Chemotherapy alone versus chemotherapy plus radiotherapy for early stage Hodgkin lymphoma

Background Combined modality treatment (CMT) consisting of chemotherapy followed by localised radiotherapy is standard treatment for patients with early stage Hodgkin lymphoma (HL). However, due to long term adverse effects such as secondary malignancies, the role of radiotherapy has been questioned recently and some clinical study groups advocate chemotherapy only for this indication. Objectives We performed a systematic review with meta-analysis of randomised controlled trials (RCTs) comparing chemotherapy alone with CMT in patients with early stage Hodgkin lymphoma with respect to response rate, progression-free survival (alternatively tumour control) and overall survival (OS). Search methods We searched MEDLINE, EMBASE and CENTRAL as well as conference proceedings from January 1980 to November 2010 for randomised controlled trials comparing chemotherapy alone to the same chemotherapy regimen plus radiotherapy. Selection criteria Randomised controlled trials comparing chemotherapy alone with CMT in patients with early stage HL. Trials in which the chemotherapy differed between treatment arms were excluded. Trials with more than 20% of patients in advanced stage were also excluded. Data collection and analysis Effect measures used were hazard ratios (HR) for tumour control and OS as well as relative risks for response rates. Two review authors independently extracted data and assessed quality of trials. We contacted study authors to obtain missing information. Since none of the trials reported progression-free survival according to our definitions, all similar outcomes were evaluated as tumour control. Main results Five RCTs involving 1245 patients were included. The HR was 0.41 (95% confidence interval (CI) 0.25 to 0.66) for tumour control and 0.40 (95% CI 0.27 to 0.61) for OS for patients receiving CMT compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another six trials were included that did not fulfil the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Authors' conclusions Adding radiotherapy to chemotherapy improves tumour control and overall survival in patients with early stage Hodgkin lymphoma.

Viral load monitoring of antiretroviral therapy, cohort viral load and HIV transmission in Southern Africa: A mathematical modelling analysis

In low-income settings, treatment failure is often identified using CD4 cell count monitoring. Consequently, patients remain on a failing regimen, resulting in a higher risk of transmission. We investigated the benefit of routine viral load monitoring for reducing HIV transmission.

Outcomes of antiretroviral treatment in programmes with and without routine viral load monitoring in Southern Africa

Objectives: To compare outcomes of antiretroviral therapy (ART) in South Africa, where viral load monitoring is routine, with those in Malawi and Zambia, where monitoring is based on CD4 cell counts. Methods: We included 18 706 adult patients starting ART in South Africa and 80 937 patients in Zambia or Malawi. We examined CD4 responses in models for repeated measures and the probability of switching to second-line regimens, mortality and loss to follow-up in multistate models, measuring time from 6 months. Results: In South Africa, 9.8% [95% confidence interval (CI) 9.1–10.5] had switched at 3 years, 1.3% (95% CI 0.9–1.6) remained on failing first-line regimens, 9.2% (95% CI 8.5–9.8) were lost to follow-up and 4.3% (95% CI 3.9–4.8) had died. In Malawi and Zambia, more patients were on a failing first-line regimen [3.7% (95% CI 3.6–3.9], fewer patients had switched [2.1% (95% CI 2.0–2.3)] and more patients were lost to follow-up [15.3% (95% CI 15.0–15.6)] or had died [6.3% (95% CI 6.0–6.5)]. Median CD4 cell counts were lower in South Africa at the start of ART (93 vs. 132 cells/μl; P < 0.001) but higher after 3 years (425 vs. 383 cells/μl; P < 0.001). The hazard ratio comparing South Africa with Malawi and Zambia after adjusting for age, sex, first-line regimen and CD4 cell count was 0.58 (0.50–0.66) for death and 0.53 (0.48–0.58) for loss to follow-up. Conclusion: Over 3 years of ART mortality was lower in South Africa than in Malawi or Zambia. The more favourable outcome in South Africa might be explained by viral load monitoring leading to earlier detection of treatment failure, adherence counselling and timelier switching to second-line ART.

Virologic failure and second-line antiretroviral therapy in children in South Africa--the IeDEA Southern Africa collaboration

Background: With expanding pediatric antiretroviral therapy (ART) access, children will begin to experience treatment failure and require second-line therapy. We evaluated the probability and determinants of virologic failure and switching in children in South Africa. Methods: Pooled analysis of routine individual data from children who initiated ART in 7 South African treatment programs with 6-monthly viral load and CD4 monitoring produced Kaplan-Meier estimates of probability of virologic failure (2 consecutive unsuppressed viral loads with the second being >1000 copies/mL, after ≥24 weeks of therapy) and switch to second-line. Cox-proportional hazards models stratified by program were used to determine predictors of these outcomes. Results: The 3-year probability of virologic failure among 5485 children was 19.3% (95% confidence interval: 17.6 to 21.1). Use of nevirapine or ritonavir alone in the initial regimen (compared with efavirenz) and exposure to prevention of mother to child transmission regimens were independently associated with failure [adjusted hazard ratios (95% confidence interval): 1.77 (1.11 to 2.83), 2.39 (1.57 to 3.64) and 1.40 (1.02 to 1.92), respectively]. Among 252 children with ≥1 year follow-up after failure, 38% were switched to second-line. Median (interquartile range) months between failure and switch was 5.7 (2.9-11.0). Conclusions: Triple ART based on nevirapine or ritonavir as a single protease inhibitor seems to be associated with a higher risk of virologic failure. A low proportion of virologically failing children were switched.

Thymic peptides for treatment of cancer patients

Background Purified thymus extracts (pTE) and synthetic thymic peptides (sTP) are thought to enhance the immune system of cancer patients in order to fight the growth of tumour cells and to resist infections due to immunosuppression induced by the disease and antineoplastic therapy. Objectives To evaluate the effectiveness of pTE and sTP for the management of cancer. Search methods We searched CENTRAL (The Cochrane Library 2010, Issue 3), MEDLINE, EMBASE, AMED, BIOETHICSLINE, BIOSIS, CATLINE, CISCOM, HEALTHSTAR, HTA, SOMED and LILACS (to February 2010). Selection criteria Randomised trials of pTE or sTP in addition to chemotherapy or radiotherapy, or both, compared to the same regimen with placebo or no additional treatment in adult cancer patients. Data collection and analysis Two authors independently extracted data from published trials. We derived odds ratios (OR) from overall survival (OS) and disease-free survival (DFS) rates, tumour response (TR) rates, and rates of adverse effects (AE) related to antineoplastic treatments. We used a random-effects model for meta-analysis. Main results We identified 26 trials (2736 patients). Twenty trials investigated pTE (thymostimulin or thymosin fraction 5) and six trials investigated sTP (thymopentin or thymosin α1). Twenty-one trials reported results for OS, six for DFS, 14 for TR, nine for AE and 10 for safety of pTE and sTP. Addition of pTE conferred no benefit on OS (RR 1.00, 95% CI 0.79 to 1.25); DFS (RR 0.97, 95% CI 0.82 to 1.16); or TR (RR 1.07, 95% CI 0.92 to 1.25). Heterogeneity was moderate to high for all these outcomes. For thymosin α1 the pooled RR for OS was 1.21 (95% CI 0.94 to 1.56, P = 0.14), with low heterogeneity; and 3.37 (95% CI 0.66 to 17.30, P = 0.15) for DFS, with moderate heterogeneity. The pTE reduced the risk of severe infectious complications (RR 0.54, 95% CI 0.38 to 0.78, P = 0.0008; I² = 0%). The RR for severe neutropenia in patients treated with thymostimulin was 0.55 (95% CI 0.25 to 1.23, P = 0.15). Tolerability of pTE and sTP was good. Most of the trials had at least a moderate risk of bias. Authors' conclusions Overall, we found neither evidence that the addition of pTE to antineoplastic treatment reduced the risk of death or disease progression nor that it improved the rate of tumour responses to antineoplastic treatment. For thymosin α1, there was a trend for a reduced risk of dying and of improved DFS. There was preliminary evidence that pTE lowered the risk of severe infectious complications in patients undergoing chemotherapy or radiotherapy.

Critical review of the use of erythropoietin in the treatment of anaemia during therapy for chronic hepatitis C

Combined pegylated interferon (PegIFN) and ribavirin represents the standard therapy for patients with chronic hepatitis C (CHC), which allows for sustained viral response (SVR) in up to 90% of patients depending on certain viral and host factors. Clinical studies have demonstrated the importance of adherence to therapy, that is, the ability of patients to tolerate and sustain a fully dosed therapy regimen. Adherence is markedly impaired by treatment-related adverse effects. In particular, haemolytic anaemia often requires dose reduction or termination of ribavirin treatment, which compromises treatment efficacy. Recent evidence points to a beneficial role of recombinant erythropoietin (EPO) in alleviating ribavirin-induced anaemia thereby improving quality of life, enabling higher ribavirin dosage and consequently improving SVR. However, no general consensus exists regarding the use of EPO for specific indications: its optimal dosing, treatment benefits and potential risks or cost efficiency. The Swiss Association for the Study of the Liver (SASL) has therefore organized an expert meeting to critically review and discuss the current evidence and to phrase recommendations for clinical practice. A consensus was reached recommending the use of EPO for patients infected with viral genotype 1 developing significant anaemia below 100 g/L haemoglobin and a haematocrit of <30% during standard therapy to improve quality of life and sustain optimal ribavirin dose. However, the evidence supporting its use in patients with pre-existing anaemia, non-1 viral genotypes, a former relapse or nonresponse, liver transplant recipients and cardiovascular or pulmonary disease is considered insufficient.

Psychosocial stress and cardiovascular risk : current opinion

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Epidemiologic research of the last half-century has clearly shown that psychosocial factors related to the social environment, personality characteristics, and negative affect increase the risk of incident CVD and also impact prognosis of cardiac patients. Several mechanisms may explain this link, including a genetic predisposition, poor lifestyle choices, low adherence to health recommendations, and direct pathophysiologic perturbations. The latter include alteration of the hypothalamic-pituitary adrenal axis and autonomic dysfunction resulting in endothelial dysfunction, inflammation, and a prothrombotic state further downstream. Screening for psychosocial factors seems appropriate as part of the standard history and based on the clinician's knowledge of the patient and the purpose of the visit. Psychological interventions generally alleviate distress in cardiac patients, but whether they reduce the risk of hard cardiovascular endpoints and all-cause mortality is less evident. Cardiac patients with more severe depression may particularly profit from antidepressant medications. Due to their pharmacologic properties, selective serotonin reuptake inhibitors were shown to improve cardiovascular outcome. The most effective psychosocial treatment is multicomponent therapy that combines elements of cognitive behaviour therapy ("stress management") and changes in health behaviours, including the adoption of a regular exercise regimen. Gender-specific issues should probably be considered. The field of behavioural cardiology has accumulated a wealth of epidemiological, mechanistic and clinical knowledge that undoubtedly has furthered our understanding about the important role of psychosocial risk factors in patients with a heart disease.

Three-year results of visual outcome with disease activity-guided ranibizumab algorithm for the treatment of exudative age-related macular degeneration

PURPOSE To evaluate 3-year follow-up treatment outcomes with ranibizumab (Lucentis(®)) 0.5 mg administered either monthly or quarterly on a pro re nata (PRN) basis according to a disease activity-guided monitoring and treatment algorithm. METHODS A total of 316 treatment-naive eyes of 316 patients with exudative age-related macular degeneration met the criteria for inclusion in this retrospective, interventional case series. Patients were treated with ranibizumab 0.5 mg according to a disease activity-guided algorithm with monthly monitoring. Optical coherence tomography and fluorescein angiography were routinely used to assess disease activity: active lesions were treated with a series of three monthly injections, whereas inactive lesions were treated with quarterly injections. RESULTS Mean Early Treatment Diabetic Retinopathy Study best-corrected visual acuity improved from 52 letters at baseline to 59 letters at 12 months, achieved with a mean of 7.1 injections, 61 letters at 24 months with a mean of 5.0 injections administered in the second year and 60 letters at 36 months with a mean number of 5.2 injections. CONCLUSIONS Monthly visits and a morphology-driven PRN regimen with 3 injections in case of recurrence plus quarterly injections in case of inactive CNV resulted in an average VA gain of 7-9 letters that could be maintained over 3 years.

Compliance and knowledge about glaucoma in patients at tertiary glaucoma units

To document the rate of self-reported compliance and glaucoma-related knowledge in Swiss patients and to identify risk factors for their poor compliance. This was an observational study, including a total of 200 consecutive patients already under glaucoma medication in two Swiss tertiary glaucoma clinics (Geneva and Bern). Personal characteristics, presence of systemic disease, compliance with glaucoma medication, attitude to the ophthalmologist, and glaucoma-related attitudes were ascertained by means of a predetermined questionnaire with 40 questions. Patients were subsequently assessed for the ability to correctly instil placebo eye drops. Non-compliance with glaucoma medication was defined as omitting more than two doses a week as reported by the patient. Logistic regression was used to evaluate how patient characteristics and knowledge about the disease were related to compliance. Overall, 81% (n = 162) of patients reported to be compliant. Forgetfulness was the most frequently cited reason for non-compliance with dosing regimen (63%). Although 90.5% (n = 181) of patients believed glaucoma medication to be efficient, only 28% (n = 56) could correctly define glaucoma. Factors positively associated with compliance were 'knowledge of glaucoma' [adjusted odds ratio (OR) 4.77 (95% CI 1.36-16.70)] and 'getting help for administration of drops' [OR 2.95 (1.25-6.94)]. These findings indicate that despite the comparatively high compliance rate among glaucoma patients, knowledge of glaucoma remains poor in long-term glaucoma sufferers. Improving knowledge about the disease is important since it is positively associated with compliance in our study.

No longitudinal mitochondrial DNA sequence changes in HIV-infected individuals with and without lipoatrophy

The potential for mitochondrial (mt) DNA mutation accumulation during antiretroviral therapy (ART), and preferential accumulation in patients with lipoatrophy compared with control participants, remains controversial. We sequenced the entire mitochondrial genome, both before ART and after ART exposure, in 29 human immunodeficiency virus (HIV)-infected Swiss HIV Cohort Study participants initiating a first-line thymidine analogue-containing ART regimen. No accumulation of mtDNA mutations or deletions was detected in 13 participants who developed lipoatrophy or in 16 control participants after significant and comparable ART exposure (median duration, 3.3 and 3.7 years, respectively). In HIV-infected persons, the development of lipoatrophy is unlikely to be associated with accumulation of mtDNA mutations detectable in peripheral blood.

Randomized, Double-Blind Trial of the Effect of Fluid Composition on Electrolyte, Acid-Base, and Fluid Homeostasis in Patients Early After Subarachnoid Hemorrhage.

Hyper- and hyponatremia are frequently observed in patients after subarachnoidal hemorrhage, and are potentially related to worse outcome. We hypothesized that the fluid regimen in these patients is associated with distinct changes in serum electrolytes, acid-base disturbances, and fluid balance.

Comparison of oral administration of lomustine and prednisolone or prednisolone alone as treatment for granulomatous meningoencephalomyelitis or necrotizing encephalitis in dogs

OBJECTIVE: To compare oral administration of lomustine and prednisolone with oral administration of prednisolone alone as treatment for granulomatous meningoencephalomyelitis (GME) or necrotizing encephalitis (NE) in dogs. DESIGN: Retrospective cohort study. ANIMALS: 25 dogs with GME and 18 dogs with NE (diagnosis confirmed in 8 and 5 dogs, respectively). PROCEDURES: Records of dogs with GME or NE were reviewed for results of initial neurologic assessments and clinicopathologic findings, treatment, follow-up clinicopathologic findings (for lomustine-treated dogs), and survival time. Dogs with GME or NE treated with lomustine and prednisolone were assigned to groups 1 (n = 14) and 3 (10), respectively; those treated with prednisolone alone were assigned to groups 2 (11) and 4 (8), respectively. RESULTS: Prednisolone was administered orally every 12 hours to all dogs. In groups 1 and 3, mean lomustine dosage was 60.3 mg/m(2), PO, every 6 weeks. Median survival times in groups 1 through 4 were 457, 329, 323, and 91 days, respectively (no significant difference between groups 1 and 2 or between groups 3 and 4). Within the initial 12 months of treatment, median prednisolone dosage was reduced in all groups; dosage reduction in group 1 was significantly larger than that in group 2 at 6, 9, and 12 months. Combination treatment most frequently caused leukopenia, but had no significant effect on liver enzyme activities. CONCLUSIONS AND CLINICAL RELEVANCE: In dogs with GME and NE, oral administration of lomustine and prednisolone or prednisolone alone had similar efficacy. Inclusion of lomustine in the treatment regimen was generally tolerated well.

Milk fatty acid profile related to energy balance in dairy cows

Milk fatty acid (FA) profile is a dynamic pattern influenced by lactational stage, energy balance and dietary composition. In the first part of this study, effects of the energy balance during the proceeding lactation [weeks 1-21 post partum (pp)] on milk FA profile of 30 dairy cows were evaluated under a constant feeding regimen. In the second part, effects of a negative energy balance (NEB) induced by feed restriction on milk FA profile were studied in 40 multiparous dairy cows (20 feed-restricted and 20 control). Feed restriction (energy balance of -63 MJ NEL/d, restriction of 49 % of energy requirements) lasted 3 weeks starting at around 100 days in milk. Milk FA profile changed markedly from week 1 pp up to week 12 pp and remained unchanged thereafter. The proportion of saturated FA (predominantly 10:0, 12:0, 14:0 and 16:0) increased from week 1 pp up to week 12 pp, whereas monounsaturated FA, predominantly the proportion of 18:1,9c decreased as NEB in early lactation became less severe. During the induced NEB, milk FA profile showed a similarly directed pattern as during the NEB in early lactation, although changes were less marked for most FA. Milk FA composition changed rapidly within one week after initiation of feed restriction and tended to adjust to the initial composition despite maintenance of a high NEB. C18:1,9c was increased significantly during the induced NEB indicating mobilization of a considerable amount of adipose tissue. Besides 18:1,9c, changes in saturated FA, monounsaturated FA, de-novo synthesized and preformed FA (sum of FA >C16) reflected energy status in dairy cows and indicated the NEB in early lactation as well as the induced NEB by feed restriction.