Efficacy and safety of human papillomavirus vaccination in HIV-infected patients: a systematic review and meta-analysis.

The prophylactic vaccines available to protect against infections by HPV are well tolerated and highly immunogenic. People with HIV have a higher risk of developing HPV infection and HPV-associated cancers due to a lower immune response, and due to viral interactions. We performed a systematic review of RCTs to assess HPV vaccines efficacy and safety on HIV-infected people compared to placebo or no intervention in terms of seroconversion, infections, neoplasms, adverse events, CD4+ T-cell count and HIV viral load. The vaccine-group showed a seroconversion rate close to 100% for each vaccine and a significantly higher level of antibodies against HPV vaccine types, as compared to the placebo group (MD = 4333.3, 95% CI 2701.4; 5965.1 GMT EL.U./ml for HPV type 16 and MD = 1408.8, 95% CI 414.8; 2394.7 GMT EL.U./ml for HPV type 18). There were also no differences in terms of severe adverse events (RR = 0.6, 95% CI 0.2; 1.6) and no severe adverse events (RR = 0.6, 95% CI 0.9; 1.2) between vaccine and placebo groups. Secondary outcomes, such as CD4 + T-cell count and HIV viral load, did not differ between groups (MD = 14.8, 95% CI - 35.1; 64.6 cells/µl and MD = 0.0, 95% CI - 0.3; 0.3 log10 RNA copies/ml, respectively). Information on the remaining outcomes was scarce and that did not allow us to combine the data. The results support the use of the HPV vaccine in HIV-infected patients and highlight the need of further RCTs assessing the effectiveness of the HPV vaccine on infections and neoplasms.

Health technology assessment-based approach to flow cytometric immunophenotyping of acute leukemias: a literature classification.

OBJECTIVE: Acute leukemia (AL) is a broad, heterogeneous group of malignant diseases. The diagnostic workup of AL is based on several clinical and laboratory findings, including flow cytometric immunophenotyping. However, the role of this assay in the diagnosis of AL has not been systematically investigated. The aim of this study was to determine the accuracy and utility of flow cytometric immunophenotyping in the identification, characterization, and staging of AL. METHODS: We performed a systematic selection and classification of the literature since 1980, focused on flow cytometric immunophenotyping of AL. We applied a 6-variables model to cover both the technical capabilities and the clinical value of flow cytometric immunophenotyping in the diagnosis of AL. RESULTS: Using 3 key words (acute leukemia, immunophenotyping, flow cytometry), we screened the literature from January 1985 to April 2015 in PubMed and Embase databases and found 1010 articles. A total of 363 were selected and submitted to the expert panel, which selected a final data set of 248 articles to be analyzed. Of these, 160 were focused on clinical and biological issues, 55 were technical articles, and 31 were reviews. These 248 articles were then analyzed according to the 6-variables model and definitively classified. CONCLUSIONS: We assessed the literature on flow cytometric immunophenotyping of AL over 3 decades as the first step toward an evidence-based analysis of the impact of this technology on the clinical management of patients with AL.

Efficacy of hysteroscopy in improving reproductive outcomes of infertile couples: a systematic review and meta-analysis.

BACKGROUND: The scientific community has been re-evaluating the clinical relevance of hysteroscopy in the diagnosis and treatment of uterine factors and its role in the infertility work-up, thanks to its potential capability to improve reproductive outcomes and reduce time to pregnancy. OBJECTIVE AND RATIONALE: The objective of this systematic review and meta-analysis was to assess the efficacy of diagnostic and operative hysteroscopy in improving the live birth rate (LBR) of infertile women, with and without intrauterine abnormalities, at any stage of the infertility work-up. SEARCH METHODS: PubMed, Embase, the Cochrane Library and the Clinical Trials Registry using Medical Subject Headings and free text terms were searched up to June 2014, without language or year restrictions. Randomized controlled trials (RCTs) enrolling infertile women with no suspected intrauterine cavity abnormalities and comparing hysteroscopy versus no hysteroscopy at any stage of the diagnostic work-up, but prior to the first attempt of standard IVF or ICSI or after (one or more) failed attempts of IVF/ICSI were included. RCTs enrolling infertile women with intrauterine abnormalities and comparing operative versus diagnostic hysteroscopy were also included. Risk of bias was assessed using the criteria recommended by the Cochrane Collaboration and the overall quality of evidence was assessed using the GRADE approach. Results were pooled by meta-analysis using the random effect model. OUTCOMES: The primary outcome evaluated was the LBR, while secondary outcomes were pregnancy rate, miscarriage rate and procedure-related complications. Five hundred and eighty-eight records were retrieved after removing duplicates. Nine studies were included, with 2976 participants. Four studies included infertile women with one or more failed IVF/ICSI cycles. Two studies included infertile women who were candidates for their first IVF/ICSI. One study included candidates both for first IVF/ICSI and with one or more failed IVF/ICSI cycles. Two studies included infertile women affected by uterine fibroids and endometrial polyps, who had not received IVF/ICSI nor were candidates. Seven studies were included in the meta-analysis. Comparing hysteroscopy with no hysteroscopy prior to any (first or subsequent) IVF/ICSI attempt in infertile women without intrauterine abnormalities, there was very low-quality evidence that hysteroscopy increased LBR (relative risk (RR) 1.48, 95% confidence interval (CI) 1.20-1.81; three studies with 1088 participants) and moderate quality evidence that it increased pregnancy rate (RR 1.45, 95% CI 1.26-1.67; seven studies, 2545 participants). Results on pregnancy rate were confirmed in the subgroup analysis of five studies including only women with one or more implantation failures (RR 1.41, 95% CI 1.14-1.75) and three studies where hysteroscopy was performed before the first IVF/ICSI attempt (RR 1.55, 95% CI 1.26-1.91). Comparing operative hysteroscopy for intrauterine abnormalities in infertile women with already diagnosed polyps or fibroids, there was low-quality evidence that operative hysteroscopy increases pregnancy rate (RR 2.13, 95% CI 1.56-2.92). None of the studies comparing operative versus diagnostic hysteroscopy assessed LBR. WIDER IMPLICATIONS: Robust and high-quality RCTs are still needed before hysteroscopy can be regarded as a first-line procedure in all infertile women, especially during the basal clinical assessment of the couple, when assisted reproductive treatment is not indicated yet.

Telerehabilitation and recovery of motor function: a systematic review and meta-analysis.

Recent advances in telecommunication technologies have boosted the possibility to deliver rehabilitation via the internet (i.e. telerehabilitation). Several studies have shown that telerehabilitation is effective to improve clinical outcomes in disabling conditions. The aim of this review was to determine whether telerehabilitation was more effective than other modes of delivering rehabilitation to regain motor function, in different populations of patients.We searched PubMed, Embase and the Cochrane library retrieving 2360 records. Twelve studies were included involving different populations (i.e. neurological, total knee arthroplasty (TKA), cardiac) of patients. Inconclusive finding were found on the effect of telerehabilitation for neurological patients (SMD = 0.08, CI 95% = -0.13, 0.29), while both for cardiac (SMD = 0.24, CI 95% = 0.04, 0.43) and TKA patients (Timed Up and Go test: MD = -5.17, CI 95% = -9.79, -0.55) the results were in favour of telerehabilitation.Conclusive evidence on the efficacy of telerehabilitation for treatment of motor function, regardless of pathology, was not reached. Nevertheless, a strong positive effect was found for patients following orthopaedic surgery, suggesting that the increased intensity provided by telerehabilitation is a promising option to be offered to patients. More and higher quality research is needed in this field especially with neurological patients.

Trastuzumab-containing regimens for metastatic breast cancer.

BACKGROUND: Patients with breast cancer are classified as having cells that over-express the human epidermal growth factor receptor 2 (known as HER2-positive) or not (HER2-negative). Typically, patients with HER2-positive disease have a worse prognosis. Trastuzumab is a selective treatment that targets the HER2 pathway. The available evidence supporting trastuzumab regimens mostly relies upon surrogate endpoints and, although the efficacy results seem to support its use, other uncertainties have been raised about its net benefit in relation to transient cardiac toxicity and a long-term increased risk of metastasis to the central nervous system. OBJECTIVES: To assess the evidence on the efficacy and safety of therapy with trastuzumab (overall) and in relation to the type of co-administered regimen and the line of treatment, i.e. first-line or beyond progression, in women with HER2-positive metastatic breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCG) Specialised Register and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL (2013, Issue 1), MEDLINE, EMBASE, BIOSIS, the WHO International Clinical Trials Registry Platform (ICTRP) search portal and ClinicalTrials.gov (up to 17 January 2013). SELECTION CRITERIA: RCTs comparing the efficacy and safety of trastuzumab alone or in combination with chemotherapy, hormonal therapy or targeted agents in women with HER2-positive metastatic breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included type of regimen (taxane-containing, anthracycline-containing, aromatase inhibitor-containing or other) and treatment line (first-line, beyond progression). MAIN RESULTS: The review found seven trials, involving 1497 patients, which met the criteria to be included. The trials were generally of moderate methodological quality; two studies have not published their results on overall survival so the presence of selective outcome reporting bias cannot be ruled out. None of the studies used blinding to treatment allocation, though this is unlikely to have biased the results for overall survival. Studies varied in terms of co-administered regimen and in terms of treatment line. In four studies, trastuzumab was administered with a chemotherapy, such as a taxane-containing, anthracycline-containing or capecitabine-containing regimen. Two studies considered postmenopausal women and administered trastuzumab with hormone-blocking medications, such as an aromatase inhibitor. One study administered trastuzumab in addition to lapatinib. Five studies out of seven included women treated with trastuzumab administered until progression as first-line treatment and two studies considered trastuzumab beyond progression. The combined HRs for overall survival and progression-free survival favoured the trastuzumab-containing regimens (HR 0.82, 95% confidence interval (CI) 0.71 to 0.94, P = 0.004; and HR 0.61, 95% CI 0.54 to 0.70, P < 0.00001, respectively; moderate-quality evidence). Trastuzumab increased the risk of congestive heart failure (RR 3.49, 90% CI 1.88 to 6.47, P = 0.0009; moderate-quality evidence) and left ventricular ejection fraction (LVEF) decline (RR 2.65, 90% CI 1.48 to 4.74, P = 0.006). For haematological toxicities, such as neutropenic fever and anaemia, there was no clear evidence that risks differed between groups, while trastuzumab seemed to raise the risk of neutropenia. The overall survival improvement was maintained when considering patients treated as first-line or patients receiving taxane-based regimens. The progression-free survival improvement was maintained when considering patients receiving taxane-based regimens, and patients treated as first-line or subsequent lines. Few data were collected on central nervous system progression. Similarly, few studies reported on quality of life and treatment-related deaths. AUTHORS' CONCLUSIONS: Trastuzumab improved overall survival and progression-free survival in HER2-positive women with metastatic breast cancer, but it also increased the risk of cardiac toxicities, such as congestive heart failure and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab as first-line treatment, or along with a taxane-based regimen, improved mortality outcomes. The evidence to support the use of trastuzumab beyond progression is limited. The recruitment in three out of seven studies was stopped early and in three trials more than 50% of patients in the control groups were permitted to switch to the trastuzumab arms at progression, making it more difficult to understand the real net benefit of trastuzumab.Trastuzumab is generally used for women with HER2-positive early breast cancer in clinical practice, while women enrolled in most of the trials in the metastatic setting were naive to trastuzumab. The effectiveness of trastuzumab for women relapsing after adjuvant trastuzumab is therefore still an open issue, although it is likely that the majority are being offered it again.

Trastuzumab containing regimens for early breast cancer.

BACKGROUND: Approximately one-fifth of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2-negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk. OBJECTIVES: To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer. SEARCH METHODS: We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010). SELECTION CRITERIA: RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer. DATA COLLECTION AND ANALYSIS: We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration. MAIN RESULTS: We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies. AUTHORS' CONCLUSIONS: Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials.

Conceptual frameworks and empirical approaches used to assess the impact of health research: an overview of reviews.

BACKGROUND: How to assess the impact of research is of growing interest to funders, policy makers and researchers mainly to understand the value of investments and to increase accountability. Broadly speaking the term "research impact" refers to the contribution of research activities to achieve desired societal outcomes. The aim of this overview is to identify the most common approaches to research impact assessment, categories of impact and their respective indicators. METHODS: We systematically searched the relevant literature (PubMed, The Cochrane Library (1990-2009)) and funding agency websites. We included systematic reviews, theoretical and methodological papers, and empirical case-studies on how to evaluate research impact. We qualitatively summarised the included reports, as well the conceptual frameworks. RESULTS: We identified twenty-two reports belonging to four systematic reviews and 14 primary studies. These publications reported several theoretical frameworks and methodological approaches (bibliometrics, econometrics, ad hoc case studies). The "payback model" emerged as the most frequently used. Five broad categories of impact were identified: a) advancing knowledge, b) capacity building, c) informing decision-making, d) health benefits, e) broad socio-economic benefits. For each proposed category of impact we summarized a set of indicators whose pros and cons are presented and briefly discussed. CONCLUSIONS: This overview is a comprehensive, yet descriptive, contribution to summarize the conceptual framework and taxonomy of an heterogeneous and evolving area of research. A shared and comprehensive conceptual framework does not seem to be available yet and its single components (epidemiologic, economic, and social) are often valued differently in different models.

Quality of life in randomized trials of cytotoxic or hormonal treatment of advanced breast cancer. Is there added value?

BACKGROUND: Since most advanced cancers are still incurable, oncologic clinical research pays considerable attention to palliation, increasingly valuing subjective measures of outcome such as quality of life (QoL). We reviewed randomised clinical trials (RCT) of cytotoxic or hormonal treatments in advanced breast cancer (ABC), published before December 2003, to evaluate the methodological quality of QoL assessment and assess its added value (over classical clinical endpoints (CCE), i.e. survival, response, time to progression, toxicity) in the choice of the best treatment option. METHODS: RCTs were classified according to treatment characteristics and the CCEs. A descriptive analysis was based on the methodological aspects of QoL assessment and the clinical value of QoL findings was judged by counting the frequency of reporting in the study abstracts and the assessment of QoL combined with CCEs. RESULTS: We retrieved 33 eligible RCTs (10,791 patients); only 20 reported the number of patients considered in QoL principal analysis and only 69% of randomized patients were included in such analyses. A total of 17 different QoL questionnaires were used, 11 only once. QoL assessment lasted from less than 12 weeks to progression, and timing of questionnaires from 2 to 12 weeks. Compliance rates were 85.7% for baseline forms and 67% for overall assessment, but this information was available for only 18 and 20 trials, respectively. Wide variability emerged in analysis strategies and statistical approaches. QoL findings were reported in 12 study abstracts (37% of patients). Eight studies reported a significant difference in QoL scores but since QoL data often failed to parallel the clinical findings (e.g. better QoL scores were reported in two of 17 trials with better CCEs and in six of 20 with significant differences in toxicity profiles), the QoL added value was difficult to ascertain and, on the whole, only moderate. CONCLUSION: In ABC trials, QoL assessment added relatively little value to CCEs in helping select the best treatment option, apparently largely because of sub-optimal methodological standards.

The contribution of handsearching European general health care journals to the Cochrane Controlled Trials Register.

A fundamental aim of any systematic review is that all relevant studies should be identified and considered for inclusion. Limitations with searching bibliographic databases led the Cochrane Collaboration to search journals by hand for reports of trials. This article presents the results of a 3-year project to identify and make accessible reports of randomized trials published in European general health care journals. Overall, 21,620 reports of controlled trials were identified from 119 journals from 16 countries. More than three quarters (76%) were published in U.K. or German journals. Only 3,640 (17%) reports were indexed in MEDLINE as controlled trials, and 6,554 (30%) were not indexed in MEDLINE at all. Bibliographic details for all reports are available by searching The Cochrane Controlled Trials Register in The Cochrane Library. This project has ensured that a large proportion of trial reports not previously identifiable has been made accessible to those preparing systematic reviews.

La profilaxis de las convulsiones febriles: análisis y meta-análisis de la literatura / The prophylaxis of the febrile convulsiones: analysis and goal-analysis of the literature

A la controvertida documentación de la que disponemos, le hacen "eco" las indicaciones más varidas y en parte opuestas, que resultan de las publicaciones de pediatría de mayor difusión en Italia. De ahí la exigencia de un repaso de los conocimientos disponibles y de los factores de riesgo relacionados al primer episodio de una convulsión febril, que representan un vínculo histórico para la pediatría y el neurólogo