tbuckley/cabot-search huggingface dataset:
Randomized trials of combination chemotherapy (combo) versus monotherapy (mono) in relapsed ovarian carcinoma (ROC): A meta-analysis of published data
Authors: M. Orlando, M. V. Costanzo, R. D. Chacon, C. D. Tajer
Journal: Journal of Clinical Oncology (2007)

5524 Background: Results of recent randomized clinical trials (RCTs) support the use of combination chemotherapy in the management of ROC, more specifically in the platinum-sensitive setting. We performed a literature-based meta-analysis of RCTs comparing combination versus monotherapy in previously treated ROC to validate or refute conclusions of individual trials. Methods: This was a systematic review of the available literature identified from multiple databases using the terms ‘combination chemotherapy‘, ‘advanced ovarian cancer‘ and ‘randomized trial‘. Data were pooled for Meta-analysis using the Mantel Hanzsel Peto model. Event-based relative odds ratios (OR) with 95% confidence intervals (CI) were derived. Heterogeneity test was applied. Results: We identified and included 8 RCTs trials fulfilling the selection criteria, 6 phase III and 2 Phase II. Seven published trials and one ASCO poster presentation. One study was conducted exclusively in patients with platinum-resistant disease, five in platinum-sensitive disease only, and 2 in a mixed population. A total of 2312 patients were included in those 8 trials. Relevant endpoints of interest for this meta-analysis were: Overall Response Rate (ORR), Progression-Free Survival (PFS) at 2 years and Overall Survival (OS) at 2 years. Results are summarized in the table : Conclusion: Acknowledging all the drawbacks related to literature-based meta-analyses, combination chemotherapy seems to improve ORR, PFS and OS when compared to monotherapy in the mangement of ROC. References: Bolis G et al Gynecol Oncol 1999, 72:60; Bolis G et al Gynecol Oncol 2001, 81:3; Cantu M et al J Clin Oncol 2002, 20:1232; ICON and AGO collaborators Lancet 2003, 361:2099; Buda et al Br J Cancer 2004, 90:2112; Gonzalez-Martin AJ et al Ann Oncol 2005, 16:749; Pfisterer J et al J Clin Oncol 2006, 24:4699; Sehouli et al Proceedings ASCO 2006, Abstract 5030 [Table: see text] No significant financial relationships to disclose.
Rapid skin repigmentation on oral ruxolitinib in a patient with coexistent vitiligo and alopecia areata (AA)
Authors: John E. Harris, Mehdi Rashighi, Nhan Nguyen, Ali Jabbari, Grace Ulerio, Raphael Clynes, Angela M. Christiano, Julian Mackay-Wiggan
Journal: Journal of the American Academy of Dermatology (2015)
Lapatinib induces HER2 stabilization and enhances the antitumor activity of trastuzumab in vivo
Authors: Maurizio Scaltriti, Chandra Verma, Marta Guzman, Jose Jimenez, Derek Smith, Stefania Landolfi, Santiago Ramon y Cajal, Joaquin Arribas, Jose Baselga
Journal: Cancer Research (2008)

2559  Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2 amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab and studies with this combination are under way in patients. In order to dissect the differential effects of these agents given alone and in combination, we have studied receptor expression and receptor signaling and have explored a new potential mechanism underlying the profound antitumor activity that we have observed with the combination in HER2 overexpressing tumor xenografts. Lapatinib given alone or in combination with trastuzumab to HER2 overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation resulting in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation. By computational protein modelling and immunoprecipitation techniques we demonstrated that, in presence of lapatinib, the accumulation of HER2 coincided with the stabilization of inactive HER2 homo- (HER2/HER2) and heterodimers (HER2/EGFR and HER2/HER3). Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by trastuzumab were observed also in vivo, where the combination of the two agents triggered complete tumor remission after 10 days of treatment. Using an in vitro model that mimicked the effects of lapatinib in stabilizing HER2 we showed that accumulation of inactive receptor at the cell surface was sufficient to enhance immune-mediated trastuzumab-dependent cytotoxicity. These findings suggest that the inhibitory effect of lapatinib on HER2 phosphorylation can influence receptor stability and dimerization, resulting in enhanced or prolonged trastuzumab binding/activity.
Are We the Barrier?
Authors: Jamie H. Von Roenn
Journal: Journal of Clinical Oncology (2001)

Article Tools EDITORIAL Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2001.19.23.4273 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11731508 Are We the Barrier? Jamie H. Von RoennxJamie H. Von RoennSearch for articles by this author Show More Northwestern University Medical School, Robert H. Lurie Comprehensive Cancer Center, Chicago, IL https://doi.org/10.1200/JCO.2001.19.23.4273 Full Text PDF Figures and Tables "Are We the Barrier?." Journal of Clinical Oncology, 19(23), pp. 4273–4274© 2001 by American Society of Clinical Oncology
Metabolic Activity by 18F-FDG-PET/CT Is Prognostic for Stage I and II Pancreatic Cancer
Authors: Jose M. Pimiento, Ashley H. Davis-Yadley, Richard D. Kim, Dung-Tsa Chen, Edward A. Eikman, Claudia G. Berman, Mokenge P. Malafa
Journal: Clinical Nuclear Medicine (2015)

Metabolic activity, as defined by F-FDG uptake on PET, is a prognostic marker for multiple malignancies; however, no study has examined the prognostic value of imaging with FDG PET in stage I and II pancreatic cancer. We examined the value of PET FDG uptake in early-stage pancreatic cancer patients.We identified patients with early-stage pancreatic cancer (I-II) who had FDG PET scan performed as part of their preoperative evaluation. The patients were divided into either high or low FDG uptake according to the median primary tumor standard uptake value (SUVmax). Our primary end points were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier estimate was used for survival analysis. Pathologic data were compared using the Fisher exact and χ tests.One hundred five patients were identified: 51 patients with low FDG uptake and 54 patients with high FDG uptake. Eighty-five patients (81%) had PET avid tumors, whereas 20 (19%) patients did not. High FDG uptake correlated with pathologic stage (P = 0.012). Patients with low FDG uptake had significantly better median OS than patients with high FDG uptake (28 vs. 16 months; P = 0.036). Patients with low-FDG uptake had significantly longer median RFS than patients with high FDG uptake (14 vs. 12 months; P = 0.049).Low FDG uptake in PET scans in patients with stage I and II pancreatic cancer correlates with improved OS and RFS. This supports the concept that glucose metabolic pathways are important in pancreatic cancer biology and that PET scan activity can be used as a prognostic biomarker after pancreatectomy.
Inhibition of ErbB-mediated breast tumor cell growth by the leucine-rich repeat protein LRIG1
Authors: Jamie Miller, David Shattuck, Kermit Carraway, Colleen Sweeney
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

2525 

Receptor tyrosine kinases (RTKs) are key mediators of normal cellular processes such as the development and maintenance of tissues, and are also critically involved in the growth and progression of human tumors. One subfamily of RTKs is the epidermal growth factor (EGF) family which consists of four members: EGF receptor (EGFR), ErbB2, ErbB3, and ErbB4. Binding of EGF-like growth factors induces receptor dimerization, leading to tyrosine phosphorylation, recruitment of intracellular signaling proteins, and subsequent changes in cellular processes including proliferation and survival. Overexpression or aberrant activation of ErbB2 and its heterodimeric partner ErbB3 is found in a significant portion of human breast tumors and correlates with poor patient prognosis. Recently, the leucine-rich repeat protein LRIG1 has been shown by our lab to interact with and downregulate ErbB2 and ErbB3 levels through enhanced receptor ubiquitination. In the present study, we seek to determine the effect of LRIG1 on endogenous ErbB receptors in breast tumor cells. Following overexpression of LRIG1, reduced ErbB2 and ErbB3 levels were seen, as well as a concomitant decrease in signaling and proliferation in response to growth factor. Further, the addition of siRNA oligos to knock-down LRIG1 levels resulted in an increased proliferative response. Finally, tumors from the mammary fat pad of transgenic mice overexpressing ErbB2, and consequently ErbB3, were found to have lowered LRIG1 levels as compared to adjacent normal samples. These data suggest that LRIG1 may help to keep cellular ErbB receptor levels balanced and that the loss of this protein may be involved in breast tumor progression. Furthermore, LRIG1 has the potential to hold either therapeutic or prognostic value for breast cancer treatments.
Rate-Control Treatment and Mortality in Atrial Fibrillation
Authors: Tze-Fan Chao, Chia-Jen Liu, Ta-Chuan Tuan, Su-Jung Chen, Kang-Ling Wang, Yenn-Jiang Lin, Shih-Lin Chang, Li-Wei Lo, Yu-Feng Hu, Tzeng-Ji Chen, Chern-En Chiang, Shih-Ann Chen
Journal: Circulation (2015)

Background— Current American and European guidelines emphasize the importance of rate-control treatments in treating atrial fibrillation with a Class I recommendation, although data on the survival benefits of rate control are lacking. The goal of the present study was to investigate whether patients receiving rate-control drugs had a better prognosis compared with those without rate-control treatment. Methods and Results— This study used the National Health Insurance Research Database in Taiwan. There were 43 879, 18 466, and 38 898 patients with atrial fibrillation enrolled in the groups receiving β-blockers, calcium channel blockers, and digoxin, respectively. The reference group consisted of 168 678 subjects who did not receive any rate-control drug. The clinical end point was all-cause mortality. During a follow-up of 4.9±3.7 years, mortality occurred in 88 263 patients (32.7%). After adjustment for baseline differences, the risk of mortality was lower in patients receiving β-blockers (adjusted hazard ratio=0.76; 95% confidence interval=0.74–0.78) and calcium channel blockers (adjusted hazard ratio=0.93; 95% confidence interval=0.90–0.96) compared with those who did not receive rate-control medications. On the contrary, the digoxin group had a higher risk of mortality with an adjusted hazard ratio of 1.12 (95% confidence interval=1.10–1.14). The results were observed consistently in subgroup analyses and among the cohorts after propensity matching. Conclusions— In this nationwide atrial fibrillation cohort, the risk of mortality was lower for patients receiving rate-control treatment with β-blockers or calcium channel blockers, and the use of β-blockers was associated with the largest risk reduction. Digoxin use was associated with greater mortality. Prospective, randomized trials are necessary to confirm these findings.
Cyclic dinucleotides (CDNs) reversed T cells tolerance in anti-tumor immunotherapy
Authors: Juan Fu, Young Kim, David Kanne, Meredith Leong, Qi Zeng, Rupashree Sen, Todd D Amstrong, Charles G Drake, Thomas Dubensky, Drew Pardoll, Shekhar Gadkare
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts One important barrier to cancer immunotherapy. We used cyclic dinucleotides (CDNs) and Listeria vaccine and LPS treated HA-specific CD8 tolerance B10. D2 mice. Our results demonstrated T cells IFN-gamma increased in CDNs and Listeria vaccine plus CDNs treatment groups. But CDNs
Sleeping Beauty Transposon Vectors in Liver-directed Gene Delivery of LDLR and VLDLR for Gene Therapy of Familial Hypercholesterolemia
Authors: Tytteli A K Turunen, Jere Kurkipuro, Tommi Heikura, Taina Vuorio, Elisa Hytönen, Zsuzsanna Izsvák, Seppo Ylä-Herttuala
Journal: Molecular Therapy (2015)

Plasmid-based Sleeping Beauty (SB) transposon vectors were developed and used to deliver genes for low-density lipoprotein and very-low-density lipoprotein receptors (LDLR and VLDLR, respectively) or lacZ reporter into liver of an LDLR-deficient mouse model of familial hypercholesterolemia (FH). SB transposase, SB100x, was used to integrate the therapeutic transposons into mice livers for evaluating the feasibility of the vectors in reducing high blood cholesterol and the progression of atherosclerosis. Hydrodynamic gene delivery of transposon-VLDLR into the livers of the mice resulted in initial 17-19% reductions in plasma cholesterol, and at the later time points, in a significant stabilization of the cholesterol level for the 6.5-month duration of the study compared to the control mice. Transposon-LDLR-treated animals also demonstrated a trend of stabilization in the cholesterol levels in the long term. Vector-treated mice had slightly less lipid accumulation in the liver and reduced aortic atherosclerosis. Clinical chemistry and histological analyses revealed normal liver function and morphology comparable to that of the controls during the follow-up with no safety issues regarding the vector type, transgenes, or the gene transfer method. The study demonstrates the safety and potential benefits of the SB transposon vectors in the treatment of FH.
Relapse of Hodgkin's lymphoma (HL) after autologous stem cell transplantation (ASCT): Prognostic factors in 462 patients registered in the database of the EBMT.
Authors: C. Martinez, C. Canals, E. Alessandrino, D. Karakasis, G. Leone, M. Trneny, J. Snowden, J. Apperley, N. Milpied, A. Sureda
Journal: Journal of Clinical Oncology (2010)

8060 Background: Autologous stem cell transplantation (ASCT) is the standard of care for patients with HL relapsing after conventional chemotherapy (CT). Nevertheless, a significant proportion of patients still relapse after the autologous procedure. Methods: We performed a retrospective review of 462 adult patients (196 F/266 M) with relapsing HL after first ASCT (January 1996-December 2005) in order to analyze prognostic factors significantly influencing outcome after relapse. Disease status at transplant was complete remission in 142 patients (31%), sensitive disease in 249 (54%), and refractory disease in 71 (15%). Median time from ASCT to relapse was 7 months (range 0.5-78), with 44% of the patients relapsing < 6 months after ASCT. HL stage at relapse was I in 19 patients (5%), II in 100 (28%), III in 80 (23%), and IV in 155 (44%). Forty-nine percent of the patients had B symptoms, 7% bulky disease, and 54% extranodal involvement. Treatment following relapse consisted on conventional CT and/or radiotherapy in 294 patients (64%), 2nd ASCT in 35 (8%), and allogeneic SCT in 133 (29%). A significant higher proportion of patients, age < 50 years, received a 2nd transplantation in comparison to older patients (39% vs. 16%, p=.006). Results: After a median follow-up of 49 months (range 1-150), the OS from relapse after ASCT was of 55% at 2 years and 32% at 5 years. In multivariate analysis, independent risk factors for OS were early relapse (< 6 months), stage IV, bulky disease, B symptoms, and extranodal involvement at relapse. Median survival time was 71 months (95% CI: 44-98), 28 months (95% CI: 21-36), and 13 months (95% CI: 8.5-18) for patients with 0, 1-2, and ≥3 risk factors, respectively (p<0.001). OS from relapse was 55%, 32%, and 12% at 5 years for patients with 0, 1-2, and ≥ 3 risk factors, respectively (p<0.001). Conclusions: According to our experience, most HL patients relapsing after ASCT were treated with chemo-radiotherapy approaches and some of them with a 2nd transplantation. Early relapse, stage IV, bulky disease, B symptoms, and extranodal involvement at relapse are relevant factors and could be used to form a prognostic score for these patients. No significant financial relationships to disclose.
Pharmacogenetics of a PARP inhibitor ABT-888 metabolic pathway
Authors: J. Li, X. Sha, P. LoRusso
Journal: Journal of Clinical Oncology (2009)

e14556 Background: Poly(ADP-ribose) polymerase (PARP) is essential for single-stranded DNA break repair and repair of DNA damage can lead to radio- and chemo-resistance. Thus, inhibition of PARP activity can sensitize cells to cytotoxic therapies. ABT-888 is a potent, orally bioavailable PARP inhibitor. Preclinical studies suggest that ABT-888 potentiates multiple cytotoxic agents and its efficacy is correlated with plasma/tumor drug concentrations. The objective of this study was to determine the pharmacogenetic effect of genetic variants in the ABT-888 metabolic pathway, with the aim to better understand molecular basis of the variation in ABT-888 pharmacokinetics (PK) and therapeutic outcome. Methods: The major enzymes responsible for ABT-888 metabolism were identified by in vitro metabolism studies with specific recombinant human cytochrome P450 (CYP) enzymes. The functional significance of genetic variants of the identified enzymes was assessed by examining ABT-888 metabolic kinetics by candidate variant enzymes and microsomes. The association of the functional significant genetic variants with the PK and clinical outcome is being evaluated in the context of an ongoing phase I trial in which ABT-888 is administered in combination with irinotecan in patients with advanced solid tumors. Results: ABT-888 was metabolized predominantly by human CYP2D6, to a less extent by CYP1A1, and to a negligible extent by CYP1A2, 2C9, 2C19, 3A4, and 3A5. CYP2D6*10 exhibited markedly reduced catalytic capability in ABT-888 overall metabolism and the metabolite (A-925088) formation, with in vitro maximum clearance being 31% and 5.3%, respectively, of that estimated from the wild-type CYP2D6. In human liver microsomes carrying homozygous CYP2D6*4, the rates of parent drug disappearance and metabolite formation were significantly lower than those observed in the microsomes carrying wild-type CYP2D6, P &lt; 0.05. Conclusions: CYP2D6 is the predominant enzyme responsible for the hepatic metabolism of ABT-888. Common allelic variants CYP2D6*10 and *4 are associated with significantly reduced metabolic activity towards ABT-888. CYP2D6 polymorphisms may influence the PK and therapeutic outcome of ABT-888. Its clinical relevance remains to be determined. No significant financial relationships to disclose.
Congenital Erythropoietic Porphyria Successfully Treated by Allogeneic Bone Marrow Transplantation
Authors: I. Tezcan, W. Xu, A. Gurgey, M. Tuncer, M. Cetin, C. Öner, S. Yetgin, F. Ersoy, G. Aizencang, K.H. Astrin, R.J. Desnick
Journal: Blood (1998)
A quantitative analysis of therapeutic cancer vaccines in phase 2 or phase 3 trial
Authors: Amabel CL Tan, Anne Goubier, Holbrook E. Kohrt
Journal: Journal for ImmunoTherapy of Cancer (2015)

Despite the progress that has been made in other forms of cancer therapy, Provenge® (Sipuleucel-T) is the only FDA-approved vaccine for the treatment of cancer. To understand the current landscape of therapeutic oncology vaccines we performed a quantitative analysis of phase 2 and phase 3 therapeutic cancer vaccine trials. We highlight shifts in trends for the vaccine platforms examined, common adjuvant use, target indications, antibody or treatment combinations between past and recent trials as well as discuss the relationship between these trends and ratio between the number of phase 3: phase 2 for different vaccine platforms. Despite the poor success rate in vaccine approvals, registration of phase 3 trials between 2010 and 2014 were stable indicating continued investment and efforts towards development of immunotherapeutic vaccines.
HYPOGLYCIN AND HYPOGLYCIN-LIKE COMPOUNDS
Authors: R. BRESSLER, C. CORREDOR, K. BRENDEL
Journal: Pharmacological Reviews (1969)

Hypoglycin and hypoglycin-like compounds cause profound hypoglycemia which may be largely attributed to their effects on gluconeogenesis. The toxicity of these agents is due to their capacity to become activated to acyl CoA derivatives whose further oxidation is impaired. Because the activated compounds serve as substrates for the carnitine acetyltransferase, tissue levels of both free carnitine and coenzyme A are depressed. The depression of these cofactors results in a decrease in long-chain fatty acid oxidation, whose products (acetyl CoA, NADH, ATP) are necessary for gluconeogenesis. Moreover, the decreased oxidation of long-chain fatty acids may also result in augmented glycolysis due to relief of the inhibitory effects of long-chain fatty acid oxidation on glycolysis. Replacement of coenzyme A and carnitine prevent inhibition of long-chain fatty acid oxidation and glyconeogenesis by 4-pentenoate. Addition of noncarnitinedependentfatty acids or palmitylcarnitine as substrates also partially prevent the 4-pentenoate depression of gluconeogenesis.

The inability to completely reverse the toxic effects of these compounds in vitro and in vivo suggests that they may be exerting as yet poorly established effects on oxidative phosphorylation and the electron transport system.
LP35 : A placebo-controlled, multicenter, double-blind, randomised, pharmacokinetic and pharmacodynamic trial of emricasan (IDN-6556) in subjects with acute-on chronic liver failure (ACLF)
Authors: R. Jalan, G. Wright, S. McPherson, C. Frenette, M. Cave, M. Morris, M. Huyghe, G. Burgess
Journal: Journal of Hepatology (2015)
Implantable pumps--opportunities for improved therapy of malignant disease.
Authors: J R Bertino
Journal: Journal of Clinical Oncology (1983)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1983.1.5.289 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 6668502 Implantable pumps--opportunities for improved therapy of malignant disease. J R BertinoxJ R BertinoSearch for articles by this author https://doi.org/10.1200/JCO.1983.1.5.289 PDF "Implantable pumps--opportunities for improved therapy of malignant disease.." Journal of Clinical Oncology, 1(5), p. 289© 1983 by American Society of Clinical Oncology