tbuckley/cabot-search huggingface dataset:
Clinical and hematological improvement in patients receiving liposome doxorubicin (Myocet) therapy for myelofibrosis with myeloid metaplasia (MMM)
Authors: F. Iuliano, S. Molica, A. Serra, P. Sterpone, A. Russo, D. Cilloni, A. Peta
Journal: Journal of Clinical Oncology (2006)

6593 Background: MMM is a chronic myeloproliferative disorder with bone marrow fibrosis, hepato-splenomegaly, extramedullary hematopoiesis,increase angiogenesis both in bone marrow and spleen. Myocet is a proprietary liposomal formulation of doxorubicin designed to enhance delivery of the drug to tumor cells and reduce side effects while maintaining equivalent anti-tumor efficacy. Liposomes are avidly removed from circulation by the macrophages of the RES or MPS and are taken up in the spleen, liver and bone marrow were show both a cytotoxic and antiangiogenic activity. Methods: We thus designed a phase II study for pts with MMM. The treatment program consisted of 25 mg total dose of Myocet given I.V. every two weeks for six months. Eligibility criteria included a histologically confirmed diagnosis, platelets ≥ 100 × 10 9 /L, neutrophils ≥ 1 × 10 9 /L, PS ≤ 2, LVEF &gt; 45%, normal liver and renal function. Eight patients (median age, 66 years; range, 60–73) were enrolled to the trial. Median duration of disease prior to protocol treatment was 45 months (range, 24–144). All pts had received prior therapy for MMM, including thalidomide (37%) hydroxyurea (100%), interferon (25%), anagrelide (25%), erythropoietin (100%). 3 pts were RBC transfusion-dependent and 1 had severe constitutional symptoms. Baseline median (range) values for palpable spleen size, leukocyte count, platelet count, CD34 cell count, and serum lactate dehydrogenase (LDH) were: 10cm BCM (median, range 6 to 30), 8.5 × 10 9 /L (3–36.2), 250 × 10 9 /L (160–950), 151.1 × 10 6 /L (1.9–3568), and 680 U/L (316–868), respectively. 8/8 pts had JAK2 V617F mutation. Results: 7/8 pts are evaluable (i.e., received six months of therapy), 1 pt discontinued for progression. Clinico-hematologic responses have been observed in 7/7 (100%) pts and were evaluated according to European Myelofibrosis Network criteria. These include CR in 1 pt, major response in 5/7 pts, minor response in one. The median time to response was 12 weeks (range, 4 to 18). Therapy has been well tolerated. Only a Grade 3 thrombocytopenia was seen. Conclusions: We conclude that Myocet has clinical activity in a subset of patients with myelofibrosis with an acceptable toxicity profile. No significant financial relationships to disclose.
Obama issues executive orders to curtail gun violence
Authors: Michael McCarthy
Journal: BMJ (2016)

Frustrated by the lack of congressional action on gun control, President Barack Obama announced on 5 January a series of executive orders aimed at reducing gun violence in the United States. Each year firearms are responsible for about 84 000 non-fatal injuries in the US and about 33 000 deaths, of which about 11 000 are homicides and 21 000 are suicides.

The orders range from closing loopholes that allow gun sales without background checks of the purchasers to enabling health providers to report people who should not be allowed to purchase firearms because of mental illness.

In an emotional speech at the White House outlining the measures that his administration would take, the president wiped tears from his eyes as he recounted how first graders died in the 2012 mass shooting at an elementary school in Newton, Connecticut, that took 26 lives, including 20 schoolchildren. “Every time I think about those kids, it gets me mad,” the president said. …
Etoposide (VP-16) with prednisone and vincristine for the treatment of refractory acute lymphoblastic leukemia.
Authors: M Abromowitch, W P Bowman, J Ochs, G Rivera
Journal: Journal of Clinical Oncology (1985)

Fifty children with acute lymphoblastic leukemia (ALL) in first to fifth relapse were treated with a three-drug reinduction regimen consisting of prednisone (40 mg/m2/d for seven days), vincristine (1.5 mg/m2 on day 1) and etoposide (VP-16, 250 mg/m2 on days 1 through 3). The intent was to assess the efficacy of VP-16 in an otherwise conventional reinduction plan, especially in patients who had previously received teniposide (VM-26), the close congener of VP-16. Among the 46 patients who received at least two courses of the therapy, 16 (0.34) achieved complete remission. Seven others showed improvement in their bone marrow status. Each child had been heavily pretreated with prednisone and vincristine, and 14 had received VM-26. That seven patients judged to be clinically resistant to VM-26 had complete responses to prednisone-vincristine-VP-16 indicates that prior treatment with one podophyllotoxin derivative does not preclude responses to the other. We are uncertain about the pharmacologic basis of these results but suggest that the increased dosage and more frequent administration of VP-16, relative to that of VM-26, was sufficient to overcome apparent resistance to the latter compound. Remission durations ranged from one to eight months (median, four months), emphasizing the need to devise more effective continuation therapy, including investigational agents such as the epipodophyllotoxins.
Multifractionated cisplatin, etoposide, and paclitaxel, (CEP) in unresectable gastric/gastro esophageal (GE) cancer: Phase II study
Authors: A. Sharma, V. Raina, N. Lokheshwar, S. V. Deo, N. K. Shukla, G. K. Rath
Journal: Journal of Clinical Oncology (2005)

4203 Background: Gastric cancer is leading cause of cancer related mortality. Unlike, Japan where screening helps in detection of early cancers, two third patients elsewhere present in advanced stage where cure is unlikely. These patients are given palliative treatment and median survival ranges from 5–7 months. Over last few years lot of advances have been made in surgical and adjuvant treatment. Still, prognosis and treatment of unresectable disease remains dismal. The most commonly used drugs are 5 fluorauracil, mitomycin, doxorubicin, etoposide, cisplatin, and taxanes either signally or in combinations. This trial was designed to evaluate safety and efficacy of low dose, multifractionated CEP in unresectable gastric/ GE cancers. Patients and Methods: Thirty-three inoperable patients were enrolled onto this study after obtaining informed consent to receive cisplatin 15mg/m2, etoposide 40 mg/m2, and paclitaxel 50mg/m2 all day 1 and 4 every week for three week in a 4 weekly cycle. Results: Median age was 56 years (range 32 to 70 years), 25 were males. Twenty nine inoperable disease and 4 had recurrent disease. Liver and ascites were commonest metastatic sites seen in 15 and 11 patients. Twenty-four patients had symptom control after 1 cycle. Total 76 cycles were administered (median 2). Grade III or IV toxicity seen in 11 (36%) patients; diarrhea (5), neutropenia (7 patients 5 with fever). One patient died of neutropenic fever. Best responses seen in 29 evaluable patients were; 2 CR (6.4%), 17 PR (55%), 3 SD (9.6%), and 4 PD (13%). Four patients were considered operable after chemotherapy. Median OS and PFS were 10 and 7 months respectively. Median OS was 13 months in responders versus 8 months in non responders (p=0.04). Seven (22%) survived 12 months or more. Conclusion: CEP has shown good clinical response and an acceptable toxicity profile in advanced cancers. Better responses may help in prolonging survival. This may be tested with other protocols in a randomized fashion. No significant financial relationships to disclose.
Prostate Cancer, Version 1.2016
Authors: James L Mohler, Andrew J Armstrong, Robert R Bahnson, Anthony Victor D'Amico, Brian J Davis, James A Eastham, Charles A Enke, Thomas A Farrington, Celestia S Higano, Eric M Horwitz, Michael Hurwitz, Christopher J Kane, Mark H Kawachi, Michael Kuettel, Richard J Lee, Joshua J Meeks, David F Penson, Elizabeth R Plimack, Julio M Pow-Sang, David Raben, Sylvia Richey, Mack Roach, Stan Rosenfeld, Edward Schaeffer, Ted A Skolarus, Eric J Small, Guru Sonpavde, Sandy Srinivas, Seth A Strope, Jonathan Tward, Dorothy A Shead, Deborah A Freedman-Cass
Journal: Journal of the National Comprehensive Cancer Network (2016)

The NCCN Guidelines for Prostate Cancer address staging and risk assessment after an initial diagnosis of prostate cancer and management options for localized, regional, and metastatic disease. Recommendations for disease monitoring, treatment of recurrent disease, and systemic therapy for metastatic castration-recurrent prostate cancer also are included. This article summarizes the NCCN Prostate Cancer Panel's most significant discussions for the 2016 update of the guidelines, which include refinement of risk stratification methods and new options for the treatment of men with high-risk and very-high-risk disease and progressive castration-naïve disease.
Abstract P3-09-01: A multicenter randomized study comparing the dose dense G-CSF-supported sequential administration of FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive breast
Authors: Dimitrios Mavroudis, Nikolaos Malamos, Pavlos Papakotoulas, Stylianos Kakolyris, Ioannis Boukovinas, Elias Athanasiadis, Nikolaos Kentepozidis, Nikolaos Ziras, Kostas Kalbakis, Charalambos Christophyllakis, Vassilis Georgoulias
Journal: Cancer Research (2015)

Abstract Background: The dose dense sequential administration of anthracycline and taxane is very effective as adjuvant therapy in node-positive early breast cancer. The non-anthracycline regimen docetaxel plus cyclophosphamide (TC regimen) was better than four cycles of doxorubicin/cyclophosphamide as adjuvant therapy. This study compared the dose dense sequential regimen versus the TC regimen as adjuvant therapy. Methods: Women with axillary node-positive, HER2-negative early breast cancer were randomized following surgery to receive either dose dense G-CSF-supported FEC (5FU 500mg/m2, epirubicin 75mg/m2, cyclophosphamide 500mg/m2 every 14 days for 4 cycles) followed by Docetaxel (75mg/m2 every 14 days for 4 cycles) (arm A) or 6 cycles of Docetaxel 75mg/m2 plus Cyclophospamide 600mg/m2 every 3 weeks (arm B). The primary endpoint of the study was the 3-year disease-free survival (DFS). Results: Six hundred fifty patients were randomized; 326 on arm A and 324 on arm B. Of them 109 (33%) and 90 (28%) were premenopausal, 196 (60%) and 218 (67%) had 1-3 positive nodes, 284 (87%) and 288 (89%) were hormone receptor positive in arm A and B, respectively. Chemotherapy was completed in 97% and 93% of patients in arm A and B, respectively. After a median follow up of 46 and 47 months, there were 37 (11.3%) and 33 (10.1%) disease relapses and the median DFS has not yet been reached (p=0.5) while the 3-year DFS rate was 89.5% and 91.1% for arm A and B, respectively. Neutropenia grade III-IV was more common in arm B and anemia, nausea, vomiting and fatigue grade II-III in arm A. No toxic deaths occurred. Conclusions: The 3-year DFS rate was similar between the dose dense sequential FEC/docetaxel combination and the TC regimen in women with node-positive HER2-negative early breast cancer. Citation Format: Dimitrios Mavroudis, Nikolaos Malamos, Pavlos Papakotoulas, Stylianos Kakolyris, Ioannis Boukovinas, Elias Athanasiadis, Nikolaos Kentepozidis, Nikolaos Ziras, Kostas Kalbakis, Charalambos Christophyllakis, Vassilis Georgoulias. A multicenter randomized study comparing the dose dense G-CSF-supported sequential administration of FEC followed by docetaxel versus docetaxel plus cyclophosphamide as adjuvant chemotherapy in women with HER2-negative, axillary lymph node-positive breast [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-09-01.
Abstract 14786: Angiotensin (1-7) Counteracting the Effects of Angiotensin II in Regulating Endothelial Progenitor Cell Function Through eNOS/NO, Nox/ROS And SDF-1α/CXCR4 Pathways
Authors: Cheng Zhang, Ji Chen, Shuzhen Chen, Xiang Xiao, Yanfang Chen
Journal: Circulation (2012)

Our previous study has shown that bone marrow (BM) derived endothelial progenitor cells (EPCs) are dysfunctional in the human rennin and angiotensinogen double transgenic (R+A+) mice. In this study, we investigated the role of angiotensin (1-7) [Ang (1-7)] in modulating the function of EPCs and the underlying mechanisms. BM derived-EPCs cultured from R+A+ mice were divided into five treatment groups (n=8/group): control (basal medium), 10-7 mmol/L Ang (1-7) alone or with A-779 (Mas antagonist, 10-7 mmol/L) or with apocynin (Nox inhibitor, 10 µmol/L) or with L-NAME (eNOS inhibitor, 1 mmol/L). EPC functions (migration and tube formation) were evaluated using the Boyden chamber and the kit for tube formation assay. The levels of stromal cell-derived factor-1α (SDF-1α), CXC chemokine receptor 4 (CXCR4), endothelial nitric oxide synthase (eNOS) and NADPH oxidase subunits (Nox2, 4) were measured by Western blot. Reactive oxygen species (ROS) and nitric oxide (NO) production was determined by dihydroethidium staining and 4, 5-diaminofluorescein method, respectively. We found (Table): 1) Adding Ang (1-7) to the culture medium improved the compromised migration and tube formation abilities of EPCs derived from the R+A+ mice. 2) Treatment with Ang (1-7) was associated with up-regulation of eNOS and SDF-1α/CXCR4 proteins, and down-regulation of Nox2, 4 proteins, as well as consequential NO and NOS production in EPCs. 3) These effects of Ang (1-7) induced were able to be totally abolished by A-799, partially inhibited by L-NAME, and partially enhanced by apocynin. In conclusion, our data demonstrate that Ang (1-7) counteracts Ang II in regulating EPC function via Mas receptors and the downstream eNOS, Nox and CXCR4 pathways.

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1126 VITAMIN D STATUS IS ASSOCIATED WITH COMPLETE EVR BUT NOT SVR IN CHRONIC HEPATITIS C GENOTYPE 1 INFECTION: ANALYSIS OF THE AUSTRALASIAN CHARIOT STUDY COHORT
Authors: M.T. Kitson, G.J. Dore, P. Button, G. McCaughan, D. Crawford, W. Sievert, M. Weltman, W. Cheng, S.K. Roberts
Journal: Journal of Hepatology (2012)
RAINBOW: A global, phase 3, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy: Results of a multiple Cox regression analysis adjusting for prognostic factors.
Authors: Hansjochen Wilke, Eric Van Cutsem, Sang Cheul Oh, Gyorgy Bodoky, Yasuhiro Shimada, Shuichi Hironaka, Naotoshi Sugimoto, Oleg N. Lipatov, Tae-You Kim, David Cunningham, Philippe Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2014)

4076 Background: RAINBOW, a global, randomized, double-blind, phase 3 trial demonstrated significant improvements in overall survival (OS), progression-free survival (PFS), and response rate in metastatic gastric adenocarcinoma patients receiving ramucirumab (RAM), a human IgG1 VEGF2-receptor targeted antibody, plus paclitaxel (PTX) after prior chemotherapy. Methods: 665 pts were randomized 1:1 to receive RAM (8 mg/kg IV q2w) or placebo (PL) plus PTX (80 mg/m2d1, 8, 15 of a 4 week cycle) until disease progression, unacceptable toxicity, or death. Primary analysis was a log-rank test stratified by geographic region, time to progression on first-line therapy and disease measurability. A prespecified stepwise Cox multiple regression analysis selected baseline covariates that were significantly associated with OS and PFS using the pooled (RAM+PTX;PL+PTX) data, and then adjusted for these potential prognostic factors in a Cox proportional hazards model that included a term for treatment arm. Results: The primary stratified analysis showed a statistically significant benefit in OS (stratified HR=0.807, 95% CI 0.678, 0.962; p=0.0169) and PFS (stratified HR=0.635, 95% CI 0.536, 0.752; p<0.0001) for the RAM+PTX arm. Factors significantly associated with OS were geographical region, ECOG PS, weight loss, number of metastatic sites, presence of ascites, tumor differentiation, and prior gastrectomy; for PFS liver metastasis, number of metastatic sites, sex, and weight loss. The HR for both OS and PFS improved after adjusting for these factors (OS HR= 0.745, 95% CI: 0.626, 0.888; p=0.0010; PFS HR=0.599, 95% CI 0.506, 0.708; p <0.0001). Conclusions: The study showed statistically significant and clinically meaningful benefit in OS and PFS for RAM+PTX as compared to PL+PTX. After adjusting for prognostic factors in the Cox regression analyses, the benefits seen in both OS and PFS improved, confirming the robustness of the primary analysis results. Clinical trial information: NCT01170663.
Parenteral opioid dose titration and ventilatory function
Authors: S. B. Legrand, B. Estfan, D. Walsh, M. P. Davis, R. L. Lagman
Journal: Journal of Clinical Oncology (2004)

8005 Background: Opioids are indicated for moderate to severe cancer pain. Among physicians the most feared adverse effect is respiratory depression, which inhibits dose titration and leads to under treated pain. Hypoventilation may result in carbon dioxide (CO2) retention and increased end tidal CO2 (ET-CO2), hypoxemia and reduced respiratory rate. ET-CO2 may increase due to reduced tidal volume despite a normal respiratory rate. This study prospectively evaluated ventilatory function in advanced cancer patients undergoing parenteral opioid titration for severe pain. Method: Patients with severe cancer pain getting intravenous opioids for cancer pain were entered on this IRB approved trial if they were not oxygen dependent, had normal cognitive function by the Bedside Confusion Scale (≤ 2) and gave informed consent. ET-CO2, O2 saturation, respiratory rate, vital signs and a delirium scale were done daily during intravenous opioid titration and at the time of pain control. Pain control was defined as pain less than 4 (0 –10) on a numerical scale and ≤ 4 rescue doses for non-incident pain. Spirotomy (FVC) was done at the end of the study. A paired two-sample T-test for the mean ET-CO2 was done pre-study and compared to the last day. The paired T-test used clinical significance of 4 (normal co-efficient of variation for repeat ET-CO2). Results: Twenty completed the trial including FVC and 3 additional patients completed the ET-CO2 but could not do the FVC. 21 maintained a RR ≥ 10, (one transiently dropped to 8 and one to 9). All maintained O2 sats ≥ 92%. The mean ET-CO2 in the 23 was 33mm Hg before opioid titration and 35mm Hg after (p = 0.33). None had an ET-CO2 ≥ 50mm Hg. Conclusion: Parenteral opioid titration to pain relief is not associated with hypoxemia nor CO2retention. No significant financial relationships to disclose.
Flavopiridol potentiates effect of oxaliplatin in vitro and in vivo and requires intact p53
Authors: M. V. Motwani, A. Racanelli, G. K. Schwartz
Journal: Journal of Clinical Oncology (2004)

3145 Background: Oxaliplatin (O) as part of the FOLFOX regimen has been approved as second line therapy in the treatment of metastatic colon cancer. However, response rates, remain quite poor (<10%). We have shown that the CDK inhibitor flavopiridol (F) potently enhances the effect of a wide range of chemotherapy agents (Motwani M, et al CCR 7: 4209, 2001). This has been translated into a series of phase I clinical trials with encouraging clinical results. In view of this we evaluated the combination of F with O to determine whether we could improve the effect of O. Methods: HCT-116 colon cancer cell lines with wild type (p53+/+) and absent (p53-/-) p53 were treated with F and O as single agents, together or sequentially in vitro and in vivo and examined for induction of apoptosis by quantitative fluorescent microscopy and PARP cleavage, inhibition of colony formation units (CFU), and delay in tumor growth. These findings were correlated to changes in p53 and p21 expression by western blot. Results: As single agents F and O induced apoptosis in 12 ±2 % and 2 ±1% of the p53 +/+ cells, respectively. This increased to 35 ±5% when both drugs were given together. When F was given before O, 40 ±4% of the cells underwent apoptosis. The reverse sequence of O followed by F induced apoptosis in only 14% of the cells. CFUs decreased from 50% and 70% with O and F alone to 25% with the two drugs given together. PARP cleavage was also higher with concurrent treatment compared to the single agents. O induced p53 and p21 in the p53 +/+ cells, and the combination therapy suppressed p21 expression with no decrease in p53. Treatment of p53-/- cells indicated no potentiation with the O/F combination under any of the conditions tested. Treatment of the p53 +/+ xenografts with O and F together resulted in an 80% decrease in tumor growth. This was compared to 47% with O alone and 69% when O was given before F Conclusions: 1) F potently enhances the effect of O, 2). O+F or F followed by O are superior to O followed by F, 3) p53 expression and the suppression of p21 may be a critical determinant in the response to therapy. 4) Based on these results, a phase I study of F with FOLFOX is planned in which F will be given with O. This work was supported by RO1 CA67819. No significant financial relationships to disclose.
Treatment of intermediate- or high-risk prostate cancer by dose escalation with high-dose 3D-conformal radiotherapy (HD-3D-CRT) or low-dose 3D-conformal radiotherapy plus HDR brachytherapy (LD-3D-CRT+HDR-B): Early results of a prospective comparative trial.
Authors: B. Guix, J. Bartrina, J. Tello, L. Quinzaños, J. Sole, T. Lacorte, J. Fernandez, I. Guix, G. Galdon, M. Espino
Journal: Journal of Clinical Oncology (2010)

4633 Background: To report early and late toxicity and preliminary biochemical outcome in 445 pts with intermediate- or high-risk clinically localized prostate cancer treated with HD-3D-CRT or LD-3D-CRT+HDR-B. Methods: Between 12/1999 and 10/2005, 445 patients (pts) with PSA ‘10, Gleason ‘6 and/or T2b-T3 N0 M0 tumor entered the study. Pts were assigned to one of the 2 treatment groups: 76 Gy HD-3D-CRT to the prostate in 38 fractions (group 1 223 pts) or 46 Gy LD-3D-CRT+ 16 Gy HDR-B given in 2 fractions of 8 Gy (group 2 222 pts). Both groups were well balanced in patient's & as tumors’ characteristics. Toxicities were scored by the EORTC /RTOG morbidity grading scales. Special attention to local, regional or distant recurrence, survival, late effects, PSA and testosterone levels and quality of life was done. Results: All pts completed treatment. None pts included in the group 1 or 2 experienced grade 3 rectal toxicity. 28 pts of group 1 (12.5%) and 6 pts of group 2 (2.7%) developed grade 2 rectal toxicity (rectal bleeding or urgency). 15 pts in group 1 (6.7%) and 3 pts in group 2 (1.3%) developed grade 1 rectal bleeding (less than 2 times/week). In group 1 and 2, 81.8%and 95,9% of pts were free from rectal reactions respectively (p<0.005). 19 pts in each group developed acute Grade 2 urinary symptoms (mainly dysuria), and none experienced urinary retention. No pts (0%) developed Grade 3 or 4 rectal or urinary complications. With a mean follow-up of 77 months, the 5-year actuarial PSA relapse-free survival rates for intermediate- and high-risk group 1 pts were 90 and 89 % respectively and 97 and 96 % for group 2 pts (p<0.05). Conclusions: High-dose 3D-EBRT +HDR brachytherapy is a safe and effective method of escalating the dose to the prostate without increasing the risk of late effects. Acute and late rectal and urinary complications were significantly reduced with the combined treatment, compared with what was observed with high-dose conventional, 3D-CRT. Intermediate-term PSA control rates tends to be better with in the HDR-boosted patients as spected by higher effective-dose. No significant financial relationships to disclose.