tbuckley/cabot-search huggingface dataset:
Proteomic profiling of the diagnostic tumor biopsy to predict response to neoadjuvant chemoradiotherapy in rectal cancer.
Authors: Paul Anthony Sutton, Rob Jones, Bushra Hamid, Gian Abbott, Chris Goldring, Daniel H. Palmer, Neil Kitteringham, Dale Vimalachandran
Journal: Journal of Clinical Oncology (2014)

e14579 Background: Neoadjuvant chemoradiotherapy has become a fundamental component of the treatment strategy for locally advanced rectal cancer. The variation in response to this treatment is diverse; around 8% of patients have a pathological complete response whilst approximately 30% will either suffer disease progression or fail to respond to treatment. We aimed to identify differentially expressed proteins which would potentially serve as novel response biomarkers to neoadjuvant chemoradiotherapy in rectal cancer. Methods: Serial tumor samples were obtained at diagnosis (n=8), immediately post-treatment (n=5) and at the time of surgical resection (n=6) from 8 patients with rectal cancer. Samples were subjected to comparative proteomic analysis using isobaric tagging for relative quantification (iTRAQ). Review of tumor regression grade apparent on H&E sections from the resection specimens, as well as radiological re-staging using the RECIST criteria allowed for stratification of patients into ‘responders’ and ‘non-responders’. Results: A total of 3,359 unique proteins were identified, of which all were present in at least half of the samples. Four proteins were significantly differentially expressed (p<0.05 and fold-change >2) between diagnostic and post-treatment samples and 14 between post-treatment and resection samples. Eight proteins were significantly differentially expressed between ‘responders’ and ‘non-responders’. Conclusions: There is demonstrable change in the phenotype of the tumor with chemoradiotherapy, but a more apparent change is observed in the subsequent period of down-staging. Pathway and network analysis of these proteins may improve our understanding of this phenomenon. Eight potential response biomarkers have been identified which are currently being validated by immunohistochemistry.
T-ACT (WJOG7112G): A randomized phase II study of weekly paclitaxel ± trastuzumab in patients with HER2-positive advanced gastric or gastro-esophageal junction cancer refractory to trastuzumab combined with fluoropyrimidine and platinum.
Authors: Taito Esaki, Akitaka Makiyama, Tomomi Kashiwada, Ayumu Hosokawa, Junji Kawada, Toshikazu Moriwaki, Yoshiki Horie, Hironaga Satake, Katsunori Shinozaki, Hiroyasu Ishida, Hiroaki Tanioka, Hiroshi Tsukuda, Keita Uchino, Kazuhiro Nishikawa, Yasutaka Sukawa, Takeharu Yamanaka, Shinichiro Nakamura, Narikazu Boku, Ichinosuke Hyodo, Kei Muro
Journal: Journal of Clinical Oncology (2017)

TPS218 Background: Trastuzumab (Tmab) is a key drug for HER2 positive breast and gastric or gastro-esophageal junction (G/GEJ) cancer. While use of Tmab beyond progression (TBP) showed a benefit in HER2-positive metastatic breast cancer, clinical significance of TBP for HER2-positive G/GEJ cancer has not been clarified. Objective:This study compares the efficacy of paclitaxel (PTX) + Tmab with PTX alone in patients with unresectable or metastatic HER2-positive G/GEJ cancer who failed first-line chemotherapy with Tmab + fluoropyrimidine + platinum. Methods: Enrolled patients will be randomized to receive PTX (80 mg/m2, on day 1, 8 15, every 4 weeks) + Tmab (8 mg/kg loading dose and 6 mg/kg thereafter, on day 1, every 3 weeks) or PTX alone. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall survival, time to treatment failure, response rate, disease control rate, safety, and translational biomarker research. A total of 69 events are required to achieve 80% power for one-sided log rank test with 10% significance level, expecting the median PFS of the PTX and the PTX + Tmab arms will be 3 and 5 months. In consideration of patient with censoring and dropout, the planned sample size is totally 90 patients. Major eligibility criteria are: HER2-positive advanced G/GEJ adenocarcinoma; refractory to first-line chemotherapy with fluoropyrimidine, platinum, and Tmab (at least three doses); within 6 weeks after last Tmab administration; no prior therapy with taxane or anti-HER2 drugs except Tmab; ECOG PS 0-2; adequate organ function; left ventricular ejection fraction ≥ 50%. Tumor tissue, blood serum, and circulating tumor DNA are collected before the study treatment for biomarker analyses to explore the predictive marker of the TBP strategy. As of September 2016, 89 patients were randomized. Clinical trial information: 000009297.
Weekly vinblastine in chemotherapy-naive children with unresectable or progressive low grade glioma: A Canadian cooperative study.
Authors: Eric Bouffet, Katrin Scheinemann, Shayna M. Zelcer, Juliette Hukin, Beverley Wilson, Nada Jabado, Anne Sophie Carret, Lucie Lafay Cousin, Valerie Larouche, Cynthia Hawkins, Gregory Russell Pond, Ken Poskitt, Ute Katharina Bartels, Uri Tabori
Journal: Journal of Clinical Oncology (2013)

10029 Background: Vinblastine has shown promising activity in a phase II study in children with recurrent/refractory LGG. The aim of this study was to assess the activity of vinblastine in chemotherapy naïve children. Methods: Patients &lt; 18 years old with unresectable or progressive LGG were eligible if they had not received any previous treatment with chemotherapy or radiation. Vinblastine was administered weekly at a dose of 6 mg/m 2 over a period of 70 weeks. Patients who showed progression on 2 consecutive imaging studies or evidence of clinical progression were removed from treatment. Results: 54 patients (23 female) were enrolled between 2007 and 2010. Median age at inclusion was 7 years, 13 patients were &lt; 3 years. 32 had chiasmatic/hypothalamic tumours, 6 had evidence of dissemination. 13 had neurofibromatosis type 1. Histology was pilocytic astrocytoma (25), pilomyxoid astrocytoma (4), low grade astrocytoma variant (8); 17 patients had no histological diagnosis. Treatment was well tolerated; however, only 14 patients received full dose for the duration of the study. Most common toxicity was haematological: 40 patients who experienced grade 3+ neutropenia. There were only 6 episodes of febrile neutropenia, 3 RBC transfusions and no toxic death. Best response to chemotherapy was assessed centrally by an independent radiologist: 1 CR, 10 PR, 3 MR, 28 SD, 12 PD, for a response rate of 24.5%. With a median follow-up of 2 years (9-48 months), progression-free survival at 2 years was 72.1% (95%CI: 58.1-82.2). One patient died of progression. Conclusions: Weekly vinblastine is well tolerated in paediatric LGG patients. Although the response rate appears inferior to other common LGG regimens, progression free survival at 2 years favourably compares to most currently used regimens. Supported by a grant from the Ontario Institute Cancer Research. Clinical trial information: 1000011227.
A phase I study of MM-302, a HER2-targeted liposomal doxorubicin, in patients with advanced, HER2-positive (HER2+) breast cancer.
Authors: Pamela N. Munster, Kathy Miller, Ian E. Krop, Navreet Dhindsa, Joe Reynolds, Elena Geretti, Clet Niyikiza, Ulrik Nielsen, Bart Hendriks, Thomas J. Wickham, Victor M. Moyo, Patricia LoRusso
Journal: Journal of Clinical Oncology (2012)

TPS663 Background: Anthracyclines have been an effective backbone of breast cancer therapies for decades. However, cardiotoxicity issues associated with free anthracyclines have limited their effective use in the clinic and led to the exploration of anthracycline-free regimens, particularly with HER2-positive cancers that require treatment with another cardiotoxic agent, trastuzumab. While liposomal doxorubicin formulations have succeeded in reducing cardiotoxicity, they have failed to demonstrate clear-cut efficacy advantages and can involve other toxicities. To address the safety and efficacy limitations of currently available anthracyclines, we have designed a new liposomal formulation, MM-302, that targets doxorubicin to HER2-overexpressing tumor cells. Antibody fragments that bind to HER2 without blocking HER2-mediated signaling are coupled to the outer surface of pegylated liposomal doxorubicin. MM-302 specifically binds and enters tumor cells overexpressing HER2 with minimal uptake into normal cells such as cardiomyocytes which express low levels of HER2. This first-in-human phase I study evaluates the safety of MM-302 in patients and provides preliminary efficacy data in HER-2+ advanced breast cancer (ABC). Methods: Patients aged &gt; 18 years with histologically confirmed HER-2+ advanced breast cancer that have progressed or recurred on standard therapy or for which no standard therapy exists who have adequate performance status, bone marrow reserve, and organ function, are eligible for the study. Following a standard 3 + 3 dose escalation design, the maximum tolerated dose (MTD) or maximum feasible dose (MFD) is determined and up to 25 additional patients with HER-2+ ABC will be enrolled for a planned total of 40-49 patients. The primary endpoint is determination of the MTD/MFD. Secondary endpoints include determination of dose-limiting toxicity, adverse event(s), and pharmacokinetic and immunogenicity profiles of MM-302, as well as overall response and clinical benefit rates of MM-302. MM-302 is administered intravenously weekly in 4-week cycles. At the time of this submission, 8 patients have been enrolled in the dose escalation portion.
Induction of atypical anoikis in glioma cells through inhibition of integrin functions.
Authors: Patrick Roth, Manuela Silginer, Michael Weller
Journal: Journal of Clinical Oncology (2013)

2079 Background: Integrins regulate cellular adhesion and transmit signals important for cell survival, proliferation, differentiation and motility. Both αvβ3 and αvβ5 integrins are upregulated in glioma cells, and therefore, integrin inhibition may represent a promising therapeutic strategy in glioblastoma. Methods: SMA-560 and GL-261 mouse glioma cells were cultured as adherent monolayers in serum-containing medium or as sphere cultures in neurobasal medium. Integrin function was inhibited using RNA interference, blocking antibodies or pharmacological inhibitors. Cell death after integrin inhibition was examined by flow cytometry. Immunoblot was used to assess apoptosis and autophagy. Results: GL-261 and SMA-560 glioma cells grown under standard conditions uniformly detached and formed large cell clusters after integrin gene silencing or pharmacological inhibition using EMD-121974 (cilengitide), a synthetic Arg-Gly-Asp-motif peptide, or GLPG0187, a non-peptidic integrin inhibitor. After 120 h, the clusters induced by integrin inhibition disintegrated and cells died. In contrast, no morphological effects were observed when cell lines were grown as stem-like sphere cultures. Since Poly-HEMA-mediated detachment had similar effects on cell viability as integrin inhibition, we postulated that cell death may result from detachment alone which was confirmed using various permissive and non-permissive substrates. No signs of apoptosis or autophagy were found using Annexin V/PI staining, DEVD-amc cleaving assay or caspase-3 and LC3A/B immunoblot. Recently, we demonstrated that integrin inhibition results in an inhibition of the TGF-β pathway in human glioma cells. Addition of recombinant TGF-β2 indeed partially rescued integrin inhibition-induced cell death, whereas exposure to the TGF-β receptor inhibitor SD-208 increased the number of dead cells. Conclusions: Cell death following integrin inhibition is essentially necrotic and may involve the TGF-β pathway.
Efficacy of the PARP Inhibitor Veliparib with Carboplatin or as a Single Agent in Patients with Germline <i>BRCA1</i>- or <i>BRCA2</i>-Associated Metastatic Breast Cancer: California Cancer Consortium Trial NCT01149083
Authors: George Somlo, Paul H. Frankel, Banu K. Arun, Cynthia X. Ma, Agustin A. Garcia, Tessa Cigler, Leah V. Cream, Harold A. Harvey, Joseph A. Sparano, Rita Nanda, Helen K. Chew, Timothy J. Moynihan, Linda T. Vahdat, Matthew P. Goetz, Jan H. Beumer, Arti Hurria, Joanne Mortimer, Richard Piekarz, Sharon Sand, Josef Herzog, Lily R. Van Tongeren, Katherine V. Ferry-Galow, Alice P. Chen, Christopher Ruel, Edward M. Newman, David R. Gandara, Jeffrey N. Weitzel
Journal: Clinical Cancer Research (2017)

Abstract Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066–76. ©2017 AACR.
Refining the target area in diffuse gliomas for radiation oncology based upon the location of cingulate gyrus tumors.
Authors: Jackson Hamilton, Christiane Matuschek, Edwin Boelke, Wilfried Budach, Sujit S. Prabhu, Michael Sabel, Brian Butler
Journal: Journal of Clinical Oncology (2013)

e13051 Background: Glioblastoma is a brain tumor with poor survival. Radiation therapy (RTX) is often not effective and the target volume could be improved. The aim of this study is to determine if the patterns of spread for cingulate region gliomas could be used to make rational decision for safely altering the treatment planning target volume. Methods: 69 pts. with cingulate gliomas were collected from the collaborating institutions and the patterns of spread were analyzed by serial MRI evaluation. Results: Most pts. present with seizures, one ischemic stroke and one acute hemorrhage was noted. Anterior cingulate was involved in 49 pts. The basal frontal lobe (orbitofrontal or gyrus rectus) was involved in 6 pts. and the insula in 1. There were 20 cases of posterior cingulate involvement including 1 case which wrapped posteriorly from the hippocampus to indusium griseum. None of the cases spread between the anterior and posterior cingulate. 4 had bilateral cingulate involvement. Given that the callosal fibers surround but do not enter the cingulate, the postoperative imaging were assessed which showed that often the callosum was thin and edematous, or had tumor herniate through the callosal isthmus (3 cases), rather than true callosal involvement. Additional cases outside of the 69 pts. showed callosal tumors sparing the cingulate and supra-cingulate frontal and parietal tumors which did not invade the cingulate sulcus. Conclusions: For RTX the areas of cingulate tumor spread which should be considered is the adjacent corpus callosum. There appear to be a relative functional border by the cingulate sulcus and also separating the anterior and posterior cingulate at the level of the paracentral lobules, suggesting the potential for dose deescalation, which may also help with avoiding the supra-cingulate supplemental motor area and leg motor fibers. Other areas to include are the opposite cingulate gyrus, head of the caudate nucleus and septum pellucidum. Anterior cingulate lesions near the genu should include the subcallosal (risky for deficit) and ipsilateral frontal basal areas (risks for frontal lobe syndrome). Sparing the major callosal marginal or pericallosal arteries may help to avoid stroke.
A randomized discontinuation phase II trial of ridaforolimus in non-small cell lung cancer (NSCLC) patients with KRAS mutations.
Authors: Gregory J. Riely, Julie R. Brahmer, David Planchard, Lucio Crinò, Robert Charles Doebele, Luis Alberto Mas Lopez, Scott N. Gettinger, Christian Schumann, Xiaoyun Li, Barbara McCormick Atkins, Scot Ebbinghaus, Rafael Rosell
Journal: Journal of Clinical Oncology (2012)

7531 Background: Mutations in KRAS are present in ~25% of patients with advanced NSCLC. Preclinical data support the role of mammalian target of rapamycin (mTOR) in KRAS mediated oncogenesis. Ridaforolimus is an inhibitor of mTOR which has been shown to have efficacy in advanced endometrial cancer and soft tissue sarcoma. Everolimus, another mTOR inhibitor was previously evaluated in unselected patients with advanced NSCLC and found to have a response rate &lt;5%. We hypothesized that by enrichment for patients with NSCLC and KRAS mutations, treatment with ridaforolimus would be associated with prolonged stable disease relative to available standard treatments for NSCLC. Methods: Patients with stage IIIB/IV non-small cell lung cancer with KRAS mutation who had received prior chemotherapy for NSCLC began treatment with oral ridaforolimus 40 mg once daily on a 5 day/week schedule. After 8 weeks, patients with &gt;30% tumor shrinkage remained on ridaforolimus and patients with &gt;20% tumor growth discontinued treatment. Patients with stable disease were randomized 1:1 to placebo or ridaforolimus. The primary endpoint of the study was progression-free survival (PFS) after randomization. Results: 79 patients were enrolled (40 women, median age 58 [range 28-85]). The overall response rate (CR+PR) at 8 weeks was 1/79 (1%, 95% CI 0-7%). 28 patients with stable disease at 8 weeks were randomized to ridaforolimus or placebo. Median PFS based on investigator assessment from randomization was significantly longer with ridaforolimus (4 months) than placebo (2 months, p=0.013, HR 0.36). Median OS from randomization was 18 months in the ridaforolimus treated arm and 5 months in the placebo treated group, (HR 0.46, p=0.09). The most common grade ≥3 adverse events were fatigue (10%), mucositis/stomatitis (10%), pneumonia (10%), dyspnea (9%), diarrhea (6%), and hyperglycemia (6%). Conclusions: In patients with KRAS mutant NSCLC who had stable disease after 8 weeks of ridaforolimus, ridaforolimus was associated with prolonged progression-free survival. Further evaluation of ridaforolimus in this patient population is warranted.
Clinical experience of a targeted TCR-IL2 fusion protein in combination with cisplatin (CDDP) in patients (pts) with metastatic melanoma.
Authors: Mohammed M. Milhem, Jeffrey S. Weber, Asim Amin, Sanjiv S Agarwala, David H. Lawson, John A. Thompson, Steven O'Day, Gregory K. Pennock, Jon M. Richards, Timothy Kuzel, Liza Hernandez, Bee-Yau Huang, Peter Rhode, Hing C. Wong
Journal: Journal of Clinical Oncology (2012)

e13088 Background: ALT-801 is recombinant human interleukin-2 (IL-2) genetically fused to a single-chain T-cell receptor specific to a peptide antigen of human p53 presented in the context of HLA-A2 positivity. In melanoma xenograft mouse models, this fusion protein alone demonstrated potent, targeted antitumor activity and synergistic efficacy was observed in combination with CDDP. A prior phase I study in pts with metastatic malignancies, including metastatic melanoma, showed that ALT-801 monotherapy could be safely administered and was associated with immunologic changes of potential antitumor relevance (Fishman 2011 CCR 17:7765). Here we report the results of a phase Ib study of ALT-801+ CDDP in pts with metastatic melanoma. Methods: The primary objectives of this multicenter study are to: 1) define an MTD and evaluate the safety of ALT-801+CDDP and 2) assess the objective response rate according to RECIST criteria in treated patients. Eligible pts (histologically confirmed advanced/metastatic melanoma, p53 peptide/HLA-A2 + tumor, chemotherapy naive, PS (ECOG) 0-1, adequate renal and cardiac functions) received 2 consecutive 4-wk courses of CDDP (70 mg/m 2 iv, Day 1) and ALT-801 (iv, Days 3, 5, 15, 17 &amp; 19). Pts with SD or better after 2 courses received 2 additional courses of treatment. Up to 5 cohorts (3+3 dose escalation) of ALT-801 (0.04 - 0.12 mg/kg) were planned with a 2-stage design of expanded pt enrollment at the MTD. Results: 22 patients (11M, 11F, 30-74 yrs) were evaluable at ALT-801 dose levels from 0.04 to 0.10 mg/kg. The MTD has not been reached at 0.10 mg/kg ALT-801. Toxicity was manageable and transient. RECIST-confirmed tumor response and disease stabilization was reported for some patients. Overall survival rates (6 mon, 87%; 12 mon, 58%) observed to date suggest durable clinical benefit. Conclusions: ALT-801+CDDP can be safely administered in an out-patient setting to pts with metastatic melanoma. Preliminary evaluation suggests durable clinical activity of the ALT-801+CDDP regimen in melanoma patients. A trial using ALT-801 at the 0.1 mg/kg dose level in combination with a BRAF kinase inhibitor is being planned for patients with metastatic melanoma (CA097550).
Unrelated placental/umbilical cord blood cell (UCBC) transplantation in children with high-risk sickle cell disease (SCO)
Authors: A. M. Yeager, P. S. Mehta, T. V. Adamkiewicz, E. Olson, L. L. Hsu, A. Kedar, T. A. Olson, M. W. Boyer, A. K. Ogden, J. R. Wingard, J. R. Eckman
Journal: Blood (2000)