatment. The main endpoint is pathological complete response (pCR) for each individual treatment arm. We also assess rate of breast conservation surgery and tumor response prior to surgery. A two-stage optimal design was used to detect a 35% pCR rate if it exists in Arm 1. Initially, 27 eligible patients will be entered into the study. If less than 6 have pCR, the study will be stopped. If the study is not stopped early, an additional 36 patients will be enrolled (total of 63). If there are 17 or more pCR in these 63 patients, the combination therapy will be further studied. This design provides 90% power to detect a difference in pCR rate of 35% vs. 20% with a two-sided significance level equal to 0.1 (type I error). With a sample size of 32 patients, the half-width of the 95% confidence interval (CI) will be less than 14% if the pCR for Arm 2 is <20%. All collected tissue in this trial will be analyzed for therapy-mediated changes in cell cycle position, proliferation, apoptosis, as well as status, levels, and phosphorylation state of S6K, p53, p73, and p63, and select p53 family target genes. We will also isolate RNA and generate microarray data sets, which we will mine to test the ability of p63 and p73 gene signatures to predict patient response. This study may inform future selection of anticancer agents for patients with TN BC. No significant financial relationships to disclose.
Long-term survival benefits of docetaxel plus cyclophosphamide compared to doxorubicin plus cyclophosphamide in the adjuvant treatment of operable breast cancer
Authors: M. Thompson, B. Seal, M. Tangirala, L. Asmar, S. Jones
Journal: Journal of Clinical Oncology (2009)

563 Background: The U.S. Oncology Adjuvant Trial 9735 recently demonstrated disease-free survival and overall survival (OS) benefits over 7 years for docetaxel plus cyclophosphamide (TC) compared with doxorubicin plus cyclophosphamide (AC) as adjuvant treatment for women with operable stage I-III invasive breast cancer (BC). The life-time benefits of TC vs. AC, however, are unknown. This analysis aimed to project potential life-time survival benefits of TC vs. AC as adjuvant therapy for operable BC. Methods: The 7-year follow-up results of the 9735 study combined with US average life expectancy were used to project the life-time survival benefits of TC vs. AC. In the base case (scenario 1), it was assumed the survival advantage of TC did not persist beyond the 7-year clinical trial period. Rather, all patients alive and disease-free at 7 years (from the starting age of 51 to the age of 58), regardless of treatment, were assumed to be cured and received the average remaining life expectancy of a 58-year old woman in the US general population. As survival benefits from chemotherapy may persist beyond the clinical trial period, two sensitivity analyses were conducted: 1) greater life expectancy in the TC arm of 1.8 months equivalent to the mean difference in OS between TC and AC within the clinical trial period (scenario 2) and 2) greater life expectancy in the TC arm of 22 months equivalent to the difference in survival at the end of 7 years (scenario 3). The total life years gained (LYs) and quality-adjusted life years gained (QALYs) were then calculated. Results: Per patient LYs gained in scenarios 1, 2, and 3 were 0.850, 0.930, and 1.755, respectively; while QALYs gained were slightly lower at 0.674, 0.736 and 1.383, respectively. Applying this benefit to a cohort of 167,133 women in the US with newly diagnosed stage I-III invasive BC in 2008, the gains were 142,063 LYs and 112,648 QALYS in scenario 1. Conclusions: In addition to survival benefit observed within the clinical trial period, the use of TC is associated with long-term survival benefits compared to AC in patients with stage I-III invasive BC. The results provide additional support of the value of TC in the management of early stage BC. [Table: see text]
Serial FDG-PET to monitor treatment of bone-dominant metastatic breast cancer predicts time to progression (TTP)
Authors: S. L. Tam, J. R. Gralow, R. B. Livingston, H. M. Linden, G. K. Ellis, E. K. Schubert, L. K. Dunnwald, D. A. Mankoff
Journal: Journal of Clinical Oncology (2005)

633 Background: The response of bone-dominant breast cancer to therapy is difficult to assess by conventional imaging approaches such as bone scan and MRI. Our preliminary studies have previously shown that quantitative serial [F-18]-2-fluoro-D-glucose positron emission tomography (FDG PET) correlates with therapeutic response of bone-dominant breast cancer, but the relationship to long-term outcome measures is unknown. The aim of this study is to evaluate the prognostic power of FDG PET imaging in bone-dominant breast cancer undergoing treatment. Methods: A retrospective analysis was performed on the medical records of 405 breast cancer patients who were previously referred for FDG PET between January 1999 and December 2003. From this population of patients, 29 patients were selected who demonstrated metastatic bone only +/- nodal breast cancer and were undergoing treatment with at least 2 serial PET scans which had clear uptake. The standard uptake value (SUV) changes for the most conspicuous bone lesion were compared to long-term prognostic outcomes (TTP, time to skeletal-related event(t-SRE), and time to death(TTD)). Time-to-progression was defined as the time from the initial index FDG PET to disease progression (>25% increase in tumor markers, clear symptomatic progression, progression on some other imaging modality, skeletal-related events, or a new lesion). A skeletal-related event was defined by hypercalcemia, radiation therapy to stabilize disease, pathologic fracture, cord compression, or surgery to stabilize spine. Results: Using hazard analysis, longer TTP correlated with greater decreases in SUV either by absolute or percentage changes. T-SRE was found to significantly correlate with higher initial SUV readings. In addition, when grouped by tertiles for absolute SUV changes, the smallest and largest tertile groups correlated with t-SRE. No correlation was demonstrated for TTD and SUV changes, however only one death occurred during this study analysis. Conclusions: Preliminary results indicate that serial FDG PET predicts TTP and t-SRE in bone-dominant breast cancer; however, larger prospective trials are needed. Supported by CA72064, CA42045, and BCRF No significant financial relationships to disclose.
HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: Preliminary phase 1 results in patients with solid tumors
Authors: K. K. Wong, P. M. Fracasso, R. M. Bukowski, P. N. Munster, T. Lynch, R. Abbas, S. E. Quinn, C. Zacharchuk, H. Burris
Journal: Journal of Clinical Oncology (2006)

3018 Background: HKI-272 is a potent, low molecular weight, orally active, irreversible pan erbB receptor tyrosine kinase inhibitor. It inhibits the growth of tumor cells that express erbB-1 (epidermal growth factor receptor, EGFR) and erbB-2 (HER-2) in culture and xenografts. HKI-272 also inhibits the growth of cultured cells that contain sensitizing and resistance-associated EGFR mutations (Kwak et al, Proc Natl Acad Sci USA 102:7665–70, 2005). We are conducting a phase 1 study in patients (pts) with advanced-stage tumors that express EGFR or HER-2 to assess HKI-272 for tolerability, safety, pharmacokinetics, and preliminary antitumor activity. Methods: Pts (3–6/cohort) received 40, 80, 120, 180, 240, 320, or 400 mg HKI-272 orally once on day 1 and then once daily beginning on day 8. Timed blood samples were collected on days 1 and 21 for pharmacokinetic analysis. Results: Enrollment of 73 pts is complete. Preliminary data for 51 pts as of 28 Nov 2005 are presented. Patients were a median 60 years and 26% men. The most frequently occurring tumor types at primary diagnosis were breast (23 pts), non-small cell lung (9), and colorectal, ovarian, and renal (3 pts each). Dose escalation ended when 2 pts who received 400 mg HKI-272/day had drug-related dose-limiting toxicity of grade 3 diarrhea. Thus, the maximum tolerated dose (MTD) was 320 mg HKI-272/day. HKI-272-related adverse events (AEs), any grade, that occurred in ≥10% of pts were diarrhea (84%), nausea (55%), asthenia (45%), anorexia (31%), vomiting (29%), chills (12%), and rash (10%). Grade 3 related AEs that occurred in &gt;1 pt were diarrhea (11) and asthenia (4). HKI-272 C max and AUC increased in a dose-dependent manner. At steady state at the MTD, mean values were C max : 112±58 ng/mL, AUC: 1618±930 ng.h/mL, t 1/2 : 15±2.5 h. Day 1 and 21 AUC values were comparable. Tumor assessments (modified RECIST criteria) were made at baseline and at the end of alternate cycles (28 days/cycle). Two breast cancer pts had confirmed partial responses (PRs) and 2 had unconfirmed PRs. Conclusions: When HKI-272 was administered on a continuous, once-daily, oral treatment schedule, the MTD was 320 mg/day, with diarrhea as the most frequently occurring related AE. HKI-272 has antitumor activity in HER-2-positive breast cancer. [Table: see text]
The importance of communication about cachexia as experienced by patients and caregivers: A qualitative cross-cultural study.
Authors: Egidio Del Fabbro, Tami R. Borneman, Guendalina Graffigna, Isabella Cecchini
Journal: Journal of Clinical Oncology (2014)

37 Background: Cancer Anorexia-Cachexia Syndrome (CACS) is a multifactorial condition defined by an ongoing loss in body weight that cannot be fully reversed through conventional nutritional support and leads to progressive functional impairment. This condition has for a long time been misrecognized and underdiagnosed. Furthermore, the burden of CACS as experienced and depicted by patients and caregivers has not been deeply explored so far. Methods: This was a narrative qualitative cross-cultural study (IT, ES, UK, DE, US) based on the collection of 30 weekly emotional diaries followed by 30 semi-structured in-depth interviews to caregivers (i.e. relatives, partners, close friends) of patients diagnosed with CACS. The aim was to understand how the disease is experienced by patients and caregivers, their feelings and unmet needs. Results: Caregivers and patients demonstrate a poor knowledge of CACS: while they spontaneously refer to a pattern of CACS symptoms, they do not verbalize the term “cachexia”. The awareness and levels of engagement in managing CACS by caregivers appear to be dependent on the degree and timing of communication on this condition with the physician: those who express a higher sense of powerlessness and despair also report that their doctor has never explicitly mentioned CACS, nor indicated any strategies to manage it. On the other hand, those who appear more confident and engaged in managing CACS report a more detailed and earlier communication on the subject. Conclusions: Scarce and/or late communication on CACS and its management options with patients and caregivers may result in a sense of powerlessness and ignorance on how to manage its symptoms. In line with the recently reported importance of an early CACS recognition [(Aapro M et al, Ann Oncol (2014). 2014 May 2)], an earlier and thorough discussion about CACS with patients and caregivers would improve their level of engagement and help relieve some of their distress.
Investigation on the serum antibodies levels against Epstein-Barr virus in pulmonary lymphoepithelioma-like carcinoma
Authors: S. Niraula, Y. S. Zong, L. Z. Zhai, C. C. Guo, T. Y. Lin
Journal: Journal of Clinical Oncology (2007)

18186 Background: Pulmonary lymphoepithelioma-like carcinoma (PLELC) belongs to large cell sub-type of non-small cell lung cancer (NSCLC) with just about 160 cases reported previously. Its epidemiology, prognosis and therapeutic approach is evidently different from other NSCLCs. EBV infection is seen in 100% of Asian PLELC patients whenever tested. The aim of this study was to analyze serum antibodies level against EBV in PLELC patients. Methods: Sera of all seven patients with re-confirmed PLELC from a single institute in Canton, China in the past 4 years were collected. Serum levels of 8 different antibodies against EBV (Epstein-Barr virus): EBNA1 (EBV nuclear antigen 1- IgA and IgG), Zta (Bam Z transactivator antigen-IgA and IgG), VCA-p18 (Viral capsid antigen-p18-IgA and IgG), VCA-antigen complex (VCA-IgA) and Early antigen complex (EA-IgA ) were measured in each of these patients using enzyme-linked immunosorbent assay and Immunoenzymatic assay respectively. Results: Out of 7 cases, 6 showed high EBNA-1 level, 4 showed high zta, 3 showed high VCA-p18, 3 showed high titer of VCA complex and 2 showed high EA complex titer ( Table 1 ) Conclusions: Though small sample size, this is the first study in this depth ever to conclude that sera of all Asian patients with pulmonary LELC have high antibody titers against EBV. The infection mainly is latency II type as seen in Nasopharyngeal carcinoma and Hodgkin’s disease as well. A small portion of PLELC express lytic products such as Zta, EA and VCA. The authors assume that pre-therapeutic measurement of serum levels of anti-EBV antibodies (at least 2 kinds) is highly warranted in suspected Asian NSCLC patients. Positive result strongly puts PLELC into differential diagnosis. [Table: see text] No significant financial relationships to disclose.
Alternative administration of paclitaxel-gemcitabine and paclitaxel-vinorelbine as first line treatment in NSCLC patients. A phase II study
Authors: J. Dimitroulis, M. Toubis, D. Antoniou, P. Giamboudakis, C. Marosis, U. Armenaki, M. Veslemes, P. Michalopoulou, F. Christou, N. Georgatou, G. P. Stathopoulos
Journal: Journal of Clinical Oncology (2005)

7319 Background: Many trials have tested the efficacy of new cytotoxic agents in NSCLC patients. The alternative administration of two different schedules has rarely been attempted. Objective: The present trial is a preliminary report of a phase II study in a cohort of non-small-cell lung cancer (NSCLC) patients, testing the efficacy and tolerability of two cytotoxic combinations, administered alternatively, every two weeks. Methods: Chemotherapy naïve with histologically or cytologically confirmed NSCLC patients were eligible to participate. The treatment included Paclitaxel 135 mg/m2 for 3 hr infusion and Gemcitabine 1000 mg/m2 given for 60’ infusion on day one, repeated on day 29th. On day 15th Paclitaxel, the same dose, combined with Vinorelbine 25 mg/m2 for 30’ infusion, was administered. This last scheme was repeated on day 42d. This treatment was planned to be given every two weeks for 9 cycles with Paclitaxel every time combined with Gemcitabine or Vinorelbine alternatively. No prophylactic GCSF was administered. Results: From April 2004 till November 2004, 60 patients have been enrolled and till now evaluable for safety and response are 46. There were 42 male and 4 female, median age was 65, range 33–78. Performance status was 0–1 in 41 patients and 2 in 5 patients. The total number of given courses was 276 and the median 6. The main adverse reaction was myelotoxicity with neutropenia of grade III and IV in 15.2% of the patients including two patients with febrile neutropenia. Anemia observed in 4 patients (8.69%) and thrombocytopenia in 2 patients (4.34%). Non-hematologic toxicities were mild. Responses (PR) were observed in 15 of 46 patients (32.6%), stable disease in 20 (43.47%) and disease progression in 11 patients (23.9%). The median follow-up time was 5 months (2–8 mo.). Conclusions: The results of this preliminary report showed that the alternative administration of Paclitaxel-Gemcitabine and Paclitaxel-Vinorelbine produces a response rate of 32.6% and the low percentage of adverse reaction dictated a high degree of tolerability. No significant financial relationships to disclose.
A phase I study dose escalation clinical study of hepatic intraarterial cisplatin, combination systemic intravenous liposomal doxorubicin in patients advanced cancer dominant liver involvement
Authors: C. Vaklavas, A. M. Tsimberidou, S. Moulder, C. Ng, A. Naing, S. Daring, A. Bedikian, C. Uehara, R. Kurzrock
Journal: Journal of Clinical Oncology (2009)

e13512 Background: Patients with liver metastases treated on phase I clinical trials have a median survival of 7.5 months (range, 6.0–9.5). We conducted a phase I study of hepatic arterial infusion (HAI) and intravenous (IV) chemotherapy in patients with advanced cancer and dominant liver involvement. Patients: Patients were treated with HAI cisplatin 100–200 mg/m 2 intraarterially D1+ 3000 IU heparin intraarterially on D1; followed by liposomal doxorubicin 20–35 mg/m 2 IV D1 every 4 wks using a conventional “3 + 3” design. Results: Thirty patients were treated (median age, 56 y; range, 15–76; 5 men, 25 women). Diagnoses were breast cancer (n=11), colorectal cancer (n= 8), ocular melanoma (n=4), and other (n=7). The median number of prior therapies was 5 (range, 1–13). Enrollment was: HAI cisplatin (mg/m 2 )/IV doxil (mg/m 2 ): 100/20 (n=3); 100/25 (n=4); 100/30 (n=3); 100/35 (n=16) and 125/35 (n=4) and the maximum tolerated dose (MTD) was 100/35. Dose-limiting toxicities were Grade 4 neutropenia (2 of 4 patients), and Grade 4 thrombocytopenia (1 of 4 patients). Among 30 patients who completed cycle 1, 7 (23%) patients had no toxicity &gt;Grade 1. Overall, 77 cycles were administered (median per patient, 4; range, 1–6). The most common toxicities were nausea/vomiting (n=23), fatigue (n=15), and constipation (n=13). Twenty-one patients were evaluable for response. Treatment resulted in a partial response (PR)(n=4) or stable disease (SD)(n=6) by RECIST in 10 (48%) patients and lasted for ≥4 months (tumor reduction by 5% to 44%). Four (19%) patients achieved a PR (tumor reduction by 38%, 42%, 44% and 51%, for 4, 4, 6, and 4 months, respectively). Of the 11 patients with breast cancer, 3 had a PR and 4 had SD. Of 4 patients with ocular melanoma, 1 had a PR and 1 SD. One patient with hepatocellular carcinoma had SD. Of 11 evaluable patients treated at the MTD, 3 (27%) had a PR and 4 (36%) had SD. Conclusions: The MTD of HAI cisplatin 100 mg/m 2 and systemic liposomal doxorubicin 35 mg/m 2 demonstrated antitumor activity in this patient subset. No significant financial relationships to disclose.