tbuckley/cabot-search huggingface dataset:
Neoadjuvant trastuzumab in a sequential nonanthracycline-based regimen for patients with stage II-III breast cancer
Authors: G. Carillio, R. Aiello, M. Alì, A. Mazzola, G. Scandurra, E. Taibi, M. Chiarenza, G. Fallica, F. Caruso, M. Caruso
Journal: Journal of Clinical Oncology (2009)

e11559 Background: Recently, some studies have demonstrated benefit from adding trastuzumab to neoadjuvant anthracycline-containing chemotherapy for HER2-positive breast cancer patients. However, trastuzumab can increase cardiotoxicity, particularly when combined with anthracyclines. This represents a relevant issue for patients who usually need to receive radiotherapy or further systemic treatment. Methods: In the late 2007 we started a phase II study for testing activity and safety of neoadjuvant trastuzumab in association with sequential chemotherapy, based on favourable in vitro combination index, proven efficacy, and moderate cardiotoxicity. Weekly trastuzumab for 18 weeks was combined with cisplatin 80 mg/m 2 on day 1 and vinorelbine 25 mg/m 2 on days 1+8 q3w for 3 courses, followed by docetaxel 100 mg/m 2 q3w for further 3 courses. Peg- filgrastim was administered to prevent neutropenia. Adjuvant trastuzumab q3w was planned for one year. Eligible patients had stage II-III core-biopsied breast carcinoma with overexpressed or amplified HER2/neu. Adequate cardiac function with LVEF ≥ 50% was required for trastuzumab administration. Primary end-point was pathologic complete responses (pCR) rate. The study is registered on the European Clinical Trials Database. Results: Among 17 enrolled patients, 15 were evaluable for primary end-point. Median age was 50 years (range 23–70), stage II and III breast cancer in 4 and 13 patients, respectively, with 4 cases of stage IIIB (2 T4b and 2 T4d), and 2 women with synchronous bilateral cancer. Neoadjuvant regimen yielded 6/15 pCR (40%). Only 3/12 patients treated with lymphadenectomy due to initial clinically suspected axillary nodes presented pN+, but none of them had more than 3 positive nodes. In two cases we observed a total pCR, involving both primary tumor and axillary nodes. Treatment was safe, with only 2 events of short G4 non febrile neutropenia on 97 chemotherapy cycles. Alopecia was moderate at the end of treatment, without any case of complete hair loss. No significant cardiac dysfunction was recorded during the neoadjuvant therapy. Conclusions: The present sequential non anthracycline-based chemotherapy associated with weekly trastuzumab showed promising results in neoadjuvant setting. No significant financial relationships to disclose.
IL-4 Exerts Opposing Effects on Surface-IgM and CXCR4 Mediated Signalling in Chronic Lymphocytic Leukaemia
Authors: Maria Montserrat Aguilar, Matthew D Blunt, Jonathan C Strefford, Francesco Forconi, Mark Cragg, Freda K Stevenson, Graham Packham, Andrew J Steele
Journal: Blood (2014)
Proteinase 3, the major autoantigen of Wegener's granulomatosis, enhances IL-8 production by endothelial cells in vitro.
Authors: S P Berger, M A Seelen, P S Hiemstra, J S Gerritsma, E Heemskerk, F J van der Woude, M R Daha
Journal: Journal of the American Society of Nephrology (1996)

Proteinase 3 is the major target antigen of antineutrophil cytoplasmic autoantibodies (ANCA) in Wegener's granulomatosis and is contained in the azurophilic granules of polymorphonuclear neutrophils, the dominant cell type in vascular lesions during the early stages of systemic vasculitis. This study questioned whether neutrophil lysosomal enzymes, once released at the site of inflammation, are able to potentiate the influx of additional neutrophils by enhancing the production of the chemotactic cytokine interleukin-8 (IL-8) by endothelial cells. Therefore, human umbilical vein endothelial cells in culture were incubated with varying concentrations of highly purified proteinase 3, human neutrophil elastase, and cathepsin G for different time periods. The supernatants were subsequently assessed for IL-8 antigen by using a sandwich ELISA. The presence of both proteinase 3 and elastase resulted in an increased production of IL-8, up to 15.6- and 4.2-fold, respectively, in a dose- and time-dependent fashion. Cathepsin G did not influence IL-8 production. Although the addition of an alpha 1-proteinase inhibitor completely abrogated elastase-mediated IL-8 production, it did not significantly influence the effect of proteinase 3. Both proteinase 3-and elastase-mediated production of IL-8 was inhibited by cycloheximide, indicating de novo synthesis. This was supported by the finding of increased IL-8 mRNA levels in proteinase 3-treated human umbilical vein endothelial cells by using Northern blot analysis. Taken together, the neutrophil lysosomal enzymes proteinase 3 and human neutrophil elastase may contribute to a self-perpetuating process of neutrophil recruitment in acute inflammation by increasing de novo synthesis of IL-8 by endothelial cells. The studies presented here also show that proteinase 3 mediates its effect independently of its enzymatic activity, indicating a hitherto unknown mode of action on endothelial cells.
Five axillary node groups beyond sentinel node observed by 3D-CT lymphography, evaluated for avoiding axillary dissection with sentinel node metastasis
Authors: K. Yamashita, K. Shimizu
Journal: Journal of Clinical Oncology (2008)

595 Background: The detailed relations between lymph nodes and lymph flow can be clarified using 3D-CT lymphangiography (LG). Systematic collection of lymph nodes based on 3D-CT LG decreases unnecessary lymph node dissection, even if the sentinel nodes (SNs) has metastasized, and can decrease complications. Moreover, endoscopy lowers infestation. We reviewed a validity of 3D-CT LG and a metastatic pattern of axillary nodes and SNs of 40 metastasis-positive cases among 186 sentinel node biopsies. Methods: 3D-CT LG was performed on the day before the surgery to mark SN on the skin. Above the tumor and near the areola, 2 ml of Iopamiron 300 was injected subcutaneously. A 16-channel multidetector-row helical CT scan images were taken at 1 min after injection for SN detection and at 3 and 5 min for observing advancement of lymph flow into venous angle. They were reconstructed to produce a 3D image of lymph ducts and lymph nodes. SN biopsy was performed by dye-staining method using endoscopy. The SNs were found by following the dye in the lymph ducts on video monitor. SNs and the second and the third nodes were sampled by same way. Results: We performed SN biopsy with 3D-CT LG in 146 patients. We can recognize the passage of lymph flow from SN into the venous angle and can classify these nodes into five groups. Detection rate was 100% for SN; 80.1% for the third group; and 30.1% for the fifth group. Multiple nodes were observed in SN (19.9%), in the second group (10.1%) and in the third group (4.3%). SN metastasis was positive in 40 patients, and only SN metastasis was found in 21 patients (52.5%) among them; SN and second group metastases were in 19 patients; SN and second and third group metastases were in 16; beyond the third group metastasis was in 11. But any skip metastasis beyond second and third nodes was not observed. Conclusions: By 3D-CT LG, we can recognize the accurate and more precise lymph flow. 52.5% of SN metastasis-positive patients had no metastasis in other nodes. They can be candidates for preserving their axillary node. 3D-CT LG guided SN biopsy for the second and third groups will predict their existence and help us to avoid dissecting needless nodes. No significant financial relationships to disclose.
Prospective randomized study on therapeutic gain achieved by addition of chemotherapy for T1–4N2–3M0 Nasopharyngeal Carcinoma (NPC)
Authors: A. W. Lee, W. H. Lau, S. Y. Tung, D. Chua, R. Chappell, L. Siu, J. Lau, S. C. K. Law, L. Xu
Journal: Journal of Clinical Oncology (2004)

5506 Background: Concurrent chemoradiotherapy (CRT) has been widely advocated as the standard treatment for advanced NPC, since the Intergroup Study 0099 showed significant survival benefit by adding concurrent/adjuvant chemotherapy. However, there are serious concerns about the exact magnitude of benefit and lack of data on late toxicity. Methods: Patients with non-keratinizing NPC staged T1–4N2–3M0 were randomized in equal proportions to RT alone or CRT. The patients were stratified by center, T-stage, and N-stage. Both arms used the same RT technique and dose in line with the policy adopted by individual centers, all patients were treated with conventional fractionation to a total dose >= 66 Gy. Those in the CRT arm were given cisplatin 100 mg/m2 IV on Day 1, 22, 43, followed by cisplatin 80 mg/m2 IV and 5-fluorouracil 1000 mg/m2/d for 96 hr starting on Days 71, 99 and 127. The primary endpoint is progression-free survival (PFS) defined as the time to first failure at any site or death due to any cause. The protocol specified analyses to be performed shortly after completion of accrual and with complete 5-year follow-up. Secondary end-points include overall survival (OS), failure-free rates (FFR), and toxicities grade >=3. To achieve 80% power for detecting a 15% difference in PFS, target accrual is 340 patients. Results: From March 1999 to January 2004, 348 patients have been accrued: 176 were randomized to RT and 172 to CRT. The median follow-up was 25 months. The 2 arms were well-balanced in all prognostic factors and RT parameters. The chemotherapy-related toxicity rate in the CRT arm was 58% (32% being leukopenia). In addition, the CRT arm had a higher incidence of acute mucositis (63% v 46%, p = 0.01). The treatment effectiveness and late toxicity rates were listed in the attached Table. Significant differences thus far observed were loco-regional control and late toxicity. Fatal toxicities occurred in 2 patients from the CRT arm. Conclusions: This preliminary report shows that chemoradiotherapy could achieve significant improvement for locoregional control, but not for distant control and overall survival. The gain in PFS did not reach statistical significance. Chemoradiotherapy induced significantly higher incidence of toxicities (both acute and late). Longer follow-up is needed to confirm the current findings. No significant financial relationships to disclose.
Preservation of Activities Daily Living (ADL) in a phase-II impact study of oral capecitabine and vinorelbine in the treatment of metastatic carcinomas in patients 70 and older: The GERICO-01 Study by the French FNCLCC Group
Authors: A. C. Braud, F. Joly, M. Rios, L. Felizot, P. Fargeot, V. Servent, B. Laguerre, F. Turpin, F. Pein
Journal: Journal of Clinical Oncology (2004)

8160 Background: In the next 2 decades, 70% of all cancers will occur in elderly patients (pts) above 70 . Methods : In Gerico-01, with pts 70 years or older, the primary endpoint of the study was the autonomy preservation as measured by the ADL in 6 item; 2nd objectives were toxicity (NCI-CTC v2), PK study of V, the serum PSA or CA 15–3 levels variation and the tumor targets evaluation (RECIST); the primary tumors were either metastatic disease from a primary Breast, or a lung or a prostate Ca. The treatment was Q-3 weeks an oral combination chemotherapy (CT) with C day 1–14 at a starting dose of 750 mg/m2 twice a day and oral V, days 1 and 8 at a starting dose of 45 mg/m2/d. After three cycles the dose could be escalated up to 1000 mg/m2 twice a day and 60 mg/m2 respectively. At inclusion, the creatinin clearance must be above 30 ml/min (Cokroft Formula). Dose adaptation was according to the observed toxicity. C+V was discontinued in progressive disease, or the loss of 2 or more ADL criteria, or any grade III-IV toxicities. Results : Between december 2002 and 2003, 65 pts were included in 8 different French centers and 12 are still under treatment. The pts' median age was 75 yrs (70–86); the primary was a breast in 28, a prostate in 31 and a lung Ca in 6 pts. ADL preservation/ improvement was seen in 22 evaluated pts at 6 cycles and decreased in 6 pts. Among breast carcinoma there were 5 partial remission, 1 in prostate and 1 in lung ca, stable disease was seen in 2 breast, 9 prostate, 1 lung; C+V was stopped in 9 progressive disease, 3 cases of toxicity, 1 pt. refusal. Among 15 Severe Adverse Events, 1 hand-foot syndroma, 2 overdosages, 1 occlusion, 1 femoral neck fracture and 1 tachycardia. Conclusion : Although response rate remains limited, this oral C+V regimen is very well tolerated in elderly pts in preserving their ADL and a good quality of life for pts with uncurable disease. No significant financial relationships to disclose.
Abstract 20635: Dipeptidyl-Peptidiase 4 Inhibitors and the Risk of Heart Failure - A Nationwide Case-Crossover Study
Authors: Yi-Cheng Chang, Chia-Hsuin Chang, Jou Wei Lin, Lee-Ming Chuang, Mei-Shu Lai
Journal: Circulation (2014)

Introduction: Dipeptidyl-peptidiase 4 (DPP4) inhibitors, a new type of oral hypoglycemic agents, have been widely used in the treatment of type 2 diabetes mellitus (DM). However, recent studies showed that the use of DPP4 inhibitors, especially saxagliptin, could be associated with an increased risk of heart failure (HF). Methods: We conducted a retrospective case-crossover study by identifying DM patients aged 20 years and above hospitalized for HF between 2009 and 2011 from Taiwan National Health Insurance Database. Diagnosis codes from inpatient claims databases were used to ascertain the index date of hospitalization. For each patient, we defined case period as 1 to 30 days before the index date and control period as 91 to 120 days before the index date. The use of DPP4 inhibitors during the case and control periods were identified from the pharmacy claims database. Odds ratios (OR) and 95% confidence intervals (CIs) were estimated by a conditional logistic regression model. Results: A total of 47,506 patients hospitalized for HF (48.2% mean and 51.8% women) was included in the analysis (mean age: 72.7±12.4 years). Among them, 2,874 patients (6.05%) used sitagliptin in the case period, and 2,318 (4.88%) did in the control period. Use of other DPP4 inhibitors, i.e., saxagliptin and vildagliptin, was rare. The analysis of the discordant medication in the two periods showed that sitagliptin use was associated with an increased risk of HF (OR: 2.85, 95% CI: 2.46-3.30). Additional analyses using different time frames as the control period showed similar results. In contrast, there was no increased risk for HF in the use of sulfonylureas or metformin. Conclusions: The nationwide case-crossover study demonstrated that sitagliptin was associated with an increased risk of hospitalization for HF. Further studies are needed to examine whether the potential risk of HF is a class effect of DPP4 inhibitors.
<i>CYP2D6</i> genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer
Authors: H. Lim, H. Lee, K. Lee, E. Lee, I. Jang, J. Ro
Journal: Journal of Clinical Oncology (2006)

634 Background: Tamoxifen is a prodrug that is metabolized to active metabolites, Z-4-hydroxy-N-desmethyltamoxifen (BX) and Z-4-hydroxy-tamoxifen (4OH) where CYP2D6 plays a major role in the conversion. Genetic polymorphisms of CYP2D6 by ethnicities are well known with CYP2D6*10 in Asians (up to 50% in Koreans), and CYP2D6 *2 and *4 in American Whites as major variant alleles. We analyzed the steady state plasma concentrations of tamoxifen and its metabolites in patients (pts) with breast cancer to evaluate their associations with various CYP2D6 genotypes. Methods: Blood samples were collected from 219 pts on tamoxifen, 20 mg daily as adjuvant therapy for more than 3 months at National Cancer Center, Korea. Plasma tamoxifen, N-desmethyltamoxifen, BX, 4OH were measured by validated HPLC with fluorescence detector, and analyzed according to CYP2D6 genotype groups by Wilcoxon rank sum test. CYP2D6*10, CYP2D6*5 and CYP2D6*2×2 were identified by PCR-RFLP methods, and the rests were classified as CYP2D6*1 (wild type). This study was approved by IRB at National Cancer Center Hospital (NCCNHS04–033) and conducted after informed consent obtained by the patients. Results: Thus far, we measured plasma concentration of tamoxifen and its metabolites for 158 pts among 198 pts genotyped. 59 pts (29.8%) carried CYP2D6*1/*1, 84 pts (42.4%) *1/*10 and 49 pts (24.7%) *10/*10. Other types were CYP2D6*1/*5 (8.6%), *5/*5 (1.0%), *1/*2×2 (2.5%). Pts with CYP2D6 *10/*10 (n=40) demonstrated significantly lower steady state plasma concentrations of BX and 4OH than those with other genotypes (n=118) (BX: 7.9 vs.19.2. ng/ml [95 % CI; 5.5–10.4 vs. 15.8–22.7 ng/ml] p&lt;0.0001; 4OH: 1.5 vs. 2.8 ng/ml [95 % CI; 1.1–2.0 vs. 2.3–3.3 ng/ml] p&lt;0.0001), whereas there were no differences with *1/*10 (n=64) vs. without *10 allele (n=54) (BX: 20.6 vs. 18.1 ng/ml; 4OH: 2.9 vs. 2.7 ng/ml). Basically no significant differences in BX/4OH or other compounds by various CYP2D6*2 ×2 and *5 alleles were observed. Conclusions: The steady state plasma concentrations of BX and 4OH were significantly low with CYP2D6 *10/*10 genotype, and their clinical implications need to be explored.(Supported by a grant NCC-0410590). No significant financial relationships to disclose.
Components of metabolic syndrome correlate with longer survival in NSCLC in bexarotene-treated patients with high hypertriglyceridemia in SPIRIT I and II trials: A retrospective analysis
Authors: Z. Dziewanowska, J. Zhang, S. Sun, E. Groves, A. Negro-Vilar
Journal: Journal of Clinical Oncology (2006)

7137 Background: Bexarotene activates RXR receptors regulating cell proliferation, differentiation, apoptosis and many aspects of lipid metabolism. Both SPIRIT I and II trials (ASCO 2005) showed that a large (36%) subgroup of bexarotene-treated patients showing high sensitivity to hypertriglyceridemia had a significantly longer survival in both studies. This subgroup included males, smokers, stage IV and weight loss, factors associated with poorer survival. A recent study in retinoid-treated patients revealed those developing high hypertriglyceridemia, as well as their parents, have a familial predisposition to hyperlipidemia and the metabolic syndrome (Ann Intern Med, 2002, 136:582). We evaluated baseline and in-treatment patient characteristics in relation to triglyceride responses and overall survival after bexarotene treatment to further extend that observation to NSCLC patients. Methods: A pooled analysis of 595 patients treated with bexarotene in SPIRIT I and II trials assessed factors related to metabolic syndrome (BMI, HDL, LDL and Total cholesterol [T-chol], T-chol/HDL ratio, triglycerides, glucose, blood pressure) at baseline and during treatment at the time of high-triglyceridemia. Individual and composite risk factor scores were evaluated by logistic and Cox-regression analysis in two subgroups, e.g., Responders (high trigs, long survival) and Non-responders (low trigs, shorter survival). Results: Among in-treatment risk factors, Responders (N = 215) had significantly higher (p &lt; 0.0001) BMI, trigs, T-chol, T-chol/HDL ratio and lower HDL (p &lt; 0.0001) than Non-responders (N = 380). A composite risk score (the sum of the individual in-treatment dichotomous risk scores) analysis also showed a significantly (p &lt; 0.0001) higher score for metabolic risk factors in the Responder/longer survival subgroup. Hazard ratio analysis by Cox-regression showed a 13% survival benefit for each composite score increase. Conclusions: Baseline and in-treatment triglycerides and other key metabolic syndrome factors are important predictors and contributors to the beneficial survival impact of bexarotene in this important subgroup of NSCLC patients. [Table: see text]
Anthracyclines vs taxanes plus trastuzumab in HER2-positive metastatic breast cancer (MBC): A cross trial comparison of pivotal studies
Authors: M. Marty, S. Chan, J. M. Extra, B. Leyland-Jones
Journal: Journal of Clinical Oncology (2005)

743 Background: Prior to trastuzumab (Herceptin; H) as specific therapy for HER2-positive MBC, anthracyclines (A) had established a major role in this aggressive cancer. Slamon et al. demonstrated that adding H to A+Cyclophosphamide (AC) led to a statistically significant survival benefit, despite increased cardiac toxicity, and the combination was not filed for clinical use. This analysis addresses the question: is there greater benefit for pts eligible for AC who cannot be treated with AC+H in offering AC followed by H + taxane upon progression, compared with H + taxane first-line? Preliminary data from M77001 suggested that H should be used upfront. Methods: Results from the 2 randomised pivotal trials were compared: Slamon et al. [H0648g; AC±H and paclitaxel (P)±H] and Marty et al. [M77001; docetaxel (D)±H]. Results: AC+H and AC alone and P+H results refer to pts with IHC 3+ Results are presented in the table. Slamon et al. found a similar outcome in pts treated with AC alone and in pts receiving P+H. However, these pt groups were distinctly different. P+H pts had received adjuvant A due to an independent treatment decision. In the study by Marty et al. a group of pts could be identified who had not received adjuvant A (also independent treatment decision) and who received D+H first-line for MBC. Subgroup analysis of the Marty trial demonstrated the benefit of adding H irrespective of prior A. This benefit was slightly higher in patients without prior A. Conclusions: These data should be interpreted with caution as this is a cross trial comparison of 2 studies conducted several years apart with 2 different taxanes. Nevertheless, the data suggest that pts with HER2-positive MBC should be treated with H + taxane upfront rather then treating with an A first-line, leaving H-containing regimens for subsequent treatments. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Hoffmann-La Roche Ltd., Genentech, Genta, Xoma Bristol-Myers Squibb, Hoffmann-La Roche Ltd., Genentech
The Authors' reply
Authors: M. Stepanova, Z. M. Younossi
Journal: Gut (2011)

We appreciate Dr Targher and colleagues' comments1 about our study.2 The authors raise two important questions: how exactly the cohort of individuals with chronic liver disease (CLD) was selected and why cardiovascular mortality (CVM) was not independently associated with CLDs.

We would like to provide additional clarification. First, regarding the inclusion criteria for alcoholic liver disease (ALD), we included data from both self-reported excessive alcohol consumption and abnormal liver enzymes. Individuals with excessive alcohol consumption accompanied by normal liver enzymes were not excluded from the entire study. Nevertheless, they were not considered as having ALD or CLD and were not included in the ‘healthy control’ group. Given the relatively low threshold selected for the definition of excessive alcohol consumption, we believe that without at least some evidence of liver damage (elevated aminotransferases), we could not model ALD reliably into our study design. Second, the overlaps between the subgroups of CLDs were also not excluded from the …
Tackling the public health needs of refugees
Authors: Ines Campos-Matos, Dominik Zenner, Gemma Smith, Paul Cosford, Hilary Kirkbride
Journal: BMJ (2016)

In their editorial, Arnold and colleagues outline their view on what is needed to respond to the health needs of refugees resettling in the UK.1 They highlight the potentially complex health needs of this group and argue that clinicians in the UK need to be appropriately prepared.

We fully agree and describe below the work that Public Health England (PHE) is engaged …