tbuckley/cabot-search huggingface dataset:
Immunologic and clinical effects of personalized selection of peptide vaccines in HLA-A2 positive patients with advanced cancer
Authors: M. Noguchi, S. Todo, H. Yanagimoto, R. Yamanaka, T. Kamura, K. Matsumoto, T. Mine, A. Yamada, K. Itoh
Journal: Journal of Clinical Oncology (2008)

3031 Background: Personalized selection of the right peptides for each patient could be a novel peptide-based immunotherapy for boosting anticancer immunity in many patients (pts). Here we describe immunologic and clinical effects of a personalized peptide vaccine for HLA-A2 positive advanced cancer pts who mostly failed the standard therapy. Methods: To evaluate safety and immune responses of vaccination, 74 HLA-A2 positive advanced cancer pts, including 27 hormone refractory prostate cancer (HRPC), 13 colon cancer (CC), 8 pancreatic cancer (PC), 6 gastric cancer (GC), 4 brain tumor (BT), and 16 other types of cancer (Others) pts were enrolled in a phase I/II clinical trial. Pre-vaccination peripheral blood mononuclear cells and/or plasma were measured for their CTL or IgG levels for each of the 14–20 candidate peptides which can induce HLA-A2-restricted CTL activity against cancer cells followed by weekly or bi-weekly subcutaneous administration of the top four peptides (3mg each) showing the strongest immune responses. The protocol was approved by each ethics committee. Results: Vaccination-related adverse events were mainly grade 1 or 2 skin reactions at the injection sites, and there were no severe adverse events except for rectal bleeding in a cervical cancer pt. In the post (6–8th)-vaccination samples, CTL responses were boosted in 46 of 70 pts tested, while IgG responses were boosted in 55 of 73 pts tested, respectively. Best clinical responses were 1 CR, 11 PR, 31 SD, and 31 PD. Objective responses were obtained in urologic and gynecologic cancers or brain tumors by vaccination in the thigh or upper back regions, respectively, suggesting that location of sentinel lymph node near to tumor site is a pivotal factor for tumor regression. Median survival times in all pts are 14.3 months: 25 months in HRPC, 9.7 in BT, 8 in GC, 7 in PC, 6 in CC, and 17 in Others, respectively. Conclusions: This personalized peptide vaccine could be recommended for further stages of clinical trials because of safety, boosting of immune responses, and potential clinical benefits. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration GreenPeptide GreenPeptide GreenPeptide GreenPeptide
Validation of the CAIX score as a prognostic biomarker for lymphatic spread and cancer-specific survival.
Authors: Karim Chamie, Jonathan W. Said, Arie S. Belldegrun, Allan J. Pantuck
Journal: Journal of Clinical Oncology (2014)

454 Background: We recently developed a novel CAIX density scoring system that was found to be a significant prognostic biomarker in a cohort of patients with high-risk clear cell renal cell carcinoma (ccRCC). We sought to validate the association of CAIX score with lymphatic spread and survival in a cohort of patients with ccRCC. Methods: We reviewed the clinical and pathologic records of 418 patients who underwent radical nephrectomy at UCLA between 1985 and 1999. Clinical features included age, gender, race/ethnicity, and ECOG performance status. Pathologic features included TNM stage, nuclear grade, UCLA Integrated Staging System (UISS), and CAIX staining. CAIX score was stratified into low (0–99), intermediate (100–199), and high (200–300). We examined the association between the CAIX score, disease severity, and survival using logistic and Cox regression analyses, respectively. Results: Mean CAIX score was 237.4 (SD 98.3). Approximately 26% of patients with low CAIX scores had lymphatic involvement, compared with 28% of those with intermediate scores, and 8% with high scores, p&lt;0.01. On multivariate analysis, patients with high CAIX scores had a significantly lower risk of lymphatic involvement (OR 0.19, p&lt;0.01). When compared with those with low CAIX scores, patients with high CAIX scores were significantly less likely to recur (HR 0.53, p=0.02) or die (HR 0.41, p&lt;0.01). Patients with intermediate scores were no less likely to recur HR 0.93, p=0.85) or die of their disease (HR 0.69, p=0.34). Lastly, patients with high-risk non-metastatic ccRCC were less likely to recur (HR 0.04, p&lt;0.01). Conclusions: The CAIX score can help identify the majority of patients presenting with lymphatic spread and serves as a statistically significant prognostic biomarker for recurrence-free and disease-free survival after nephrectomy. We recommend that utility CAIX score be quantified for all patients with high-risk disease.
A window-of-opportunity trial of vorinostat (V) in patients with resectable non-small cell lung cancer (NSCLC).
Authors: K. H. Dragnev, T. Ma, F. Galimberti, C. P. Erkmen, V. Memoli, W. Nugent, J. R. Rigas, D. Johnstone, A. Frandsen, S. Simeone, J. Czum, H. Li, J. DiRenzo, S. Freemantle, E. Dmitrovsky
Journal: Journal of Clinical Oncology (2011)

7062 Background: Lung cancer is the most common cause of cancer mortality in the United States and novel treatments are needed. We previously engineered murine transgenic cyclin E models that recapitulated frequent features of human lung cancer including chromosome instability, hedgehog pathway, cyclin D1 activation and pre-malignant and malignant lung lesions. Cell lines (ED-1 and ED-2) were derived from these lung cancers as models to identify promising anti-neoplastic agents. Among a panel of drugs that caused growth inhibition of lung cancer cells and repression of cyclin D1, the histone deacetylase inhibitor vorinostat (V) was found to be most potent. V repressed cyclin D1 and cyclin E proteins, but increased p27 expression in ED-1 cells. V treatment also significantly reduced lung tumor formation in mice harboring transplanted syngeneic lung cancer cells. To translate studies into the clinic, a window of opportunity trial of V was conducted in patients (pts) with early stage NSCLC. Methods: Pts with resectable NSCLC received 400 mg V once daily orally for 7 days prior to undergoing surgical resection. Post- versus pre-treatment tumor biopsies were scored for changes in immunohistochemical profiles of cyclin D1, cyclin E, EGFR, phospho-EGFR and Ki-67. Results: Ten pts were enrolled, median age 66 (60-73) years, 60% were women, 1 was a never smoker, 4 were current smokers, pathological stages IA-IIB, 2 had squamous cell carcinoma, 7 had adenocarcinoma, 1 had poorly differentiated carcinoma. Five pts completed the study treatment, 3 pts received V for less than 7 days, 2 did not take the study medication. Ki-67 staining decreased in all examined pairs, cyclin D1 levels decreased in 1 sample, 3 pts had reduced cyclin E expression, 2 pts had reduced EGFR expression, and there was no change in phospho-EGFR detection. Four pairs showed necrosis in the posttreatment specimens. Results for p27, other exploratory markers, and dynamic CT will be reported at the meeting. Conclusions: Preoperative treatment with V decreased Ki-67 and other biomarkers in resected NSCLC. The results from this window of opportunity trial demonstrate the value of clinically-relevant mouse lung cancer models to guide NSCLC clinical trials.
A pharmacokinetics/pharmacodynamics study of sequence specificity of the PARP inhibitor olaparib with carboplatin in refractory/recurrent women’s cancers: NCT01237067.
Authors: J. Lee, J. Squires, J. L. Hays, H. L. Kotz, D. Nielsen, N. D. Houston, E. C. Kohn
Journal: Journal of Clinical Oncology (2011)

TPS158 Background: The combination of carboplatin, C, and the PARP inhibitor olaparib, O, has activity in BRCA1/2mut or BRCA-like breast and ovarian cancers (Br/OvCa). The role of sequence specificity affecting DNA damage and cell injury and death is unknown. We modeled exposure to C and O in Br/OvCa cell lines, including BRCA1mut+ cells. Results indicated exposure to O prior to C (C>O) reduced double stranded DNA damage and cell loss, compared with exposure to C followed by O (O>C) or concomitant treatment. Our trial tests the hypothesis that C>O is more effective. Women will be randomized to receive either Ox7 days followed by C (O>C) or C followed by Ox7 days (C>O) with schedule flip on cycle 2, allowing both intra-patient and inter-cohort examination of PK/PD endpoints. Pts will receive O days 1-7 with C on d1 or 2 on subsequent cycles, following our current schedule (NCTNCT00647062). PMBCs will be collected C1 and 2 for measures of platination and DNA damage/repair. Clinical endpoints of frequency and duration of response, and AEs will follow standard phase II definitions. Objectives: To determine the safe q12h dose of O tablet formulation given with C AUC4; To estimate the PK and PD effects of two schedules of O and C using PBMCs; To determine the schedule-associated safety of O and C in women’s cancers. Eligibility: Women with histologically documented recurrent women’s cancers (e.g. Br, gynecologic cancers) for whom standard curative therapies do not exist or are no longer effective; No platinum compound for 6 months; Evaluable disease and good end organ function. Methods: A 3+3 safety run-in will examine the new O tablet formulation and will precede and inform the randomized PK/PD portion of the study. All women will receive C AUC4 with no more than 8 C-containing cycles given; subsequent cycles will consist of daily oral O. O will be continued in all patients until progression or recurrence of disease. PBMCs will be collected prior to and during C1 and 2 for PD and PK analyses. Clinical benefit will be reassessed every other cycle. Biopsy at progression of disease will be requested of mutation carriers to evaluate development of BRCA1/2 re-expression mutations.
Radiogenomics of prostate cancer: Association between qunatitative multiparametric MRI features and PTEN.
Authors: David James VanderWeele, Stephanie McCann, Xiaobing Fan, Tatjana Antic, Yulei Jiang, Aytekin Oto
Journal: Journal of Clinical Oncology (2015)

126 Background: Better methods are needed to assess prior to prostatectomy the risk of aggressive prostate cancer. Radiogenomics is a promising new paradigm that aims to gain molecular and genomic insights from clinical images. Loss of PTEN expression correlates with clinically aggressive disease and is associated with a 7-fold increase in the risk of prostate cancer death. Methods: From 38 patients who had undergone multi-parametric prostate MRI prior to prostatectomy, a pathologist and a radiologist simultaneously identified 45 peripheral-zone cancer regions of interest (ROIs). Histologic sections of the cancer foci underwent immunohistochemical analysis and were scored according to percent of tumor cells expressing PTEN as: negative (0-20%), mixed (20-80%), or positive (80-100%). From the MRI ROIs, the average and 10th percentile ADC values, T2-weighted signal-intensity histogram skewness, and quantitative perfusion parameters were calculated. Both dynamic perfusion two-compartment model and an empirical mathematical model (EMM) were used to fit the average contrast concentration curves within the ROIs as a function of time. Associations between the quantitative image features and PTEN expression were analyzed with Pearson's correlation coefficient (r). Results: The PTEN scores were: positive (n = 21, 47%), mixed (n = 12, 27%), and negative (n = 12, 27%). Two perfusion imaging contrast uptake parameters obtained from EMM correlated with PTEN scores (r = 0.25, p &lt; 0.1 and r = 0.43, p &lt; 0.01), and T 2 -weighted signal-intensity skewness also showed some correlation tendency (r = −0.25, p &lt; 0.1). No correlation was seen between mean ADC and 10th percentile ADC values and PTEN score. Conclusions: This preliminary study of radiogenomics of prostate cancer suggests that fast contrast uptake of cancer on DCE-MR imaging and a T 2 -weighted imaging feature are potentially associated with prostate cancer PTEN expression, which warrants further studies and validation.
The role of biologic therapy in phase II breast cancer clinical trials.
Authors: K. Patel, A. Kamal, T. Zhang, A. Schneider, E. P. Hamilton, J. M. Peppercorn
Journal: Journal of Clinical Oncology (2011)

e13048 Background: Molecularly-targeted biologics (BioRx) hold the promise of improving outcomes and reducing toxicity of breast cancer therapy. We evaluated outcomes and trial characteristics of recently published breast cancer phase II trials (BCT) compared to other systemic therapy interventions. Methods: We reviewed all English language phase II BCT published between June 2005 and June 2010 identified in Pubmed. Eligible trials reporting disease specific outcomes were each abstracted by two investigators. We recorded intervention, treatment setting, correlative science, and disease outcomes. Results were analyzed by descriptive statistics, chi-square analysis, student’s t-test, and Wilcoxon ranked sums test. Results: 297 trials enrolling 18,319 patients were abstracted. 98 (32.7%) trials incorporated 31 unique BioRx interventions. Among these trials, 37 (37.8%) used BioRx as single agent therapy and 61 (62.2%) used BioRx combined with chemotherapy or hormone therapy. Neoadjuvant BCT were less likely to include BioRx than metastatic trials (17.4% vs. 37.2%, p = 0.006). 1st or 2nd line metastatic BCT were also less likely to include BioRx vs. late/any line trials (46.4% vs 70.4%; p<0.0003). In the metastatic setting, the median ORR for BioRx vs non-BioRx was 26.0% vs 44.2% (p<0.001). However, neither mean of medians for TTP (6.9 mo vs 7.5 mo; p=0.48) nor OS (19.6 mo vs 19.9 mo; p=0.51) were different for BioRx vs non-BioRx. Among metastatic BCT with single agent BioRx, median ORR = 6.0%, (interquartile range 1.4%-18.0%), TTP = 2.4 mo (interquartile range 1.8-5.5 mo), OS = 13.0 mo (interquartile range 6.9 -16.8 mo). Among all BioRx trials, 35.9% report no hematologic grade III/IV toxicity and 6.4% report no grade III/IV non-hematologic toxicity. Absence of grade III/IV hematologic toxicity was more common among single agent BioRx vs. combination BioRx (61.1% vs. 19%, p < 0.001). Conclusions: BioRx were used in 1/3 of recently published phase II BCTs. As single agents, BioRx often have reduced toxicity, but efficacy is highly variable. While median reported ORR for all BioRx trials is lower than that for other interventions, TTP and OS appear similar, supporting the belief that ORR may not be the optimal measure of BioRx efficacy.
Adjuvant docetaxel and cyclophosphamide (DC) with prophylactic growth colony stimulating factor (GCSF) on days 8 and 12 in breast cancer patients: A retrospective analysis.
Authors: Rinat Yerushalmi, Salomon M. Stemmer, Daniel Hendler, Victoria Neiman, Noa Beatrice Ciuraru, Luisa Bonilla, Irit Ben-Aharon, Limor Amit, Tal Granot, Alona Zer, Aaron Sulkes, Shulamith Rizel
Journal: Journal of Clinical Oncology (2012)

202 Background: Four cycles of docetaxel/cyclophosohamide (DC) produced superior survival compared with doxorubicin/cyclophosphamide in the treatment of early breast cancer. The study reported 5% of febrile neutropenia (FN) events using prophylactic antibiotics with no growth factor (GF) support. The worldwide adoption of this protocol yielded several reports on substantially higher rates of FN events (up to 46%), prompting the addition of GCSF by most centers. We explored the use of GF support on days 8 and 12 to the original DC protocol. This report summarizes treatment related morbidity of the DC protocol with GF support given on days 8 and12. Methods: All consecutive patients with stages I-II breast cancer who were treated with the DC protocol in our institute from April 2007 to March 2012 were included. Patient characteristics and toxicity were reported. Results: 131 patients were identified. Median age- 60y (25-81), 65y and older- 25%; 5 patients did not complete the 4 planned cycles (12/524 cycles were missed). Fifteen patients (11.5%) experienced at least one event of FN (4 patients had 2 events), all requiring hospitalization. FN events occurred in 19 out of 512 cycles (3%). Median age of the patients who required hospitalization due to FN was 60y (42-73). Results were comparable in the older group (≥65): 15% developed FN with 6 NF events out of 130 cycles (4.6%), p&gt;0.05. There were additional 14 hospitalizations events due to other causes (diarrhea n=2, chest pain=2, cellulitis n=2, COPD n=1, tonsillitis n=1, fever n=2, bone pain n=1, observation after treatment n=1 and hearing problem n=1, unknown n=1). Six patients had grade 2-3 diarrhea. 2/6 required hospitalization. There was no treatment related mortality. Conclusions: Primary prophylactic growth factor support on days 8 and 12 provides a safe and economic option to deliver the DC protocol. Our results are in line with other retrospective protocols using longer schedules of GF support.
Radiotherapy and chemotherapy in cerebral metastases.
Authors: L. Markulin-Grgic
Journal: Journal of Clinical Oncology (2011)

e12515 Background: Cerebral metastases are becoming more evident as the survival of patients and diagnostic methods are improving. Methods: 234 patients with cerebral metastases are discussed.Most patients were in the age group of 51-60 years ( min 23 y, max 79 y). Male to female ratio was 1.86:1. The most common primary tumor was bronchial carcinoma (62.3%), followed by breast carcinoma (14.5%), melanoma (4.5%), gastrointestinal carcinoma (4.5%), ovarian carcinoma (3.2%), hypernephroma (2.7%), testicular tumors (1.8%), cervical small cell carcinoma (1.4%). The primary tumor was unknown in 5.1 %. The patients were treated by various combinations of radiotherapy, chemotherapy and surgery. Stereotactic radiosurgery treatment was not included into this group. Results: Better survival results were achieved in younger patients, median of age being 57 years (p<0.005). Significantly better survival was obtained in patients with breast and ovarian carcinoma, median survival being 11 months (p<0.001). Considering the free interval duration, better results were achieved in patients with longer symptom-free period. If the symptom-free period was less than 3 months, the 1 year survival rate was 10% and the 2 year survival rate wa 2.7%. The patients with the symptom free period of 12 months and more had 1 year survival rate 40.3% and 2 year survival rate 10.5% (p<0.001). Conclusions: The results of patients treated by surgery, radiotherapy and chemotherapy are better than results of treatment by radiotherapy or chemotherapy only, or in combination (p<0.001). Better survival rates are achieved in female patients with breast and ovarian carcinoma. The symptom-free period appears to be significant prognostic factor, reflecting the biology of the primary tumor.
Systemic treatment patterns in small bowel and appendiceal adenocarcinomas (SBA and AA): A population-based study.
Authors: Jaclyn Marie Beca, Saber Fallahpour, Kelvin K. Chan, Ruby Redmond-Misner, Erin Diane Kennedy, Craig Earle, Scott R. Berry, Brandon Matthew Meyers, Stephen Welch, Jeffrey S. Hoch, Anna Liovas, Asmaa Maloul, Scott Gavura, James Joseph Biagi
Journal: Journal of Clinical Oncology (2016)

242 Background: There is uncertainty regarding the optimal systemic treatment for patients with SBA and AA due to the limited available evidence for these uncommon malignancies and conflicting recommendations in existing guidelines. However, on the basis of biologic similarities between SBA, AA and colorectal cancer (CRC), common practice is to use the same systemic therapies as for CRC. We compared the utilization of chemotherapeutic agents for SBA and AA to that of CRC patients in Ontario, Canada. Methods: The provincial tumour registry in Ontario, Canada was used to identify patients diagnosed with SBA, AA or CRC from 2010-2014. Subsequent chemotherapy utilization and costs were captured from single-payer government administrative databases. We studied the use of oxaliplatin, irinotecan, capecitabine, bevacizumab, cetuximab, panitumumab, and raltitrexed, which are funded for CRC treatment. Patients were excluded if they had multiple primary cancer sites, morphology codes inconsistent with adenocarcinomas, or missing identification data. Statistical analyses were used to report and test patterns of utilization and average costs per patient. Results: Our cohort consisted of 30,946 patients over a 5-year period. On average, 160 and 80 patients were diagnosed annually in Ontario with SBA and AA, respectively, together representing less than 4% of the total diagnoses each year. Among SBA and AA patients, 30-40% initiated therapy with the selected systemic therapies, similar to the proportion in CRC. SBA and AA patients were less likely to receive adjuvant oxaliplatin (SBA 9%, AA 13%) compared to CRC (18%) patients, but more likely to use first and second-line oxaliplatin or irinotecan for metastatic disease. Bevacizumab was added to first-line therapy for SBA and AA patients in fewer cases than CRC (SBA 29%, 45% AA, 72% CRC). Third-line EGFR inhibitors panitumumab and cetuximab were used infrequently in all groups ( &lt; 2% of those diagnosed). Average per patient costs were similar across disease sites (p &gt; 0.05). Conclusions: On a population level, SBA and AA patients appear to be managed similarly to CRC patients and at similar cost. Future research will evaluate survival outcomes.
The Public Repository of Xenografts Enables Discovery and Randomized Phase II-like Trials in Mice
Authors: Elizabeth C. Townsend, Mark A. Murakami, Alexandra Christodoulou, Amanda L. Christie, Johannes Köster, Tiffany A. DeSouza, Elizabeth A. Morgan, Scott P. Kallgren, Huiyun Liu, Shuo-Chieh Wu, Olivia Plana, Joan Montero, Kristen E. Stevenson, Prakash Rao, Raga Vadhi, Michael Andreeff, Philippe Armand, Karen K. Ballen, Patrizia Barzaghi-Rinaudo, Sarah Cahill, Rachael A. Clark, Vesselina G. Cooke, Matthew S. Davids, Daniel J. DeAngelo, David M. Dorfman, Hilary Eaton, Benjamin L. Ebert, Julia Etchin, Brant Firestone, David C. Fisher, Arnold S. Freedman, Ilene A. Galinsky, Hui Gao, Jacqueline S. Garcia, Francine Garnache-Ottou, Timothy A. Graubert, Alejandro Gutierrez, Ensar Halilovic, Marian H. Harris, Zachary T. Herbert, Steven M. Horwitz, Giorgio Inghirami, Andrew M. Intlekofer, Moriko Ito, Shai Izraeli, Eric D. Jacobsen, Caron A. Jacobson, Sébastien Jeay, Irmela Jeremias, Michelle A. Kelliher, Raphael Koch, Marina Konopleva, Nadja Kopp, Steven M. Kornblau, Andrew L. Kung, Thomas S. Kupper, Nicole R. LeBoeuf, Ann S. LaCasce, Emma Lees, Loretta S. Li, A. Thomas Look, Masato Murakami, Markus Muschen, Donna Neuberg, Samuel Y. Ng, Oreofe O. Odejide, Stuart H. Orkin, Rachel R. Paquette, Andrew E. Place, Justine E. Roderick, Jeremy A. Ryan, Stephen E. Sallan, Brent Shoji, Lewis B. Silverman, Robert J. Soiffer, David P. Steensma, Kimberly Stegmaier, Richard M. Stone, Jerome Tamburini, Aaron R. Thorner, Paul van Hummelen, Martha Wadleigh, Marion Wiesmann, Andrew P. Weng, Jens U. Wuerthner, David A. Williams, Bruce M. Wollison, Andrew A. Lane, Anthony Letai, Monica M. Bertagnolli, Jerome Ritz, Myles Brown, Henry Long, Jon C. Aster, Margaret A. Shipp, James D. Griffin, David M. Weinstock
Journal: Cancer Cell (2016)