tbuckley/cabot-search huggingface dataset:
The diverse genomic landscape of low−risk prostate cancer.
Authors: Matthew R. Cooperberg, Nicholas Erho, June M. Chan, Felix Y Feng, Shuang Zhao, Jeff Simko, Janet E. Cowan, Jonathan Lehrer, Nick Fishbane, Mohammed Alshalalfa, Tyler Kolisnik, Jijumon Chelliserry, Jennifer Margrave, Maria Aranes, Marguerite Du Plessis, Christine Buerki, Imelda Tenggara, Elai Davicioni, Peter Carroll
Journal: Journal of Clinical Oncology (2018)

74 Background: Among men with clinically low-risk prostate cancer, we have previously documented heterogeneity in terms of clinical characteristics and genomic risk scores. In this study, we aimed to study the underlying tumor biology of this patient population, by interrogating patterns of gene expression among men with clinically low-risk tumors. Methods: Prostate biopsies from 427 patients considered potentially suitable for active surveillance underwent central pathology review and genome-wide expression profiling. These cases were compared to 1290 higher-risk biopsy cases with diverse clinical features from a prospective genomic registry. Average genomic risk (AGR) was determined from 18 published prognostic signatures, and MSigDB Hallmark gene sets were analyzed using bootstrapped clustering methods. These sets were examined in relation to clinical variables and pathologic and biochemical outcomes using multivariable regression analysis. Results: 408 (96%) of biopsies passed RNA quality control. Based on average genomic risk quartiles defined by the high-risk multicenter cases, the UCSF low-risk patients were distributed across the quartiles as 219 (54%), 107 (26%), 61 (15%), and 21 (5%). Unsupervised clustering analysis of the Hallmark gene set scores revealed 3 clusters, which were enriched for the previously described PAM50 luminal A, luminal B and basal subtypes. These three clusters did not associate with existing clinical or known genomic risk characteristics, suggesting a novel and independent classification for low-risk prostate cancer. AGR was associated with both pathological (OR: 1.3, p &lt; 0.001) and biochemical outcomes (OR: 1.5, p = 0.001 ) but the clusters were not. Conclusions: Prostate cancers that are largely homogeneously low-risk by traditional characteristics demonstrate substantial diversity at the level of genomic expression. Molecular sub-stratification of low-risk prostate cancer may facilitate better decision-making with respect to both timing and intensity of cancer surveillance and treatment.
Targeting dopamine receptor 2 (DRD2) signaling in combination with temozolomide chemotherapy as a novel therapeutic concept in glioblastomas.
Authors: Tor-Christian Aase Johannessen, Amra Grudic, Huaiyang Zhu, Halala Saed, Jobin Varughese, Ning Yang, Terje Sundstrom, Bassam Janji, Jian Wang, Morten Lund-Johansen, Rolf Bjerkvig, Lars Prestegarden
Journal: Journal of Clinical Oncology (2015)

2069 Background: Glioblastomas are highly resistant to therapy and carry a poor prognosis. Novel therapeutic strategies are urgently needed to improve patient outcome. This study was designed to identify drugs that would sensitize glioblastoma cells to temozolomide (TMZ) chemotherapy. Methods: A genome-wide RNAi synthetic lethality screen was performed in glioblastoma cells to identify functional gene sets that would potentiate the effect of TMZ. The Connectivity Map database was then interrogated to identify potential drug candidates that would induce corresponding changes in gene expression. The highest ranked prospective compounds were validated in combination with TMZ in low-throughput cytotoxicity assays. Based on these findings, the most promising compound, the established anti-psychotic agent Thioridazine, was evaluated further in combination with TMZ in vivo in a clinically relevant orthotopic xenograft model. Results: Thioridazine significantly improved TMZ sensitivity in established glioblastoma cell lines as well as patient-derived cells. The specific chemosensitizing effect of Thioridazine was due to antagonism of dopamine receptor 2 (D2 receptor; DRD2). Inhibition of D2 receptor signaling by Thioridazine decreased MAPK and PI3K/AKT/mTor pathway activity through a DRD2/β-arrestin-2/AKT signaling complex. Inhibition of this complex induced non-apoptotic cell death caused by impaired autophagy leading to catastrophic vacuolization. The combination of TMZ and Thioridazine significantly decreased intracranial glioblastoma growth, and improved survival of tumor-bearing mice compared to treatment with TMZ alone. Conclusions: Our findings demonstrate that the DRD2/β-arrestin-2/AKT signaling complex connects dopamine signaling to tumor cell survival. We have also identified a novel strategy to inhibit autophagy in glioblastoma cells by antagonizing the D2 receptor. Due to the low toxicity of Thioridazine and its advantageous pharmacological properties, the presented work suggests that Thioridazine plus TMZ could be used for glioblastoma treatment in an adjuvant setting.
Erratum: Regulation of the gp80 and gp130 subunits of the il-6 receptor by sex steroids in the murine bone marrow (Journal of Clinical Investigation (October 1997) 100:8 (1980-1990))
Authors: S. C. Lin, T. Yamate, Y. Taguchi, V. Z C Borba, G. Girasole, C. A. O'Brien, Teresita Bellido, E. Abe, S. C. Manolagas
Journal: Journal of Clinical Investigation (1997)
Preclinical studies using Nativis Voyager RFE System, a novel non-invasive, low energy, non-thermal, non-ionizing radiofrequency energy (RFE) device in glioblastoma mouse models.
Authors: Rajesh Mukthavaram, Pengfei Jiang, Natsuko Nomura, Sandeep C. Pingle, John Butters, Bennett M Butters, Santosh Kesari
Journal: Journal of Clinical Oncology (2015)

e13050 Background: Cancer treatment using radiofrequency energy (RFE) devices have been used in the past and have recently shown benefit in clinical trials of glioblastoma. Here we report a proof-of-concept application using the Nativis Voyager RFE System, which provides specific, low energy, non-invasive, non-thermal and non-ionizing oscillating electromagnetic signals. These signals inhibit in vitro glioblastoma tumor cell proliferation via an anti-mitotic effect. Methods: We tested the ability of Voyager RFE System signals to inhibit tumor growth in both immunocompromised and immunocompetent mouse models. The immunocompetent model study, using white noise signal compared to control showed no difference in growth in the two groups. After establishing this, in the immunocompromised model, we implanted human U87 cells subcutaneously into 6-8 week old nude mice. In the immunocompetent model, we implanted mouse GL261 cells subcutaneously into 6-8 week old C57/BL6 mice. Voyager RFE signal was started ~10-14 days after cells were implanted, when there were small, measurable tumors. There were two treatment groups (N = 10 tumors each group). The control group was housed in a separate room and was not treated with any RFE signal. The treatment group was treated with Voyager RFE signal 24 hours daily. Voyager RFE signal was applied using a rectangular 40mG coil placed under the cage. Tumors were measured ~weekly. Results: In the immunocompromised U87 model, tumor growth was significantly delayed in Voyager RFE signal group compared to control group (at day 39; p < 0.0001). Moreover, in the immunocompetent GL261 model, tumor growth was significantly delayed in Voyager RFE signal group compared to control group (at day 28; p < 0.0001). Conclusions: We show that Nativis Voyager RFE System signal delays glioblastoma tumor growth in SQ immunocompromised and immunocompetent mouse models.
A randomized clinical trial for the treatment of glioblastoma multiforme with the individualized dendritic cell-based cancer immunotherapy AV0113.
Authors: Thomas Felzmann, Johanna Buchroithner, Christine Marosi, Martha Nowosielski, Gord von Campe, Stefan Oberndorfer, Reinhard Ruckser, Karin Bordihn, Amedeo A. Azizi, Karl Roessler, Josef Pichler, Guenther Stockhammer, Georg Widhalm, Claudius Thome, Manfred Muehlbauer, Michel Loyoddin, Thomas Czech, Michael B Fischer, Christian Gabriel, Harald Schennach
Journal: Journal of Clinical Oncology (2014)

2052 Background: We recruited 78 patients aged 18-70 years suffering from newly diagnosed glioblastoma multiforme (GBM) into a randomized clinical trial designed for demonstrating the efficacy of the individualized dendritic cell-based cancer immunotherapy concept AV0113 (GBM-Vax, EudraCT 2009-015979-27). DC are charged with autologous tumor antigens and contacted with lipopolysaccharide (LPS) in the presence of Interferon (IFN) -γ enabling IL-12 secretion for 1 day thus priming cytolytic anti-tumor immune responses. Exposure to LPS/IFN-γ is limited to 6 hours in order to permit DC/T-lymphocyte interaction in the presence of IL-12. Methods: Patients underwent first line GBM therapy (surgery, radiotherapy, chemotherapy) according to the standard of care; patients randomized into the treatment group received AV0113 as add-on therapy. Primary and secondary objectives were PFS and OS. After progression, patients were treated with Bevacizumab, which was not part of the protocol. The study still collects follow up information. Results: AV0113 DC-CIT was well tolerated. Reactions at the injection site were mild and included redness and swelling; some patients developed fever. There are some imbalances of severe adverse events between control and treatment groups, which, however, didn’t appear to be linked to CIT. No signs of autoimmunity were observed. A trend analysis of one-year survival revealed that 45% of control group patients died during the first year; in the AV0113 treatment group only 16% died during the first year of their disease. A similar trend is observed in overall survival. DC-CIT didn’t improve progression free survival, but increased the number of surviving patients. Accompanying immunological assays demonstrated a correlation of longer survival with signs of polarization of the immune system towards cytotoxicity. Conclusions: Randomization for the GBM-Vax study was completed in May 2013; hence we expect a complete data set for the one-year survival in May 2014 and will present this outcome. If the current trend is confirmed, we expect a first demonstration of efficacy for IL-12 secreting DC in the treatment of GBM. Clinical trial information: 2009-015979-27.
The efficacy of stratifying patients with laparoscopic gastrectomy at age, body mass index and preoperative serum C-reactive protein level for predicting an incidence ratio of postoperative complications.
Authors: En Amada, Hiroya Takeuchi, Rieko Nakamura, Koichi Suda, Norihito Wada, Hirofumi Kawakubo, Yuko Kitagawa
Journal: Journal of Clinical Oncology (2017)

31 Background: Wide variety of Predictive factors (PF) of postoperative complications (PC) in patients with gastric cancer(GC) that have undergone laparoscopic gastrectomy(LG) has been reported. The aim of this study is to devise simple PF for PC for LG that can estimate risk of PC preoperatively. Methods: Two hundred and ninety-eight patients that have been underwent curative LG against GC during May 2012 to March 2016 were enrolled. Patients’ characteristics, preoperative (pre-) laboratory data, operative information and pathological factors were analyzed. Also PC with Clavien-Dindo classification Grade (CD)≥II (PC≥II), pancreatic fistula (PF), intraabdominal abscess (IA), pneumonia (PN) and anastomotic leakage (AL) with CD≥III were examined. Results: Patients with pStage I, II, III and IV was 83%, 11%, 5.6% and 0.4%, respectively. Patients with PC≥II, PF or IA, PN and AL was 17.4%, 5%, 1% and 2.3%, respectively. Patients with PC≥II were significantly elder (p=0.01) and had higher pre-serum-C-reactive protein level (CRP) (p=0.02). Also, patients with AL had significantly higher Body Mass Index (BMI) (p=0.04). We devised “ABC score” by Age, BMI and CRP. It is defined as a number of factors in age, BMI and CRP that are higher than cutoff value of 66 years’ old, 23 kg/m 2 and 0.04 mg/dL, respectively. Patients with ABCs 0, 1, 2, and 3 were 26%, 33%, 34% and 7%, respectively. Patients with ABCs 3 had significant high risk of PC≥II and AL (HR 2.8, p=0.03 and HR 9.9, p=0.004, respectively). Also we found higher ABCs has higher risk of AL (HR1.2, p=0.07 for ABCs 2 and HR2.2, p=0.04 for ABCs 3). Conclusions: ABCs can be a PF for PC in patients with LG. Especially it may evaluate an incidence ratio of AL.
Health care costs and treatment patterns among metastatic pancreatic cancer (MPC) patients (pts) initiating first-line (1L) on nab-paclitaxel/gemcitabine (<i>nab</i>-P+G) or FOLFIRINOX (FFX).
Authors: Ali McBride, Machaon Bonafede, Qian Cai, Nicole Princic, Oth Tran, Corey Pelletier, Manish Patel
Journal: Journal of Clinical Oncology (2017)

415 Background: The economic burden of MPC is substantial while treatment options are limited. This study aimed to compare healthcare costs and treatment patterns in MPC patients who initiated nab-P+G or FFX in a large insured US population. Methods: A retrospective study was conducted using the Truven Health MarketScan administrative claims databases. Adults who had ≥2 claims for pancreatic cancer, ≥1 claim with a secondary malignancy, completed ≥ 1 cycle of nab-P+G or FFX as 1L during 1/1/2013 and 3/31/2015, and had continuous enrollment in health plans for ≥6 months prior to and 3 months following the start of 1L were selected. Total healthcare costs and MPC-related treatment costs were measured per patient per month (PPPM) during 1L. Kaplan-Meier curve was used to describe time to treatment discontinuation (TTD) between groups. Results: 550 MPC patients met selection criteria ( nab-P+G, n=294; FFX, n=256). Patients on nab-P+G were significantly older (mean age: 63.6 vs 58.8 years; p&lt;0.001) and had higher counts of unique diagnostic categories (21.2 vs 19.0, p&lt;0.001) vs FFX. There was no significant difference in median TTD of 1L (3.8 vs 4 months; log-rank test p=0.602) between nab-P+G and FFX. Compared with FFX, nab-P+G pts had higher chemotherapy drug costs but incurred lower total healthcare, supportive care, and treatment administration costs (Table). Conclusions: This claims analysis suggests patients treated with FFX had similar treatment duration and higher total healthcare costs driven by treatment administration and supportive care. Table: Mean Healthcare and Select MPC-related Treatment Costs During 1L (PPPM) [Table: see text]
Predictors of recurrent thrombosis and anticoagulant-related bleeding in patients with cancer
Authors: A. Lee, S. Parpia, J. Julian, F. Rickles, M. Prins, M. Levine
Journal: Journal of Clinical Oncology (2009)

9565 Background: Anticoagulant therapy is treatment of choice for cancer-associated thrombosis. However, the risk of symptomatic recurrent thrombosis (RT) is approximately 9% on low molecular weight heparin (LMWH) and 17% on vitamin K antagonist (VKA) therapy, while the risk of anticoagulant-related major bleeding is about 5%. Given such complications are associated with morbidity and increased resource utilization, prognostic factors that identify patients at high risk for RT or bleeding would be useful for individualizing therapy. We performed a post-hoc analysis of the CLOT study (N Eng J Med 2003;349,146–53) for predictors of RT and bleeding in patients with proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) who were randomized to receive either dalteparin LMWH or VKA for 6 months. Methods: Cox proportional hazards modeling analyses were performed using prospectively collected data from the CLOT study database. Potential baseline factors associated with RT and bleeding examined in the models were identified a priori based on published literature. Factors for RT were: dalteparin, age, gender, ECOG status, smoking status, presence of metastases, tumor site, history of DVT or PE, recent surgery, cancer treatment and body mass index. Factors for bleeding were: dalteparin, age, gender, ECOG, tumor type, major surgery, cancer treatment, platelet count, body mass index, creatinine, and concurrent use of antiplatelet agents. Results: Data from 673 cancer patients were available for the analysis. There were 80 patients with RT, 31 with major bleeds and 77 with minor bleeds. Three statistically significant predictors for RT were identified (with their hazard ratio and corresponding 95% CI): dalteparin (0.52; 0.32–0.82), every 10 year increase in age (0.77; 0.66–0.90) and presence of metastases (2.59; 1.20–6.60). Of the tumour sites investigated, lung (3.51; 1.62–7.62) and unknown primaries (3.63; 1.36–1.90) were predictive of RT. None of the factors examined in the models were found to be predictive of bleeding. Conclusions: Baseline factors may identify cancer patients with a higher risk of RT despite anticoagulant therapy. The risk of anticoagulant-related bleeding is not predictable at treatment onset. [Table: see text]
Effect of interferon-gamma on chemotherapy-induced apoptosis in breast cancer cells
Authors: Katherine Rogers, M. Thomas, Leeona Galligan, Daniel Longley, Patrick Johnston
Journal: Cancer Research (2005)

5342  Anthracyclines are DNA topoisomerase-II (topo-II) poisons that are widely used in the treatment of breast cancer. We have shown that these drugs can potentiate the activation STAT1 in a number of breast cancer cell lines when these cells are treated with interferon-gamma (IFNγ). Furthermore, IFNγ potentiates doxorubicin-induced cell death in these cell lines in a STAT1-dependent manner. Further studies have revealed that the enhanced apoptotic phenotype mediated by IFNγ was not specific to doxorubicin, but was also observed with etoposide (topo-II targeted agent), SN38 (topo-I targeted agent) and the anti-metabolite, 5-Fluorouracil (5-FU). The degree of synergy between IFNγ and these agents was investigated using MTT cell viability assays and quantified using the CalcuSyn® programme which calculates combination index (CI) values indicative of synergy, additivity or antagonism. Investigations into the apoptotic mechanism responsible for the synergistic cell death in this model have suggested an important role for caspase-8. We found that procaspase-8 expression was up-regulated in response to treatment with IFNγ, concurrent with an increase in cleavage of the apoptotic marker PARP. Furthermore, a 4-fold increase in levels of caspase-8 activity was observed in response to co-treatment with IFNγ and doxorubicin. In addition, we have shown that a caspase-8 inhibitor (Z-IETD-FMK) repressed caspase-8 activation in response to treatment with IFNγ and doxorubicin and reduced apoptotic death as demonstrated by reduction in PARP cleavage. These data suggest that caspase-8 is responsible for the observed apoptotic phenotype. In light of these findings, we analysed the expression of the cell death receptors, Fas, DR4, DR5 and their ligands, FasL and TRAIL in response to IFNγ and doxorubicin. Initial results demonstrated that DR5 was up-regulated in response to treatment with doxorubicin. Studies are on going to determine the relative importance of the Fas/FasL and DR5/TRAIL apoptotic pathways for mediating the synergistic interaction between IFNγ and chemotherapy in breast cancer cells.
Matching-Adjusted Indirect Comparison of Relative Efficacies Is Feasible and Useful in the Multiple Myeloma Therapy Landscape: A Comparison of Pomalidomide Plus Low-Dose Dexamethasone Versus Daratumumab
Authors: Kejal Parikh, Irina Proskorovsky, Safiya Abouzaid, Stanimira Krotneva, Veronique Page, Christopher G Pelligra, Shien Guo, Jorge L Mouro, Sikander Ailawadhi
Journal: Blood (2016)
Health-related quality of life (HRQoL) following pancreatic resection in RCT of pasireotide.
Authors: Anne Eaton, Mithat Gonen, Paul Jack Karanicolas, Michael Ian D'Angelica, Ronald P. DeMatteo, Yuman Fong, T. Peter Kingham, William R. Jarnagin, Peter J. Allen
Journal: Journal of Clinical Oncology (2014)

e15234 Background: Morbidity following pancreatic resection is common. Changes in health related quality of life (HRQoL) following pancreatic resection have not been well studied. Using data from a recent RCT of prophylactic pasireotide we measured the associations between 1) resection and HRQoL and 2) postoperative pancreatic fistula (POPF) and HRQoL. Methods: Patients enrolled in a prospective, randomized, double blind, placebo controlled trial of pasireotide to reduce POPF after distal pancreatectomy or pancreaticoduodenectomy completed the EORTC QLQ-Core 30 and PAN26 at baseline, 14 and 60 days post op (BL, 14D, 60D). Differences from BL were compared using t-tests. Results: 100% of 300 trial participants completed a survey; 87% percent completed all 3. At 14D, 97% and 86% respectively reported pain and digestive symptoms. A significant (p<.01) worsening of function at 14D was detected on all PAN26 function scales except hepatic. These findings were improved at 60D, however remained significantly decreased compared to baseline with the exception of sexuality. POPF occurred in 15% (45/300) of patients, and patients with POPF experienced a sustained negative effect on body image compared to patients without POPF (p<.01 at 14D and 60D), and a negative effect on many individual symptoms, including worse outcomes at both 14D and 60D for limb weakness, treatment side effects and limit in planning activities (p<0.05). Health satisfaction was high. Conclusions: Pancreatic resection was followed by a short term decline in HRQoL. By 60D HRQoL recovered, although not to BL levels. POPF resulted in measurable decreases in HRQoL. Clinical trial information: NCT00994110. PAN26 scale BL 14D 60D No POPF 14D POPF 14D No POPF vs POPF 14D p-value Pancreatic pain 18 40 21 39 48 0.09 Digestive symptoms 19 47 27 47 48 0.94 Altered bowel habit 20 28 26 27 36 0.60 Hepatic 15 11 7 11 10 0.94 Body image 15 29 24 28 35 0.005 Satisfaction with health care* 78 85 79 85 86 0.76 Sexuality 35 54 38 52 70 0.12 * Higher is better
Frequency of oncogenic alterations in five driver genes in Chinese female lung adenocarcinoma.
Authors: Ren Xu, Jie Ma, Li-Qun Xie, Hui-Qing Tao, Bing Wei, Yong-Jun Guo, Wen-Jing Bao, Guang-Quan Tong, Lu Ding, Min-Ning Zhan, Ma Zhi Yong
Journal: Journal of Clinical Oncology (2013)

1588 Background: Currently, 5 driver genes (EGFR, K-RAS, B-RAF, ALK, RET) have been widely explored and become new targets of NSCLC, however no report has been found in Chinese female lung adenocarcinoma, who were prone to EGFR mutations and therefore, are the targets for TKIs therapy. Methods: FFPE-tissues from 310 female lung adenocarcinoma adopted in Hunan or Henan province between 2000 and 2012 were investigated. Oncogenic alterations in newly found 5 driver genes were analyzed. ARMS was used to study EGFR, K-RAS and B-RAF mutation. The reverse transcription and real-time PCR were performed to detect either ALK and RET fusions or ALK and RET gene expression. Sequencing was further applied to confirm the subtypes of fusions. Results: Among 310 samples, 149 (48.1%) EGFR mutations, 16 (5.2%) KRAS mutations, 0 (0%) BRAF mutations, 23 (7.4%) ALK fusions and 5 (1.6%) RET fusions were detected. Only EML4-ALK fusion but no other ALK fusions were found. Further research showed that cases (22, 95.6%) with high ALK expression were often accompanied by EML4-ALK fusion and poorly differentiated adenocarcinoma. Two RET fusions, KIF5B-RET and CCDC6-RET were found, with 2 cases and 3 cases, respectively. The ratio of RET/ABL mRNA levels was significantly higher in CCDC6-RET samples with poorly differentiated adenocarcinoma. However, with KIF5B-RET fusion, relatively high RET/ABL mRNA expression was detected in one KIF5B-RET sample with moderately differentiated adenocarcinoma, while no RET expression was detected in other two KIF5B-RET samples with highly differentiated adenocarcinoma. Conclusions: This is the first research about the oncogenic alterations of 5 important driver genes in Chinese female lung adenocarcinoma, as well as the correlation between ALK fusion and ALK expression or between RET fusion and RET expression, thus laying good foundation for understanding the genetic mutation spectrum in female lung adenocarcinoma.