tbuckley/cabot-search huggingface dataset:
Hepatitis C Virus-Related Human Hepatocellular Carcinoma: Predictive Markers Using Proteomic Analysis (Methodology)
Authors: Yasuhiro Kuramitsu, Kazuyuki Nakamura
Journal: Liver Cancer (2009)

It was reported by El-Serag and Mason (1999) that hepatocellular carcinoma (HCC) is one of the most common fatal cancers world-wide. From the repots by Okuda (1992, 2000) and Seow et al. (2001), the most apparent risk factor for HCC is thought to be the chronic infection with hepatitis B or C virus (HBV or HCV). Although in the other Asian countries HCCs developed from HBV-infection, the characteristic of HCCs in Japan is that they develop from the liver tissues infected with HCV or of liver cirrhosis. From the reports by Yano et al. (2003) and Yatsuhashi (2004), 80% of the death cases of HCC patients have HCV-infection, and the number of HCV-carriers in Japan is 2 million. The number of patients with HCC is still on the increase, although diagnostic and therapeutic techniques have become remarkably advanced. It was reported by Yatsuhashi (2004) that the incidence of HCC is increasing in many developed countries in parallel to an increase in chronic HCV infection. Therefore, it is important to identify the predictive marker proteins by which we can predict the carcinogenesis of HCC in HCV-infected patients.
Complications and costs associated with febrile neutropenia in hospitalized adult cancer patients
Authors: N. M. Kuderer, J. Crawford, D. C. Dale, G. H. Lyman
Journal: Journal of Clinical Oncology (2004)

6049 Background: Fever in the setting of neutropenia (FN) frequently requires hospitalization for empiric broad-spectrum antibiotics. More complete understanding of the medical complications and costs associated with hospitalization for FN is needed. Methods: Hospitalization of cancer patients with FN at 115 academic medical centers between 1995 and 2000 was studied using the discharge database of the University HealthSystem Consortium. Primary outcomes included length of stay (LOS), cost, infectious complications and mortality. Logistic regression analysis was used to estimate relative risk based on adjusted odds ratios (OR). Results: Hospitalization with FN was reported in 41,779 adult cancer patients. Mean (median) LOS was 11.2 (6) days while the average (median) cost was $19,110 ($8,376) per episode. The 35% of patients hospitalized ≥ 10 days accounted for 74% of hospital days and 78% of total cost. Over the six years of observation, LOS decreased 10% while cost per day and total cost increased 28% and 13% respectively. Documented infection was reported in 38% of patients including sepsis in 19% and pneumonia in 10%. Death during hospitalization was reported in 11% of admissions. Mortality was most commonly associated with gram-negative sepsis (34%), pneumonia (27%) or comorbidities including renal (30%), cerebrovascular (30%), liver (28%) and lung disease (27%). Mortality rates increased with the number of comorbidities (P-trend<.001). Odds ratios for death were: gram-negative sepsis (4.8), pneumonia (2.4), renal (3.1), cerebrovascular (3.2), liver (2.9) and lung disease (3.9). Odds ratios for complicated hospitalization (length of stay ≥ 10 days) were: leukemia (3.4), gram-positive sepsis (2.5) and comorbidities with lung (2.1), renal (2.1), cerebrovascular (2.1) and liver disease (2.0) after adjustment for other comorbidities and infectious complications. Conclusions: Hospitalization for FN is associated with considerable morbidity and mortality. Numerous patient characteristics, comorbidities and infectious complications are associated with increased mortality, length of stay and cost. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Inc. Amgen, Inc. Amgen, Inc.
Relationship of progression to acute myeloid leukemia (AML) from myelodysplastic syndrome (MDS) and cytogenetic status
Authors: E. Hellstrom-Lindberg, P. Fenaux, G. J. Mufti, A. F. List, V. Santini, S. Gore, J. F. Seymour, J. Backstrom, D. McKenzie, C. L. Beach
Journal: Journal of Clinical Oncology (2008)

7089 Background: A recent phase III trial showed that azacitidine (AZA) significantly prolonged overall survival in pts with high-risk MDS, regardless of a good, intermediate, or poor IPSS karyotype (Fenaux, Blood 2007;110,817). Using cytogenetic data from this trial, our subgroup analysis assessed changes in baseline (BL) cytogenetic status in MDS pts who subsequently transformed to AML (>30% bone marrow blasts). Methods: In all, 358 pts met inclusion criteria of high-risk MDS, defined as RAEB, RAEB-T, or CMMoL per FAB with an IPSS of Int-2 or High. Pts were randomized to AZA (75 mg/m2/d x 7d, q 28d) or CCR with both groups receiving concomitant best supportive care (BSC: transfusions, antibiotics, and G-CSF only for neutropenic infection) as needed. CCR consisted of 3 treatments: BSC only, low-dose ara-C (20 mg/m2/d x 14d, q28d), or standard chemotherapy (7+3 regimen, induction/consolidation). No erythropoietin was allowed. Results: For this subgroup analysis, complete cytogenetic data were available from 78 (40 AZA; 38 CCR) of the 358 pts. Baseline characteristics were similar across the 2 arms (70% male; median age, 69 years). In all, 92% of pts had RAEB/RAEB-T disease; 87% an IPSS of Int-2 or High. Median time to transformation to AML during the treatment period was 26.1 months and 12.4 months in the AZA and CCR groups (p=0.004), respectively; 33% of AZA pts versus 31% of CCR pts transformed. In either arm, the IPSS cytogenetic status (good, intermediate, or poor) of the majority of pts remained unchanged from BL to transformation to AML (Table). Conclusion: These data demonstrate that transformation to AML in high-risk pts is rarely accompanied by a worsening in IPSS cytogenetic status and that treatment with AZA is associated with a significant delay in transformation. BL Cytogenetic Status Cytogenetic Status at AML Transformation AZA CCR AZA CCR Good Int Poor Good Int Poor Good 20 20 20 0 0 18 2 0 Int 7 9 0 6 1 1 8 0 Poor 10 7 1 0 9 0 0 7 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Pharmion Amgen, Celgene, EMB Statistical Solutions, LLC, Pharmion Pharmion Amgen, Celgene, Cephalon, Johnson & Johnson, Novartis, Pharmion, Roche Pharmion
Multicenter phase III comparison of cisplatin/S-1 (CS) with cisplatin/5-FU (CF) as first-line therapy in patients with advanced gastric cancer (FLAGS): Secondary and subset analyses
Authors: J. A. Ajani, W. Rodriquez, G. Bodoky, V. Moiseyenko, M. Lichinitser, V. Gorbunova, I. Vynnychenko, A. Garin, I. Lang, S. Falcon
Journal: Journal of Clinical Oncology (2009)

4511 Background: The primary analysis of FLAGS (ASCO-GI-2009) showed that CS and CF had similar overall survival (OS) but CS had a significantly superior safety profile. Methods: 1,053 (1,029 treated; CS=521/CF=508) patients with untreated, advanced gastric/gastroesophageal adenocarcinoma were randomized to either S-1 (25 mg/m 2 bid, d 1–21)/cisplatin (75 mg/m 2 d 1) q 28 d or 5-FU (1,000 mg/m 2 /d 5-d infusion)/cisplatin (100 mg/m 2 d 1) q 28 d. OS analyses for non-inferiority (NI), by pre-specified stratifications, and by the largest histologic subset (diffuse type histology) were performed. Results: OS for NI: OS from CS compared to CF had a HR=0.92 (two-sided 95% CI, 0.80–1.05). HR=1.05 being much lower than HR=1.22 derived from the literature. Using a stringent HR non-inferiority margin of 1.10, CS remains statistically significantly non-inferior (p=0.0068) to CF. The 74% preserved control effect by CS is well above the suggested 50% by Rothmann et al. (Statist-Med2003;22:239–264). OS by stratifications: Of 12 stratification sub-categories, CS produced OS HR=&lt;1.0 in 9 and HR=&gt;1.0 in 3. Subset analysis: OS analysis for diffuse type histology (n=590) showed that CS (median survival=9.0 months) resulted in a superior OS (Log rank p=0.0413; HR, 0.83 [95% CI, 0.70 to 0.99]) than CF (median survival=7.1 months). Conclusions: CS is statistically non-inferior to CF while proving much safer for the patients. CS resulted in a HR=&lt;1.0 in the majority of pre-specified stratifications and CS produced statistically superior OS for patients with diffuse type histology (needs prospective studies). CS is an optimum substitute for CF. Supported by Taiho Pharma, USA. No significant financial relationships to disclose.
RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction (GEJ) and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy rainbow IMCL CP12-0922 (I4T-IE-JVBE).
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, Atsushi Ohtsu, Philippe Rougier, Michael Emig, Roberto Carlesi, Kumari Chandrawansa, Kei Muro
Journal: Journal of Clinical Oncology (2014)

LBA7 Background: RAM is a human IgG1 monoclonal antibody VEGF-receptor 2 antagonist. We conducted a global, placebo-controlled, double-blind, phase III trial to evaluate the efficacy and safety of PTX +/- RAM in patients with metastatic GEJ or gastric adenocarcinoma who had disease progression on or within 4 months after first-line platinum- and fluoropyrimidine-based combination therapy. Methods: Pts received RAM (8 mg/kg IV q2w) or placebo (PL) plus PTX (80 mg/m 2 d1, 8, 15 of a 4 week cycle) until disease progression, unacceptable toxicity, or death. Eligible pts had ECOG PS ≤ 1; and adequate organ function. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), time to progression (TTP), and safety. Results: From Dec 2010 to Sep 2012, 665 pts were randomized (RAM+PTX: 330; PTX: 335). Baseline characteristics were generally balanced between arms. The OS hazard ratio (HR) was 0.807 (95% CI 0.678, 0.962; p=0.0169). Median OS was 9.63m for RAM+PTX and 7.36m for PTX. The HR for PFS was 0.635 (95% CI 0.536, 0.752; p &lt;0.0001). Median PFS was 4.40m and 2.86m. Median TTP was 5.5m RAM+PTX; 3.0m PTX (p &lt;0.0001). ORR was 28% RAM+PTX;16% PTX (p=0.0001). Grade ≥ 3 adverse events (AEs) occurring in &gt;5% of patients on RAM+PTX were: neutropenia (40.7% RAM+PTX;18.8% PTX), leukopenia (17.4% vs 6.7% ), hypertension (14.1% vs 2.4%), anemia (9.2% vs 10.3%), fatigue (7.0% vs 4.0%), abdominal pain (5.5% vs 3.3%), and asthenia (5.5% vs 3.3%). Febrile neutropenia was reported in 3.1% RAM+PTX; 2.4% PTX. Conclusions: The primary endpoint of improved OS was met. A statistically significant and clinically meaningful OS benefit of &gt; 2 months was observed for RAM+PTX vs. PTX in gastric and GEJ cancer after progression on 1st-line therapy, as were significant benefits in PFS and ORR. Neutropenia was more frequently reported in the RAM+PTX arm but incidence of febrile neutropenia was comparable between arms. Clinical trial information: NCT01170663.
MSc in translational medicine
Authors: Tim Wilkinson
Journal: BMJ (2012)

Translational medicine is a discipline that aims to maximise the application of knowledge gained in the basic sciences to patient care—commonly known as the “bench to bedside” approach. The MSc in translational medicine is run by the University of Edinburgh and is delivered as a part time distance e-learning programme. The course was designed by a multidisciplinary team of doctors and scientists, is chaired by Brian Walker (professor of endocrinology), and is directed by Douglas Roy (senior research fellow). 

This course is aimed at doctors of all grades, particularly those with an interest in research and drug development. The course is multidisciplinary and attracts students from basic science, veterinary, and pharmaceutical backgrounds from around the world.

I began the course as a foundation year 1 doctor and am currently in the third year.

I had heard that the translational approach to drug development is being adopted increasingly by universities, research institutions, and government bodies in an attempt to increase the number of novel drugs reaching the market and therefore becoming available to doctors and patients. I thought that gaining an …
Mitotic checkpoint gene CHFR methylation in pretreatment serum DNA of docetaxel (doc)/cisplatin (cis)-treated stage IV non-small cell lung cancer (NSCLC) patients (p)
Authors: D. Isla, F. Salazar, J. Ramirez, M. Sanchez Ronco, M. Cobo, A. Montes, J. Sanchez, S. Catot, M. Taron, R. Rosell
Journal: Journal of Clinical Oncology (2006)

7056 Background: CHFR (checkpoint with forkhead-associated and ring finger) regulates a prophase delay in cells exposed to agents that disrupt microtubules. Epigenetic inactivation of CHFR is a frequent event in human tumors, leading to impaired checkpoint function and enhanced sensitivity to docetaxel. We hypothesized that serum DNA methylation of CHFR could be a predictor of longer survival in p treated with doc/cis. Methods: Sodium bisulfite modified serum DNAwas used as the template for methylation-specific PCR assay. DNA was obtained from 600 doc/cis-treated stage IV NSCLC p. Results: Preliminary data on 301 p is available. The frequency of CHFR hypermethylation was 32.6%. There was no association between methylation and performance status (PS), age, gender, histology, response, 14–3-3σ serum DNA methylation, polymorphisms in lymphocyte DNA (ERCC1 118 C/T, ERCC1 C8092A, XRCC3 241 ThrMet), or tumor ERCC1 mRNA levels. Overall, there was a tendency to better median survival (MS) for p with methylated CHFR. In p with PS 0, MS was 33 months (m) for 41 p with methylated CHFR and 12 m for 64 p with unmethylated CHFR (P = 0.23). In p &gt;66 years (y), MS was not reached for 31 p with methylated CHFR and 9.6 m for 80 p with unmethylated CHFR (P = 0.01), while in p &lt;66 y, MS was 9.4 m for 67 p with methylated CHFR and 10 m for 123 p with unmethylated CHFR (P = 0.62). p with both 14–3-3σ and CHFR methylation showed a tendency to longer survival. Final data on 600 p will be presented. Conclusions: Early findings indicate that CHFR methylation in elderly p predicts a significant survival benefit in doc/cis-treated NSCLC. No significant financial relationships to disclose.
A phase II study of weekly docetaxel (T) and capecitabine (X) in patients with metastatic gastric cancer (GC)
Authors: H. K. Kim, J. H. Chun, J. S. Lee, J. Y. Choi, H. G. Lee, I. J. Choi, K. W. Ryu, Y.-W. Kim, J. S. Lee, J.-M. Bae
Journal: Journal of Clinical Oncology (2004)

4057 Background: Docetaxel (T) and capecitabine (X) are active agents against GC with synergistic antitumor effects. We conducted the current, single-center phase II trial to assess the efficacy and toxicity of combination TX regimen in metastatic GC patients (pts). Methods: Eligibility required no prior chemotherapy, ECOG PS of 0–1, and adequate bone marrow, hepatic, and renal functions. Treatment consisted of T 36 mg/m2 IV on days 1 and 8, and X 1,000 mg/m2 PO BID on days 1–14 of a 3-week cycle, until progression without a limit in number of cycles. Results: From 12/2001 to 5/2003, 55 GC pts (M/F=34/21) were enrolled with median age 54 yrs (range: 22–73) and ECOG PS 0/1=20/35; 47 pts had measurable lesions. A total of 328 cycles of treatment were given, with a median of 5 (range: 1–17) per patient. Objective responses were documented in 19 (40.4%) of 47 pts with measurable lesions, with the median response duration of 5.6 months (range, 2.1∼11.0+). Of the 8 pts with nonmeasurable disease, 5 showed improvement, 1 no change, and 2 aggravation of evaluable lesions. At the time of follow up (median 13.3 months), the median time to progression and overall survival were 4.5 months (95% CI, 3.4–5.5) and 12.0 months (95% CI, 7.6–16.5) for all 55 pts, respectively. Hematologic toxicities were generally mild to moderate. Grade 3/4 neutropenia occurred in 20 pts (36.4%) with febrile neutropenia in 5 pts. Nonhematologic toxicities, the most frequent of which was stomatitis, were generally manageable. Grade 2/3 nonhematologic toxicities included stomatitis (19/12 pts), diarrhea (15/10), fluid retention (10/2), hand-foot syndrome (8/2), nail changes (29/0), and tearing (11/0). Three pts experienced pneumonitis, but all of them responded to steroid treatment. Conclusions: The TX regimen was relatively well tolerated and effective against metastatic GC, with the added advantage of being an outpatient regimen (Supported in part by NCC Grant 0210070: Docetaxel was in part provided by Aventis Pharma Korea). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Docetaxel was partially provided by Aventis Pharma Korea.
Inter- and intra-country variations in the use of trastuzumab in Norway, Spain and Sweden
Authors: N. Wilking, J. Bergh, U. Wilking, B. Jönsson
Journal: Journal of Clinical Oncology (2007)

1069 Background: Breast cancer mortality is similar in Norway, Spain and Sweden (14–16/100,000 Age Standardized Rate). There are only small regional differences in incidence and mortality within the countries. Trastuzumab (T) was approved for metastatic breast cancer (MBC) in Norway, Spain and Sweden in second half of year 2000. T represents a unique new treatment for MBC that delays disease progression and improves survival. HER2 over expression (H+) is used to identify patients eligible for trastuzumab treatment (T). Methods: This study use sales data from IMS Health and incidence and mortality data from regional and national cancer registries as well as data from International Agency for Research on Cancer. We examines the variation in the use of T in different health care regions of Norway (4 regions), Spain (19 regions) and Sweden (6 regions) as well as differences in use between the countries. These results were also put into a global comparison. Results: There are marked differences in both the rate and level of uptake between the countries. Three years after approval the Spanish uptake was close to 90 % and twice the Swedish and 3–4 times the Norwegian uptake. The regional variations within the countries are of the same magnitude, a factor 2–3. Based on an assumed H+ rate of 25% and a treatment time of 38 weeks we estimate the proportion of H+ MBC patients that have been treated with T during the period 2000–2005 to be 24% in Norway; 66% in Spain and 44% in Sweden. In all countries there has been an increase in the use during the second half of 2005, indicating a use also in the adjuvant situation. T was approved for adjuvant treatment of BC in Europe in April 2006. Conclusions: Access of trastuzumab to patients with MBC in Norway, Spain and Sweden has been very variable. Spanish MBC patients have had earlier access to T than Swedish patients. Norwegian patients have had the lowest access. Regional differences in the use are in the magnitude of a factor 2–3. On a global level the Spanish uptake is in line with the uptake in the USA, Switzerland and Austria; the Swedish uptake is at an average European level and the Norwegian uptake is at a low level, similar to Czech Republic, Hungary, New Zealand, Poland and the UK. No significant financial relationships to disclose.
Anemia, renal disease, and chemotherapy in the IRMA study
Authors: V. Launay-Vacher, N. Janus, J. Morere, S. Oudard, J. Spano, X. Pourrat, P. Beuzeboc, J. Gligorov, G. Deray, I. L. Ray-Coquard
Journal: Journal of Clinical Oncology (2008)

20649 Background: Both anticancer drugs and kidney disease (KD) may induce anemia. In this analysis, we studied hemoglobin (Hb) levels of the pts in parallel with their renal function (RF) and their anticancer drugs. Methods: From IRMA data, the frequency of anemia was evaluated as defined by the WHO, and according to its severity (11 to 9 and <9 g/dL), with regards to the treatment. We then studied the frequency of KD (aMDRD<60) in anemic vs non-anemic pts, for each treatment. Results: Table 1 shows the frequency of anemia and the frequency of KD in patients with and without anemia, for each treatment. Conclusions: Anemia and aMDRD<90 were highly frequent. In some anticancer protocols, the frequency of aMDRD <60 was higher in anemic patients as compared to non-anemic patients (Taxanes x1.5), FOLFIRI (x3.9), and Trastuzumab (x4.6)). For this level of RF, renal anemia is a frequent complication of KD and may participate in the decreased Hb levels observed in our patients in addition to drug toxicity. Table 1. Anticancer Protocol (N) Anemia Yes/No (% of pts) Anemia (g/dL) (% of pts) aMDRD (mL/min/1.73 m2) (% of pts) 11 to 9 < 9 < 90 < 60 CEF (451) Y: 40.6% N: 56.5% 15.3% - 0.4% - 44.8% 45.9% 3.3% 3.5% Taxanes (418) Y: 60.0% N: 37.6% 23% - 4.8% - 50.2% 45.2% 11.6% 7.6% FOLFOX (190) Y: 52.6% N: 37.4%% 14.2% - 2.1% - 50.0% 63.4% 8.0% 5.6% FOLFIRI (171) Y: 56.1% N: 36.8% 19.3% - 1.2% - 55.2% 60.3% 18.8% 4.8% Carboplatin + Paclitaxel (130) Y: 63.8% N: 34.6% 23.8% - 3.8% - 60.2% 71.1% 19.3% 17.8% Vinorelbine (110) Y: 67.3% N: 25.5% 30% 3.6% 46.0% 57.1% 9.5% 7.1% Trastuzumab (123) Y: 30.9% N: 61.0% 8.1% - 5.3% - 47.4% 64.0% 18.4% 4.0% Hb: Hemoglobin; WHO Definition of anemia: <12 g/dL in women and <13 g/dL in men; CEF: Cyclophosphamide + Epirubicin + Fluorouracil; Taxanes: Paclitaxel or Docetaxel; FOLFOX: Folinic acid + Fluorouracil + Oxaliplatin; FOLFIRI: Folinic acid + Fluorouracile + Irinotecan No significant financial relationships to disclose.
A simplified method at lowest cost for autologous, non-cryopreserved, unmanipulated, periphral hematopoetic stem cells transplant in multiple myeloma and non-Hodgkin's lymphoma: Asian scenario.
Authors: S. K. Jasuja, N. Kukar(jasuja), R. Jain, A. Bhateja, A. Jasuja, Rohit Jain
Journal: Journal of Clinical Oncology (2010)

e18545 Background: Methods to simplify the stem cell transplantation procedure are needed mainly in the developing countries for the affordability factor and need for transplant in the huge population. Unprocessed leukapheresis material is useful to restore hemopoesis after high dose chemotherapy. Methods: Over a period of 18 months in hospital setting, we prospectively performed auto transplants in 6 multiple myeloma and 5 non-Hodgkin's lymphoma patients using non-cryopreserved (2 days for myeloma and 5-7 days for lymphoma cases at 4°C) and unmanipulated peripheral blood stem cells mobilized from the bone marrow to the peripheral blood by means of GCSF (10mg/kg/day) and GMCSF (5mg/kg/day) using a 5-7 day conditioning regimen. The median collection of CD34+ stem cells in myeloma was 2.5 × 106/cumm (range 1.8-4.6 × 106/cumm) and in lymphoma was 2.8 × 106/ cumm (range 2-4.8 × 10 6/cumm) Results: The median time to achieve > 0.5 × 109/l granulocytes was 14 and 12 days for lymphoma and myeloma patients respectively. The median time to achieve > 20 × 109/l platelets was 16 and 14 days for lymphoma and myeloma patients respectively. CR was achieved in 5 myeloma and 4 lymphoma cases. A very good partial response was achieved in 1 myeloma and partial in 1 lymphoma case. The 100-day mortality was zero. The overall median post-transplant survival has not been reached, being above 76 months but the patients are in close follow up. The approximate cost of the each graft was US$6,000. Conclusions: Our simplified method to autograft patients avoiding purging procedures and cryopreservation of the cells, is feasible and results in a substantial decrease in the cost of autologous hematopoietic stem cell transplant to perhaps lower than that of anywhere in the world. No significant financial relationships to disclose.