tbuckley/cabot-search huggingface dataset:
Interim safety analysis from TYTAN: A phase III Asian study of lapatinib in combination with paclitaxel as second-line therapy in gastric cancer.
Authors: T. Satoh, Y. Bang, J. Wang, J. Xu, H. C. Chung, K. Yeh, J. Chen, A. Mukaiyama, P. Yoshida, A. Ohtsu
Journal: Journal of Clinical Oncology (2010)

4057 Background: The standard care for advanced gastric adenocarcinoma varies between Western and Asian countries. In patients with HER2-positive advanced gastric cancer, the anti-HER2 antibody trastuzumab recently showed a significant survival benefit in the first-line therapy (ASCO 2009). Second-line weekly paclitaxel has shown favorable response rates (14.3-40.0%) in patients with gastric cancer and is now used widely in Japan and well accepted in other Asian countries. Successful data with lapatinib, a dual inhibitor of HER2 and EGFR, in combination with paclitaxel have been reported from several breast cancer trials. In vitro, lapatinib showed an anti-proliferative activity on N87, a HER2-positive gastric cancer cell line. Based on these backgrounds, we planned TYTAN (lapatinib [Tykerb] with paclitaxel [Taxol] in Asian ErbB2+[HER2+] Gastric Cancer Study), an open-label, randomized phase III study of second-line therapy with paclitaxel with or without lapatinib in patients with HER2-positive gastric cancer. Methods: Patients with advanced gastric cancer who showed a progression during the first-line therapy were screened for HER2 status by fluorescence in situ hybridization. Then, HER2-amplified patients were randomized to either weekly paclitaxel (80 mg/m2) alone or with daily lapatinib (1,500 mg/day). The primary endpoint is overall survival with a required sample size of 260 being enrolled from 5 Asian countries. Interim safety assessment to evaluate feasibility of this regimen has been planned after approximately every 50 patients enrolled. Results: At data cut-off, 107 patients were included in the combined safety analysis of both treatment arms. Rash (25 patients), neutropenia (37 patients), and diarrhea (37 patients) were reported, with 2 (8%), 33 (89%) and 6 (16%) patients, respectively, having grade 3 or greater events. No unexpected adverse events have been observed with this drug combination. Conclusions: Interim safety analysis of TYTAN study showed no significant safety issues and the Independent Data Monitoring Committee has recommended that the trial proceed as planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline Bristol-Myers Squibb, Chugai Pharma, Daiichi Sankyo, EMD Serono, GlaxoSmithKline, sanofi-aventis, Taiho Pharmaceutical, Yakult Honsha GlaxoSmithKline GlaxoSmithKline
Imatinib for hepatocellular cancer (HCC)—Focus on PK/PD modelling and liver function
Authors: G. Treiber, T. Wex, S. Eberhard, C. Hosius, P. Malfertheiner
Journal: Journal of Clinical Oncology (2006)

13088 Background: Imatinib represents standard medical care for treatment of gastrointestinal stroma tumors (GIST) and chronic myeloic leucemia (CML). Indications for other malignancies are evolving, especially in the context of antiangiogenesis, mediated by the inhibition of platelet-derived growth factor (PDGF). Liver metastasis occurs often in GIST patients, usually not affecting liver function. No reliable data about imatinib metabolisation under conditions of true hepatic impairment are available. Methods: Phase-II trial, involving 10 patients with hepatocellular cancer (HCC) as a model disease, we attempted to (1) study short-term changes in serum biomarkers following treatment with octreotide (targeting VEGF) alone or octreotide added by imatinib (400 mg/d, additionally targeting PDGF); (2) to explore a potentially decreased metabolisation of imatinib because of hepatic impairment; and (3) to correlate pharmakokinetic and pharmacodynamic findings (PK/PD modelling). Results: Compared to literature results, PK parameters for imatinib are similiar to patients with normal liver function, however, the main active metabolite N-DMI shows a more prolonged half-life. The AUC of N-DMI depends on liver function as expressed by CPT score (r= −0.67) and serum bilirubine (r= −0.70), p&lt;0.05 each. During short-termed imatinib treatment (4 weeks), plasma PDGF significantly decreased at week 2 compared to controls only receiving octreotide treatment. VEGF secretion was unaffected by imatinib. The AUC of N-DMI could be attributed to the pharmacodynamic effect of PDGF inhibition (r= −0,679 [−0.917 to −0.0868], p = 0.031). Conclusions: In HCC patients with different stages of liver cirrhosis, the metabolisation of N-DMI, but not imatinib, is impaired. PK of imatinib is closely correlated to PDGF inhibition. Whether this translates into antiangiogenesis and tumor regression must be awaited by long term clinical studies. [Table: see text] No significant financial relationships to disclose.
Evaluating response with endoscopic ultrasound (EUS) after preoperative chemoradiation (CHRT) in gastric cancer
Authors: J. A. Diaz-Gonzalez, J. Rodriguez, C. Olier, L. Arbea, A. Viudez, J. Aristu, A. Chopitea, J. C. Subtil, S. Martin- Algarra, J. Garcia-Foncillas
Journal: Journal of Clinical Oncology (2008)

15552 Background: Combined modality treatment is the cornerstone in locally advanced gastric cancer management. Neoadjuvant approaches, including chemoradiation (CHRT) is an emergent and promising proposal (ASCO GI 2008, #60). In this context, while endoscopic ultrasound (EUS) has been proved as the diagnostic test of choice in local staging in gastric cancer (Kwee RM, JCO 2007), the value of EUS evaluating response after preoperative CHRT has not been established yet. Methods: Pretreatment clinical staging with CT scan and EUS (uTpre) was performed. Neoadjuvant treatment consisted in chemotherapy [docetaxel 60 mg/m2 and oxaliplatin 85 mg/m2 d1 weekly and capecitabine 650mg/m2 bid × 14d/21 d × 2] followed of CHRT [oxaliplatin 50 mg/m2 and docetaxel 15–25mg/m2; weeks 1,2,4, 5 plus capecitabine 650 mg/m2 bid M-F concurrently to RT 45 Gy in 5 weeks]. 4–6 weeks after completion CHRT re-staging with EUS was done (uTpost) and patients underwent radical surgery. Pathological staging was set up (pT). Response was defined as T-downstaging: clinical downstaging (uTpre vs uTpost) and pathological downstaging (uTpre vs pT). Results: 23 patients completed treatment and underwent surgery. According to Becker response criteria, major pathological response (Ia-Ib) was achieved in 69% of patients. Clinical downstaging was identified in 9/21 (43%) patients, and pathological downstaging was achieved in 19/23 (83%). Specificity and positive predictive value of EUS was 100%. However, the sensibility of EUS assessing response after preoperative CHRT was 47% and the negative predictive value 29%. Globally, accuracy was 62%. Conclusions: The EUS may have a role detecting response after preoperative CHRT and previously to surgery. However, lack of EUS-based response after CHRT does not predict absence of pathological response. No significant financial relationships to disclose.
First experience of effectiveness and safety of bedaquiline for 18 months within an optimised regimen for XDR-TB
Authors: Joseph M. Lewis, Paul Hine, Jenny Walker, Saye H. Khoo, Miriam Taegtmeyer, S. Bertel Squire, Derek J. Sloan
Journal: European Respiratory Journal (2016)

Extensively drug-resistant (XDR) tuberculosis (TB) is a type of multidrug-resistant (MDR) TB that is resistant to isoniazid, rifampicin, fluoroquinolones and at least one injectable second-line drug. There are insufficient antibiotics for effective combination therapy and mortality exceeds 70% [1]. Following successful phase IIb trials [2] in 2013, the novel mycobacterial ATP-synthase inhibitor bedaquiline was approved in Europe and the USA for the first 24 weeks of MDR/XDR-TB treatment alongside a World Health Organization (WHO)-approved optimised background regimen. Phase III trials are ongoing but cohort data describe good early bacteriological outcomes in France [3, 4], Italy [5], the UK [6], the USA [7], India [8] and South Africa [9]. The first successful use of bedaquiline for 18 months for XDR-TB as part of an optimised background regimen <http://ow.ly/XE34x>
Prognostic significance of leptin (L) and leptin receptor (OB-R) expression in human breast cancer (BC)
Authors: S. Kulkarni, S. Saxena, N. Watroba, J. Groth, W. Brady, S. Edge, J. Geradts
Journal: Journal of Clinical Oncology (2006)

20054 Background: L is a cytokine-like hormone that controls adipocyte mass and energy balance by binding to OB-R. Both L and OB-R have been implicated in carcinogenesis and were recently identified in human BC. The clinical significance of increased expression of L and OB-R in human BC is unclear. Methods: The anti-L rabbit (A-20) and anti-OB-R goat (M-18) polyclonal antibodies (ABs) from Santa Cruz Biotechnology were applied in indirect immunohistochemical (IHC) assays. Following antigen retrieval, ABs were reacted with 5 μm paraffin sections of tissue microarrays (TMAs). TMAs included 1mm cores of 316 women with operable BC and contained invasive cancer (IC), ductal carcinoma insitu (DCIS), surrounding histologically normal tissue (N) and nodal metastases (M). For L, nuclear (LN) and cytoplasmic (LC) staining were evaluated separately. For OB-R, one qualitative score (0, +1, +2, +3) was applied to each case. For analysis, 0, +1 were considered low and +2, +3 were considered high expression. Expression of LN, LC, and OB-R were evaluated with respect to clinicopathologic variables; disease free survival (DFS) and survival (S) were evaluated using Cox regression. Results: Median S and DFS were 11.4 and 10.1 years. Tissue from 113 patients with IC, 93 patients with N, 49 patients with M, and 36 patients with DCIS were evaluable for LC, LN and OB-R. OB-R expression was significantly higher in lobular vs. ductal carcinomas (p &lt; .001). Increased expression of LC, LN, or OB-R was not associated with aggressive pathologic features studied in IC and DCIS. On multivariate analysis, highest expression of LN (+3) in IC was significantly associated with poor survival, p = .038, HR 3.51 (1.07–11.51 95% CI). Strong expression of LN in N was also associated with decreased survival, p = .043, HR 8.43 (1.07, 66.30 95% CI). Strong expression of OB-R expression in N was significantly associated with increased DFS and S, p = .004, HR 0.21 (.07–0.61 95% CI) and p = .007, HR .29 (.11–.71 95% CI). Conclusions: In this limited study, LN appears to have a negative impact on survival in women with invasive BC when elevated in IC and N. Elevated levels of LR appear to have a protective effect when elevated in N. Larger studies are needed to confirm our findings and elucidate the mechanisms responsible for these observations. No significant financial relationships to disclose.
Outcome of patients of CML in AP and BC with imatinib: A retrospective analysis of patients from India
Authors: H. Menon, S. S. Hingmire, R. Bharath, K. Jain, N. Ghadyalpatil, N. Prasad, G. Biswas, C. Deshmukh, P. Sastry, P. M. Parikh
Journal: Journal of Clinical Oncology (2007)

17531 Background: Imatinib is a very active agent in advanced phase CML. The present study assesses the impact of Imatinib therapy on the outcome of Indian patients with CML in Accelerated Phase (AP) and Blast Crisis (BC). Methods: Patients of CML in AP or BC who were treated with Imatinib based therapy between 2001 and 2006 were analyzed retrospectively. Results: A total of 65 patients who received Imatinib based treatment for CML in AP or BC were analyzed. Thirty eight (58.46 %) patients diagnosed in chronic phase (CP) were initiated on Imatinib based treatment at time of progression to AP or BC. The remaining 27 (41.53 %) patients had AP or BC of CML at initial diagnosis. At the time of start of Imatinib treatment 36 (55.38 %) patients had AP and 29 (44.61 %) were in BC. Imatinib as a single agent was used in 41 (63.07 %) patients (27 in AP and 14 in BC) and in combination with oral 6-MP and Etoposide was used in 24 (36.92 %) patients (14 in AP and 10 in BC). Hematological response (HR) was seen in 64.61% (42 out of 65) patients, complete HR in 32 (49.23 %) and partial HR in 10 (15.38 %). Cytogenetic response (CR) was noted in 21 (32.31%) patients (Complete -10, Partial -9, and Minor - 2). Twenty eight (43.07%) patients remained progression free (HR+CR in 16 and only HR in 12 patients) till the last date of follow up (median duration of follow-up was 17 months).For the whole group (n=65) the overall survival from the diagnosis of AP or BC after commencing Imatinib treatment was 65.3%, 51.6% and 34.4% at 1, 2 and 3 years respectively. The median survival was 25 months. The median survival and OS at 1 year, as expected, was significantly better for patients in AP (36 months, 77.4 %) as compared to those in BC (11 months, 48.2%)(p=0.004) and both were much longer than previously reported with non-Imatinib therapy. Outcome in patients with AP or BC was not significantly improved by addition of 6-MP and Etoposide. Temporary discontinuation of Imatinb for grade III/IV toxicity was done in 27 (41.53 %) patients for a median duration of 28 days. Conclusions: Imatinib has improved the outcome of patients with advanced phase CML. Our data also documents this in patients from India. However, Imatinib needs to be studied with newer combinations to achieve long term disease control in patients with CML, particularly those in BC. No significant financial relationships to disclose.
Effects of Immunosuppressants on Shope Rabbit Fibroma
Authors: A. C. Allison, Robert M. Friedman
Journal: JNCI Journal of the National Cancer Institute (1966)

In adult domestic rabbits treated with the immunosuppressant, Methotrexate, which blocks delayed-type hypersensitivity and antibody formation, regression of fibromas was retarded so that the tumors became much larger than in untreated control rabbits; moreover, secondary fibromas developed distant from the original inoculation sites. Second injedions of fibroma virus on the 5th and 7th days induced fibromas at the later inoculation sites, whereas control rabbits were resistant at these times. In Methotrexate-treated rabbits, administration of hyperimmune antifibroma serum prevented the appearance of secondary fibromas, but did not produce necrosis or regression of the fibromas. In the animals treated with cortisone, delayed-type hypersensitivity was suppressed but some antibody was formed. Regression of fibromas was retarded but no secondary fibromas developed. From these and other observations it is concluded that the regression of fibromas is not due to interferon or any other Factor inherent in the fibroma cells but to a cell-mediated immune response. Humoral antibody prevents formation of secondary fibromas but does not play an important part in the regression of the primary tumors.
Abstract 9113: Metabolic Syndrome and Principal Component Analysis: Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Subhashish Agarwal, Jerome Rotter, Dhananjay Vaidya, Neal Jorgensen, David Jacobs, Christopher Sibley, Yii-Der Ida Chen, David Herrington
Journal: Circulation (2010)

Introduction: The NCEP definition of the Metabolic Syndrome (MetS) is based on an ad hoc and non-linear combination of six metabolic risk factors from predominantly Caucasian populations. We propos...
Five-year survival analysis of liver metastasis of colorectal cancer after hepatic resection
Authors: J. Xu, Y. Zhong, J. Fan, J. Zhou, J. Zhou, L. Qin, W. Niu, Y. Wei, L. Ren, X. Qin, Z. Wu
Journal: Journal of Clinical Oncology (2007)

14571 Background: To evaluate the relation between hepatic resecion and survival rate of liver metastasis of colorectal cancer ( LMCC). Methods: Use retrograde case analysis method, 133 cases of LMCC received hepatic resection from 1/1/2000 to 31/12/2005 were included,with attention to the relation between hepatic resection and survival rate. Results: There were 133 cases underwent curative hepatic resection in all 470 LMCC cases, of which 30 cases (30/196,15.3%) in synchronous liver metastasis (SLM) group and 103 cases (103/274,37.6%) in metachronous liver metastasis (MLM) group, P&lt;0.01. Mortality rate related to operation was 3.3%(1/30) in SLM and 1.9%(2/103) in MLM(P&lt;0.05). Until 31/6/2006, all 133 cases were followed-up, 1,3,5 years survival rate and median survival time of SLM (81.0%, 40.3%, 16.5%, 22 months) is similar to that of MLM (88.2%, 49.1%, 31.7%, 25 months, P &gt; 0.05), but the recurrence rate is higher(36.7% vs 20.4%,P=0.03). Compared to 49 cases whose liver metastases focus can be resected but chosen non- operative therapy, 1, 3, 5 years survival rate of 133 resected cases is higher (55.6%, 11.0%, 0 vs 86.2%, 39.2%, 29.4%, P=0.0034). In SLM, 22 cases received I stage resection of the primary colorectal tumor and liver metastasis and 8 cases received liver metastasis resection after the primary surgery (II stage operation). 1, 2, 3 years survival are 90.0% vs 87.5%(P &gt; 0.05),61.4% vs 55.3%(P &gt; 0.05)and 35.4% vs 30.0%(P &gt; 0.05) and the median survival time is 28 months vs 26months(P &gt; 0.05).COX multivariate analysis was used to analyze the prognositic factors. Incision margin =1cm(β=-0.8351,P=0.0363)and reoperation after recurrence(β=- 0.9428,P=0.0411)were protective survival factors, and postoperation recurrence (β=0.6471,P=0.0226) was survival risk factor. Conclusions: Curative hepatic resection is the first choice of liver metastasis of colorectal cancer and can improve survival. No significant financial relationships to disclose.
Prevention of Thrombocytopenia by Thrombopoietin in Myelosuppressed Rhesus Monkeys Accompanied by Prominent Erythropoietic Stimulation and Iron Depletion
Authors: Karen J. Neelis, Luo Qingliang, G. Roger Thomas, Bob L. Cohen, Dan L. Eaton, Gerard Wagemaker
Journal: Blood (1997)
Use of day 4 CEP and baseline CXCR4 plus CEC as predictive markers for bevacizumab in mCRC.
Authors: S. Matsusaka, Y. Mishima, M. Suenaga, K. Takagi, E. Shinozaki, Y. Terui, N. Mizunuma, K. Hatake
Journal: Journal of Clinical Oncology (2010)

3599 Background: Bevacizumab plus chemotherapy has become a standard therapy for metastatic colorectal cancer (mCRC). The purpose of this study is to examine the role of the circulating endothelial cell (CEC) subpopulations in bevacizumab. Methods: All patients were enrolled using institutional review board-approved protocols in the Cancer Institute Hospital and from whom written informed consent had been obtained. Eligibility criteria: PS (ECOG) of 0 to 2; histopathology of adenocarcinoma; adequate major organ functions. CEC subpopulations from whole blood drawn before treatment initiation (baseline), day 4, two weeks, and eight-twelve weeks after initiation of chemotherapy were isolated and enumerated using flow cytometry. The proportions of CECs or CEPs were calculated as percentages of the total number of mononuclear cells after an evaluation of at least 50,000 cellular events to detect CECs and CEPs (CD31 positive, CD34 highly positive, CD133 positive, and CD45 slightly positive fraction). To further characterize CEC subpopulations, four different cell surface markers including VEGFR1, VEGFR2, Tie-2, and CXCR4 were used for categorizing CECs. Results: From July 2007 to January 2009, 82 patients with measurable mCRC were enrolled into a prospective study. Combining bevacizumab with FOLFOX4 markedly decreased CEP levels on day 4 as compared with an FOLFOX alone (p = 0.03). The logistic regression interaction test revealed that bevacizumab affected the level of CEP of day 4 whereas it did not affect the other factors including adverse effects. The cases that have CEPs less than 0.04% of PBMC on day 4 were significantly associated with longer PFS and OS as compared with the cases of 0.04% or more CEPs (logrank test; p < 0.001, p = 0.02, respectively). In addition, less than 20% of CXCR4+ cells in CECs at baseline were associated with significant longer PFS and OS as compared with that of others (p = 0.006, p = 0.018, respectively). In contrast, there was no correlation between baseline VEGFR1, VEGFR2, or Tie-2 positive CEC levels and outcome. Conclusions: The levels of CEPs on day4 and the proportion of CXCR4+ CECs at the baseline were correlated with the prognosis of bevacizumab combination chemotherapy. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Chugai Pharma, Yakult Honsha Co., Ltd
Detection by polymerase chain reaction of residual cells with the bcl-2 translocation is associated with increased risk of relapse after autologous bone marrow transplantation for B-cell lymphoma
Authors: JG Gribben, D Neuberg, AS Freedman, CD Gimmi, KW Pesek, M Barber, L Saporito, SD Woo, F Coral, N Spector
Journal: Blood (1993)
Global health agencies response to malaria. Shooting the messenger: authors reply [letter]
Authors: Yamey G
Journal: BMJ (2001)

Questions are being raised about whether donor funding for the Roll Back Malaria project is being used effectively and whether the project is employing worldwide expertise on malaria control. Respected sources in South Asia have confirmed that UNICEF supported the use of chloroquine for treating malaria in Burmese towns along the Thai border.  Yet no systematic identification of Plasmodium spp. was done before treating patients in these region and no other effective treatment was provided.  Chloroquine was therefore given to patients with P. falciparum.  The use of cost recovery by the World Bank remains a contentious issue.
UK exit from EU would be serious threat to science and healthcare, experts warn
Authors: Adrian O’Dowd
Journal: BMJ (2016)

The possible exit of the United Kingdom from the European Union could cause serious damage to the country’s science infrastructure and research funding and could cut universities’ income, science experts have predicted.

After the government’s announcement of a referendum on 23 June on whether the UK should leave the EU, so called “Brexit,” scientists and health experts have started to debate the pros and cons.

Most early commentators seem to believe that leaving the EU would be detrimental to the UK’s science base and to healthcare. They say there would be a negative effect on research collaboration, funding, movement of researchers, access to data, and regulation.

A letter published in the Sunday Times on 21 February, signed by more than 100 UK university leaders, said that an exit would harm UK research and damage universities’ education alliances.1

“Now the prime minister has announced the referendum date, we urge the British public to consider the vital role the EU plays in supporting our world-class universities,” said the letter’s signatories, who include heads of the London School of Hygiene and Tropical Medicine, King’s College London, and the universities of Oxford, Cambridge, Edinburgh, Liverpool, and Birmingham.

They continued, “Inside the EU we are better able to collaborate with partners across Europe to carry out cutting-edge research, from medical and healthcare advances to new materials, products and services.

“In the EU the UK is also a more attractive destination for global talent, ensuring that our students are taught by the best minds from across Europe. While no one is suggesting that UK universities could not survive …