Therapy Responders Research Articles

Virologic Response to Therapy Increases Health-Related Quality of Life for Patients With Chronic Hepatitis B

We evaluated changes in health-related quality of life (HRQoL) in a longitudinal study of patients given antiviral therapy for chronic hepatitis B (CHB). We analyzed changes in HRQoL reported by 2856 Korean patients with CHB who started first-line or rescue antiviral therapy from January 2007 to June 2007; the mean age of the study subjects was 43.3 years, 72% were male, 80% were positive for hepatitis B e antigen, 20% had cirrhosis, and 13% had concomitant disease. These subjects all completed the translated version of the Chronic Liver Disease Questionnaire (CLDQ) and the EuroQol-5 Dimension (EQ5D) when the study began (baseline), and at the end of a 24-week follow-up period. We analyzed changes in utility scores from baseline to 24 weeks of antiviral treatment. After 24 weeks of antiviral therapy, patients had significant improvements in liver function and reduced mean levels of hepatitis B virus DNA (from 6.3 to 3.9 log(10) copies/mL). Utility scores from the visual analogue scale and EQ5D improved after 24 weeks of antiviral therapy (from 0.84 ± 0.19 to 0.94 ± 0.14; P < .0001). Improved CLDQ scores were associated with virologic response (level of hepatitis B virus DNA, <4 log(10) copies/mL); scores increased from 5.21 ± 0.99 at baseline to 6.09 ± 0.72 after 24 weeks of antiviral therapy in responders, but from 5.31 ± 0.94 at baseline to 6.06 ± 0.66 in nonresponders (P = .003). Patients with CHB who have a virologic response to 24 weeks of antiviral therapy also have significant improvements in HRQoL, measured by EQ5D and CLDQ.

Continued azacitidine therapy beyond time of first response improves quality of response in patients with higher‐risk myelodysplastic syndromes

In the AZA-001 trial, azacitidine (75 mg/m(2) /d subcutaneously for Days 1-7 of every 28-day cycle) demonstrated improved survival compared with conventional care regimens in patients with International Prognostic Scoring System-defined intermediate-2- or high-risk myelodysplastic syndrome and World Health Organization-defined acute myeloid leukemia with 20% to 30% bone marrow blasts. This secondary analysis of the AZA-001 phase 3 study evaluated the time to first response and the potential benefit of continued azacitidine treatment beyond first response in responders. Overall, 91 of 179 patients achieved a response to azacitidine; responding patients received a median of 14 treatment cycles (range, 2-30). Median time to first response was 2 cycles (range, 1-16). Although 91% of first responses occurred by 6 cycles, continued azacitidine improved response category in 48% of patients. Best response was achieved by 92% of responders by 12 cycles. Median time from first response to best response was 3.5 cycles (95% confidence interval [CI], 3.0-6.0) in 30 patients who ultimately achieved a complete response, and 3.0 cycles (95% CI, 1.0-3.0) in 21 patients who achieved a partial response. Continued azacitidine therapy in responders was associated with a quantitative increase in response to a higher response category in 48% of patients, and therefore may enhance clinical benefit in patients with higher-risk MDS.

Increasing levels of circulating Th17 cells and interleukin-17 in rheumatoid arthritis patients with an inadequate response to anti-TNF-α therapy.

IntroductionThe objective of this study was to investigate the effects of tumor necrosis factor (TNF)-α inhibitors on circulating T helper-type 17 (Th17) cells and Th17-related cytokines in patients with rheumatoid arthritis (RA).MethodsThe frequencies of circulating Th17 cells and serum levels of Th17-related cytokines were determined using flow cytometry analysis and ELISA, respectively, in 48 RA patients both before (baseline) and six months after anti-TNF-α therapy. Therapeutic response was evaluated using European League Against Rheumatism (EULAR) response criteria.ResultsSignificantly higher baseline frequencies of circulating Th17 cells and serum levels of interleukin (IL)-6, IL-17, IL-21, IL-23 and TNF-α were observed in active RA patients than in 12 healthy controls (all P < 0.001). After anti-TNF-α therapy, 36 patients (75%) were EULAR responders (20 good responders and 16 moderate responders) and 12 (25.0%) were non-responders. The mean levels of circulating Th17 cells and IL-17 significantly decreased (1.13% vs. 0.79%; 43.1 pg/ml vs. 27.8 pg/ml; respectively, both P < 0.001) in parallel with clinical remission in responders. Levels of IL-6, IL-21, IL-23 and TNF-α were significantly decreased after anti-TNF-α therapy in responders. In contrast, the mean levels of circulating Th17 cells and IL-17 significantly increased after anti-TNF-α therapy (2.94% vs. 4.23%; 92.1 pg/ml vs. 148.6 pg/ml; respectively, both P < 0.05) in non-responders. Logistic regression analysis identified a high baseline level of IL-17 as a significant predictor of poor therapeutic response.ConclusionsThe beneficial effect of anti-TNF-α therapy might involve a decrease in Th17-related cytokines in responders, whereas rising levels of circulating Th17-cells and IL-17 were observed in patients with an inadequate response to anti-TNF-α therapy.

Multiparametric Magnetic Resonance Imaging, Spectroscopy and Multinuclear ( 23Na) Imaging Monitoring of Preoperative Chemotherapy for Locally Advanced Breast Cancer

The aim of this prospective study was to investigate using multiparametric and multinuclear magnetic resonance imaging during preoperative systemic therapy for locally advanced breast cancer. Women with operable stage 2 or 3 breast cancer who received preoperative systemic therapy were studied using dynamic contrast-enhanced magnetic resonance imaging, magnetic resonance spectroscopy, and ²³Na magnetic resonance. Quantitative metrics of choline peak signal-to-noise ratio, total tissue sodium concentration, tumor volumes, and Response Evaluation Criteria in Solid Tumors were determined and compared to final pathologic results using receiver-operating characteristic analysis. Hormonal markers were investigated. Statistical significance was set at P < .05. Eighteen eligible women were studied. Fifteen responded to therapy, four (22%) with pathologic complete response and 11 (61%) with pathologic partial response. Three patients (17%) had no response. Among estrogen receptor-positive, HER2-positive, and triple-negative phenotypes, observed frequencies of pathologic complete response, pathologic partial response, and no response were 2, 5, and 0; 1, 4, and 0; and 1, 1, and 3, respectively. Responders (pathologic complete response and pathologic partial response) had the largest reductions in choline signal-to-noise ratio (35%, from 7.2 ± 2.3 to 4.6 ± 2; P < .01) compared to nonresponders (11%, from 8.4 ± 2.7 to 7.5 ± 3.6; P = .13) after the first cycle. Total tissue sodium concentration significantly decreased in responders (27%, from 66 ± 18 to 48.4 ± 8 mmol/L; P = .01), while there was little change in nonresponders (51.7 ± 7.6 to 56.5 ± 1.6 mmol/L; P = .50). Lesion volume decreased in responders (40%, from 78 ± 78 to 46 ± 51 mm³; P = .01) and nonresponders (21%, from 100 ± 104 to 79.2 ± 87 mm³; P = .23) after the first cycle. The largest reduction in Response Evaluation Criteria in Solid Tumors occurred after the first treatment in responders (18%, from 24.5 ± 20 to 20.2 ± 18 mm; P = .01), with a slight decrease in tumor diameter noted in nonresponders (17%, from 23 ± 19 to 19.2 ± 19.1 mm; P = .80). Multiparametric and multinuclear imaging parameters were significantly reduced after the first cycle of preoperative systemic therapy in responders, specifically, choline signal-to-noise ratio and sodium. These new surrogate radiologic biomarkers maybe able to predict and provide a platform for potential adaptive therapy in patients.

673 DOCETAXEL - RECHALLENGE AT PSA RELAPSE AFTER DOCETAXEL CHEMOTHERAPY AT HORMONE REFRACTORY PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Advanced II1 Apr 2010673 DOCETAXEL - RECHALLENGE AT PSA RELAPSE AFTER DOCETAXEL CHEMOTHERAPY AT HORMONE REFRACTORY PROSTATE CANCER Peter Firek, David Pfister, David Thüer, Bernhard Brehmer, Robin Epplen, and Axel Heidenreich Peter FirekPeter Firek More articles by this author , David PfisterDavid Pfister More articles by this author , David ThüerDavid Thüer More articles by this author , Bernhard BrehmerBernhard Brehmer More articles by this author , Robin EpplenRobin Epplen More articles by this author , and Axel HeidenreichAxel Heidenreich More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1060AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Chemotherapy with docetaxel represents the guideline conformed standard therapy for castration resistant prostate cancer (CRPC). Currently, there exists no standard protocol for PSA relapse after first line therapy with docetaxel. Aim our analysis was to evaluate the oncological outcome of docetaxel second line therapy in responders of first line therapy. METHODS 35 patients with CRPC and PSA progression after first line therapy with docetaxel have been reexposed to docetaxel based chemotherapy. All patients have been responders of the first line therapy and showed PSA progression > 50% with a median progression free interval of 7,5 (3-15) months. 25 patients received a weekly docetaxel therapy with 35 mg/m2 for three weeks followed by a one week drug holiday. This 4-week cycle was repeated three times. PSA response rate, median progression-free survival (PFS) and overall survival (OS) were analysed. RESULTS Mean age of patients was 65.3 (42-75) years. 23 of 35 (65%) showed a PSA decrease of > 50%. After a mean follow up of 24 (3-37) months the mean OS was 15,3 (3-32) months and the mean PFS was 6,2 (1-15) months. Treatment related toxicity after 2nd line therapy was not different from primary docetaxel therapy with leukopenia, alopecia, conjunctivitis and fatigue WHO grade 3/4 < 10%. None of the patients had to stop therapy prematurely. CONCLUSIONS Docetaxel - rechallenge therapy for progressive CRPC after initial docetaxel therapy is a therapeutic alternative for first line responders patients and might represent a new standard approach until more effective second line regimes have been developed. Aachen, Germany© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e263 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Peter Firek More articles by this author David Pfister More articles by this author David Thüer More articles by this author Bernhard Brehmer More articles by this author Robin Epplen More articles by this author Axel Heidenreich More articles by this author Expand All Advertisement Advertisement PDF DownloadLoading ...

Phase II Trial of Low Dose, Subcutaneous Decitabine in Myelofibrosis

DNA hypermethylation of promoter-specific CpG islands has been implicated in the pathogenesis and progression of myelofibrosis (MF). We have evaluated Decitabine, a DNA methyltransferase inhibitor in patients (pts) with MF, including primary MF (PMF), and MF arising after polycythemia vera or essential thrombocythemia (post-PV or post-ET MF). This was a multicenter, single stage Phase II trial, with a planned accrual of 20 patients. The regimen would be deemed worthy of further investigation if ≥ 5 pts responded. Eligibility criteria included myelofibrosis associated with anemia (hemoglobin <11g/dL) and/or palpable splenomegaly. Decitabine was administered subcutaneously (SQ) at a dose of 0.3mg/kg/d on days 1–5 and days 8–12; cycles were repeated every 6 weeks, in the absence of dose limiting toxicities. Response was determined every 12 weeks as an improvement in cytopenias and/or splenomegaly. A maximum of 9 cycles was allowed; pts who had a complete remission (CR) had treatment discontinued provided they had received at least 4 cycles of therapy. Peripheral blood obtained at baseline and on days 5 and day 12 of the first 2 cycles of therapy was analyzed for potential biomarkers predictive of response to decitabine. Biomarkers evaluated included CD34+ cells measured by flow cytometry, as elevated CD34+ counts have been associated with advanced stage and evolution to blast phase in MF. CXCR4 gene expression levels were measured by REAL-time RT-PCR; reduced expression of CXCR4 on CD34+ cells has been linked to the abnormal stem cell trafficking in this disease, and decitabine has been shown to upregulate CXCR4 levels in primary MF cells in vitro. Hemoglobin F levels were evaluated by HPLC as induction of hemoglobin F levels has been demonstrated with decitabine therapy in primates and in patients with sickle hemoglobinopathy. Twenty-one pts were enrolled on the study. Pt characteristics: M/F:12/9, median age 67 years (range 42–89), median absolute CD34+ cell count 350 × 106/L (1.2–4959), Dupriez score of 2, 1 and 0 in 24%, 57% and 19% respectively, PMF= 76%, post PV-MF=19%; post ET MF=5%; 4 pts had blast phase disease (blast phase- MF) and 12 pts (57%) had transfusion dependent anemia and/or thrombocytopenia. Eight pts (38%) were previously untreated and 38% had abnormal bone marrow karyotype at baseline. Median number of cycles administered was 4 (range 1–9) and four pts remain on treatment. Grade 3/4 neutropenia (ANC) and grade3/4 thrombocytopenia occurred in 95% and 52% of pts respectively. Nine pts have developed febrile neutropenia. Two pts have died of sepsis-related complications while on study, both pts had significant impairment of hematopoiesis at baseline: 1 had blast phase-MF, the other had advanced PMF with a baseline ANC of 50/μL. Drug related non-hematologic toxicities have been infrequent and include gradeI/II fatigue and liver function abnormalities. 19 pts are evaluable for response: A total of 7 pts (37%) have responded, including 2 with blast phase-MF. CR=1 (normalization of counts and transfusion-independence), PR=2 (hemoglobin increase to normal levels, multilineage improvement including ANC and/or platelets). Hematologic improvement in erythroid lineage n=2: (both of these patients achieved red cell transfusion- independence) and platelets n=2: (>50% increase in platelet levels) have also been observed. Median time to response was 2 cycles (range 1–6); median duration of response was 5 months (range 2–15). Two pts are maintaining their responses at 2 and 14 months. All responders who developed disease progression did so while off therapy. Analysis of the effects of decitabine on CD34+ cells revealed a 61% reduction (p<0.001) in mean levels between cycles 1 and 2 of therapy in responders (n=7), in contrast to non-responders (n=12), in whom there was no change (p=0.45). There was no statistically significant change in CXCR4 or hemoglobin F levels over time, but responders to decitabine had higher levels of hemoglobin F (>1%) than non-responders at baseline and post-therapy (p<0.01)Conclusions: Low dose SQ decitabine is feasible, has clinical activity and deserves further investigation in myelofibrosis. Myelosuppression is common and requires close monitoring. A decline in circulating CD34+ progenitor cells that persists into cycle 2 of therapy may serve as a novel biomarker that predicts response to decitabine in myelofibrosis.

Rituximab Therapy after Response to R-CHOP Induction Therapy for Patients with Previously Untreated Indolent Non-Hodgkin's Lymphoma (NHL): Clinical Outcomes and Pharmacokinetics (PK)

The addition of rituximab (R) therapy significantly improves PFS in patients with relapsedl/refractory disease responding after CHOP as well as responders after R-CHOP induction (van Oers, 2005). The aim of this study was to assess, in patients with previously untreated indolent NHL, the safety, efficacy and PK of additional R therapy in responders to R-CHOP induction. Between 10/01 and 08/06, 102 patients aged 28–84 (mean 57 yr) yrs with Ann Arbor Stage III (28.4%) or IV (71.6%) indolent NHL were treated on this Phase II single-arm, open-label, multi-center, community-based trial. Baseline LDH and β2 microglobulin were above normal in 20.6% and 66.3% of patients, respectively. Treatment consisted of 6 cycles of R-CHOP (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, and doxorubicin 50 mg/m2 all IV on Day 1 of each 21-day cycle; prednisone 100 mg/d po Days 1–5; and R 375 mg/m2 IV 2–3 days prior to first dose of CHOP and thereafter on Day 1 of each cycle). Patients with ongoing response (CR/CRu or PR) received R 375 mg/m2 weekly x 4, repeated every 6 months x 2 yrs, for a total of up to 16 R doses, within 28 days after completion of R-CHOP. Median follow-up was 39 mos. ORR after R-CHOP was 86.3% (95% CI: 78.3, 92.1), with CR/CRu 48% (95% CI: 38.0, 58.2). As measured from initiation of R-CHOP, PFS at 2 and 3 yrs was 75.2% (95% CI: 64.0, 83.3) and 67.3% (95% CI: 54.6, 77.2), respectively. OS at 2 and 3 yrs was 92.9% (95% CI: 85.7, 96.6) and 89.4% (95% CI: 81.2, 94.2), respectively. Infusion-related toxicity with R given after R-CHOP was less frequent than seen with R-CHOP in this study. The overall incidence of serious adverse events during R therapy given after R-CHOP was 8.5%, including 3 NCI-CTC grade 3/4 events: viral encephalitis (n=1), patellar fracture (n=1) & development of colon cancer (n=1). Serum R concentrations were collected over serial timepoints from 12 patients. Both pre- and end of infusion serum R concentrations were similar across cycles 2–4 of R therapy given after R-CHOP. R concentration was higher just prior to infusion of the first R dose given after R-CHOP due to residual concentration from the R-CHOP treatment. Concentrations were very low (< 10 ug/mL) just prior to initiation of the subsequent R cycles. During R therapy given after R-CHOP, serum R concentrations were similar to those previously reported during R monotherapy treatment (Berinstein, 1998). In summary, this study demonstrated that R therapy given after R-CHOP to be generally well-tolerated, and associated with 75.2% PFS and 92.9% OS at 2 yrs, and 67.3% PFS and 89.4% OS at 3 yrs. Moreover, the current study demonstrates that PK data from R induction can be extrapolated to R given after R-CHOP. The benefit of adding additional R therapy to responders to R-chemotherapy will be addressed in the analysis of the ongoing Phase III PRIMA study, wherein patients with advanced follicular lymphoma who respond to R-chemotherapy induction are randomized to receive further R therapy vs. observation.

Chemoradiotherapy for T3 and T4 squamous cell carcinoma of the esophagus using low-dose FP and radiation: A preliminary report

We conducted this study to evaluate the clinical significance of preoperative concurrent chemoradiotherapy (CRT) followed by esophagectomy in the management of T3 and T4 esophageal cancer. Thirty patients with squamous cell carcinoma of the esophagus received CRT followed by surgery. Preoperative CRT consisted of 5-fluorouracil (500 mg/m(2) by 24 h infusion for 5 days), cisplatin (15 mg/m(2) on days 1-5), and concurrent radiotherapy (a total dose of 40 Gy delivered in daily fractions of 2 Gy, 5 times per week). Esophagectomy was planned for 4-6 weeks after treatment and restaging. All 30 patients completed preoperative CRT. A clinical response (PR+CR) of the primary tumor was obtained in 82.8%, and a response of metastatic nodes was seen in 23.1%. Radical resection was possible in 17 of 29 operated patients (58.6%). The postoperative mortality rate was 6.9%, and the hospital mortality rate was 10.3%. Ten out of 29 operated patients (34.5%) had no residual cancer in the resected esophagus, corresponding to pathological CR. The 1-year survival rate was 80.6%, the 2-year survival rate was 62.7%, and the 3-year survival rate was 53.8%. The clinical response group and the R0 or R1 group showed better survival than other patients. Preoperative CRT should be given to patients with squamous cell carcinoma, while esophagectomy remains the standard therapy for responders and has a tolerable mortality.

SALVAGE RADIATION THERAPY FOR PROSTATE SPECIFIC ANTIGEN PROGRESSION FOLLOWING RADICAL PROSTATECTOMY: 10-YEAR OUTCOME ESTIMATES

We evaluated men treated with salvage radiation therapy for increasing serum prostate specific antigen (PSA) following radical retropubic prostatectomy (RRP). We retrospectively reviewed the records of 3,478 consecutive men who underwent radical retropubic prostatectomy (RRP) between 1983 and 2003, as performed by a single surgeon. A total of 307 men received salvage radiation therapy for persistently increased or increasing PSA after RRP. We compared perioperative and peri-radiotherapy clinicopathological parameters in men who achieved an undetectable PSA level after radiation therapy (responders) vs those who did not (nonresponders). We then evaluated the durability of the PSA response. Median time from RRP to PSA progression was 23 months (range 1 to 129). Median followup from RRP was 104 months (range 7 to 225). Median followup from salvage radiotherapy was 56 months (range 0 to 188). Of 223 men with sufficient followup information 162 (73%) subsequently had undetectable PSA (less than 0.3 ng/ml) in response to salvage radiation therapy. There was no significant difference between responders and nonresponders in the distribution of clinical and pathological tumor stages, age at RRP, surgical margin status, and the interval between RRP and salvage radiation therapy. A Gleason score of 8 to 10 was more prevalent in nonresponders than responders (28% vs 13%). Median PSA at salvage radiation therapy was 1.2 ng/ml in nonresponders vs 0.7 ng/ml in responders. Actuarial 5 and 10-year progression-free (PSA less than 0.3 ng/ml) survival probabilities in all 223 men following salvage radiation therapy were 40% (95% CI 32 to 48) and 25% (95% CI 15 to 36), respectively. Actuarial 5 and 10-year biochemical progression-free survival estimates following salvage radiation therapy in responders only were 55% (95% CI 45 to 64) and 35% (95% CI 21 to 49), respectively. Only seminal vesicle invasion was significantly associated with progression-free survival following radiation therapy on multivariate analysis. An undetectable PSA level following salvage radiation therapy is more frequently achieved in men with lower pre-radiation serum PSA and those without seminal vesicle or lymph node involvement. Overall approximately a fourth of men with PSA evidence of cancer progression following RRP had a durable response 10 years after the initiation of salvage radiation therapy in the protocols used in this patient cohort.

Changes in serum lipid concentrations in patients with chronic hepatitis C virus positive hepatitis responsive or non‐responsive to interferon therapy

Changes in serum lipid concentrations during the administration of interferon to patients with chronic hepatitis C virus (HCV) infection have not been fully investigated. The present study was designed to compare changes in serum lipid concentrations before, during and after interferon therapy in responders and non-responders to treatment. In total, 101 patients with chronic HCV positive hepatitis were enrolled in this study. High dose interferon alpha was given on alternate days for 6 months. Six months after the end of treatment patients were assessed for the presence or absence of HCV RNA to determine the results of interferon treatment. The time courses of changes in serum lipid concentrations were measured in all patients. The total cholesterol level increased gradually during and after interferon therapy, and its pattern of change coincided with that of serum cholinesterase activity. Pretreatment serum cholesterol concentrations did not differ between responders and non-responders to interferon therapy. The serum triglyceride concentration, conversely, showed a sharp increase during interferon administration and returned to its basal level after the end of treatment. Responders to interferon therapy tended to have higher pretreatment triglyceride concentrations than did non-responders. We clarified that serum cholesterol and triglyceride levels showed different patterns of change during interferon therapy.

Increased urine phenylethylamine after methylphenidate treatment in children with ADHD.

The urine levels of beta-phenylethylamine, 3-methoxy-4-hydroxyphenyl glycol, homovanillic acid, and 5-hydroxyindoleacetic acid were measured to clarify the neurochemical mechanism in attention deficit hyperactivity disorder. beta-Phenylethylamine levels were significantly lower in attention deficit hyperactivity disorder individuals (n = 37) than in controls (n = 21). The 22 children with attention deficit hyperactivity disorder were treated with methylphenidate, and they were further divided into methylphenidate responders (n = 18) and nonresponders (n = 4). beta-Phenylethylamine levels significantly increased after methylphenidate therapy in responders, whereas they did not increase in nonresponders.

Etanercept in the treatment of active refractory Crohn’s disease: a single-center pilot trial

OBJECTIVES: Etanercept, an injectable tumor necrosis factor (TNF) receptor fusion protein, binds and inactivates human TNF and is used in active rheumatoid arthritis. Blocking TNF with monoclonal antibodies has also been beneficial in Crohn’s disease. We attempted to determine the efficacy and safety of etanercept for induction of clinical, endoscopic, and histological improvement in patients with moderate to severe Crohn’s disease despite standard treatment. METHODS: Ten patients with active Crohn’s disease were treated with etanercept (25 mg s.c.) twice per week for 12 wk. Background therapy was kept stable during the trial. Crohn’s disease activity index (CDAI), Inflammatory Bowel Disease Questionnaire, and C-reactive protein levels were measured at weeks 0, 2, 4, 8, and 12. Colonoscopies were performed before and after therapy in responders; endoscopic biopsies were scored for inflammation. RESULTS: At week 2 after the start, a clinical response (ΔCDAI ≥ 70) was observed in 6/10 patients (median = 305 [294–418] to 166 [107–392]), with reduction in serum C-reactive protein levels (median = 17.2 [6.8–67.2] to 9.1 [0.9–17.2] mg/dl). Colonoscopies showed a reduction in inflammatory lesions in the four patients who attained remission (CDAI < 150), whereas the inflammatory score of the biopsies did not decrease significantly. No moderate or severe adverse events were observed. CONCLUSIONS: Etanercept may be effective in Crohn’s disease refractory to standard therapy.

Inhaled nitric oxide: Current and future uses in neonates

Inhaled nitric oxide (iNO), a selective pulmonary vasodilator, is available for treatment of persistent pulmonary hypertension of the newborn in term and near-term neonates. iNO decreases pulmonary vascular resistance leading to diminished extrapulmonary shunt and also has a microselective effect which improves ventilation/perfusion matching. Clinical trials indicate the need for extracorporeal membrane oxygenation (ECMO) is diminished by iNO. Information suggests a 20 ppm starting dose; doses greater than 40 ppm offer no advantage. The typical duration of therapy in responders is less than one week. Several approaches to weaning have been successful. Abrupt discontinuation should be avoided. Ventilatory management remains important when parenchymal lung disease accompanies pulmonary hypertension of the newborn; HFOV used to optimize lung inflation facilitates the action of iNO. Non-ECMO centers should be able to provide iNO during transport to an ECMO center. Data suggest a possible role for iNO in preterms with hypoxemic respiratory failure and studies in this group should proceed.

Resting energy expenditure in chronic hepatitis C

Background/Aims: Hypermetabolism is considered to be of clinical interest in liver disease and in several chronic viral infections. Whether resting energy expenditure (REE) increases during chronic hepatitis C is not known. Our aims were: (a) to determine the metabolic state of patients with chronic hepatitis C, and (b) to evaluate the effects of interferon therapy on REE. Methods: Forty-seven patients and 20 controls were studied. Sixteen patients failed to respond to interferon and 12 patients stopped the treatment during the first 2 months for various reasons. The 19 responders all received 1 year of interferon. REE (indirect calorimetry) and fat-free mass (FFM, bioelectric impedance analysis) were evaluated before (day 0) and after 90, 180, and 360 days of interferon. The visus load was evaluated in patients before treatment. Results: On day 0, REE expressed as a ratio of FFM (REE/FFM) was higher in patients than in controls (129.2±14.7 vs 117.9±9.6 kJ kgFFM −1 24 h −1, p<0.01), and was positively correlated with the viral load ( r=0.45, p=0.01). On day 90, REE/FFM had significantly decreased in responders but it did not decrease in non-responders ( p<0.01). In responders, REE/FFM on days 180 and 360 was similar to that of the controls. Conclusions: Chronic hepatitis C induces hypermetabolism that is normalized by interferon therapy in responders. The underlying mechanisms of chronic hepatitis C-induced hypermetabolism and its clinical relevance remain to be determined.

Prospective randomized study to compare imipenem 1.5 grams per day vs. 3.0. grams per day in infections of granulocytopenic patients

The objective of this presented prospective randomized study was to compare the efficacy of empirical antimicrobial monotherapy with imipenem 3 x 0.5 g per day to 3 x 1.0 g per day for treatment of infections in neutropenic patients. A total of 192/220 febrile episodes were evaluable for clinical efficacy. The overall response rate was 53/93 (57%) vs. 57/99 (58%). Of the different infection types, fever of unknown origin (FUO) showed the best response, with defervescence in 29/41 (71%) and 36/42 (86%) cases, respectively (not significant). Unfavourable results were found in pneumonias [5/20 (25%) vs. 4/23 (17%)]. The median time until persistent defervescence was equal in both groups (2 days), likewise the median duration of imipenem therapy in responders (7 days). The most frequent micro-organisms were Gram-negative, documented in 22% of the febrile episodes in the lower dosage group vs. 17% of all episodes in the patients with imipenem 3.0 g per day (Gram-positives 17% vs. 14%, fungal 5% vs. 8%). In the lower dosage group, fever with abdominal symptoms occurred less frequently (8% vs. 15%), and significantly more patients tolerated imipenem without any side-effects (95.8% vs. 79.4%), especially regarding severe nausea/vomiting (2.1% vs. 11.8%). Of the initial non-responders, 35/40 (88%) vs. 41/42 (98%) were cured after therapy modification. There was no significant difference in the use of further antibiotics such as aminoglycosides, glycopeptides, ceftazidime or amphotericin B, except a marginally higher use of metronidazole in patients with imipenem 3.0 g per day (3% vs. 10%). Overall, we found no significant differences in efficacy between the two study groups, but more frequent side-effects with imipenem 3.0 g per day.

Immunoglobulin M antibody to hepatitis C virus core antigen: Correlations with viral replication, histological activity, and liver disease outcome

Immunoglobulin M (IgM) antibody to hepatitis C core antigen (anti-HCV-core) was tested by enzyme immunoassay against a synthetic peptide representing amino acids 1 to 62 of the core protein. Of 214 patients with different categories of histological activity, 193 (90%) showed positive results for IgM anti-HCV-core, and 207 (97%) had HCV RNA; most cases (186, 87%) had both markers detectable simultaneously. No differences in the frequency of IgM anti-HCV-core were observed with respect to epidemiological, biochemical, or histological parameters. In 175 interferon alfa (IFN-α) recipients, and in 39 untreated controls, pretreatment IgM antiHCV-core frequencies were similar: 28 of 32 (88%) in sustained responders; 55 of 61 (90%) in responders with relapse; 72 of 82 (88%) in nonresponders; and 38 of 39 (97%) in untreated controls. After IFN-α therapy, IgM antiHCV-core levels became undetectable with significantly greater frequency in sustained responders ( P = .014); a similar trend was observed for HCV RNA ( P < .0001). IgM anti-HCV-core levels decreased after therapy in responders ( P < .001) but increased in nonresponders. Fifty-one cases were longitudinally tested in relation to long-term disease outcome. Both markers remained detectable in most nonresponders with persistent liver disease, in most responders before relapse, and in all but one case at the time of biochemical relapse. IgM antiHCV-core and HCV RNA became undetectable in most sustained responders, but reappeared despite a longlasting transaminase normalization, behaving as asymptomatic HCV carriers; the possibility that disease reactivation may take place years afterwards cannot be excluded. These data indicate that IgM anti-HCV-core may be useful in the assessment of HCV replication and in monitoring biochemical and virological responses to IFN-α treatment.

Immunoglobulin M antibody to hepatitis C virus core antigen: Correlations with viral replication, histological activity, and liver disease outcome

Immunoglobulin M (IgM) antibody to hepatitis C core antigen (anti-HCV-core) was tested by enzyme immunoassay against a synthetic peptide representing amino acids 1 to 62 of the core protein. Of 214 patients with different categories of histological activity, 193 (90%) showed positive results for IgM anti-HCV-core, and 207 (97%) had HCV RNA; most cases (186, 87%) had both markers detectable simultaneously. No differences in the frequency of IgM anti-HCV-core were observed with respect to epidemiological, biochemical, or histological parameters. In 175 interferon alfa (IFN-alpha) recipients, and in 39 untreated controls, pretreatment IgM anti-HCV-core frequencies were similar: 28 of 32 (88%) in sustained responders; 55 of 61 (90%) in responders with relapse; 72 of 82 (88%) in nonresponders; and 38 of 39 (97%) in untreated controls. After IFN-alpha therapy, IgM anti-HCV-core levels became undetectable with significantly greater frequency in sustained responders (P = .014); a similar trend was observed for HCV RNA (P < .0001). IgM anti-HCV-core levels decreased after therapy in responders (P < .001) but increased in nonresponders. Fifty-one cases were longitudinally tested in relation to long-term disease outcome. Both markers remained detectable in most nonresponders with persistent liver disease, in most responders before relapse, and in all but one case at the time of biochemical relapse. IgM anti-HCV-core and HCV RNA became undetectable in most sustained responders, but reappeared despite a long-lasting transaminase normalization, behaving as asymptomatic HCV carriers; the possibility that disease reactivation may take place years afterwards cannot be excluded.(ABSTRACT TRUNCATED AT 250 WORDS)

801–3 Differential Effect of d-Sotalol on QT Dispersion in Acute Drug Responders Versus Non-Responders

QT interval dispersion measured as interlead variability of QT, is a marker of dispersion of ventricular repolarization and, hence, of cardiac electrical instability. The influence of the new class III agent d-sotalol on QT dispersion (QT disp) was investigated in 20 patients (pts) with recurrent sustained ventricular tachycardia (VT) and/or ventricular fibrillation (VF). All pts had inducibile VT/VF at baseline and were electrophysiologically studied under oral d-sotalol (460 ± 94 mg/day). In 10 pts d-sQTalol suppressed the induction of VT/VF, whereas 10 pts did not respond. QTand RR intervals of 3 consecutive beats were measured in 6 simultaneously recorded precordial leads (VI-V6) by two independent blinded investigators. Under oral d-sotalol, the QT disp was reduced in 9/10 responders but only in 4/10 non-responders, despite comparable doses of the drug in both groups. The relative changes between control and under d-sotalol therapy in responders and non-responders of corrected maximal QT (QTc max.), QT disp., dispersion of the QTc (QTc disp.) and adjusted QTc (adj. QTc disp) are presented as means ± SD. responder non-responder p Δ QTc max. 32.9 ± 69.2 27.5 ± 41.4 NS Δ QT disp. - 30.3 ± 16.8 20.3 ± 38.2 0.001 Δ QTc disp. - 34 ± 31 18.5 ± 37.8 0.003 Δ adj. QTc disp - 13.3 ± 12.9 7.5 ± 15.6 0.004 Dosage 480 ± 103 440 ± 84 NS The new class III agent d-sotalol produced a significant reduction of QTc dispersion in responders in contrasts to non-responders. QT dispersion may be potentially useful in the assessment of the efficacy of class III antiarrhythmic drugs. This effect may be due to homogenization of repolarization in both normal and diseased myocardium representing the arrhythmogenic substrate.

Albendazole therapy for persistent, solitary cysticercus granulomas in patients with seizures

We treated 11 patients with a persistent (> 3 months), solitary small cysticercus granuloma and seizures with albendazole in a daily dose of 15 mg/kg body weight for 14 days. At repeat CT examinations performed at intervals of 2.5 to 6 weeks after initiation of therapy, the lesions had resolved in two patients and become significantly smaller (less than 50% of their pretreatment size) in two. Albendazole therapy in responders hastened the resolution of the lesions and confirmed the diagnosis.