tbuckley/cabot-search huggingface dataset:
Autologous Dendritic Cells Pulsed with Allogeneic Tumor Cell Lysate in Mesothelioma: From Mouse to Human
Authors: Joachim G.J.V. Aerts, Pauline L. de Goeje, Robin Cornelissen, Margaretha E.H. Kaijen-Lambers, Koen Bezemer, Cor H. van der Leest, Niken M. Mahaweni, André Kunert, Ferry A.L.M. Eskens, Cynthia Waasdorp, Eric Braakman, Bronno van der Holt, Arnold G. Vulto, Rudi W. Hendriks, Joost P.J.J. Hegmans, Henk C. Hoogsteden
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Mesothelioma has been regarded as a nonimmunogenic tumor, which is also shown by the low response rates to treatments targeting the PD-1/PD-L1 axis. Previously, we demonstrated that autologous tumor lysate–pulsed dendritic cell (DC) immunotherapy increased T-cell response toward malignant mesothelioma. However, the use of autologous tumor material hampers implementation in large clinical trials, which might be overcome by using allogeneic tumor cell lines as tumor antigen source. The purpose of this study was to investigate whether allogeneic lysate–pulsed DC immunotherapy is effective in mice and safe in humans. Experimental Design: First, in two murine mesothelioma models, mice were treated with autologous DCs pulsed with either autologous or allogeneic tumor lysate or injected with PBS (negative control). Survival and tumor-directed T-cell responses of these mice were monitored. Results were taken forward in a first-in-human clinical trial, in which 9 patients were treated with 10, 25, or 50 million DCs per vaccination. DC vaccination consisted of autologous monocyte–derived DCs pulsed with tumor lysate from five mesothelioma cell lines. Results: In mice, allogeneic lysate–pulsed DC immunotherapy induced tumor-specific T cells and led to an increased survival, to a similar extent as DC immunotherapy with autologous tumor lysate. In the first-in-human clinical trial, no dose-limiting toxicities were established and radiographic responses were observed. Median PFS was 8.8 months [95% confidence interval (CI), 4.1–20.3] and median OS not reached (median follow-up = 22.8 months). Conclusions: DC immunotherapy with allogeneic tumor lysate is effective in mice and safe and feasible in humans. Clin Cancer Res; 24(4); 766–76. ©2017 AACR.
A phase 2, open-label study of rucaparib in patients with pancreatic cancer and a known deleterious BRCA mutation.
Authors: Susan M. Domchek, Robert R. McWilliams, Andrew Eugene Hendifar, Rachna T. Shroff, Lawrence P. Leichman, Ron Epelbaum, Ravit Geva, George P. Kim, Steven R. Alberts, Robert A. Wolff, Andrew R. Allen, Heidi Giordano, Mitch Raponi, Jeffrey D. Isaacson, Lindsey Rolfe, Andrew Biankin, Robert H. Vonderheide
Journal: Journal of Clinical Oncology (2014)

TPS4161 Background: Approximately 5% of unselected pancreatic cancer (PC) patients (pts), 10% of PC pts of Ashkenazi Jewish descent, and up to 19% of familial PC families, harbor a germline BRCA mutation. PARP inhibitors (PARPi) have exhibited clinical activity in pts with a BRCA mutation. Rucaparib, an oral PARPi, is being developed for treatment of cancers associated with homologous recombination repair (HRR) deficiency due to a BRCA mutation or other HRR pathway defect. Rucaparib has demonstrated clinical activity (RECIST and CA-125 responses) in pts with BRCAmut pancreatic, ovarian, or breast cancer in an ongoing Phase 1/2 study (NCT01482715). Clinical activity of PARPi in BRCAmut PC combined with the paucity of active 2nd-line therapies support evaluation of rucaparib in PC pts with a deleterious BRCA mutation. Methods: Study CO-338-023 (NCT02042378) is a single-arm, open-label Phase 2 trial of continuous rucaparib in up to 100 pts with pancreatic ductal adenocarcinoma (or related subtype) and a known deleterious BRCA mutation (germline or somatic). Pts must have received at least 1, but no more than 2, prior regimens for locally advanced or metastatic disease and have relapsed disease, or are no longer able to tolerate chemotherapy due to toxicity and radiologic assessment confirms no response to such treatment. Other key inclusion criteria include measurable disease, ECOG PS 0 or 1, and adequate organ function. Pts with endocrine tumors or prior PARPi treatment are excluded. Pts will take rucaparib continuously and be evaluated for safety every 2–4 wks, disease status (CT scans, CA19–9) every 4–8 wks until disease progression, and then survival every 4 wks. Blood and archival tumor tissue (if available) will be collected from all pts. The primary endpoint is ORR by RECIST v1.1. Key secondary endpoints include duration of response, PFS, OS, and safety. Exploratory analyses include gene sequence and structural rearrangements of tumor DNA, and evaluation of circulating tumor DNA. A group sequential interim monitoring plan will be implemented to stop the study early for either superior efficacy or futility. Interim analyses will occur after every 10th pt enrolled has sufficient disease assessment data available. Clinical trial information: NCT02042378.
Experience with a Therapeutic Platelet Transfusion Strategy in Acute Myeloid Leukemia: Preliminary Results of a Randomized Multicenter Study After Enrolment of 175 Patients.
Authors: Hannes Wandt, Kerstin Schaefer-Eckart, Bettina Pilz, Markus Thalheimer, Anthony D Ho, Markus Schaich, Martin Kaufmann, Walter E. Aulitzky, Mathias Haenel, Regina Herbst, Gottfried Doelken, Anne Friederike Klenner, Mathias Freund, Christian Junghanss, Gerhard Ehninger
Journal: Blood (2009)
Lymph Node Metastases in Colon Cancer Are Polyclonal
Authors: Peter J. Ulintz, Joel K. Greenson, Rong Wu, Eric R. Fearon, Karin M. Hardiman
Journal: Clinical Cancer Research (2017)

Purpose: Recent studies have highlighted the existence of subclones in tumors. Lymph nodes are generally the first location of metastasis for most solid epithelial tumors, including colorectal cancer. We sought to understand the genetic origin of lymph node metastasis in colorectal cancer by evaluating the relationship between colorectal cancer subclones present in primary tumors and lymph nodes.Experimental Design: A total of 33 samples from seven colorectal cancers, including two or three spatially disparate regions from each primary tumor and one to four matched lymph nodes for each tumor, underwent next-generation whole-exome DNA sequencing, Affymetrix OncoScan SNP arrays, and targeted deep confirmatory sequencing. We performed mapping between SNPs and copy number events from the primary tumor and matched lymph node samples, allowing us to profile heterogeneity and the mutational origin of lymph node metastases. The computational method PyClone was used to define subclones within each tumor. The method Clonality Inference in Tumors Using Phylogeny (CITUP) was subsequently used to infer phylogenetic relationships among subclones.Results: We found that there was substantial heterogeneity in mutations and copy number changes among all samples from any given patient. For each patient, the primary tumor regions and matched lymph node metastases were each polyclonal, and the clonal populations differed from one lymph node to another. In some patients, the cancer cell populations in a given lymph node originated from multiple distinct regions of a tumor.Conclusions: Our data support a model of lymph node metastatic spread in colorectal cancer whereby metastases originate from multiple waves of seeding from the primary tumor over time. Clin Cancer Res; 24(9); 2214-24. ©2017 AACRSee related commentary by Gerlinger, p. 2032.
Oncologic outcome and technical consideration of nipple-sparing mastectomy in breast cancer: The St. Marianna experience with 384 patients.
Authors: Ayaka Koike-Shimo, Koichiro Tsugawa, Hisanori Kawamoto, Yoshihide Kanemaki, Ichiro Maeda
Journal: Journal of Clinical Oncology (2014)

e12024 Background: Nipple-sparing mastectomy (NSM) is an increasingly utilized surgical option for breast cancer. However, the oncologic safety is controversial. We evaluated the oncologic outcome of 384 patients underwent NSM. Methods: A retrospective chart review was performed of 384 patients undergoing NSM during January 2000 to December 2011. In our institute, the indication of NSM is no suspicious infiltration to nipple-areolar complex by preoperative MRI imaging, and negative subareolar biopsy by intraoperative frozen section. We collected the data included patient age, the size of tumor, number of metastatic lymph node, histologic type, subtype, biomarker, and adjuvant therapies, analyzed as the risk factors of the nipple-areola recurrence. Results: Three hundred ninety-seven breasts in 384 patients underwent NSM. Thirty-four cases underwent nipple-areolar complex removal because of positive biopsies. One hundred fifty patients underwent immediate reconstructions and 9 patients underwent delayed reconstructions. Median follow-up time after surgery was 49.5 months (range13-154). Three cases (0.8%) had the nipple loss complications due to nipple necrosis after NSM. The local recurrence rate after NSM was 5.2% (19 cases), and it was similar to the conventional total mastectomies in the same periods, 5.0% (39 in 773 cases). Furthermore, the localized nipple-areolar recurrence rate after NSM was 2.2% (8 cases). The HER2-enriched tumors and young age (< 40 years old) were significantly increasing factors to the nipple-areolar recurrences. Nevertheless, the sites of nipple recurrence were able to be excised easily, and the good cosmetic results were kept in the breast reconstruction cases. The distant recurrence rate after NSM was 6.9% (25 patients), and it was similar to the conventional total mastectomies in the same periods, 9.7% (75 in 773 patients). Conclusions: The nipple-areolar recurrence rate as 2.2% was low. The NSM could be performed in safety with the low complications. The NSM was technically feasible and provided good oncologic outcomes.
Phase I study of procaspase activating compound -1 (PAC-1) in the treatment of advanced malignancies.
Authors: Oana Cristina Danciu, Martin Kelly Nicholas, Matthias Holdhoff, Neeta K. Venepalli, Paul J. Hergenrother, Theodore M Tarasow, Arkadiusz Z. Dudek
Journal: Journal of Clinical Oncology (2016)

TPS2605 Background: Members of the caspase family of cysteine proteases are key players in both the initiation and execution of apoptosis; the activation of procaspase-3 to caspase-3 is a critical event in the apoptotic cascade. Procaspase-3 levels are elevated in: glioblastoma, breast cancer, colon cancer, lung cancer, lymphoma, neuroblastoma, melanoma, and liver cancer. As a consequence, caspase-3 levels are abnormally low in these tumors, allowing the tumors to avoid apoptosis. PAC-1 is a small molecule that directly activates procaspase-3 and induces apoptosis of cancer cells in culture. PAC-1 showed efficacy across a wide range of cancer cell lines, as well as in animal models of cancer, including brain cancer. This novel compound potently synergizes with chemotherapy agents (e.g.doxorubicin, temozolomide, etoposide, carboplatin). Methods: This is a Phase I dose escalation study with a modified- Fibonacci 3+3 design, consisting of two parts: to determine the maximum tolerated dose (MTD) of PAC-1 in advanced malignancies, and to determine the MTD of PAC-1 when combined with temozolomide in patients with primary brain tumors. For both parts the MTD dose level will expand to a total of 9 patients to ensure safety. Primary objectives: establish MTD, tolerability and toxicity. Secondary and correlative objectives: pharmacokinetics, pharmacodynamics, preliminary antitumor activity correlation with procaspase-3 expression in tumor, clinical response and adverse effects. Neurological symptoms of CNS toxicity will be assessed throughout the trial. Inclusion criteria: diagnoses of advanced malignancies (for part 1) and high grade glioma (for part 2), ECOG PS 0-2, adequate organ function. Exclusion criteria: received prior cytotoxic therapy in the last 3-6 weeks (duration based on prior therapy) or uncontrolled chronic illness. Administration and design: Part 1, PAC-1 (PO) is dosed at 75-450 mg daily (up to 5 dose levels) on days 1-21 on 28 days cycle. In Part 2, the first PAC-1 dose will be 1 dose lower than the PAC-1 MTD established in Part 1 (up to 3 dose levels).Temozolomide (PO) will be dosed at 150 mg/m2 daily for 5 days starting on day 8 of each cycle. The study is currently enrolling patients in Part 1, NCT02355535. Clinical trial information: NCT02355535.
Abstract 13850: Severity Assessment of Coronary Artery Aneurysm by Z-score of the Internal Diameter in Kawasaki Disease
Authors: Masaru Miura, Naoya Fukushima, Tetsuji Kaneko, Tohru Kobayashi, Kenji Suda, Hiroyuki Yamagishi, Taichi Kato, Shinya Shimoyama, Hitoshi Kato, Tsutomu Saji, Kenji Hamaoka, Yuichi Nomura, Kenji Waki, Ryuji Fukazawa, Keiichi Hirono, Shigeto Fuse
Journal: Circulation (2015)

Introduction: The severity of coronary artery aneurysms (CAA) in patients with Kawasaki disease (KD) has been recently classified according to the z-score. However, it is not known whether this classification can predict coronary events such as stenosis, obstruction, and thrombosis. Methods: In this multicenter retrospective study, data on height, weight, CAA diameter measured by echocardiography in the acute phase, and the clinical course in KD patients 18 years of age or younger who received a coronary angiography between 1992 and 2011 were collected. Time-dependent occurrence of coronary events was analyzed by Kaplan-Meier method according to small (z-score, &lt; 5.0), medium (≥ 5.0 to &lt; 10.0), and large (≥ 10.0) CAA using a 5 increment scale scheduled to be included in the new American Heart Association criteria. Cox regression analysis was used to identify risk factors for coronary events. The occurrence rate of major cardiac events such as angina pectoris, myocardial infarction, and cardiac death was also analyzed. Results: Data were analyzed for 1,002 patients from 44 institutions. Both the body surface area and CAA diameters were available in 741 cases for the right coronary artery (RCA) and 609 cases for the left anterior descending artery (LAD). Coronary events occurred in 83 (11.2%) of the RCA group and 57 (9.4%) of the LAD group, while major events occurred in 30 cases (3.0%). The 10-year event-free survival rate for coronary events for small, medium, and large aneurysms was 100, 95.5, and 64.9% in the RCA group, and 100, 94.4, and 63.5% for aneurysms in the LAD group, respectively. The rate of major cardiac events was 98.5, 98.1, and 87.6% for the RCA group, and 100, 97.5, and 86.8% for the LAD group, respectively. Cox regression analyses showed that the z-score of the CAA diameter was an independent risk factor for coronary events for the RCA [large versus medium aneurysm; hazard ratio (HR) 2.8, 95% confidence interval (CI) 1.5 to 5.3, p = 0.002] and the LAD [HR 3.2, 95% CI 1.6 to 6.5, p = 0.015] groups. Conclusions: The severity assessment of CAA using the 5-increment z-score for coronary arterial diameter can predict the time-dependent occurrence of coronary events in patients with KD.
Abstract 17227: Transplantation of Cardiac Cell Sheet Including Human Ips Cell-derived Cardiomyocytes and Vascular Cells to Infarcted Porcine Heart Restores Impaired Left Ventricular Global Function and Dyssynchrony
Authors: Masanosuke Ishigami, Hidetoshi Masumoto, Takayuki Aoki, Fumie Takai, Takeshi Ikuno, Akira Marui, Kenji Minakata, Tadashi Ikeda, Ryuzo Sakata, Jun K Yamashita
Journal: Circulation (2014)

BACKGROUNDS: Previously we reported beneficial effects of transplantation of all mouse ES cell-derived cardiac cell sheets composed of CMs and vascular cells (endothelial cells [ECs]/ vascular mural cells [MCs]) in a rat myocardial infarction (MI) model and importance of co-existence of vascular cells in the cell sheets (Stem Cells, 2012). Here we report a transplantation of human induced pluripotent stem cell (hiPSC)-derived cardiac cells to a porcine MI model. METHODS &amp; RESULTS: We induced a mixture of CMs and vascular cells from hiPSCs with a 2-D serum-free method (modified from Uosaki, PLoS One, 2011). We generated cell sheets using 10cm-sized temperature-responsive culture dishes (UpCell; CellSeed, Tokyo, Japan). Self-pulsating cardiac cell sheets were approximately 3.5cm in diameter with 6.8х106±0.8 (n=5) of cells containing cTnT+-CMs (19.4±5.9%), VE-cadherin+-ECs (3.8±4.4%) and PDGFRβ+-MCs (67.2±7.8%). We induced MI in micromini-pigs (12-45 month old) by ameroid constriction of coronary artery and transplanted cell sheets (Tx) 2 weeks after MI induction (4 sheets / recipient) under immunosuppression. In Tx group, echocardiogram showed a significant improvement of systolic function of left ventricle (fractional shortening: 22.6±5.0 vs 39.7±8.7%, p&lt;0.01, n=5). Ejection fraction evaluated by left ventriculogram improved significantly in Tx group (25.3±6.2% vs 39.8±4.2%, p&lt;0.01, n=5). Speckle tracking echocardiogram showed significant increase of attenuated circumference strain in infarcted and border regions leading to restored dyssynchrony (anterior: 10.8±4.1 vs 20.6±3.5%, p&lt;0.01, antero-lateral: 13±6.5% vs 24.8±7.6%, p&lt;0.05, n=5, 2 weeks after Tx). Capillary density in the border region significantly elevated indicating angiogenic effect of the sheet transplantation (75.9±42.6/mm2 vs 137.4±44.8/mm2, p&lt;0.001, n=5). CONCLUTION: HiPSC-derived cardiac cell sheets potentially ameliorate cardiac dysfunction of human-size infarct heart.
Clinical application of different operative approach of total knee replacement in knee valgus patients. Retrospective cohort study
Authors: Chong-Jun Guo, Jun Liu, Dong-Sheng Niu, Jun Ma, Bo Kou, Hai-Jiao Zhang, Shao-Wei Xu, Xiao-Di Mu, Lv-Lin Yang, Hua Zhang
Journal: International Journal of Surgery (2017)
Association of Age With Risk of Hospitalization for Respiratory Syncytial Virus in Preterm Infants With Chronic Lung Disease
Authors: Almut G. Winterstein, Yoonyoung Choi, H. Cody Meissner
Journal: JAMA Pediatrics (2017)

It is unknown whether the age threshold (≤24 months) for preterm infants with chronic lung disease (CLD) to receive immunoprophylaxis for respiratory syncytial virus (RSV) as currently recommended by American Academy of Pediatrics guidelines correctly identified infants at higher risk for hospitalization for RSV.To determine the age when the risk of hospitalization for RSV among preterm infants with CLD becomes equivalent to the risk for healthy, 1-month-old term infants who do not qualify for immunoprophylaxis.A retrospective cohort study was conducted of 1 018 593 healthy term infants and 5181 preterm infants with CLD using Medicaid billing records (Medicaid Analytic eXtract files) from January 1, 1999, to December 31, 2010, linked to Florida and Texas birth and death certificates.Age-trend discrete time logistic regression models within a survival analysis framework were developed, adjusting for covariates including the use of immunoprophylaxis, to compare the risk of hospitalization of preterm infants (<32 weeks' gestational age) with CLD at 3 through 34 months of age with the risk of hospitalization of term infants (37-41 weeks' gestational age) at 1 month of age.Age at which risk of hospitalization for RSV among preterm infants with CLD equals the risk for healthy term infants at age 1 month.The study cohort included 1 018 593 healthy term infants and 5181 preterm infants with CLD; because patients could reenter the cohort for a second or third season, the total study cohort consisted of 1 880 531 healthy term infant-seasons (926 206 girls and 954 325 boys; mean [SD] age at first season entry, 12.6 [9.6] months) and 8680 CLD infant-seasons (3519 girls and 5161 boys; mean [SD] age at first season entry, 15.1 [9.1] months). Among term infants with siblings, the risk of hospitalization for RSV averaged across all covariate strata was 9.0 (95% CI, 8.4-9.6) per 1000 patient season-months at 1 month of age. The risk of hospitalization for RSV among preterm infants with CLD became similar to that of 1-month-old term infants at an age of 18.5 months (95% CI, 15.6-22.8).The age threshold at which the risk of hospitalization for RSV among qualifying preterm infants with CLD approximates that of healthy term infants supports the current American Academy of Pediatrics practice guideline recommending RSV prophylaxis until a maximum of 24 months of age.
Clinical and Molecular Spectrum of Liposarcoma
Authors: Alex Thomas John Lee, Khin Thway, Paul H. Huang, Robin Lewis Jones
Journal: Journal of Clinical Oncology (2017)

Liposarcomas are rare malignant tumors of adipocytic differentiation. The classification of liposarcomas into four principal subtypes reflects the distinct clinical behavior, treatment sensitivity, and underlying biology encompassed by these diseases. Increasingly, clinical management decisions and the development of investigational therapeutics are informed by an improved understanding of subtype-specific molecular pathology. Well-differentiated liposarcoma is the most common subtype and is associated with indolent behavior, local recurrence, and insensitivity to radiotherapy and chemotherapy. Dedifferentiated liposarcoma represents focal progression of well-differentiated disease into a more aggressive, metastasizing, and fatal malignancy. Both of these subtypes are characterized by recurrent amplifications within chromosome 12, resulting in the overexpression of disease-driving genes that have been the focus of therapeutic targeting. Myxoid liposarcoma is characterized by a pathognomonic chromosomal translocation that results in an oncogenic fusion protein, whereas pleomorphic liposarcoma is a karyotypically complex and especially poor-prognosis subtype that accounts for less than 10% of liposarcoma diagnoses. A range of novel pharmaceutical agents that aim to target liposarcoma-specific biology are under active investigation and offer hope of adding to the limited available treatment options for recurrent or inoperable disease.
A Polymorphism within the Vitamin D Transporter Gene Predicts Outcome in Metastatic Colorectal Cancer Patients Treated with FOLFIRI/Bevacizumab or FOLFIRI/Cetuximab
Authors: Martin D. Berger, Sebastian Stintzing, Volker Heinemann, Shu Cao, Dongyun Yang, Yu Sunakawa, Satoshi Matsusaka, Yan Ning, Satoshi Okazaki, Yuji Miyamoto, Mitsukuni Suenaga, Marta Schirripa, Diana L. Hanna, Shivani Soni, Alberto Puccini, Wu Zhang, Chiara Cremolini, Alfredo Falcone, Fotios Loupakis, Heinz-Josef Lenz
Journal: Clinical Cancer Research (2017)

Purpose: Vitamin D exerts its inhibitory influence on colon cancer growth by inhibiting Wnt signaling and angiogenesis. We hypothesized that SNPs in genes involved in vitamin D transport, metabolism, and signaling are associated with outcome in metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI and bevacizumab.Experimental Design: 522 mCRC patients enrolled in the FIRE-3 (discovery cohort) and TRIBE (validation set) trials treated with FOLFIRI/bevacizumab were included in this study. 278 patients receiving FOLFIRI and cetuximab (FIRE-3) served as a control cohort. Six SNPs in 6 genes (GC, CYP24A1, CYP27B1, VDR, DKK1, CST5) were analyzed.Results: In the discovery cohort, AA carriers of the GC rs4588 SNP encoding for the vitamin D-binding protein, and treated with FOLFIRI/bevacizumab had a shorter overall survival (OS) than those harboring any C allele (15.9 vs. 25.1 months) in both univariable (P = 0.001) and multivariable analyses (P = 0.047). This association was confirmed in the validation cohort in multivariable analysis (OS 18.1 vs. 26.2 months, HR, 1.83; P = 0.037). Interestingly, AA carriers in the control set exhibited a longer OS (48.0 vs. 25.2 months, HR, 0.50; P = 0.021). This association was further confirmed in a second validation cohort comprising refractory mCRC patients treated with cetuximab ± irinotecan (PFS 8.7 vs. 3.7 months) in univariable (P = 0.033) and multivariable analyses (P = 0.046).Conclusions:GC rs4588 SNP might serve as a predictive marker in mCRC patients treated with FOLFIRI/bevacizumab or FOLFIRI/cetuximab. Whereas AA carriers derive a survival benefit with FOLFIRI/cetuximab, treatment with FOLFIRI/bevacizumab is associated with a worse outcome. Clin Cancer Res; 24(4); 784-93. ©2017 AACR.