Extended Treatment Group Research Articles

Extended peptide receptor radionuclide therapy: evaluating nephrotoxicity and therapeutic effectiveness in neuroendocrine tumor patients receiving more than four treatment cycles.

Currently, the most used peptide receptor radionuclide therapy (PRRT) regimen for neuroendocrine tumors comprises 4 treatment cycles, and there is not enough large-scale data to support the safety of more individualized extended PRRT. This study aims to evaluate the therapeutic effectiveness and potential nephrotoxicity related to PRRT using more than four treatment cycles. In this retrospective analysis, we included patients who had received at least four PRRT cycles and had available follow-up data. We analyzed renal function indicators before and after multiple treatments, comparing nephrotoxicity in patients receiving four cycles ("standard") with those receiving more than four ("extended treatment"). Nephrotoxicity was assessed via creatinine levels and CTCAE creatinine grades. Treatment effectiveness was gauged using Kaplan-Meier survival analysis, focusing on overall survival and disease-specific survival (DSS). Statistical analyses were performed using SPSS version 26 (IBM), R 4.2.3, and GraphPad Prism 9.0.0. Statistical significance was defined as a P-value of less than 0.05. Our study cohort consisted of 281 patients in the standard group and 356 in the extended treatment group. No significant differences in baseline characteristics or renal function were noted between the two groups pre-treatment. Mean post-treatment creatinine levels did not significantly differ between the standard (89.30 ± 51.19μmol/L) and extended treatment groups (93.20 ± 55.98μmol/L; P = 0.364). Similarly, there was no statistical significance between the CTCAE creatinine grades of the two groups (P = 0.448). Adverse renal events were observed in 0.4% of patients in the standard group and 1.1% in the extended treatment group. After a median follow-up time of 88.3months, we found that median overall survival was significantly higher in the extended treatment group (72.8months) compared to the standard treatment group (52.8months). A Cox regression analysis further supported these findings, indicating a better prognosis for the extended treatment group in terms of overall survival (HR: 0.580, P < 0.001) and DSS (HR: 0.599, P < 0.001). Our findings suggest that extending PRRT treatment beyond the standard four cycles may be a safe and effective therapeutic strategy for NET patients. This approach could be particularly beneficial for patients experiencing disease recurrence or progression following standard treatment.

Trajectories of adherence to extended treatment with direct oral anticoagulants and risks of recurrent venous thromboembolism and major bleeding.

BACKGROUND: Little is known about medication adherence patterns and their association with effectiveness and safety among patients with venous thromboembolism (VTE) receiving direct oral anticoagulant (DOAC) therapy beyond 3-6 months of initial treatment. OBJECTIVE: To examine the associations between adherence trajectories of extended treatment with DOAC and the risks of recurrent VTE and major bleeding among patients with VTE. METHODS: We conducted a retrospective cohort study of patients with incident VTE who completed 6 months of initial anticoagulant treatment and received either DOAC extended therapy or no extended therapy using MarketScan Commercial and Medicare Supplemental databases (2013-2019). We used group-based trajectory models to identify distinct adherence patterns during extended treatment. Using inverse probability treatment weighted Cox proportional hazards models, we examined the association between the adherence trajectories and the risks of recurrent VTE and major bleeding. RESULTS: Among 10,960 patients with extended treatment with DOACs (rivaroxaban, apixaban, dabigatran, edoxaban) and 5,133 patients with no extended treatment, we identified 4 distinct trajectories (consistently high, gradually declining, rapidly declining, and no extended treatment). Compared with the no extended treatment group, the groups with consistently high adherence (hazard ratio = 0.09, 95% CI = 0.05-0.17) and with gradually declining adherence (0.13, 0.03-0.53) showed decreased recurrent VTE risk without increased major bleeding risk (consistently high adherence 1.19, 0.71-1.99; gradually declining adherence 1.96, 0.81-4.70). There was no difference in the risk of recurrent VTE (0.34, 0.10-1.16) for the group with rapidly declining adherence, but this group was associated with increased major bleeding risk (2.65, 1.01-6.92). CONCLUSIONS: Our findings underscore the clinical importance of continuing and remaining adherent to extended DOAC treatment without increased major bleeding risk for patients with VTE. DISCLOSURES: This research was supported by the BMS/Pfizer Alliance American Thrombosis Investigator Initiated Research Program. The funding source had no role in the design, collection, analysis, or interpretation of the data or the decision to submit the article for publication. Dr Lo-Ciganic reported receiving research funding from Merck Sharp & Dohme Corp. Dr Dietrich reported receiving honorarium for training and education from BMS/Pfizer. Dr DeRemer is a stockholder of Portola Pharmaceuticals and reported receiving personal fees for advisory board meeting from BMS. No other disclosures were reported.

Short versus extended treatment with a carbapenem in patients with high-risk fever of unknown origin during neutropenia: a non-inferiority, open-label, multicentre, randomised trial

Early antibiotic discontinuation has been advocated in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia, but its safety is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. This non-inferiority, open-label, multicentre, randomised trial was done in six hospitals in the Netherlands. Adult patients (≥18 years) who were treated with intensive chemotherapy or haematopoietic stem-cell transplantation (HSCT) for a haematological malignancy, and had fever of unknown origin during high-risk neutropenia (<0·5 × 109/L expected for ≥7 days) were eligible. After onset of fever, patients received either 500 mg intravenous imipenem-cilastatin four times a day or 1000 mg intravenous meropenem three times a day. Between 48 h and 72 h of treatment, participants were randomly assigned (1:1) by a computer-generated sequence to receive a short-term (72 h [60-84]; short treatment group) or extended (≥9 days until being afebrile for 5 days or neutrophil recovery; extended treatment group) carbapenem regimen. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock or respiratory failure or death from day 4 until neutrophil recovery. The study was designed to assess the non-inferiority of the short treatment compared with the extended treatment regimen, with a non-inferiority margin of 10%. The primary outcome was adjudicated by an independent outcome committee, who were masked to treatment allocation, and was analysed in the intention-to-treat and per-protocol populations. The trial is completed and registered with ClinicalTrials.gov, NCT02149329. Between Dec 1, 2014, and July 1, 2019, 281 patients were included in the intention-to-treat analysis: 144 (51%) patients were assigned to the short treatment group and 137 (49%) to the extended treatment group. Median age was 59 years (IQR 52-65); 109 (39%) patients were women and 172 (61%) were men; 205 (73%) patients received HSCT. In the intention-to-treat analysis, 28 (19%) of 144 patients in the short treatment group versus 21 (15%) of 137 patients in the extended treatment group had treatment failure (adjusted risk difference [ARD] 4·0% [90% CI -1·7% to 9·7%]; p=0·25). In the per-protocol analysis (n=225), 24 (23%) of 104 patients in the short treatment group and 19 (16%) of 121 patients in the extended treatment group had treatment failure (ARD 7·3% [0·3% to 14·9%]; p=0·11). The most common grade 3-5 infection-related adverse events were mucositis (23 [20%] of 114 adverse events in the short treatment group vs 28 [29%] of 98 adverse events in the extended treatment group), fever of unknown origin (20 [18%] vs 16 [16%] events), and bacteraemia (15 [13%] vs 13 [13%] events). The number of serious adverse events were higher in the short treatment group (23 [16%] of 144 patients) than in the extended treatment group (14 [10%] of 137 patients), due to an increased rate of readmission (17 [12%] patients in the short treatment group vs ten [7%] in the extended treatment group). Death before 30 days after neutrophil recovery occurred in five (3%) participants in the short treatment group: two due to progressive leukaemia, two due to candidaemia, and one due to Enterococcus faecium bacteraemia and drug-induced pneumonitis. One (1%) patient died in the extended treatment group due to candidaemia. None of the deaths were related to carbapenem-sensitive infections. Early discontinuation of carbapenem treatment in patients with febrile neutropenia of unknown origin does not result in increased treatment failure. Our study supports short treatment if patients are afebrile after 3 days of carbapenem treatment. However, because secondary analyses suggested that serious adverse events and all-cause mortality occurred more often in patients who are persistantly febrile the short treatment group, we recommend vigilance for non-susceptible pathogens and early resumption of empirical therapy in patients who are deteriorating. The Netherlands Organisation for Health Research and Development and Fonds NutsOhra.

Effectiveness and safety of extended treatment with direct oral anticoagulants for venous thromboembolism in Japan: A retrospective cohort study using claims data

PurposeWe aimed to evaluate the risk of recurrent venous thromboembolism (VTE) among patients receiving direct oral anticoagulant (DOAC) therapy (extended and non-extended) using claims data. MethodsPatients treated with DOACs at the first VTE event were identified using Japanese claims data; Cox proportional hazard models were used to evaluate the risk of recurrence. Unadjusted, adjusted, and stabilized inverse probability treatment weighting (s-IPTW) analyses were used to assess the differences between patients treated for more than 90 days after the index date (extended treatment group) and those treated within 90 days (nonextended treatment group). Bleeding was assessed separately from recurrent VTE evaluation during the observation period. ResultsWe included 4,010 patients (mean age, 69 years; 57.9% females; extended: 2,684, nonextended: 1,326). After IPTW, all patient characteristics were well balanced. When the follow-up was censored at 18 months, the hazard ratio (extended/nonextended) for unadjusted, adjusted, and two s-IPTW analyses were 1.31 (P = 0.2762), 1.25 (P = 0.372), 1.32 (P = 0.2579), and 1.33 (P = 0.2498), respectively. The proportions of those who experienced intracranial, gastrointestinal, respiratory, and renal/urinary tract bleeding during the observation period in both groups were 2.9% vs. 3.8%, 2.1% vs. 2.3%, 1.0% vs. 0.5%, and 1.4% vs. 0.7% (extended vs. nonextended), respectively. ConclusionsThere were no differences in VTE recurrence between the two groups. In clinical practice and with a risk-benefit evaluation, both VTE treatment types were well controlled. Further evaluation is required, considering patient background within the observation period of 90 days and safety of treatment for bleeding events.

What is the optimal duration for vigabatrin monotherapy in patients with infantile spasms: 6 months or longer?

Vigabatrin (VGB) is approved as monotherapy for pediatric patients with Infantile Spasms (IS). Duration of VGB use should be limited because of the risk of retinal and neurotoxicity, but the optimal length of treatment is unknown. Our study aimed to determine the risk of spasms relapse after 6 months of VGB as first-line therapy in IS patients deemed VGB good responders.The participants were 44 infants with IS who demonstrated both absence of clinical spasms and hypsarrhythmia four weeks after starting VGB, obtained from two cohorts: 29 patients from a multicenter prospective cohort and 15 patients from a retrospective single-center cohort. We divided them post hoc into two groups according to the duration of VGB treatment: 6-month group (n=34) and >6-month group (n=10) and compared outcome between the two groups.No patient in either group had a relapse of spasms. For patients with non-identified etiology (NIE) in the 6 months treatment group, no other seizure types were observed. Late epilepsy, in the form of focal seizures, emerged in only 5/37 patients (3/30 in the 6-month treatment group; 2/7 in the extended treatment group); all within the first 6-9 months after VGB initiation.Our study provides substantial evidence that a shortened VGB course of 6 months could be sufficient to treat and prevent relapse of spasms in children with IS, particularly those with NIE.

Short Versus Extended Treatment with a Carbapenem in Haematology Patients with High Risk Fever of Unknown Origin During Neutropenia: An Open-Label Multicentre Randomised Clinical Trial

Background: Early antibiotic discontinuation in haematology patients with fever of unknown origin during chemotherapy-induced neutropenia has been advocated to reduce unnecessary antibiotic treatment, but the safety of this strategy is unknown. We aimed to assess if short treatment with carbapenems is non-inferior to extended treatment. Methods: In this randomised, multicentre, non-inferiority trial we assigned 292 haematology patients with fever of unknown origin during high-risk neutropenia (≥7 days) to short treatment, with carbapenem discontinuation after 72 hours (± 12 hours), or extended treatment, with carbapenem continuation for ≥ 9 days until being afebrile for 5 days or neutrophil recovery. The composite primary endpoint was treatment failure, defined as recurrent fever or a carbapenem-sensitive infection between day 4 and day 9 and septic shock/respiratory failure or death from day 4 until neutrophil recovery. Findings: Treatment failure in the intention-to-treat analysis (281 patients) was 19·4% (28/144) in the short treatment versus 15·3% (21/137) in the extended treatment arm (adjusted risk difference 4·0%, 90% confidence interval [CI] -1·7% to 9·7%, excluding the 10% non-inferiority threshold). Mortality until 30 days after neutrophil recovery occurred in five patients (3·5%) in the short treatment group and in one (0·7%) in the extended treatment group (adjusted risk difference 2·6%, 95% CI % 1·2 to 5·4%), of which none were related to infections with carbapenem-sensitive microorganisms. Interpretation: Early discontinuation of carbapenem treatment in neutropenic patients with fever was non-inferior to extended treatment with regard to treatment failure, but all-cause mortality before 30 days after neutrophil recovery was significantly higher in patients with persistent fever at day 3. Early discontinuation of carbapenem treatment is therefore possible in afebrile patients, but caregivers should be vigilant of other non-carbapenem susceptible infections in patients with persistent fever.: Clinical Trial Registration Details: This trial is registered with ClinicalTrials.gov (number NCT02149329). Funding Information: Dutch Research Council (ZonMw) and Fonds NutsOhra. Declaration of Interests: The authors 408 declare no competing interests. Ethics Approval Statement: The protocol was approved by the research ethics review committee of VU university medical centre (current name: Amsterdam University medical centres, location VUmc) and ethical bodies of each participating centre. An independent data and safety monitoring board oversaw study procedures and data quality during conduct of the study and performed a planned interim safety analysis. All participants provided written informed consent.

Long-Term Outcomes of Implantable Cardioverter-Defibrillator Therapy in the SCD-HeFT

BackgroundThe SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) randomized 2,521 patients with moderate heart failure (HF) to amiodarone, placebo drug, or implantable cardioverter-defibrillator (ICD) therapy. Original trial follow-up ended October 31, 2003. Over a median 45.5-month follow-up, amiodarone, compared with placebo, did not affect survival, whereas randomization to an ICD significantly decreased all-cause mortality by 23%. ObjectivesThis study sought to describe the extended treatment group survival of the SCD-HeFT cohort. MethodsMortality outcomes for the 1,855 patients alive at the end of the SCD-HeFT trial were collected between 2010 and 2011. These data were combined with the 666 deaths from the original study to compare long-term outcomes overall and for key pre-specified subgroups. ResultsMedian (25th to 75th percentiles) follow-up was 11.0 (10.0 to 12.2) years. On the basis of intention-to-treat analysis, the ICD group had overall survival benefit versus placebo drug (hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.76 to 0.98; p = 0.028). When treatment benefit was examined as a function of time from randomization, attenuation of the ICD benefit was observed after 6 years (p value for the interaction = 0.0015). Subgroup analysis revealed long-term ICD benefit varied according to HF etiology and New York Heart Association (NYHA) functional class: ischemic HF HR: 0.81; 95% CI: 0.69 to 0.95; p = 0.009; nonischemic HF HR: 0.97; 95% CI: 0.79 to 1.20; p = 0.802; NYHA functional class II HR: 0.76; 95% CI: 0.65 to 0.90; p = 0.001; NYHA functional class III HR: 1.06; 95% CI: 0.86 to 1.31; p = 0.575. ConclusionsFollow-up of SCD-HeFT patients to 11 years demonstrated heterogenous treatment-related patterns of long-term survival with ICD benefit most evident at 11 years for ischemic HF patients and for those with NYHA functional class II symptoms at trial enrollment. (SCD-HeFT 10 Year Follow-up [SCD-HeFT10 Yr]; NCT01058837)

Extended duration versus standard duration of peginterferon alfa-2a in treatment of chronic hepatitis B: A systematic review and meta-analysis

In the last decade, PEG-IFNa-2a has been widely used in the treatment of chronic hepatitis B (CHB). The current standard duration is 48 weeks; however, several studies based on small sample sizes have indicated that treatment extended beyond 48 weeks improved clinical outcomes than standard 48 weeks of therapy. Therefore, we performed a meta-analysis to compare the efficacy and safety of extended duration versus standard duration treatment with PEG-IFNa-2a monotherapy for patients with CHB. Four studies comprising of 350 patients were included in our study. Our analysis showed that extended treatment resulted in a higher HBsAg clearance rate compared with the standard treatment at the end of treatment, 24 and 48 weeks post-treatment [odds ratio (OR)=2.45, 95% confidence intervals (CI) (1.17-5.11), P=0.02; OR=3.17, 95% CI (1.62-6.21), P<0.01; OR=5.02, 95% CI (1.63-15.45), P<0.01, respectively]. Higher HBeAg seroconversion rates were also obtained in the extended treatment group than the standard treatment group at the end of treatment and 48 weeks post-treatment [OR=2.09, 95% CI (1.10-3.98), P=0.02, and OR=2.67, 95% CI (1.39-5.13), P<0.01, respectively]. In addition, extended treatment was superior to standard treatment in HBV-DNA inhibition rate at 48 weeks post-treatment [OR=3.15, 95% CI (1.51-6.57), P<0.01]. Therefore, extended treatment with PEG-IFNa-2a beyond 48 weeks may be a promising strategy to achieve higher rates of sustained HBV-DNA inhibition, HBeAg seroconversion and HBsAg clearance off-therapy for patients with CHB.

Quality of Life and Safety Outcomes Following Irreversible Electroporation Treatment for Prostate Cancer: Results from a Phase I-Ii Study

Objective: Prostate cancer treatment as radical prostatectomy or radiation therapy is associated with collateral tissue damage resulting inside-effects. Irreversible electroporation is a minimally invasive technique that has shown to be effective in destroying tumour cells and has been proposed to diminish the treatment related morbidity. The aim of the study was to evaluate the safety and quality of life (QoL) and functional outcomes of extended and focal irreversible electroporation (IRE) in prostate cancer. Methods: IRE-ablations of the prostate were performed using two treatment protocols (focal and extended) to assess potential variation in outcomes. The safety of IRE was assessed by the device-related, periprocedural- and post procedural adverse events. Post-procedural quality of life was measured by prostate cancer-specific QoL questionnaires. Several validated questionnaires were used to determine the following outcomes: genitourinary side effects, urinary and erectile function. Post-procedural pain was scored using the visual analogue scale and the length of hospital stay was documented. Results: Mainly mild adverse events (grade 1-2) occurred during the short-term follow-up, mostly concerning lower urinary tract symptoms. Nearly all resolved between the first and fourth week post treatment. Quality of life assessment showed deterioration in the urinary domain for both treatment protocols. Functional outcome questionnaire results remained stable over time. The reported post-procedural pain was low with a median of 0.5 one day post-IRE, and the length of hospital stay was short (mean of 3 days). Analysis per treatment protocol showed a significant increase between one and four weeks post treatment (p=0.03) in the extended treatment group. Conclusion: Irreversible electroporation can be performed safely in patients suffering from prostate cancer. The adverse events are mostly temporary. Quality of life assessment shows deterioration in the urinary domain; however, functional outcomes remain stable over time.

Efficacy of extended cefquinome treatment of clinical Staphylococcus aureus mastitis

Clinical Staphylococcus aureus mastitis is difficult to cure. Extended antimicrobial treatment is often advocated as a practical approach to improve cure rates; however, scientific evidence of this hypothesis is lacking. A multi-centered, nonblinded, randomized, positive-controlled clinical trial was conducted in 5 European countries—France, Hungary, Italy, the Netherlands, and the United Kingdom—to study the efficacy of an extended intramammary cefquinome treatment (5 d) compared with a standard intramammary cefquinome treatment (1.5 d) of Staph. aureus clinical mastitis. Least squares means estimates of bacteriological cure during lactation were 34% [standard error (SE)=9.9%] for the standard treatment group and 27% (SE=8.4%) for the extended treatment group. In the final model, extended therapy was not significantly better. The only factor predicting bacteriological cure was pretreatment cow somatic cell count (SCC). Cows with >250,000 cells/mL in milk before treatment were less likely to cure. Least squares means of clinical cure during lactation was 60% (SE=19%) for the standard treatment group and 82% (SE=12%) for the extended treatment group. In the final model, clinical cure after extended treatment was significantly better. Pretreatment cow udder firmness predicted clinical cure. Firm udders were less likely to cure clinically. Irrespective of treatment regimen, new infection rates with pathogens other than Staph. aureus were higher (42%) after bacteriological cure than after nonbacteriological cure (22%) and cured cows had a significantly lower SCC. In conclusion, independent of the treatment protocol, cows with an SCC <250,000cells/mL before treatment showed a higher probability of bacteriological cure. It appears that successful treatment of clinical Staph. aureus mastitis with cefquinome is associated with an increased number of new infections with coagulase-negative staphylococci. Extended treatment improved clinical, but not bacteriological, cure rates compared with the standard treatment. These results indicate that extending treatment of clinical Staph. aureus mastitis with cefquinome should not be recommended.

A Randomized Clinical Trial of the Efficacy of Extended Smoking Cessation Treatment for Adolescent Smokers

Relatively few well-designed smoking cessation studies have been conducted with teen smokers. This study examined the efficacy of extended cognitive-behavioral treatment in promoting longer term smoking cessation among adolescents. Open-label smoking cessation treatment consisted of 10 weeks of school-based, cognitive-behavioral group counseling along with 9 weeks of nicotine replacement (nicotine patch). A total of 141 adolescent smokers in continuation high schools in the San Francisco Bay Area were randomized to either 9 additional group sessions over a 14-week period (extended group) or 4 monthly smoking status calls (nonextended group). Intention-to-treat logistic regression analysis was used to assess the primary outcome of biologically confirmed (carbon monoxide < 9 ppm) point prevalence abstinence at Week 26 (6-month follow-up from baseline). At Week 26 follow-up, the extended treatment group had a significantly higher abstinence rate (21%) than the nonextended treatment (7%; OR = 4.24, 95% CI: 1.20-15.02). Females also were more likely to be abstinent at the follow-up than males (OR = 4.15, 95% CI: 1.17-14.71). The significantly higher abstinence rate at follow-up for the extended treatment group provides strong support for continued development of longer term interventions for adolescent smoking cessation.

Relationship between in vitro antimicrobial sensitivity of bovine subclinical mastitis isolates and treatment outcome in lactating dairy cows

Summary The objective of the present study was to determine whether there was an association between the in vitro antimicrobial sensitivity test results of subclinical mastitis pathogens and bacteriological cure following intramammary treatment using a combination of nafcillin, penicillin, and streptomycin (NPS). Eighty-six intramammary pathogens from 43 cows were examined in this study. Most intramammary infections were due to coagulase-negative staphylococci, coliforms, and environmental streptococci. The antibiotic sensitivity to NPS was determined using the Kirby-Bauer disc diffusion method. Bacteriological cure rates for sensitive, intermediate, and resistant isolates in the standard treatment group (3 intramammary infusions of NPS once daily) were 84.4, 88.9, and 100%, respectively. These figures in the extended treatment group (6 intramammary infusions of NPS once daily) were 100% for the 3 categories. Bacteriological cure was not associated with the sensitivity test result. Based on this study, Kirby-Bauer sensitivity test results were not useful as predictors of the bacteriological outcome of subclinical mastitis treated with intramammary NPS.

Relationship between in vitro susceptibility of bovine subclinical mastitis isolates and bacteriological outcome of intramammary treatment with cefquinome

The objective of the present study was to determine whether there was an association between the in vitro antimicrobial susceptibility test results of subclinical mastitis pathogens and bacteriological outcomes of intramammary treatments using cefquinome. A total of 110 intramammary pathogens from 51 cows were assessed in this study. Most intramammary infections were due to coagulase-negative staphylococci, environmental streptococci, and coliforms. The antimicrobial susceptibility to cefquinome was determined using the Kirby-Bauer disc diffusion method. Bacteriological cure rates for the sensitive, intermediate, and resistant isolates in the standard treatment group (three intramammary infusions of 75 mg cefquinome at 16 h intervals) were 82.4%, 90%, and 87.5%, respectively. These figures in the extended treatment group (six intramammary infusions of 75 mg cefquinome at 16 h intervals) were 83.3%, 100%, and 100%, respectively. Treatment outcomes were not associated with the results of sensitivity tests in the standard group. However, in the extended group, the probability of a bacteriological cure was lower in quarters from which cefquinome-sensitive pathogens were isolated than the quarters from which intermediate or resistant pathogens were isolated. Based on this study, the Kirby-Bauer susceptibility test result is a poor predictor for the bacteriological cure of subclinical mastitis treated with intramammary cefquinome.

A clinical phase I/II trial with the monoclonal antibody cG250 (RENCAREX®) and interferon-alpha-2a in metastatic renal cell carcinoma patients

To evaluate the efficacy and safety of WX-G250, a chimeric monoclonal antibody that binds to carboxy anhydrase IX, combined with low-dose interferon-alpha (LD-IFNα) in patients with progressive metastatic renal cell carcinoma (mRCC). Thirty-one patients, nephrectomized for the primary tumor, clear cell progressive mRCC, were enrolled to receive weekly infusions of WX-G250 (20 mg i.v.; week 2-12) combined with LD-IFNα (3 MIU s.c. 3 times/week; week 1-12). At week 16, patients were evaluated for response and stratified into two groups: (a) responders into the extended treatment group for an additional 6 weeks of treatment or (b) the progressive group with no further study treatment. Of the 31 treated patients, 26 were evaluable for response to treatment. Two patients showed partial remission and 14 patients had stable disease as assessed in week 16. One patient experienced partial remission resulting in a complete remission lasting at least 17 months. Nine patients had durable stable disease of 24 weeks or longer. Clinical benefit was obtained in 42% (11/26) patients. The median overall survival achieved was 30 months and the 2-year survival was 57%. Patients receiving extended treatment showed a significantly longer 2-year survival rate than discontinued patients (79 vs. 30%; P=0.0083). In general, treatment was well tolerated with little toxicity. Treatment with the antibody WX-G250 in combination with LD-IFNα is safe, well tolerated, led to clinically meaningful disease stabilization and demonstrated clinical benefit in this progressive mRCC patient population.

Dual-Targeting Topotecan Liposomes Modified with Tamoxifen and Wheat Germ Agglutinin Significantly Improve Drug Transport across the Blood−Brain Barrier and Survival of Brain Tumor-Bearing Animals

Chemotherapy of brain tumors remains a big challenge owing to the low drug transport across the blood-brain barrier (BBB), multidrug resistance (MDR), and poor penetration into the tumor tissue. We developed a novel dual-targeting liposomal carrier that enabled drug to transport across the BBB and then target the brain tumor. In the dual-targeting liposomal carrier, tamoxifen (TAM) was incorporated into the lipid bilayer membrane of liposomes and wheat germ agglutinin (WGA) was conjugated to the liposomes' surface. Topotecan was then loaded into the above liposomes. In vitro, topotecan liposomes modified with TAM and WGA were applied to the glioma cells, BBB model, and avascular C6 glioma spheroids, respectively. In vivo, they were systemically administered via vein to brain C6 glioma-bearing rats. In view of the microtiter tetrazolium (MTT) results, topotecan liposomes modified with TAM and WGA exhibited a significant inhibitory effect compared to unmodified topotecan liposomes, suggesting that TAM plus WGA contributed strong drug delivery effects into the brain tumor cells after direct drug exposure. In the experiments of drug transport across the BBB model following drug exposure to tumor cells, topotecan liposomes modified with TAM and WGA exhibited the most robust dual-targeting effects: crossing the BBB and then targeting brain tumor cells. Similar strong activity was found in the reduction of C6 glioma tumor spheroid volume and in the apoptosis of the spheroids. In the brain tumor-bearing rats, the dual-targeting effects of topotecan liposomes modified with TAM and WGA could be evidently observed, resulting in a significant improvement in the overall survival of the brain tumor-bearing rats compared with free topotecan and topotecan liposomes. Moreover, results from an extended treatment group indicated that the survival could be further significantly enhanced, indicating that an extended chemotherapy with topotecan liposomes modified with TAM and WGA would be beneficial for treatment. The dual-targeting effects in vivo of topotecan liposomes modified with TAM and WGA could be related to an enhanced effect by TAM via inhibiting efflux of MDR proteins in the BBB and the brain tumor, and an enhanced effect by WGA via endocytosis in the BBB and in the brain tumor. In conclusion, topotecan liposomes modified with TAM and WGA significantly improve topotecan transport across the blood-brain barrier and the survival of brain tumor-bearing animals, showing dual-targeting effects. These findings would encourage further developments of noninvasive therapy for brain tumor.

Nonsurgical Home Treatment of Middle Ear Effusion and Associated Hearing loss in Children. Part II: Validation Study

In this prospective follow-up investigation, we examined the efficacy of a modified Politzer device in the home treatment of persistent middle ear effusion (MEE) and associated hearing loss in children who had previously participated in a similar clinical trial. Our study group was made up of 38 patients who had been either (1) untreated control participants in the previous study whose hearing in one or both ears had not returned to normal within 11 weeks of their initial audiologic pretest ("former control group"; n = 30), or (2) active-treatment participants in the previous study whose hearing sensitivity in at least one ear had not improved to within normal limits after treatment and who elected to undergo a continuation of treatment ("extended-treatment group"; n = 8). Treatment efficacy was determined by comparing differences in pre- and posttreatment air-conduction thresholds and otoscopic findings. Following treatment, the former control group experienced significant improvements in hearing sensitivity at all frequencies; at the posttreatment test, hearing sensitivity was within normal limits in 43 of 60 ears (71.7%), and normal or moderate tympanic membrane mobility was observed in 30 of 34 otoscopically examined ears (88.2%). In the extended-treatment group, hearing sensitivity returned to within normal limits in 9 of 10 impaired ears (90.0%). These findings further substantiate the efficacy of our modified Politzer device in improving middle ear function and hearing sensitivity in children with MEE, and they support the reliability of the findings reported in our previous study. These results also indicate that many patients in whom initial treatment is not successful may benefit from extended treatment.

A RANDOMIZED COMPARISON OF TWO ANEMIA TREATMENT REGIMENS IN TANZANIAN CHILDREN

We used a prospective, open-label randomized trial to evaluate two treatment regimens in Tanzanian children two months to four years of age presenting to a hospital with a packed cell volume (PCV) < 25%. Treatment was either standard (14 days of ferrous sulfate and an antimalarial) or extended (three months of ferrous sulfate and three antimalarial treatments). The prevalence of anemia was measured two weeks after completion of treatment and six months after recruitment. Two weeks after completing treatment, the prevalence of PCV < 33% was 58% in the standard treatment arm and 44% in the extended treatment group (P = 0.04), and the mean PCV was significantly higher in the extended treatment arm (32.1%, SD = 4.5% versus 30.8%, SD = 4.9%; P = 0.031). However, there was no difference in the prevalence of PCV < 25% in the first survey, and the benefits of extended therapy were only apparent six months after recruitment in children compliant with the extended treatment (odds ratio of PCV < 25% = 0.16, P = 0.06). Compliance was satisfactory in only 39% (82 of 209) of the children in the first week of treatment. Extending the duration of therapy and improving compliance may have health benefits for anemic children in malaria-endemic settings.

A comparison of the hardness of different types of titanium and conventional metal ceramics

This study compared the surface hardness of machine milled titanium and cast titanium, and the surface hardness profile of a gold-palladium alloy, a nickel chromium alloy, milled and cast titanium. For each group, 15 discoid specimens, 10 mm in diameter and 5 mm thick, were fabricated by either casting or milling. Five specimens of each group underwent one of three treatments: (1) no heat treatment, (2) a standard heat treatment, or (3) an extended heat treatment. Knoop hardness values were determined. Results indicated that the Knoop hardness of cast titanium was less than that of the cast titanium standard treatment group, which was less than the Knoop hardness of the cast titanium extended treatment group. Knoop hardness of milled titanium was less than that of the milled titanium standard treatment and milled titanium extended treatment groups. For the surface hardness profile, cast titanium showed a decreasing surface hardness as the distance from the surface of the specimen increased. No such trend was identified for the other groups tested.

Utilization of outpatient mental health services after inpatient alcoholism treatment.

It is generally agreed that use of aftercare services following discharge from alcoholism treatment is optimum for patients to achieve long-term recovery. However, the quantity and duration of utilization of such services in non-experimental settings are generally unknown. Using secondary data sources, we studied 5,635 alcoholics completing formal extended inpatient treatment and 1,860 alcoholics discharged from brief inpatient hospitalizations in Department of Veterans Affairs medical centers. Weekly use of outpatient mental health services (OPMH) prior to hospital admission was equally low for both patient groups (approximately 2-3% of patients) until four weeks prior to admission, at which time OPMH use increased, particularly for the extended treatment group. In the four weeks after discharge, use of OPMH services was substantially higher for patients with extended treatment compared to those with brief hospitalizations (40% vs. 18%), with 22% of patients completing treatment utilizing such services in the first week after discharge. Utilization steadily decreased until only 8% and 4% of both groups, respectively, were using OPMH services at the end of six months after discharge. Study results suggest the need to examine barriers to outpatient mental health utilization after discharge as well as interventions to increase compliance with long-term aftercare.