tbuckley/cabot-search huggingface dataset:
The role of S-1 in gemcitabine-refractory pancreatic cancer: A retrospective single-institution study
Authors: Y. Nakai, H. Isayama, T. Sasaki, N. Sasahira, K. Hirano, T. Tsujino, M. Tada, T. Kawabe, M. Omata
Journal: Journal of Clinical Oncology (2009)

e15648 Background: S-1 was reported to be active against gemcitabine (Gem)-refractory pancreatic cancer (PaC) in Japan and was introduced in February 2005 in our institution. The aim of this study was to elucidate the impact of S-1 on prognosis of patients with Gem- refractory PaC. Methods: A total of 108 patients (pts) with advanced PaC who were treated with Gem and had disease progression (PD) at the University of Tokyo Hospital were analyzed. The introduction rates of second-line chemotherapy and the causes of introduction failure were assessed. Prognostic factors for residual survival (RS) for Gem-refractory PaC were analyzed by the Cox proportional hazard model. Results: Of 108 pts with Gem-refractory PaC, 47 pts (PreS-1 Group) had PD before February 2005, the time of S-1 introduction in our institution, and 61 pts (PostS-1 Group) after February 2005. There were no differences in baseline characteristics at PD for Gem between PreS-1 and PostS-1 Groups, except for metastasis to peritoneum more prevalent in PreS-1 Group (44.7% in PreS-1 Group and 23.0% in PostS-1 Group, p=0.023). The introduction rate of second-line chemotherapy increased from 12.8% in PreS-1 Group to 45.9% in PostS-1 Group. Second-line chemotherapy was administered in 34 pts, 29 by S-1, 4 by 5-FU-based chemoradiation, and 1 by 5-FU. The causes of introduction failure of second line chemotherapy were poor PS in 64.9%, patients’ refusal in 16.2%, infection in 2.7%, adverse effects of Gem in 1.4% and jaundice in 1.4%. RR, PFS, and OS for second-line S-1 were 17.2%, 2.5 Mo, and 7.8 Mo, respectively. PFS for Gem was not prognostic of PFS for S-1 (2.5 Mo both in pts with PFS &gt;6Mo and in pts with PFS &lt;6Mo for Gem). RS after PD for Gem was prolonged from 3.1 Mo in PreS-1 Group to 6.5 Mo in PostS-1 Group (p&lt;0.001). The Cox hazard model revealed PreS-1 Group (HR2.42, p=0.001) in addition to male gender (HR1.83, p=0.019), poor PS (HR3.52, p&lt;0.001), liver metastasis (HR2.36, p=0.037), elevated LDH (per 100U/L increase) (HR 1.30, p=0.046), elevated CRP (HR 1.14, p=0.023) at PD for Gem as poor prognostic factors of RS for Gem-refractory PaC. Conclusions: Introduction of S-1 might lead to improvement of prognosis in patients with Gem-refractory PaC. No significant financial relationships to disclose.
Abstract 1347: NTRK1/TRKA as a therapeutic target in castration resistant prostate cancer
Authors: James E. Korkola, Moqing Liu, Rebecca Smith, Tiera Liby, Joe W. Gray
Journal: Cancer Research (2016)

Abstract Treatment options remain limited for men with castration resistant prostate cancer, with current chemotherapy offering mainly palliative benefits. Thus, there is an urgent need to identify new targets for therapeutic intervention in men who have progressed on anti-androgen therapy. We have compiled a panel of 20 prostate cancer cell lines that has been extensively characterized at the molecular level that enables us to perform high throughput drug and siRNA screens to identify novel therapeutic targets. We performed an siRNA screen targeting kinases using eight representative lines, both in the presence and absence of the anti-androgen MDV3100. Knockdown of NTRK1 (TRKA) significantly inhibited growth in 4/8 of the cell lines tested. To confirm this, we screened the entire panel of cell lines with the inhibitor CEP-701, which targets FLT3, JAK2, and TRK-A/B/C. CEP-701 showed GI50 values (dose required to inhibit growth by 50%) less than 400 nM in 8/20 cell lines. Since this drug had already been tested in clinical trials for prostate cancer and the trials were discontinued due to lack of PSA decline, we looked for other drugs that also inhibit TRKA. Both BIBF-1120 and GSK-1363089 are also known to inhibit TRKA, but neither have been tested in prostate cancer expressing TRKA. We tested GSK-136089 in a subset of 9 prostate cell lines, and found that 4/9 lines reached GI50 at 1 uM or less, including AR mutant or null lines such as 22rv1 and PC3 that are non-responsive to MDV3100. Additional tests with BIBF-1120 and GSK-1363089 are underway. These data suggest that NTRK1 may be a potential target for patients with castration resistant prostate cancer. Citation Format: James E. Korkola, Moqing Liu, Rebecca Smith, Tiera Liby, Joe W. Gray. NTRK1/TRKA as a therapeutic target in castration resistant prostate cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1347.
Comparison of ondansetron, granisetron and dolasetron with dexamethasone in the prevention of acute nausea and vomiting associated with platinum-based therapy
Authors: M. H. Hamadani, A. Tfayli, K. Kojouri, A. Awab
Journal: Journal of Clinical Oncology (2005)

8056 Background: Chemotherapy-induced nausea and vomiting (CINV) is usually classified as acute (within 24hrs), delayed (>24hrs) and anticipatory. 5-Hydroxytryptamine-3 receptor (5-HT3) antagonists have revolutionized the management of CINV. No study to date has compared the relative efficacy of Ondansetron, Granisetron, and Dolasetron, with Dexamethasone (DEX) in the prevention and control of acute CINV in patients receiving Platinum-based therapy. Methods: Retrospective data were reviewed for 123 consecutive patients receiving Platinum-based therapy in our infusion center between November 1999 and April 2004. Patients getting 5-HT3 antagonists without steroids (n=9), or those receiving Palonosetron (n=16) were not eligible for the study. Further 8 patients were excluded because of no documentation of CINV. The remaining 90 patients constitute the subject of this study. Patient characteristics including age, sex, race, diagnosis, history of heavy alcohol intake, chemotherapy regimen administered, number of cycles, and performance status at the start of therapy were noted. Primary outcome measure was complete control of acute CINV. National Cancer Institute (NCI) Common Toxicity Criteria Version 2 was used to assess toxicity. Results: The 90 patients received 369 cycles of platinum-based therapy. Dolasetron (n=157), granisetron (n=81), and ondansetron (n=131) (each given with DEX) achieved complete control of vomiting in 89.8%, 95.5% and 92.3% (P=0.67) of cycles respectively. Respectively, complete nausea control was observed in 68.1%, 75.3% and 69.4% (P=0.50). DEX 20 mg was not superior to 10mg in complete control of nausea and vomiting (P=0.15 and P=0.63 respectively). However complete nausea control was significantly better in subgroup of patients getting cisplatin compared to carboplatin based regimens (78.8% Vs 68.25%, P<0.05). Conclusions: We conclude that there is no difference in the efficacy of the three 5-HT3 antagonists in controlling acute CINV and that higher dose of DEX confers no added benefit over the lower 10mg dose. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer
Abstract 289: Melphalan and XPO1 inhibition are synergistic in pre-clinical models of multiple myeloma
Authors: Joel G. Turner, Jana L. Dawson, Daniel M. Sullivan
Journal: Cancer Research (2016)

Abstract Introduction: Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies, with estimated numbers of new cases and deaths for 2015 in the US at 26,850 and 11,240, respectively. Significant increases in response/survival have been seen over the past several years; however, MM remains incurable and patients ultimately die from progressive disease refractory to anti-myeloma therapy. There is clearly a need for additional effective therapies. Materials and Methods: Human MM parental and melphalan (MEL) resistant cell lines were treated with XPO1 inhibitors (XPO1i) KPT330 or KPT8602 +/- MEL and assayed for apoptosis and viability by flow cytometry. Treated cells were assayed for DNA damage by comet assay and phospho-H2AX protein expression. XPO1/MEL treated cells were assayed for p53, NFkB, IKKα, FANCF, and FANCL by Western blot. Cells from patients with newly diagnosed or relapsed/refractory MM treated with XPO1i/MEL were assayed for apoptosis. NOD/SCID-gamma mice with MM tumors were treated with XPO1i/MEL and assayed for tumor growth, survival, and toxicity. Results: MM cell viability was decreased synergistically and apoptosis increased by XPO1I/MEL treatment in all MM cell lines tested. XPO1/MEL drug combination significantly increased DNA damage when compared to either MEL or XPO1 alone, as shown by comet assay and increased phospho-H2AX expression. Western blot showed that XPO1i treatment of MM cells increased p53 and decreased NFkB, IKKα, FANCF, and FANCL. MEL-resistant MM cell lines were found to be sensitized by XPO1i to MEL as shown by apoptosis assay (20-fold). CD138+/light chain+ MM cells from newly diagnosed and relapsed/refractory MM patients were also sensitized (5-10 fold) by XPO1i to MEL (apoptosis assay). NOD/SCID-gamma mice challenged with MM tumors demonstrated a strong synergistic antitumor effect in XPO1i/MEL-treated mice, with increased survival and no significant toxicity. Conclusions: XPO1i's improved the response of human MM cell lines and patient MM cells to MEL in vitro and ex vivo. It is possible that this synergy may be due to increased nuclear p53 in combination with decreased NFkB and IKKα and decreased DNA repair proteins FANCL and FANCF reversing MEL resistance by the Fanconi Anemia/BRCA pathway. These preliminary data suggest that XPO1i's augment MEL-induced DNA damage and may also block the repair of the DNA damage—both of which could result in synergistic cell kill. Combination therapies using XPO1i, especially the clinical compounds KPT330 (selinexor) and KPT8602 +/- MEL, may significantly improve the treatment outcomes of MM. Citation Format: Joel G. Turner, Jana L. Dawson, Daniel M. Sullivan. Melphalan and XPO1 inhibition are synergistic in pre-clinical models of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 289.
The Novel Pan-PIM Kinase Inhibitor, PIM447, Displays Dual Antimyeloma and Bone-Protective Effects, and Potently Synergizes with Current Standards of Care
Authors: Teresa Paíno, Antonio Garcia-Gomez, Lorena González-Méndez, Laura San-Segundo, Susana Hernández-García, Ana-Alicia López-Iglesias, Esperanza M. Algarín, Montserrat Martín-Sánchez, David Corbacho, Carlos Ortiz-de-Solorzano, Luis A. Corchete, Norma C. Gutiérrez, María-Victoria Maetos, Mercedes Garayoa, Enrique M. Ocio
Journal: Clinical Cancer Research (2016)

Abstract Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. Experimental Design: In vitro/ex vivo cytotoxicity of PIM447 was evaluated on myeloma cell lines and patient samples. Synergistic combinations with standard treatments were analyzed with Calcusyn Software. PIM447 effects on bone cells were assessed on osteogenic and osteoclastogenic cultures. The mechanisms of PIM447 were explored by immunoblotting, qPCR, and immunofluorescence. A murine model of disseminated multiple myeloma was employed for in vivo studies. Results: PIM447 is cytotoxic for myeloma cells due to cell-cycle disruption and induction of apoptosis mediated by a decrease in phospho-Bad (Ser112) and c-Myc levels and the inhibition of mTORC1 pathway. Importantly, PIM447 demonstrates a very strong synergy with different standard treatments such as bortezomib + dexamethasone (combination index, CI = 0.002), lenalidomide + dexamethasone (CI = 0.065), and pomalidomide + dexamethasone (CI = 0.077). PIM447 also inhibits in vitro osteoclast formation and resorption, downregulates key molecules involved in these processes, and partially disrupts the F-actin ring, while increasing osteoblast activity and mineralization. Finally, PIM447 significantly reduced the tumor burden and prevented tumor-associated bone loss in a disseminated murine model of human myeloma. Conclusions: Our results demonstrate dual antitumoral and bone-protective effects of PIM447. This fact, together with the very strong synergy exhibited with standard-of-care treatments, supports the future clinical development of this drug in multiple myeloma. Clin Cancer Res; 23(1); 225–38. ©2016 AACR.
P1152 : A Comparative study of pruritus in PBC cohorts from UK, USA and Italy
Authors: V.S. Hegade, G.F. Mells, C. Lammert, B. Juran, A. Lleo, M. Carbone, K. Lazaridis, P. Invernizzi, S. Kendrick, R. Sandford, G. Hirschfield, D.E. Jones
Journal: Journal of Hepatology (2015)
Therapeutic replicon-based immunotherapy targeting the breast cancer tumor antigens neu and BORIS: Advantages and constraints.
Authors: A. K. Laust, M. Mkrtichyan, H. Davtyan, J. Khlgatyan, A. Ghochikyan, H. Liu, M. G. Agadjanyan, E. L. Nelson
Journal: Journal of Clinical Oncology (2010)

e13156 Background: Immunotherapy using the Venezuelan equine encephalitis replicon (VRP) vector system, with intrinsic tropism for dendritic cells, has shown exceptional promise. Previously, we reported the capacity of this vector system to cure up to 40% of animals with pre- existing tumor when targeting the tumor-associated antigen (TAA) rat neu in a stringent fully tolerant rat mammary tumor model. We also reported the outgrowth of tumors that had down regulated the overexpression of the targeted tumor antigen, so-called antigen loss variants. Thus, we hypothesized that targeting more than a single TAA would lead to increased therapeutic efficacy. Methods: Fisher 344 rats received heterotopic 13762 MAT B III mammary tumor cells 48 hours prior to initiation of therapeutic immunotherapy. Individual VRP encoding truncated rat neu, the recently described cancer testis (CT) antigen, Brother of the Regulator of Imprinted Sites (BORIS), or a control irrelevant antigen were administered as a subcutaneous injection alone or in combination. Animals were followed for survival and tumor growth. Additional studies were conducted to evaluate initial results and to characterize the elicited immune responses. Results: We observed a similar although slightly improved treatment efficacy when targeting the truncated neu TAA as in our previous studies (45%). Targeting BORIS alone yielded a cure rate of 43%. Interestingly, administering these two VRP as a mixture at a single anatomic site decreased the efficacy to <20%, whereas administering individual VRP at separate anatomic sites provided increased therapeutic efficacy resulting in a cure rate of >50%. Conclusions: This is the first report of polyvalent VRP-based antitumor immunotherapy to demonstrate increased efficacy when more than one TAA is targeted. This represents an exceptionally promising foundation upon which to build more efficacious VRP-based antitumor immunotherapeutic strategies. Although the tropism for a subset of dendritic cells is likely to play an important role in the in the potency of this vector system, it also may contribute to the requirement for separate administration sites when targeting more than one TAA. No significant financial relationships to disclose.
Abstract 19254: Sex Differences for Patients With New-onset Atrial Fibrillation During Hospitalization
Authors: Philip W Chui, Ashwini Erande, Shaista Malik
Journal: Circulation (2015)

Introduction: New-onset atrial fibrillation (AF) during hospitalization has been associated with worse outcomes. However, there is little information on the risk factors associated with the development of new-onset AF. We assessed whether there are sex differences in the incidence and mortality of hospitalized patients with new-onset AF. Methods: We utilized the National Inpatient Sample to analyze new-onset AF in a sample of inpatient hospitalizations from 2001 to 2011. New-onset AF was defined by an ICD-9 discharge code of 427.3 not present on admission. We performed multivariate logistic regression for incidence and all-cause in-hospital mortality of female versus male sex for new-onset AF, adjusting for comorbid conditions and other demographic factors (described in Table). We separated our analyses by principal diagnosis of guideline-defined acute conditions associated with new-onset AF: noncardiac surgery, cardiac surgery, myocardial infarction, sepsis, pulmonary embolism, myocarditis, and thyrotoxicosis. Results: A total of 38,403,360 cases of new-onset AF were identified. The majority of new-onset AF cases (85%) were associated with admissions for noncardiac surgery (Table). Female sex was associated with decreased incidence of new-onset AF across all acute conditions (p &lt;0.05). Female sex was also associated with decreased mortality of new-onset AF patients admitted for noncardiac surgery and thyrotoxicosis but increased mortality for new-onset AF patients admitted for cardiac surgery, sepsis, myocardial infarction, and pulmonary embolism (p &lt;0.05). Conclusion: Female sex is associated with a decreased incidence for new-onset AF; however, it is also a risk factor for in-hospital mortality for a majority of acute conditions linked to new-onset AF. Further quality improvement measures should elucidate and target the mechanisms for this discrepancy.
Low-Risk Multiple Myeloma By SKY92+ISS Validated in the Multiple Myeloma Genomics Initiative Study
Authors: Erik van Beers, Martin van Vliet, Leonie de Best, Kenneth C. Anderson, Ajai Chari, Sundar Jagganath, Andrzej Jakubowiak, Shaji K. Kumar, Daniel Lebovic, Joan Levy, Daniel Auclair, Sagar Lonial, Donna Reece, Paul G. Richardson, David Siegel, A. Keith Stewart, Suzanne Trudel, Ravi Vij, Todd Zimmerman, Rafael Fonseca
Journal: Blood (2015)
P0845 : Comparative study on the effectiveness of simeprevir or telaprevir in combination with peginterferon and ribavirin for chronic HCV genotype 1b infection
Authors: E. Ogawa, N. Furusyo, E. Kajiwara, H. Nomura, A. Kawano, K. Takahashi, K. Dohmen, T. Satoh, K. Azuma, M. Nakamuta, T. Koyanagi, K. Kotoh, S. Shimoda, J. Hayashi
Journal: Journal of Hepatology (2015)
Nivolumab ± ipilimumab in treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC) with and without high microsatellite instability (MSI-H): CheckMate-142 interim results.
Authors: Michael J. Overman, Scott Kopetz, Raymond S. McDermott, Joseph Leach, Sara Lonardi, Heinz-Josef Lenz, Michael A. Morse, Jayesh Desai, Andrew Hill, Michael D. Axelson, Rebecca Anne Moss, Chen-Sheng Lin, Monica Goldberg, Thierry Andre
Journal: Journal of Clinical Oncology (2016)

3501 Background: Evidence supports use of nivolumab (N) in MSI-H mCRC. N, a fully human anti-PD-1 mAb and ipilimumab (I), a humanized anti-CTLA-4 mAb, have favorable safety & efficacy in other tumors. CheckMate-142, a phase 2 study, evaluates N ± I in pts with mCRC, MSI-H and non-MSI-H. Methods: Pts had ECOG PS 0–1, and intolerance/progression on ≥ 1 tx. MSI-H pts received N 3 mg/kg q2 wk (N3) or N 3 mg/kg + I 1 mg/kg q3 wk (N3+I1) x 4 doses followed by N3 until disease progression (PD) or other discontinuation. Initial evaluation of N+I at 3 doses was completed in non-MSI-H pts. Primary endpoint was investigator-reported ORR by RECIST 1.1; other endpoints were safety, OS, and PFS. Results: 33 (N3) and 26 (N3+I1) MSI-H pts, and 3 (N1+I1), 10 (N1+I3), and 10 (N3+I1) non-MSI-H pts were enrolled. 82% (N3) and 92% (N3+I1) of MSI-H and 100% of non-MSI-H pts had ≥ 2 prior regimens. 15% (N3) and 25% (N3+I1) of MSI-H pts had known BRAF V600E. 17 (52%; N3) and 19 (73%; N3+I1) MSI-H pts remain on tx. Efficacy results are shown in the Table. In MSI-H pts, tx-related adverse events (TRAEs) occurred in 26 (79%; N3) and 22 pts (85%; N3+I1); most common were diarrhea and fatigue (27% each; N3) and diarrhea (46%; N3+I1). Grade 3–4 TRAEs occurred in 7 (N3) and 8 pts (N3+I1). One pt on N3 had a Grade 5 TRAE (sudden death). In non-MSI-H pts median (95% CI) PFS was 1.4 mo (1.2–1.9; pooled N+I). Conclusions: N and N+I were well tolerated in most pts and demonstrated encouraging clinical activity and survival in MSI-H mCRC. This study is ongoing. Clinical trial information: NCT02060188.MSI-Ha efficacy. N3 (n = 33) N3+I1 (n = 26) ORR, n (%) 9 (27) 4 (15) CR 0 0 Confirmed PR 9 (27) 4 (15) SD 8 (24) 17 (65) PD 11 (33) 3 (12) Not determined/not reported 5 (15) 2 (8) Median duration of response (95% CI), mo NR (4.2–NE) NR (NE–NE) Median PFS (95% CI), mo 5.3 (1.4–NE) NR (NE–NE) 4-mo PFS rate,b % 55 80 Median OS (95% CI), mo 16.3 (8.3–NE) NR (NE–NE) 5-mo OS rate,c % 75 100 NR, not reached; NE, not estimable aBy local screen bPFS Kaplan-Meier plot estimate, N3 = 17/33 events, N3+I1 = 4/26 events cPFS Kaplan-Meier plot estimate, N3 = 11/33 events, N3+I1 = 0/26 events
Increased dependence on slow filling for left ventricular diastolic filling in patients with coronary artery disease and a depressed systolic function. Assessment with radionuclide ventriculography.
Authors: Takashi Yamagishi, Masaharu Ozaki, Yuhji Furutani, Kouzo Yamamoto, Atsushi Saeki, Shinichi Satoh, Reizo Kusukawa
Journal: Circulation (1990)

Contributions of rapid filling, slow filling and atrial systole to the left ventricular (LV) filling volume were analyzed with the use of radionuclide ventriculography at rest, both globally and regionally, in 34 patients with isolated disease of the left anterior descending coronary artery. The patients included 17 with a normal ejection fraction (EFg50%; group 1 ) and 17 with a depressed EF (<50%; group 2), and the data were compared with those. obtained from 13 normal subjects. A computer program subdivided the LV image into 4 regions, and time-activity curves were constructed globally and regionally by reverse-gating from the R wave. In both groups the contribution of rapid filling to the LV filling volume was decreased significantly in the affected septal and apical regions, and in the global left ventricle compared with that in normal subjects. In group l, the contribution of atrial systole showed an increase in these affected regions and in the global left ventricle. In contrast, in group 2, the atrial contribution was not increased globally or regionally as much as was expected. However, the contribution of slow filling was either increased significantly or tended to increase in the affected regions an, d in the global left ventricle. There were negative correlations between the contribution of rapid filling and that of slow filling in the global left ventricle (r = -0.73, p<0.001) and in each of the septal, apical and lateral regions (r g-0.60, p<0.001), which suggested that the contribution of slow filling as well as of atrial systole undergoes an increase as rapid filling is impaired . Thus, in patients with coronary artery disease, the left ventricle relies on slow filling as well as atrial systole to affect diastolic LV filling in the affected regions and in the global left ventricle In the presence of LV systolic dysfunction.