tbuckley/cabot-search huggingface dataset:
M402, a heparan sulfate mimetic and novel candidate for the treatment of pancreatic cancer.
Authors: Birgit Corinna Schultes, Martijn P.J.K. Lolkema, Chia Lin Chu, He Zhou, Alison Long, Michelle Lockley, William Avery, Elma Kurtagic, Zoya Galcheva-Gargova, Paul Miller, Jay Duffner, Birgit J Maschek, Donna Jarlenski, David A. Tuveson, Jim Roach, Ganesh Venkataraman, Takashi K Kishimoto, Keith T. Flaherty
Journal: Journal of Clinical Oncology (2012)

4056 Background: Recent advances in pancreatic cancer research implicate the involvement of several heparin-binding growth factors (such as HGF, HB-EGF, PDGF, hedgehogs, and TGFs) that control tumor-stroma interactions. We have rationally designed a heparan sulfate mimetic, M402, which has been previously shown to affect tumor progression and metastasis through disruption of multiple pathways. We hypothesized that M402 could modulate tumor-stroma interactions and enhance the efficacy of gemcitabine, and evaluated its efficacy in two preclinical models. Methods: A genetically engineered mouse model (GEMM; KrasLSL G12D p53LSL R172H ) featuring spontaneous pancreatic tumor formation and metastasis assessed M402’s effect on tumorigenesis and metastasis. The orthotopic Capan-2 model in nude mice evaluated the effect of M402 on desmoplasia, a fibrotic response that hinders effective delivery of chemotherapeutics, via inhibition of sonic hedgehog (SHH) signaling in fibroblasts and stellate cells. In both models, M402 was studied as monotherapy and with gemcitabine. Results: In the GEMM, M402 significantly prolonged survival in combination with gemcitabine while each monotherapy showed modest efficacy. M402, alone and in combination, also reduced metastases and local invasion and inhibited epithelial-to-mesenchymal transition. In the Capan-2 model, gemcitabine was increasingly less effective as desmoplasia progressed over time. The addition of M402 to gemcitabine increased its efficacy with respect to primary tumor burden. Metastasis, invasion, and surrounding fibrotic lesions appeared particularly impacted by the combination treatment. M402 was also effective as monotherapy with dose-dependency, which correlated with reduced SHH signaling. Conclusions: M402 can modulate tumor-stroma interactions involved in the metastatic and desmoplastic pathways in two pancreatic cancer models supporting the translation of these findings into a clinical study. A first-in-human study is planned that will evaluate the safety, pharmacokinetics, efficacy, and biomarker profiles of escalating M402 doses in combination with gemcitabine in patients with metastatic pancreatic cancer.
Phase I study of vorinostat with concurrent chemoradiotherapy (CRT) for locally advanced non-squamous non-small cell lung cancer (NSCLC).
Authors: Ranee Mehra, Aruna Turaka, Joshua E. Meyer, Brian L. Egleston, Tawee Tanvetyanon, Mary Colleen Pinder, Thomas J. Dilling, Charles C. Williams, Jhanelle Elaine Gray, Keisuke Shirai, R. Katherine Alpaugh, Debbie Riordan, Neeta Somaiah, Prashant C. Shah, Walter Joseph Scott, George R. Simon, Hossein Borghaei
Journal: Journal of Clinical Oncology (2015)

7553 Background: Vorinostat (V) is a potent class I & II (HDAC 6) inhibitor of histone deacetylases. In A549 and A375 cell lines (CL’s), V intensified RT induced decrease in clonogenic survival via impaired DNA repair. In CL's V downregulated thymidylate synthase (TS), a target of pemetrexed (P). Methods: This is a phase I trial of V plus C (cisplatin) or CP (carboplatin), P and RT for ECOG PS 0-1 pts with stage IIIA/B non-squamous NSCLC. V was dose-escalated in a 3+3 design (V at dose levels (DL1-3) 100, 200 and 300mg) with CRT: C (75 mg/m2) and P (500mg/m2) Q21 days x 4 with folic acid, B12, steroids), and RT (60 Gy). DL1b included CP AUC 5, P, RT and V 100mg. V was dosed for 3 consecutive days before cycle 1, and was then taken orally once a day 3 times/week during CRT. Surgical resection after CRT was allowed. The primary endpoint was to determine the MTD. Correlative analyses include TS and HDAC expression. This study was approved & funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc. Results: Eighteen pts (51 - 80 years) enrolled from May 2010 to September 2014. Three evaluable (Ev) pts were treated on DL 1 (V 100), with no DLT. 3 Ev pts, and 2 Non-Ev pts (1 not eligible, 1 discontinued due to P-associated rash) were treated on DL 2 (V 200). At DL2, 2 pts had a DLT of grade (G) 4 hyponatremia (HNa). Accrual resumed with 3 pts on DL1, with 2 DLTs at DL1 (HNa and heart failure). Six pts were treated on DL1b with no DLTs. G 1 & 2 toxicities: nausea, anorexia, dysphagia, dehydration, esophagitis, fatigue, pain. G 3 toxicities: nausea, hyperglycemia, anemia, leukopenia. Fourteen pts completed 4 cycles of CRT and V. Two pts stopped V due to myelosuppression. One pt developed CLL 18 months after therapy. Among all pts the best response to date is CR:2, PR:4, SD: 8 pts. Three pts underwent resection, with no viable tumor in 2 specimens. With a median follow up of 15.4 months, the median PFS/OS have not been reached. Conclusions: With the exception of G4 HNa, no unexpected toxicities were noted with V and CRT. Esophagitis was mild. Assessment of PFS/OS and correlatives are ongoing. The recommended Phase 2 dose is CP AUC 5, P 500mg/m2 and V100mg 3x/week with RT. Clinical trial information: NCT01059552.
Cancer Stem Cell Genetic Profile as Predictor of Relapse in Radically Resected Colorectal Cancer
Authors: R. Giampieri, M. Scartozzi, F. Piva, C. Loretelli, A. Mandolesi, L. Faloppi, M. Bianconi, A. Bittoni, I. Bearzi, S. Cascinu
Journal: Annals of Oncology (2012)
The relationship between antitumor effects and relative dose intensity of gemcitabine plus nab-paclitaxel for unresectable pancreatic cancer.
Authors: Kazunaga Ishigaki, Masato Ozaka, Seita Kataoka, Ryo Kanata, Ikuhiro Yamada, Takashi Sasaki, Masato Matsuyama, Kouichi Takano, Naoki Sasahira
Journal: Journal of Clinical Oncology (2017)

419 Background: Gemcitabine plus nab-paclitaxel (GEM+nab-PTX) is the standard first-line chemotherapy for unresectable pancreatic cancer, but the relationship between antitumor effects and relative dose intensity (RDI) remains unclear. Methods: A retrospective analysis of pancreatic cancer patients treated with GEM+nab-PTX as first-line chemotherapy between January 2015 and July 2016 at Cancer Institute Hospital of JFCR was performed. The RDI of GEM+nab-PTX was calculated as the delivered dose intensity divided by standard dose intensity. The patients were divided into two groups by median RDI. Kaplan Meier curves were constructed in order to analyze progression-free survival (PFS), time to treatment failure (TTF) and overall survival (OS), and differences between the two groups were compared with a log-rank test. Results: A total of 102 patients (52 male, a median age of 66 years) were enrolled. Eighty-two (80%) had metastatic disease. The best overall response was partial response in 30 (29%) and stable disease in 53 (52%). The median PFS, TTF and OS of the total cohort was 188 days (95% confidence interval: CI, 162 to 224), 161 days (95% CI, 146 to 183) and 369 days (95% CI, 309 to 440) respectively. The median RDI were 77% (range 30-100). In the RDI &lt; 77% (n = 50) and the RDI ≥ 77% (n = 52) groups, the median PFS was 196 and 183 days (p = 0.33), the median TTF was 162 and 160 days (p = 0.186) and the median OS were 410 and 312 days (p = 0.10), respectively. Twenty-nine (28%) were eventually administered GEM+nab-PTX biweekly. The median RDI of biweekly regimen was 63% (range 29-86). The TTF of biweekly regimen and original weekly regimen was 196 and 160 days (p = 0.004) respectively. Conclusions: RDI is not a significant predictor of antitumor effects, and an appropriate dose reduction and extension of dosing interval may be permitted in pancreatic cancer patients treated with GEM+nab-PTX.
Dexabeam versus ICE salvage regimen prior to autologous transplantation for relapsed or refractory aggressive peripheral T-cell lymphoma: A retrospective evaluation of parallel patient cohorts of one center.
Authors: Jan-Henrik Mikesch, Mareike Kuhlmann, Angela Demant, Utz Krug, Eva Schmidt, Torsten Kessler, Christoph Schliemann, Michele Pohlen, Michael Mohr, Gabriele Koehler, Johannes Wessling, Rolf M. Mesters, Carsten Mueller-Tidow, Wolfgang E. Berdel, Nils Heinrich Thoennissen
Journal: Journal of Clinical Oncology (2013)

8548 Background: High-dose chemotherapy (HDT) followed by autologous stem-cell transplantation (ASCT) is considered standard in the treatment of patients with relapsed or refractory aggressive peripheral T-cell lymphoma (PTCL). However, the optimal salvage regimen before ASCT has not yet been established. Methods: We retrospectively analyzed 31 patients with relapsed or refractory aggressive PTCL after anthracycline based first-line chemotherapy who received either DexaBEAM (n=16) or ICE (n=15) regimen as first salvage chemotherapy followed by HDT and ASCT between 1996 and 2009. The median patient age was 46 years (range, 18-66) in the DexaBEAM group and 40 years (range, 17-59) in the ICE group. Patients were included independent of WHO stage and IPI score. Results: The overall response rate (OR) was significantly higher for patients treated with DexaBEAM (69%) as compared to the ICE group (20%; P=0.01), with higher complete response (CR; 38% vs. 7%) as well as partial response (PR; 31% vs. 13%) rate. Changing regimen due to failure of the first salvage therapy, 12 patients initially receiving ICE still achieved an OR of 58% (33% CR, 25% PR) with DexaBEAM as second salvage therapy, whereas in 3 patients receiving ICE after DexaBEAM failure only 1 patient achieved an OR (1 PR). Median progression-free survival (PFS) was significantly higher in the DexaBEAM group (6.4 vs. 2 months; P=0.01). Median overall survival (OS) was not different between the two groups (22.8 vs. 29.8 months; P=0.72), most likely due to the good response rate of patients to DexaBEAM as 2nd salvage regimen after failure of ICE chemotherapy. Major adverse event in both groups was myelosuppression with higher but tolerable treatment-related toxicity for patients in the DexaBEAM group. Conclusions: In this retrospective comparison DexaBEAM salvage chemotherapy was superior to ICE for patients with relapsed or refractory aggressive PTCL for remission induction prior to autologous transplantation, with higher but manageable treatment-related toxicity.
Dose-escalation study of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation for stage III non-small cell lung cancer.
Authors: Naruo Yoshimura, Shigeki Mitsuoka, Tatsuo Kimura, Hidenori Tanaka, Tomohiro Suzumura, Misato Nagata, Kanako Umekawa, Toshiyuki Nakai, Masako Hosono Hosono, Takuhito Tada, Kazuto Hirata, Shinzoh Kudoh
Journal: Journal of Clinical Oncology (2013)

7564 Background: To determine a recommended dose (RD) of chemoradiotherapy with use of involved-field conformal radiotherapy and accelerated hyperfractionation (AHF) for stage III non-small cell lung cancer (NSCLC). Methods: Eligible patients had unresectable stage III NSCLC, age of less than 75 years, PS: 0 or 1, V20 of 35% or less. PET was used for staging. Cisplatin (80mg/m 2 ) was administered on day 1 and vinorelbine (20mg/m 2 ) was administered on days 1 and 8 for two cycle. Twice-daily radiation therapy (1.5 Gy per fraction) without elective nodal irradiation started on day 1. Total doses were 60Gy in 40 fractions and 66Gy in 44 fractions at levels 1 and 2 respectively. After concurrent chemoradiotherapy, consolidation chemotherapy regimen was cisplatin (80mg/m 2 ) on day 1 and vinorelbine (20mg/m 2 ) on days 1 and 8 every 4 week for three cycles. The dose-limiting toxicity (DLT) was defined as grade ≥ 3 esophagitis, grade 3 neutropenic fever, grade ≥ 3 other non-hematologic toxicities and interruption of irradiation for more than 2 weeks. DLT was monitored for 90 days. Results: A total of 12 patients were enrolled (6 patients in Level 1, 6 patients in Levels 2). DLTs were noted in 2 patients at Level 1, which were grade 3 esophagitis and grade 3 febrile neutropenia. Radiation dose was escalated up to 66 Gy in 44 fractions (Level 2), and there was no DLT. In principle, Sixty-six Gy in 44 fractions (Level 2) should be the RD. Major toxicities were leucopenia, neutropenia, and anemia. The response rate, the median progression free survival time, and the median overall survival time was 83.3%, 10.4 months, and 36.3 months for all patients, respectively. Conclusions: The RD was 66 Gy in 44 fractions (Level 2). The toxicity of this chemoradiothrapy regimen was manageable and efficacy is promising. The efficacy and safety of this regimen should be confirmed in a phase II study. Clinical trial information: UMIN000003769.
Direct-to-Consumer Advertising of Androgen Replacement Therapy
Authors: Richard L. Kravitz
Journal: JAMA (2017)

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MET overexpression as a promising therapeutic target in non-small cell lung cancer with acquired resistance to EGFR TKIs.
Authors: Xuchao Zhang, Jinji Yang, Huajun Chen, Zhi Xie, Qing Zhou, Jian Su, Hai-Yan Tu, Zhen Wang, Chongrui Xu, Yisheng Huang, Ben-Yuan Jiang, Bin-Chao Wang, Xiao-Yan Bai, Yi-Long Wu
Journal: Journal of Clinical Oncology (2014)

e19047 Background: MET amplification is recognized as one of common molecular mechanisms of acquired resistance (AR) to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) in advanced non-small-cell lung cancer (NSCLC). The aim of the present study is to investigate the frequency of MET overexpression, the correlated clinicopathologic features and the possible treatments in NSCLC with AR. Methods: Advanced NSCLC patients with AR to EGFR TKIs were detected for MET overexpression by immunohistochemistry (IHC). ≥50% tumor cells with moderate to high intensity staining were defined as MET positive. MET positive patients were recommended to participate a clinical trial if eligible or receive other molecularly targeted therapies. The statuses of EGFR, ALK, KRAS and ROS1 were also tested. Results: From January 2013 to January 2014, 58 advanced NSCLC patients with AR to gefitinib or erlotinib were enrolled prospectively. The frequencies of MET overexpression was 32.8% (19/58), MET overexpression+T790M 6.9% (4/58), T790M 29.3% (17/58), small cell lung cancer or squamous cell transformation 3.4% (2/58), KRAS mutation 1.7% (1/58), ROS1 fusion 1.7% (1/58) and unknown mechanism 24.1% (14/58), respectively. No significant differencies were found in terms of clinicopathologic features (age, gender, smoking, performance status, histology, clinical stage, EGFR mutation types, and lines of EGFR TKIs), response rate of EGFR TKIs (69.6% versus 74.3%, p=0.694) and median progression-free survival (10.6 versus 13.0 months, p=0.569 ) for EGFR TKIs between MET positive and negative patients. Five of MET positive patients received gefitinib plus crizotinib (3 cases; 2 of them attaining partial response [PR] and 1 waiting for assessment of response), crizotinib (one case waiting for assessment) and axitinib (one case achieving PR) treatment, and all got prominently clinical benefit. Conclusions: MET overexpression is one of common molecular mechanisms of AR to EGFR TKIs and has no correlated clinicopathologic features in NSCLC, but might serve as a promising therapeutic target when gefitinib plus crizotinib or other targeted therapy is provided.
Abstract P211: MRP4: A Novel Protein Involved in Camp Homeostasis in the Heart
Authors: Aniella Abi-Gerges, Yassine Sassi, Nathalie Mougenot, Adeline Jacquet, Stefan Engelhardt, Stéphane N Hatem, Jean-Sébastien Hulot, Anne-Marie Lompré
Journal: Circulation Research (2011)

Rationale: Transporters of the ABCC family, called MRP4 and MRP5, have been described to control cAMP homeostasis by extruding it from various cell types. Objective: The aim of our study was to determine the role of MRP4 in cAMP homeostasis and heart function and its impact on cardiac hypertrophy (CH). Methods and results: MRP4 KO mice and MRP4 KO with cardiac overexpression of the HCN-based cAMP sensor were used. Echocardiography and morphology studies showed that 3 month-old MRP4 KO mice displayed normal cardiac function (FS: 35.7% ± 1.02 in KO vs 36% ± 1.97 in WT) and cardiac phenotype (HW/TL: 7.59 ± 0.14 in WT mice vs 7.75 ± 0.15 in KO) in basal condition. Stimulation of WT and MRP4 KO mice by increasing concentrations of isoproterenol (ISO: 0.1μg/kg to 3 mg/kg) induced dose-dependent positive inotropic and chronotropic effects but there was no difference in the rate of contraction (Vmax: 11214 ± 682 in WT vs 10697 ± 691 in KO) or in the heart rate (724 ± 21 in WT vs 711 ± 21 in KO) between both groups. Cardiac myocytes were isolated from WT and MRP4 KO mice with cardiac expression of the HCN-based FRET sensor and intracellular cAMP concentrations were measured by FRET. Application of ISO (1nM) induced a similar increase in cAMP level in WT and MRP4 KO mice (YFP/CFP: 4.4 ± 0.15 in WT vs 4.1 ± 0.44 in KO cells), whereas cAMP signal was greater in MRP4 KO compared to WT mice after PDE inhibition by IBMX (ISO 1nM + IBMX 300µM: 8.1 ± 0.6 in WT vs 11.8 ± 0.62 in KO cells; p&lt;0.01). PDE3A and PDE4A mRNA level was 1.6 fold higher in the myocardium of MRP4 KO compared to WT mice. MRP4 KO mice displayed age-dependent CH (HW/TL in 9 month-old mice: 9.8 ± 0.57 in KO vs 7.82 ± 0.13 in WT mice; p&lt;0.01). 3 month-old MRP4 KO and WT mice were subjected to thoracic aortic clamping (TAC) or sham operated (Sh) and CH was assessed at 12 weeks after the surgery by echocardiography and morphometric studies. Heart function was also examined by hemodynamic technique in basal conditions and upon a β-adrenergic stimulation in WT (Sh and TAC) and MRP4 KO (Sh and TAC) mice. Alteration of left ventricular dP/dt upon β-adrenergic stimulation after TAC was more severe in MRP4 KO compared to WT mice. Conclusion: Taken together, our results show that both PDEs and MRP4 are important in cAMP homeostasis.
Access to basic surgical oncologic services in 54 countries: Where to go from here?
Authors: Andre Ilbawi, Meena Cherian, Bente Mikkelson, Rengaswamy Sankaranarayanan, Richard Sullivan
Journal: Journal of Clinical Oncology (2015)

e17525 Background: In low- and middle-income countries (LMIC), there are significant deficits in access to core cancer services including surgical care. Surgical biopsy is an essential modality in the diagnosis and staging of cancer and, thus, functions as an index indicator for access to basic cancer services in LMIC. The objective of this study is to describe the existing capacity of and access to cancer services in LMIC. Methods: Responses to the World Health Organization Emergency and Essential Surgical Care survey are analyzed, assessing service availability in 1269 health facilities in 54 countries. Responses describe the capacity to perform surgical biopsies along with facility and personnel characteristics. Results: Surgical biopsy is available in 608 (48%) surveyed health facilities. The most commonly stated reason for an inability to perform biopsies is a lack of necessary skills (79%). There are an estimated 1.65 physicians able to perform basic surgical procedures and 0.58 trained surgeons per 100,000 population. Non-surgeon physicians provide an estimated increase in capacity of approximately 26 basic oncologic procedures per 100,000 per year. Five hundred four health facilities do not have trained surgeons, and 31% of these facilities offer surgical biopsies, generally performed by non-surgeon physicians (77%). Patients travel an average of 41km to reach health facilities where non-surgeon physicians provided surgical biopsy compared to 100km to access trained surgeons. Referral hospitals (i.e., provincial, general, private) are more likely to offer core cancer-related services such as radiographic studies and management guidelines (p < 0.05). Conclusions: Major obstacles exist to accessing cancer and surgical services in LMIC including limited surgical capacity, geographic barriers to care, deficits in guidelines for care, and lack of essential cancer-related services. Additional health system investments are needed in human resources, infrastructure and equipment, and the coordination of services and should be structured according to region-specific barriers to care.
Identification of new BMP6 pro‐peptide mutations in patients with iron overload
Authors: Chiara Piubelli, Annalisa Castagna, Giacomo Marchi, Monica Rizzi, Fabiana Busti, Sadaf Badar, Monia Marchetti, Marco De Gobbi, Antonella Roetto, Luciano Xumerle, Eda Suku, Alejandro Giorgetti, Massimo Delledonne, Oliviero Olivieri, Domenico Girelli
Journal: American Journal of Hematology (2017)

Hereditary Hemochromatosis (HH) is a genetically heterogeneous disorder caused by mutations in at least five different genes (HFE, HJV, TFR2, SLC40A1, HAMP) involved in the production or activity of the liver hormone hepcidin, a key regulator of systemic iron homeostasis. Nevertheless, patients with an HH-like phenotype that remains completely/partially unexplained despite extensive sequencing of known genes are not infrequently seen at referral centers, suggesting a role of still unknown genetic factors. A compelling candidate is Bone Morphogenetic Protein 6 (BMP6), which acts as a major activator of the BMP-SMAD signaling pathway, ultimately leading to the upregulation of hepcidin gene transcription. A recent seminal study by French authors has described three heterozygous missense mutations in BMP6 associated with mild to moderate late-onset iron overload (IO). Using an updated next-generation sequencing (NGS)-based genetic test in IO patients negative for the classical HFE p.Cys282Tyr mutation, we found three BMP6 heterozygous missense mutations in four patients from three different families. One mutation (p.Leu96Pro) has already been described and proven to be functional. The other two (p.Glu112Gln, p.Arg257His) were novel, and both were located in the pro-peptide domain known to be crucial for appropriate BMP6 processing and secretion. In silico modeling also showed results consistent with their pathogenetic role. The patients' clinical phenotypes were similar to that of other patients with BMP6-related IO recently described. Our results independently add further evidence to the role of BMP6 mutations as likely contributing factors to late-onset moderate IO unrelated to mutations in the established five HH genes.