tbuckley/cabot-search huggingface dataset:
Irinotecan and mitomycin C (MMC) as salvage therapy for patients with metastatic colorectal cancer previously treated with fluoropyrimidine, irinotecan and/or oxaliplatin based chemotherapy
Authors: J. Rodriguez, A. Viudez, E. Salgado, J. García-Foncillas, J. De La Cámara, J. Espinós, C. Garrán, A. Chopitea, O. Fernández-Hidalgo, S. Martín-Algarra
Journal: Journal of Clinical Oncology (2004)

3758 Background: Preclinical data have shown a synergistic effect when MMC and CPT-11 are combined. In addition, this combination proved to be effective and well-tolerated in patients with fluoropyrimidine-resistant metastasic colorectal cancer Methods: To evaluate the safety and efficacy of MMC 5 mg/m2 day 1 plus CPT-11 200 mg/m2 on day 1, every three weeks, in a retrospective series of heavily pretreated metastasic CCR patients with good performance status (ECOG 1–2). Results: From September 2002 to October 2003, 20 pts (M/F: 13/7; ECOG 2: 50%; Median age: 55) were included. Sites of metastasic disease included peritoneal carcinomatosis (65%), lung (35%), liver (65%) and bone (15%). 12 pts (60 %) had received at least 3 lines of therapy. Prior chemotherapy included 5-fluorouracil (90%), oxaliplatin (100%) irinotecan (65%), capecitabine (85%) and raltitrexed (60%). Previous FOLFOX, FOLFIRI, FOLFOXIRI or XELOX had been administered in 50%, 15%, 25% and 35% of the patients, respectively. 4 pts (20%) achieved a partial response, stable disease was found in 10 pts (50%), while 6 pts (30%) progressed while on-therapy.After a median follow-up of 7.5 months (1.7–15.2), median progression-free survival was 4.07 months (95% CI; 2.04–6.09) and median overall survival was 4.4 months (95% CI;1.3–7.5). Grade 3–4 toxicities includad leucopenia (10%), neutropenia (10%), anemia (30%), asthenia (15%) and diarrhea (20%). Conclusions: The combination of MMC and CPT-11 shows modest activity in this subgroup of heavily pretreated CCR patients No significant financial relationships to disclose.
Long-term results of high-dose chemotherapy (HDCT) supported by hematopoietic circulating (ASCT) or bone marrow (BMT) stem cell autografting as first salvage treatment for refractory or relapsed Hodgkin’s lymphoma
Authors: S. Viviani, V. Bonfante, M. Di Nicola, S. Cortelazzo, C. Carlostella, P. Valagussa, G. Bonadonna, T. Barbui, A. M. Gianni
Journal: Journal of Clinical Oncology (2006)

7567 Background: The aim of this retrospective study was to evaluate with a long follow-up the efficacy of HDCT + ASCT or ABMT for refractory or relapsed HL. Methods: Data were collected from 99 pts who failed or relapsed after first-line CT± radiotherapy and were treated with HDCT+ASCT or ABMT between Oct 1984 and Dec 2003. Thirty-two pts had late relapse (CR≥12 months), 31 had early relapse (CR&lt;12 months), while 36 had primary refractory (IF) HL.The main pts characteristics at relapse/progression were as follows: M/F: 50/49; median age 28 years; stage III-IV:54%; B symptoms: 33%; bulky disease 22%; extranodal ± nodal disease 54%; IPI≥3 39%. HDCT program consisted in a debulking phase with sequential high-dose chemotherapy (Cyclophosphamide 7gr/mq followed by ASC or BM harvest, Methotrexate 8 gr/mq+ Vincristine 1.4 mg/mq, VP16 2 gr/mq) in 71 cases; 3–4 courses of Ifosfamide (3gr/mq × 4 days)+ Vinorelbine (25mg/mq day 1+5) in 28 cases. Final myeloablative course was BEAM (63%), or high-dose Melphalan combined with high-dose Mitoxantrone (11%) or with high-dose Carmustine (9%) or TBI (17%) followed by ABMT or ASCT. Results: Ninety-two pts (93%) completed the HDCT program, while seven pts (7%) progressed during debulking CT. Early and late toxicity were mild. After a median follow-up of 66 months both 10-year freedom from second progression (FF2P) and overall survival (OS) were 61% for all pts. FF2P and OS were respectively 70% and 66% for pts with late relapse; 64% and 60% for pts with early relapse; 52% and 56% for primary refractory pts. Multivariate analysis showed that prognostic factors for FF2P were stage III-IV vs I-II (HR 2.09; p=0.04), response to first-line CT: CR≥12 vs CR&lt;12 vs IF (HR 2.19; p=0.058) and bulky vs non bulky (HR 1.96; p=0.07). Prognostic factors for OS were response to first-line CT (HR 2.59; p=0.05), stage III-IV vs I-II (HR 1.37; p=0.39) and bulky vs non bulky (HR 2.06; p=0.06).Conclusion: These long-term results confirm that HDCT + ASCT or ABMT was feasible, safe and very effective for the treatment of relapsed/refractory HL.Our data support the use of this strategy for the salvage therapy even in the unfavourable group of primary refractory pts. No significant financial relationships to disclose.
Sequential TKI treatments for iodine-refractory differentiated thyroid carcinomas.
Authors: Christelle de la Fouchardiere, Marie-Helene Massicotte, Isabelle Borget, Maryse Brassard, Mederic Claude-Desroches, Anne Laure Giraudet, Christine Docao, Francoise Bonichon, Cecile Chougnet, Sophie Leboulleux, Eric Baudin, Martin Schlumberger
Journal: Journal of Clinical Oncology (2013)

6092 Background: Tyrosine kinase inhibitors (TKI) are currently used to treat patients with advanced iodine-refractory differentiated thyroid cancers (DTC) but none has been approved by the FDA or the EMA until now. Sometimes, patients are treated with off-label TKI when a clinical trial is not available or in second- and third-line therapy. Methods: We hereby report the efficacy of “off-label” sorafenib and sunitinib treatments as first-, second- and third-line therapy in metastatic DTC patients from the French TUTHYREF (TUmeurs THYroïdiennes REFractaires) network. Primary endpoints were progression free survival (PFS) and tumor response according to sequential TKI treatment. Secondary endpoint was organ-specific metastatic site analysis. Results: 45 patients with advanced iodine-refractory DTC treated with off-label TKI were included in this study (26 men, mean age: 62 years). 22 had papillary, 10 had follicular and 13 had poorly DTC. 24/45 patients were treated with two and 3/45 with three lines of TKIs. Sorafenib was the most frequently used (57%) followed by sunitinib (21.5%) and vandetanib (21.5%). Partial response (PR) rate was of 29% in the 21 patients who received first-line sorafenib therapy whereas PR was observed in 57% of the 7 first-line sunitinib patients. There was no PR with second- (n=24) and third-line (n=3) treatments. However, median progression free survival (PFS) was similar in second- as compared to first-line sorafenib or sunitinib treatment (6.7 vs. 7.6 months, HR 0.85 (95CI 0.45-1.61) p=0.6). Liver metastases were the most responsive to treatment (n=7; mean of -30%), followed by lung (n=57; mean of -19%) and lymph node (n=43; mean of -13%) metastases. Bone (n=14) and pleural (n=9) lesions were the most refractory to treatment (mean of -1% and -5%, respectively). Conclusions: Due to the small number of patients, we could not recommend a specific treatment sequence (sorafenib then sunitinib) over another (sunitinib then sorafenib). But TKI therapy appears to be beneficial in refractory DTC patients even in second- and third-line therapy, with similar PFS and stable disease as best response. Bone and pleural metastases were the most refractory and liver lesions the most responsive to treatment.
Transplantation for Myeloma — Now or Later?
Authors: Charles A. Schiffer, Jeffrey A. Zonder
Journal: New England Journal of Medicine (2017)

The outlook for patients with multiple myeloma has improved dramatically during the past two decades. The median overall survival is now more than 6 years, as compared with an overall survival of 3 to 4 years during the era of treatment with alkylating agents and anthracyclines.1 This progress resulted from the introduction of new classes of agents (immunomodulatory drugs, proteasome inhibitors, and more recently, monoclonal antibodies) and the intensification of therapy with autologous stem-cell transplantation, as well as incremental improvements that are attributable to refinements of drugs within these same therapeutic classes.Following the pioneering efforts of Dr. Bart Barlogie, . . .
A phase I study of immunotherapy with tumor cell-dendritic cell fusion vaccine in patients with advanced or recurrent gastrointestinal cancer
Authors: K. Okinaga, H. Iinuma, T. Ogiwara, F. Ogawa
Journal: Journal of Clinical Oncology (2004)

2615 Background: Immunotherapy with tumor cell-dendritic cell fusion vaccine has been shown to induce the immune response against multiple tumor antigens including unknown tumor antigens. The aim of this study was to test safety, feasibility, and clinical response of immunotherapy with tumor cell-dendritic cell fusion vaccine. Methods: Nine patients with advanced or recurrent gastrointestinal cancer that is unresponsive to standard surgical therapy and chemotherapy were enrolled in this study after informed consent was obtained. Monocytes were separated from the peripheral blood by leukapheresis and were cultured with GM-CSF and IL-4 for 6 days. Then TNFα, IL-1β, IL-6, and PGE2 were added for maturation of dendritic cells. Fusion of irradiated tumor cells and dendritic cells was created by polyethylene glycol and electroporation. Fusion vaccine was subcutaneously injected in the inguinal region four times every two weeks. Safety and adverse effects were evaluated after vaccination. Delayed hypersensitivity skin-test, cytokine array, Th1/Th2, Tc1/Tc2, and clinical response were compared before and after vaccination. Results: There were neither adverse effects nor autoimmune responses after vaccination in all the patients. Delayed skin tests became positive in six of nine patients after vaccination. Th1/Th2 balance and Tc1/Tc2 balance were improved in six of nine patients after vaccination. IAP levels were decreased in five patients after vaccination. Clinical response was stable disease in five patients and progressive disease in four patients. Conclusions: Safety and feasibility of immunotherapy with tumor cell-dendritic cell fusion vaccine were confirmed in patients with advanced or recurrent gastrointestinal cancer by this study. No significant financial relationships to disclose.
Revalidation of FLIPI in patients with follicular lymphoma (FL) registered in the F2 study and treated upfront with immunochemotherapy
Authors: M. Federico, M. Bellei, B. Pro, A. Lopez-Guillermo, L. Marcheselli, M. Trneny, P. Soubeyran, P. McLaughlin, S. Pileri, P. Solal-Céligny
Journal: Journal of Clinical Oncology (2007)

8008 Background: The Follicular Lymphoma International Prognostic Index (FLIPI) has become a widely accepted tool for risk assessement of FL. However, the recent shift to upfront immuno-chemotherapy (ICHT) requires confirmation studies of FLIPI discriminant power to ensure that the advent of Anti-CD20 MoAb did not modify its predictive value. Methods: We looked for the role of rituximab and its impact on the predictive value of FLIPI in the group of 1,093 patients diagnosed with FL between January 2003 and May 2005 and registered by 69 European and American Institutions in the F2-study. We identified 827 patients = 18 years of age and treated with systemic therapy. For the purposes of the present examination the prognosis was investigated in terms of progression-free survival (PFS) and the impact of rituximab explored by Cox analysis. Results: Patients characteristics are as follows: median age 57 yrs (21–93), male 50.1%, advanced stage 77.2%, elevated LDH 22.3%. To date central pathology review has been performed in 406 cases and the diagnosis of FL was confirmed in 98.3%. Patients at low risk (LR), intermediate risk (IR) and high risk (HR) on the basis of FLIPI were 40.3%, 32.6% and 27.1% respectively. Five-hundred sixty patients (67.7%) received ICHT, and 267 (32.3%) were treated with CHT only. After a median follow-up of 26 months the 3-yr PFS is 63.0%. Overall, the FLIPI remains highly predictive, being the 3-yr PFS of 77.8%, 60.5% and 49.1% for patients at LR, IR and HR respectively. Moreover, the 3-yr PFS predicted from Cox analysis is 81%, 62%, and 50% for patients at LR, IR and HR treated with ICHT (p&lt;0.001), and 76%, 56%, 43% in those treated with CHT only (p&lt;0.001). Finally, the relative risk for progression adjusted by the use of Anti-CD20 MoAb confirmed the efficacy of rituximab in all risk groups. The relative risk of progression for patients at IR was 2.01 as compared to patients at LR (p&lt;0.001), and that for patients at HR was 1.47 as compared to patients at IR (p=0.021). Conclusions: Our study demonstrates that the FLIPI remains a useful tool to predict outcome even in the era of ICHT. Moreover, rituximab added to upfront chemotherapy improves the outcome of patients with FL in any risk group and in association with any chemotherapy regimen. No significant financial relationships to disclose.
Quality of information addressing treatment options for women with breast cancer on NCI cancer center websites.
Authors: Caleb Dulaney, Daniel Victor Wakefield, Gabrielle Betty Rocque, Jennifer F. De Los Santos
Journal: Journal of Clinical Oncology (2017)

135 Background: The internet is increasingly utilized by cancer patients for information that may influence treatment decisions. National Cancer Institute (NCI)-designated cancer center websites and nationally recognized cancer research agencies are trusted sources of information, however little data exists regarding the quality of information on these sites. We evaluated the quality and accessibility of breast cancer treatment information on cancer center websites addressing therapeutic options. Methods: Websites of all NCI cancer centers, the NCI, and Susan G. Komen were reviewed. Quality was measured using 33 questions from three validated Breast Cancer Decision Quality Instruments (DQI). Two blinded reviewers determined if websites provided information to answer each question. Number of clicks to reach the breast-specific webpage, evaluation time, and Spanish and mobile accessibility were recorded. Kappa coefficient was used to measure inter-observer variability. Correlation between evaluation time and questions answered was measured using Pearson coefficient. Results: Of the 63 cancer center websites evaluated, 94% had breast cancer webpages reached in a median of 2 clicks. Average evaluation time was 11 minutes. 24% were Spanish accessible. 59% were mobile friendly. No site provided information that addressed all questions. The most informative cancer center site addressed 76% of questions. On average, 21% of questions were addressed per site. 16% of sites did not have sufficient information to answer any question. In comparison, the NCI and Komen sites covered higher proportions of questions than cancer center sites (85 and 88%). Inter-observer variability was fair to moderate (avg. Kappa 0.37). Evaluation time strongly correlated with number of questions answered (r = 0.75). Conclusions: NCI cancer center websites provided informative feedback for breast cancer patients across an average 21% of key knowledge points in a validated DQI. This information is less accessible to Spanish speaking patients and patients using mobile devices. Website improvements represent an opportunity to enhance knowledge that may improve shared decision making for women with breast cancer.
A phase 1 trial of motexafin gadolinium and docetaxel for advanced solid tumors
Authors: N. Ramnath, G. Chatta, M. Egorin, S. Phan, P. J. Creaven
Journal: Journal of Clinical Oncology (2004)

3171 Background: Motexafin gadolinium (MGd) is a redox mediator that selectively targets tumor cells, producing reactive oxygen species. In preclinical models, MGd enhances the activity of several chemotherapy drugs including taxanes. Based on this, a multi-center Phase 1 study with MGd and docetaxel was carried out in patients (pts) with advanced solid tumors, with normal bone marrow, hepatic and renal function. Experimental design: Cohorts of 3–6 pts were treated with MGd, starting at 2.5 mg/kg weekly with docetaxel starting at 30 mg/m2on a weekly X 3 schedule every 28 days. The primary objective was to determine the maximum tolerated dose (MTD) of the combination on this schedule and the dose limiting toxicities (DLT). Results: Eight pts were treated at MGd (2.5- 5mg/kg weekly) along with docetaxel (30mg/m2). The MGd was infused over 0.5h, 30 minutes prior to docetaxel (given IV over 0.5h). There were 8 males with a median age of 61yrs (range 54–76). Diagnoses were NSCLC (3); SCLC (2); Gastric (1); bladder (1); and penile (1). (No of pts in parenthesis) Pts had had a median of 3 prior chemotherapy regimens (range 1–5); 3 pts had had prior radiation. Two pts received 1.5 cycles. At dose level (DL) 1, toxicities >/= 2 were fatigue, diarrhea, leucopenia, neutropenia, hyperglycemia, elevated APTT, seen in 3 pts. At DL 2 (MGd 5.0 mg/kg with docetaxel 30 mg/m2), 1 pt had a DLT (gr 3 rash). Other toxicities >/= gr 2 at DL 2 were nausea, vomiting, diarrhea, fatigue, and dehydration in 2 pts. Data on the last 3 pts is pending. Accrual is ongoing to determine the MTD. Conclusion: MGd in combination with weekly docetaxel is feasible and preliminary results show that there were no gr 4 toxicities. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pharmacyclics
Methodological Rigor in Preclinical Cardiovascular Studies
Authors: F. Daniel Ramirez, Pouya Motazedian, Richard G. Jung, Pietro Di Santo, Zachary D. MacDonald, Robert Moreland, Trevor Simard, Aisling A. Clancy, Juan J. Russo, Vivian A. Welch, George A. Wells, Benjamin Hibbert
Journal: Circulation Research (2017)

Methodological sources of bias and suboptimal reporting contribute to irreproducibility in preclinical science and may negatively affect research translation. Randomization, blinding, sample size estimation, and considering sex as a biological variable are deemed crucial study design elements to maximize the quality and predictive value of preclinical experiments.To examine the prevalence and temporal patterns of recommended study design element implementation in preclinical cardiovascular research.All articles published over a 10-year period in 5 leading cardiovascular journals were reviewed. Reports of in vivo experiments in nonhuman mammals describing pathophysiology, genetics, or therapeutic interventions relevant to specific cardiovascular disorders were identified. Data on study design and animal model use were collected. Citations at 60 months were additionally examined as a surrogate measure of research impact in a prespecified subset of studies, stratified by individual and cumulative study design elements. Of 28 636 articles screened, 3396 met inclusion criteria. Randomization was reported in 21.8%, blinding in 32.7%, and sample size estimation in 2.3%. Temporal and disease-specific analyses show that the implementation of these study design elements has overall not appreciably increased over the past decade, except in preclinical stroke research, which has uniquely demonstrated significant improvements in methodological rigor. In a subset of 1681 preclinical studies, randomization, blinding, sample size estimation, and inclusion of both sexes were not associated with increased citations at 60 months.Methodological shortcomings are prevalent in preclinical cardiovascular research, have not substantially improved over the past 10 years, and may be overlooked when basing subsequent studies. Resultant risks of bias and threats to study validity have the potential to hinder progress in cardiovascular medicine as preclinical research often precedes and informs clinical trials. Stroke research quality has uniquely improved in recent years, warranting a closer examination for interventions to model in other cardiovascular fields.
Conflicts of interest within England’s NHS
Authors: Iona Heath, Kate Adlington
Journal: BMJ (2017)

New NHS guidance is overshadowed by uncontrolled conflicts within government

On 7 February 2017 NHS England issued guidance on Managing Conflicts of Interest in the NHS .1 The guidance will come into force on 1 June. Along with the publication of similar guidance for clinical commissioning groups last summer,2 it suggests a genuine commitment at the highest level within the NHS to pursue a culture of increased transparency.

However, in the UK at least, the onus has so far been on individual clinicians to declare their conflicts of interest voluntarily. There has been less focus on the responsibilities of healthcare organisations to minimise the opportunities for conflict or on the role of professional bodies in regulating this area.

The new NHS guidance brings clarity to issues such as acceptable values of gifts and hospitality, and when and how to declare private practice. It also attempts to address the complicated issue of non-financial interests, including loyalty interests. Yet several important concerns remain.

The guidance is supposed to ensure that the more …
SETD1B Activates iNOS Expression in Myeloid-Derived Suppressor Cells
Authors: Priscilla S. Redd, Mohammed L. Ibrahim, John D. Klement, Sarah K. Sharman, Amy V. Paschall, Dafeng Yang, Asha Nayak-Kapoor, Kebin Liu
Journal: Cancer Research (2017)

Abstract Inducible nitric oxide synthase (iNOS) generates nitric oxide (NO) in myeloid cells that acts as a defense mechanism to suppress invading microorganisms or neoplastic cells. In tumor-bearing mice, elevated iNOS expression is a hallmark of myeloid-derived suppressor cells (MDSC). MDSCs use NO to nitrate both the T-cell receptor and STAT1, thus inhibiting T-cell activation and the antitumor immune response. The molecular mechanisms underlying iNOS expression and regulation in tumor-induced MDSCs are unknown. We report here that deficiency in IRF8 results in diminished iNOS expression in both mature CD11b+Gr1− and immature CD11b+Gr1+ myeloid cells in vivo. Strikingly, although IRF8 was silenced in tumor-induced MDSCs, iNOS expression was significantly elevated in tumor-induced MDSCs, suggesting that the expression of iNOS is regulated by an IRF8-independent mechanism under pathologic conditions. Furthermore, tumor-induced MDSCs exhibited diminished STAT1 and NF-κB Rel protein levels, the essential inducers of iNOS in myeloid cells. Instead, tumor-induced MDSCs showed increased SETD1B expression as compared with their cellular equivalents in tumor-free mice. Chromatin immunoprecipitation revealed that H3K4me3, the target of SETD1B, was enriched at the nos2 promoter in tumor-induced MDSCs, and inhibition or silencing of SETD1B diminished iNOS expression in tumor-induced MDSCs. Our results show how tumor cells use the SETD1B–H3K4me3 epigenetic axis to bypass a normal role for IRF8 expression in activating iNOS expression in MDSCs when they are generated under pathologic conditions. Cancer Res; 77(11); 2834–43. ©2017 AACR.