tbuckley/cabot-search huggingface dataset:
Cardiovascular safety profile of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor: Results from two independent phase I trials in patients with advanced cancer
Authors: C. MacRae, P. G. Richardson, J. Walker, D. S. Grayzel, G. D. Demetri
Journal: Journal of Clinical Oncology (2009)

e14539 Background: Heat shock protein 90 (Hsp90) is a protein chaperone that regulates the proper folding, stability, and function of multiple mutated and wild type signaling proteins that promote malignant phenotypes. Numerous clinical trials are investigating the activity of the Hsp90 inhibitor IPI-504. Since Hsp90 is a novel cancer target that is ubiquitously expressed in normal cells, a comprehensive evaluation of potential cardiac effects, including the risk of ventricular arrhythmia, was performed in two Phase I trials. Methods: ECG data were pooled and analyzed from 60 pts in two-open label Phase I trials of patients with advanced cancers. Pts received 90 to 400 mg/m 2 of IPI-504 IV twice weekly for 2 out of 3 weeks. Subset analyses for 35 pts who received the MTD of 400 mg/m 2 were performed. ECGs were obtained in triplicate at 5, 60, and 360 minutes after IPI-504 infusion. Interpretation was conducted at a central, independent laboratory. Results: Over 6,500 ECGs were obtained from 60 pts. At the MTD 3,000 ECGs were obtained from 35 patients. No ventricular arrhythmias or changes in QTcF of ≥60 msec were noted, and no statistically significant relationship between the concentration or dose of IPI-504 and QTcF was observed. At the MTD 5 minutes post infusion, changes from baseline were observed in QTcF (5.4 ms increase), heart rate (15.2 bpm decrease), and PR interval (27.9 ms increase). All of these changes reversed by 6 hours post-infusion and no clinical hemodynamic disturbances were observed. Conclusions: In phase I studies, IPI-504 was not associated with any significant ventricular arrhythmia and no clinically significant QTcF interval changes were noted. These studies did show however that IPI-504 administration was associated with transient, dose-related bradycardia and PR interval lengthening, suggestive of autonomic effects associated with the drug infusion. No clinically significant and IPI-504 related cardiac safety events were observed at the MTD dose of 400 mg/m 2 . Given these findings, appropriate monitoring of heart rate immediately post-infusion is recommended during further studies with IPI-504. [Table: see text]
Phase II trial of oral imatinib in combination with every-three-week intravenous docetaxel in patients with metastatic, hormone- refractory prostate cancer
Authors: L. J. Appleman, D. Friedland, C. Chaussard, W. Gooding, T. Feinstein, M. Sulecki, T. Evans, S. Corgnati, H. Strausser, G. Chatta
Journal: Journal of Clinical Oncology (2007)

15603 Background: Imatinib is a small molecule tyrosine kinase inhibitor specific for Bcr-Abl, platelet-derived growth factor receptor (PDGFR) and c-Kit. Inhibition of PDGFR abrogates pericyte migration and perturbs regulation of interstitial fluid pressure, suggesting potential anti-tumor effect in combination with chemotherapy. Docetaxel is a microtubule-stabilizing cytotoxic agent shown to prolong survival in men with androgen-refractory prostate cancer (AIPC) when administered at 75 mg/m 2 every 21 days. We have previously established that imatinib 400 mg daily plus docetaxel 60 mg/m 2 every 21 days is well tolerated and now hypothesize that this combination will prolong time to disease progression (TTP) in patients with AIPC. Methods: Subjects with progressive AIPC received docetaxel 60 mg/m 2 intravenously every 21 days (day 1; up to 8 cycles) plus imatinib 400 mg by mouth daily starting on day -3. After the first 6 subjects, the study treatment was modified so that subjects receive oral imatinib 400 mg only on days -3 thru +7 of each 21-day cycle. The primary endpoint is TTP. The sample size is 43 patients, providing 90% power to detect an increase in TTP from 5 to 8 months. Results: Nineteen subjects have enrolled in the study between August 2005 and October 2006. Age range of subjects was 54 to 84 years (median 69 years). Serious adverse events (=Grade (G) 3) were principally hematologic: neutropenia (G4=5, G3=2); thrombocytopenia (G4=1, G3=1), hemoglobin (G4=1). There was one G4 myocardial infarction and one incident of G5 sepsis associated with methicillin-resistant S. aureus bacteremia and normal neutrophil count. One instance each of the following G3 toxicities were observed: fatigue, myalgia, dyspnea, nausea/vomiting, diarrhea, chest pain, dizziness, urinary retention. Five subjects had &gt;50% decrease in serum PSA. Eight subjects received 4 or more cycles of docetaxel, and 4 subjects continued on imatinib maintenance after completing 6–8 cycles of docetaxel plus imatinib. Conclusions: Intravenous docetaxel on day 1 plus oral imatinib on days -3 thru +7 of a 21-day cycle is generally well- tolerated in men with AIPC. Prolonged stable disease and/or serum PSA response was observed in several subjects. [Table: see text]
Phase II study of sorafenib combined with gemcitabine and 5-fluorouracil in patients with metastatic renal cell carcinoma: Preliminary results
Authors: L. Hongyun, C. Zhihong, Y. Xiangqing, S. Lu, C. Chuanliang, S. Xinan, S. Lin, G. Jun
Journal: Journal of Clinical Oncology (2009)

e16093 Background: The tyrosine kinase inhibitors sorafenib and sunitinib have been approved for use in patients with advanced RCC and have supplanted immunotherapy as first-line therapy. Nevertheless, complete responses have been observed only rarely with these agents and only 10% of patients experience PR. The vast majority of responding patients will ultimately progress despite continued therapy. In order to improve the objective response rate and the durability of those responses in patients, we conducted a single-institution, single-arm phase II trial of gemcitabine and 5-fluorouracil (5-FU) combined with sorafenib in patients with RCC. Methods: Eligibility criteria included advanced, histologically confirmed RCC; age &gt;18 years; ECOG PS ≤ 2, adequate bone marrow, renal and hepatic function; measurable/evaluable lesions. Gemcitabine was administered at 1,000 mg/m 2 over 30 min i.v. on days 1 and 8, followed by 5-FU 400 mg/m 2 i.v. bolus on day 1 and 1,200 mg/m 2 /day × 2 days continuous infusion (28-day cycle). From day 1 of cycle 1, 400 mg sorafenib was continuously given twice daily. The sample size of 21 patients was sufficient to provide 80% power to detect an objective response rate that was greater than 10% with significance that 0.05 level. Results were expressed as mean±SD or median ± 95% CI. The primary study endpoint was objective response rate and the secondary were toxicity, progression-free survival and overall survival. Results: Patients (n = 21) were enrolled from May 2006 to Dec. 2007. The rate of objective response and disease control (including stable disease, complete responses and partial responses) were 38% (95% CI, 18–62%) and 86% (95% CI, 64–97%), respectively. Among them, there is 1 complete response and 2 pts occurred completely liquefaction deliquesce in metastatic lesions. The median PFS time is longer than 13 months, with 6/21 patients remaining progression free at 2008.12.26 the data were compiled for this report (three are longer than 26 months and there other three longer than 13 months ). The median OS time have not yet been reached, because of the amount of censoring data. Conclusions: The combination of sorafenib with gemcitabine and 5-FU shows promising activity for patients with metastatic RCC. No significant financial relationships to disclose.
ESM1 as a Marker of Macrotrabecular-Massive Hepatocellular Carcinoma
Authors: Julien Calderaro, Léa Meunier, Cong Trung Nguyen, Marouane Boubaya, Stefano Caruso, Alain Luciani, Giuliana Amaddeo, Hélène Regnault, Jean-Charles Nault, Justine Cohen, Frédéric Oberti, Sophie Michalak, Mohamed Bouattour, Valérie Vilgrain, Georges Philippe Pageaux, Jeanne Ramos, Nathalie Barget, Boris Guiu, Valérie Paradis, Christophe Aubé, Alexis Laurent, Jean-Michel Pawlotsky, Nathalie Ganne-Carrié, Jessica Zucman-Rossi, Olivier Seror, Marianne Ziol
Journal: Clinical Cancer Research (2019)

Macrotrabecular-massive hepatocellular carcinoma (MTM-HCC) is a novel morphological subtype of HCC associated with early relapse after resection or percutaneous ablation, independently of classical clinical and radiological prognostic factors. The aim of the present study was to identify immunohistochemical markers of MTM-HCC, to ease its diagnosis and implementation into clinical practice.To identify potential biomarkers of MTM-HCC, we first analyzed gene expression profiling data from The Cancer Genome Atlas study and further selected two candidate biomarkers. Performance of both biomarkers for diagnosis of MTM-HCC was further tested by immunohistochemistry in two independent series of 67 and 132 HCC biopsy samples.Analysis of RNA sequencing data showed that MTM-HCC was characterized by a high expression of neoangiogenesis-related genes. Two candidate biomarkers, Endothelial-Specific Molecule 1 (ESM1) and Carbonic Anhydrase IX (CAIX), were selected. In the discovery series, sensitivity and specificity of ESM1 expression by stromal endothelial cells for the detection of MTM-HCC were 97% (28/29), and 92% (35/38), respectively. Sensitivity and specificity of CAIX were 48% (14/29) and 89% (34/38). In the validation set, sensitivity and specificity of ESM1 for the identification of MTM-HCC were 93% (14/15) and 91% (107/117), respectively. Interobserver agreement for ESM1 assessment was good in both series (Cohen Kappa 0.77 and 0.76).Using a molecular-driven selection of biomarkers, we identified ESM1 as a reliable microenvironment immunohistochemical marker of MTM-HCC. The results represent a step toward the implementation of HCC morpho-molecular subtyping into clinical practice.
Elevation of Cardio-Ankle Vascular Index in Patients with Malignant Lymphoma Treated with R-CHOP Regimen
Authors: Naomi Shimizu, Yasuhiro Watanabe, Shouko Nakamura, Sho Tanaka, Rena Oka, Yuta Sato, Haruki Imamura, Takashi Yamaguchi, Chiaki Nakaseko, Emiko Sakaida, Hideaki Bujo, Kohji Shirai, Ichiro Tatsuno
Journal: Blood (2017)
Correlation of VEGFR activation within the tumor-associated stroma with an aggressive colon cancer phenotype.
Authors: Anouck Huijbers, Elisa Pin, Mariaelena Pierobon, Gabi W. van Pelt, Claudio Belluco, Alessandra Silvestri, Lance A. Liotta, Rob A Tollenaar, Emanuel Petricoin, Wilma E Mesker
Journal: Journal of Clinical Oncology (2012)

e14151 Background: The tumour microenvironment, and especially the stroma surrounding the tumor cells, is an important target for cancer therapy. Previous results published by our group showed that colon cancer (CC) patients with a high (&gt;50%) intra-tumor stroma ratio had poor prognosis compared to patients with low intra-tumor stroma ratios. In order to evaluate the contribution of the underpinning signalling and molecular architecture of the tumor associated stroma (TAS) to this aggressive phenotype, we utilized laser capture microdissection (LCM) coupled to broad-scale protein pathway activation mapping using reverse phase protein microarrays (RPMA). Such analysis could identify new stromal-based targeted treatment options through the identification of activated pathways within the TAS of patients with aggressive CC. Methods: CC stage II and III tissue specimens were scored for the amount of stroma and a stroma-high and a stroma-low group were defined. Correspondent frozen tumor specimens were selected for a pilot study (n=30; 15 high and 15 low TAS) and subjected to LCM to enrich for TAS cells. RPMA was performed on the resultant lysates whereby an initial set of 30 total and phospho-proteins, known to be involved in stroma proliferation and activation, were analyzed. Results: Unsupervised hierarchical clustering analysis showed partial grouping of stroma high and stroma low samples with phosphorylation of VEGFR-2 being significantly higher in the stroma high group compared to the stroma low (p=0.030). Conclusions: These preliminary results reveal the potential presence of biochemical derangements in the TAS of tumors from patients with aggressive CC with increased activation of VEGFR-2. Considering the central role this protein plays in angiogenesis and cell migration, these results suggest that anti-VEGFR targeted therapy could be considered for a pre-stratified group of patients with aggressive tumors with high recurrence rates. Ongoing expanded pathway analysis with additional signalling proteins including downstream signalling components of VEGFR are being conducted in order to validate this pilot finding and identify new TAS related signalling derangements.
Abstract 13796: Collagen Turnover Markers Are Associated With New Onset of Atrial Fibrillation in Asymptomatic Subjects: The Multi-Ethnic Study of Atherosclerosis (MESA) Study
Authors: Daniel A Duprez, Alvaro Alonso, Myron Gross, Jorge R Kizer, Joachim Ix, Russell Tracy, Susan Heckbert, Richard Kronmal, David R Jacobs
Journal: Circulation (2017)

Atrial fibrosis is a hallmark of structural remodeling in atrial fibrillation (AF). Procollagen Type III N- Terminal Propeptide (PIIINP) and Collagen Type I Carboxy-Terminal Telopeptide (ICTP) refl...
Peripheral immunosuppressive cell levels as predictive marker for the clinical outcome in stage IV colorectal carcinoma.
Authors: Anna Koutoulaki, Zafeiris Zafeiriou, Dimitra Skalidaki, Despoina Aggouraki, Kiriaki E Vetsika, Dimitrios Mavroudis, Vassilis Georgoulias, Athanasios Panayotis Kotsakis
Journal: Journal of Clinical Oncology (2013)

e14639 Background: Immune suppressive cells,Myeloid-Derived Suppressor Cells (MDSCs) and T Regulatory Cells (Tregs) have been identified as negative prognostic biomarkers in distinct solid tumors. In colorectal cancer (CRC), increased peripheral levels of MDSCs have been correlated to worse survival (Solito S et al.; Blood 2011). Although Tregs infiltrated in tumors have been associated with favourable clinical outcome (Salama P et al.; JCO 2009), their significance in peripheral blood remains unclear. The aim of the present study was to evaluate the role of these cells in the peripheral blood as a prognostic marker in CRC patients. Methods: Blood sample was collected from 49 CRC naïve patients (Stage IV) prior to 1 st line treatment and 33 healthy donors. Flow cytometric analysis of MDSCs (HLA-DR - Lin -/low CD33 + CD11b + ) and Tregs (CD3 + CD4 + CD25 high CD127 low/- FoxP3 + CD39 + ) was performed in fresh samples. MDSC and Treg levels of patients and normal controls were analyzed by using unpaired t-test. ROC analysis (area = 0.8539) was used to define high versus low MDSC levels, whereas the median value of Tregs in normal controls was used as a cut-off. Among patients that relapsed, Kaplan-Meier analysis was used to compare time to tumor progression (TTP) with high and low levels of MDSCs and Tregs. Results: The median percentages of MDSCs and Tregs in patients were significantly increased compared to controls (Mann Whitney test: p &lt; 0.0001; p = 0.0111, respectively). MDSCs were positively correlated to Treg levels (Spearman's r 2 = +0.408; p = 0.048). Patients with high levels of MDSCs at baseline, but not Tregs (p = 0.7165), relapsed earlier to those with low levels (p= 0.0348; 9.83 vs. 4.93 months, respectively). Conclusions: CRC patients have elevated peripheral levels of immunosuppressive cells. MDSCs seem to be an independent prognostic factor for TTP. The significance of the observed correlation of MDSCs with Tregs and the suppressive mechanisms of these cells will be further investigated. Updated survival data will be presented in an increased cohort of patients.
A subset of HLA-DP molecules serve as ligands for the natural cytotoxicity receptor NKp44
Authors: Annika Niehrs, Wilfredo F. Garcia-Beltran, Paul J. Norman, Gabrielle M. Watson, Angelique Hölzemer, Anaïs Chapel, Laura Richert, Andreas Pommerening-Röser, Christian Körner, Mikki Ozawa, Glòria Martrus, Jamie Rossjohn, Jar-How Lee, Richard Berry, Mary Carrington, Marcus Altfeld
Journal: Nature Immunology (2019)
Pancreatic endocrine tumors (PETs): Incidence and recent trend toward improved survival
Authors: T. R. Halfdanarson, K. Rabe, J. Rubin, G. M. Petersen
Journal: Journal of Clinical Oncology (2007)

4584 Background: PETs (islet cell tumors) are uncommon and often indolent tumors, but little is known about the incidence of PETs in the US and trends in survival. Methods: The SEER registry was used to identify cases of functional PETs (fPETs) and non-functional PETs (nfPETs) diagnosed from 1973–2000. Benign insulinomas were excluded. Incidence rates were age adjusted to the standard US population for 2000. Results: Of 971 patients with PETs, 824 (85%) were nfPETs, 37 (4%) were malignant insulinomas, 88 (9%) were fPETs other than insulinoma, and data were missing for 22 (2%). The crude annual incidence of PETs (per 100,000) for all ages was 0.1 in females and 0.2 in males. The incidence was highest in the age group &gt;70 years (0.4, Table ). Tumors were localized in 109 (11%), regionally advanced in 228 (23%), and distant metastases were present in 545 (56%). Patients with fPETs were younger than patients with nfPETs (mean age 54.2 vs. 57.6, p=0.038) and had a longer median survival (MS) (47 vs. 30 months (mos), p=0.001) but were as likely to have advanced disease (p=0.50). The 5 and 10 year overall survival was 45.3% vs. 32.7% and 31.7% vs. 18.1% for fPETs vs. nfPETs, respectively. MS was 95 mos for localized PETs, 66 mos in regionally advanced PETs and 19 mos for distant metastases (p&lt;0.001). Race did not influence incidence and survival. On multivariate analysis, only age (p&lt;0.0001) and stage (&lt;0.0001) were independently associated with prognosis but the functional status of the tumor approached significance (p=0.053). Survival has improved over time with longer MS in patients diagnosed in later quartiles of the observation period (p&lt;0.001, Table). This difference is not explained by stage migration, as patients in all four quartiles had a similar stage distribution (p=0.79). Conclusions: PETs are uncommon tumors and the prognosis is highly dependent on the stage and the age of the patients. Patients with fPETs may have a better prognosis than nfPETs. Survival has improved over time. [Table: see text] No significant financial relationships to disclose.
A phase II study of neoadjuvant chemotherapy with docetaxel, capecitabine and cisplatin (DXP) in patients with advanced unresectable or intra-abdominal metastatic gastric cancer
Authors: S. Sym, H. Chang, M. Ryu, J. Lee, T. Kim, J. Yook, S. Oh, B. Kim, Y. Kang
Journal: Journal of Clinical Oncology (2007)

4640 Background: The prognosis of gastric cancer is dismal once R0 resection is impossible due to local invasion or distant metastasis. Previous studies have suggested the possible efficacy of neoadjuvant chemotherapy for the patients with locally advanced gastric cancer (AGC). The aim of the present study was to evaluate the feasibility, the impact on R0 resection of neoadjuvant chemotherapy in locally advanced, unresectable or intra-abdominal metastatic gastric cancer Methods: Patients with advanced gastric cancer, clinically unresectable because of local invasion or intra-abdominal metastasis in paraaortic lymph nodes and/or peritoneum based on CT scan were entered into this study. Preoperative chemotherapy consisted of docetaxel 60 mg/m 2 IV on day 1, cisplatin 60 mg/m 2 IV on day 1, and capecitabine 1,875 mg/m 2 /day PO on days 1 - 14 every 21 days. After 2 cycles of chemotherapy, the tumors were evaluated. Unless disease progression was encountered, surgery was performed after total 3 - 6 cycles of chemotherapy and followed by two cycle of adjuvant therapy with the same regimen if R0 resection was done. Results: Total 49 patients were accrued. Among them, 36 (74%) could undergo surgery, and 31 (63%) had R0 resection. R0 resection was possible in 15 (71%) of 21 patients with initially unresectable T4 lesions and in 12 (70%) of 17 patients with paraaortic lymph node enlargement, while only in 3 (42%) of 7 patients with suspicious peritoneal seeding. After a median follow up of 18.2 months for the surviving patients, median overall survival and progression free survival of total enrolled patients were 19 months (95% C.I, 10.5 - 27.4) and 11.6 months (95% C.I, 9.6 - 13.7), respectively. Among 31 patients who underwent R0 resection, median OS was 33.4 months and median PFS was 18.2 months. Major toxicity was neutropenia and grade 3/4 neutropenia occurred in 77% of patients, but there was only 4% of neutropenic fever and no treatment related mortality. Postoperative morbidities were observed in 4 patients. Conclusions: These data suggested that neoadjuvant DXP chemotherapy could offer a reasonable chance for curative surgery in AGC patients with local invasion or paraaortic lymph node enlargement. No significant financial relationships to disclose.
A model for multi-institutional, multidisciplinary sarcoma videoconferencing.
Authors: Steven Attia, Robert G. Maki, Jonathan C. Trent, Scott H. Okuno, Daniel J. Indelicato, Nicolas P Webber, Kelly Kevelin Curtis, Kevin Robert Kozak
Journal: Journal of Clinical Oncology (2013)

10521 Background: Sarcomas are rare cancers, with &gt; 50 subtypes, and require multi-disciplinary care. Their management benefits from multi-institutional input due to the paucity of concentrated experience with each subtype. However, sarcoma tumor boards, wherein a patient-specific, consensus treatment approach is determined, are predominantly conducted in isolation at individual centers. Methods: Since March 2010, we have conducted a weekly multi-institutional, multi-disciplinary sarcoma tumor board to combine knowledge and experience in the management of our most challenging patients. The Mayo Clinic bridge links sites by interactive videofeed. Each site may contribute cases. De-identified history, radiology and pathology are reviewed. A didactic series reviews a rotation of seminal papers, newly published research, or our own data. An “Expert Guest" series allows outside experts to connect to one conference. A yearly participant survey assesses quality. Conference is free to sites and is CME accredited. Results: Currently, 8 sarcoma programs connect Mondays from 8-9am ET. Median attendance is 20 (range: 8-27). In 2012, 342 cases were reviewed over 43 conferences (median: 8 cases/conference; range: 4-12 cases/conference). The 2012 survey revealed 96% (25/26) agreed HIPAA rules are followed; 93% (25/27) agreed conference is educational; 93% (25/27) agreed recommendations are evidenced-based or reasonable; 100% (27/27) agreed participants are respectful; and 86% (18/21) agreed input from other sites has changed their management. Staff attendance (quantity) rated as meets/exceeds needs was 100% (25/25) for medical oncology; 96% (26/27) for pathology; 93% (25/27) for orthopedic oncology; 92% (23/25) for radiation oncology, surgical oncology and radiology; and 61% (17/23) for thoracic oncology. Conclusions: To our knowledge, this is the only weekly multi-institutional sarcoma tumor board in existence. It permits consistent oncology care across a wide geographic area, and is a model for providing consensus recommendations regardless of the remoteness of the patient and care team. Future plans for this group include prospective collection of outcomes data.