Extracorporeal photopheresis for systemic sclerosis: A meta-analysis of randomized clinical trials.

Systemic sclerosis (scleroderma) (SSc) is a rare autoimmune disorder characterized by excessive production of collagen. Extracorporeal photopheresis (photochemotherapy, phototherapy) (ECP) involves repeated exposure of peripheral blood lymphocytes to ultraviolet A (UVA) radiation. The rationale for treating patients with SSc by ECP lies in its presumed immunomodulatory effects, though, rigorous data on the specific effects of ECP are limited, particularly in patients with SSc. The objective was to evaluate the effects of extracorporeal photopheresis as a treatment modality for patients with SSc. We searched the databases CENTRAL and MEDLINE on 13 March 2022 and included randomized clinical trials (RCTs) on patients diagnosed with SSc and treated with ECP. Primary outcome was the change of skin scores. We applied independent extraction and judgment by multiple observers. We conducted a meta-analysis applying the inverse variance method and the random effects model; the main outcome measure was standard mean difference of skin scores. We identified three relevant RCTs including 162 randomized (132 analyzed) people who received ECP in a simple parallel design. Pooled data of the three studies were indifferent. We estimated a standard mean difference from baseline of -0.11 (95% confidence interval -0.45 to 0.23), p = 0.54, I2  = 0%. We did not identify serious treatment-related adverse events. The evidence base for extracorporeal photopheresis on skin scores in patients with systemic sclerosis was not high enough to support a superior effect when compared to no treatment, sham photopheresis, or D-penicillamine.

Indoor balneophototherapy for chronic plaque psoriasis: Abridged Cochrane Review.

Artificial exposure to ultraviolet B light (UVB) while soaking in an indoor salt bath, also called balneophototherapy, could simulate the natural exposure to the sun while bathing in the Dead Sea. We aimed to assess the effects of this intervention on patients with chronic plaque psoriasis. We searched CENTRAL, MEDLINE, Embase, and LILACS up to June 2019. We included randomized controlled trials (RCTs). The primary efficacy outcome was psoriasis area and severity index (PASI)-75 to detect people with a 75% or more reduction in the PASI score from baseline. The primary adverse outcome was treatment-related adverse events requiring withdrawal. We included eight RCTs (2105 participants; 1976 analyzed). With respect to PASI-75, two studies found that salt bath + UVB may improve psoriasis when compared to UVB alone (risk ratio 1.71, 95% confidence interval 1.24 to 2.35; 278 participants). With respect to treatment-related adverse events requiring withdrawal, two other studies found little to no difference when compared to UVB alone (risk ratio 0.96, 95% confidence interval 0.35 to 2.64; 404 participants). Salt bath + UVB could improve psoriasis when compared to UVB alone, though, results are based on a limited number of studies and provide low-certainty evidence.

Indoor salt water baths followed by artificial ultraviolet B light for chronic plaque psoriasis.

BACKGROUND: Chronic plaque psoriasis is an immune-mediated, chronic, inflammatory skin disease, which can impair quality of life and social interaction. Disease severity can be classified by the psoriasis area and severity index (PASI) score ranging from 0 to 72 points. Indoor artificial salt bath with or without artificial ultraviolet B (UVB) light is used to treat psoriasis, simulating sea bathing and sunlight exposure; however, the evidence base needs clear evaluation. OBJECTIVES: To assess the effects of indoor (artificial) salt water baths followed by exposure to artificial UVB for treating chronic plaque psoriasis in adults. SEARCH METHODS: We searched the following databases up to June 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trial registers, and checked the reference lists of included studies, recent reviews, and relevant papers for further references to relevant trials. SELECTION CRITERIA: Randomised controlled trials (RCTs) of salt bath indoors followed by exposure to artificial UVB in adults who have been diagnosed with chronic plaque type psoriasis. We included studies reporting between-participant data and within-participant data. We evaluated two different comparisons: 1) salt bath + UVB versus other treatment without UVB; eligible comparators were exposure to psoralen bath, psoralen bath + artificial ultraviolet A UVA) light, topical treatment, systemic treatment, or placebo, and 2) salt bath + UVB versus other treatment + UVB or UVB only; eligible comparators were exposure to bath containing other compositions or concentrations + UVB or UVB only. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We used GRADE to assess the certainty of the evidence. The primary efficacy outcome was PASI-75, to detect people with a 75% or more reduction in PASI score from baseline. The primary adverse outcome was treatment-related adverse events requiring withdrawal. For the dichotomous variables PASI-75 and treatment-related adverse events requiring withdrawal, we estimated the proportion of events among the assessed participants. The secondary outcomes were health-related quality of life using the Dermatology Life Quality Index, (DLQI) pruritus severity measured using a visual analogue scale, time to relapse, and secondary malignancies. MAIN RESULTS: We included eight RCTs: six reported between-participant data (2035 participants; 1908 analysed), and two reported within-participant data (70 participants, 68 analysed; 140 limbs; 136 analysed). One study reported data for the comparison salt bath with UVB versus other treatment without UVB; and eight studies reported data for salt bath with UVB versus other treatment with UVB or UVB only. Of these eight studies, only five reported any of our pre-specified outcomes and assessed the comparison of salt bath with UVB versus UVB only. The one included trial that assessed salt bath plus UVB versus other treatment without UVB (psoralen bath + UVA) did not report any of our primary outcomes. The mean age of the participants ranged from 41 to 50 years of age in 75% of the studies. None of the included studies reported on the predefined secondary outcomes of this review. We judged seven of the eight studies as at high risk of bias in at least one domain, most commonly performance bias. Total trial duration ranged between at least two months and up to 13 months. In five studies, the median participant PASI score at baseline ranged from 15 to 18 and was balanced between treatment arms. Three studies did not report PASI score. Most studies were conducted in Germany; all were set in Europe. Half of the studies were multi-centred (set in spa centres or outpatient clinics); half were set in a single centre in either an unspecified settings, a psoriasis daycare centre, or a spa centre. Commercial spa or salt companies sponsored three of eight studies, health insurance companies funded another, the association of dermatologists funded another, and three did not report on funding. When comparing salt bath plus UVB versus UVB only, two between-participant studies found that salt bath plus UVB may improve psoriasis when measured using PASI 75 (achieving a 75% or more reduction in PASI score from baseline) (risk ratio (RR) 1.71, 95% confidence interval (CI) 1.24 to 2.35; 278 participants; low-certainty evidence). Assessment was conducted at the end of treatment, which was equivalent to six to eight weeks after start of treatment. The two trials which contributed data for the primary efficacy outcome were conducted by the same group, and did not blind outcome assessors. The German Spas Association funded one of the trials and the funding source was not stated for the other trial. Two other between-participant studies found salt bath plus UVB may make little to no difference to outcome treatment-related adverse events requiring withdrawal compared with UVB only (RR 0.96, 95% CI 0.35 to 2.64; 404 participants; low-certainty evidence). One of the studies reported adverse events, but did not specify the type of events; the other study reported skin irritation. One within-participant study found similar results, with one participant reporting severe itch immediately after Dead Sea salt soak in the salt bath and UVB group and two instances of inadequate response to phototherapy and conversion to psoralen bath + UVA reported in the UVB only group (low-certainty evidence). AUTHORS' CONCLUSIONS: Salt bath with artificial ultraviolet B (UVB) light may improve psoriasis in people with chronic plaque psoriasis compared with UVB light treatment alone, and there may be no difference in the occurrence of treatment-related adverse events requiring withdrawal. Both results are based on data from a limited number of studies, which provided low-certainty evidence, so we cannot draw any clear conclusions. The reporting of our pre-specified outcomes was either non-existent or limited, with a maximum of two studies reporting a given outcome. The same group conducted the two trials which contributed data for the primary efficacy outcome, and the German Spas Association funded one of these trials. We recommend further RCTs that assess PASI-75, with detailed reporting of the outcome and time point, as well as treatment-related adverse events. Risk of bias was an issue; future studies should ensure blinding of outcome assessors and full reporting.

Topical azelaic acid, salicylic acid, nicotinamide, sulphur, zinc and fruit acid (alpha-hydroxy acid) for acne.

BACKGROUND: Acne is an inflammatory disorder with a high global burden. It is common in adolescents and primarily affects sebaceous gland-rich areas. The clinical benefit of the topical acne treatments azelaic acid, salicylic acid, nicotinamide, sulphur, zinc, and alpha-hydroxy acid is unclear. OBJECTIVES: To assess the effects of topical treatments (azelaic acid, salicylic acid, nicotinamide, zinc, alpha-hydroxy acid, and sulphur) for acne. SEARCH METHODS: We searched the following databases up to May 2019: the Cochrane Skin Group Specialised Register, CENTRAL, MEDLINE, Embase, and LILACS. We also searched five trials registers. SELECTION CRITERIA: Clinical randomised controlled trials of the six topical treatments compared with other topical treatments, placebo, or no treatment in people with acne. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Key outcomes included participants' global self-assessment of acne improvement (PGA), withdrawal for any reason, minor adverse events (assessed as total number of participants who experienced at least one minor adverse event), and quality of life. MAIN RESULTS: We included 49 trials (3880 reported participants) set in clinics, hospitals, research centres, and university settings in Europe, Asia, and the USA. The vast majority of participants had mild to moderate acne, were aged between 12 to 30 years (range: 10 to 45 years), and were female. Treatment lasted over eight weeks in 59% of the studies. Study duration ranged from three months to three years. We assessed 26 studies as being at high risk of bias in at least one domain, but most domains were at low or unclear risk of bias. We grouped outcome assessment into short-term (less than or equal to 4 weeks), medium-term (from 5 to 8 weeks), and long-term treatment (more than 8 weeks). The following results were measured at the end of treatment, which was mainly long-term for the PGA outcome and mixed length (medium-term mainly) for minor adverse events. Azelaic acid In terms of treatment response (PGA), azelaic acid is probably less effective than benzoyl peroxide (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.72 to 0.95; 1 study, 351 participants), but there is probably little or no difference when comparing azelaic acid to tretinoin (RR 0.94, 95% CI 0.78 to 1.14; 1 study, 289 participants) (both moderate-quality evidence). There may be little or no difference in PGA when comparing azelaic acid to clindamycin (RR 1.13, 95% CI 0.92 to 1.38; 1 study, 229 participants; low-quality evidence), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). Low-quality evidence indicates there may be no differences in rates of withdrawal for any reason when comparing azelaic acid with benzoyl peroxide (RR 0.88, 95% CI 0.60 to 1.29; 1 study, 351 participants), clindamycin (RR 1.30, 95% CI 0.48 to 3.56; 2 studies, 329 participants), or tretinoin (RR 0.66, 95% CI 0.29 to 1.47; 2 studies, 309 participants), but we are uncertain whether there is a difference between azelaic acid and adapalene (1 study, 55 participants; very low-quality evidence). In terms of total minor adverse events, we are uncertain if there is a difference between azelaic acid compared to adapalene (1 study; 55 participants) or benzoyl peroxide (1 study, 30 participants) (both very low-quality evidence). There may be no difference when comparing azelaic acid to clindamycin (RR 1.50, 95% CI 0.67 to 3.35; 1 study, 100 participants; low-quality evidence). Total minor adverse events were not reported in the comparison of azelaic acid versus tretinoin, but individual application site reactions were reported, such as scaling. Salicylic acid For PGA, there may be little or no difference between salicylic acid and tretinoin (RR 1.00, 95% CI 0.92 to 1.09; 1 study, 46 participants; low-quality evidence); we are not certain whether there is a difference between salicylic acid and pyruvic acid (1 study, 86 participants; very low-quality evidence); and PGA was not measured in the comparison of salicylic acid versus benzoyl peroxide. There may be no difference between groups in withdrawals when comparing salicylic acid and pyruvic acid (RR 0.89, 95% CI 0.53 to 1.50; 1 study, 86 participants); when salicylic acid was compared to tretinoin, neither group had withdrawals (both based on low-quality evidence (2 studies, 74 participants)). We are uncertain whether there is a difference in withdrawals between salicylic acid and benzoyl peroxide (1 study, 41 participants; very low-quality evidence). For total minor adverse events, we are uncertain if there is any difference between salicylic acid and benzoyl peroxide (1 study, 41 participants) or tretinoin (2 studies, 74 participants) (both very low-quality evidence). This outcome was not reported for salicylic acid versus pyruvic acid, but individual application site reactions were reported, such as scaling and redness. Nicotinamide Four studies evaluated nicotinamide against clindamycin or erythromycin, but none measured PGA. Low-quality evidence showed there may be no difference in withdrawals between nicotinamide and clindamycin (RR 1.12, 95% CI 0.49 to 2.60; 3 studies, 216 participants) or erythromycin (RR 1.40, 95% CI 0.46 to 4.22; 1 study, 158 participants), or in total minor adverse events between nicotinamide and clindamycin (RR 1.20, 95% CI 0.73 to 1.99; 3 studies, 216 participants; low-quality evidence). Total minor adverse events were not reported in the nicotinamide versus erythromycin comparison. Alpha-hydroxy (fruit) acid There may be no difference in PGA when comparing glycolic acid peel to salicylic-mandelic acid peel (RR 1.06, 95% CI 0.88 to 1.26; 1 study, 40 participants; low-quality evidence), and we are uncertain if there is a difference in total minor adverse events due to very low-quality evidence (1 study, 44 participants). Neither group had withdrawals (2 studies, 84 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Compared to benzoyl peroxide, azelaic acid probably leads to a worse treatment response, measured using PGA. When compared to tretinoin, azelaic acid probably makes little or no difference to treatment response. For other comparisons and outcomes the quality of evidence was low or very low. Risk of bias and imprecision limit our confidence in the evidence. We encourage the comparison of more methodologically robust head-to-head trials against commonly used active drugs.

Anti-GD2 antibody-containing immunotherapy postconsolidation therapy for people with high-risk neuroblastoma treated with autologous haematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease that primarily affects children. The tumours mainly develop in the adrenal medullary tissue, and an abdominal mass is the most common presentation. High-risk disease is characterised by metastasis and other primary tumour characteristics resulting in increased risk for an adverse outcome. The GD2 carbohydrate antigen is expressed on the cell surface of neuroblastoma tumour cells and is thus a promising target for anti-GD2 antibody-containing immunotherapy. OBJECTIVES: To assess the efficacy of anti-GD2 antibody-containing postconsolidation immunotherapy after high-dose chemotherapy (HDCT) and autologous haematopoietic stem cell transplantation (HSCT) compared to standard therapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. Our primary outcomes were overall survival and treatment-related mortality. Our secondary outcomes were progression-free survival, event-free survival, early toxicity, late non-haematological toxicity, and health-related quality of life. SEARCH METHODS: We searched the electronic databases CENTRAL (2018, Issue 9), MEDLINE (PubMed), and Embase (Ovid) on 20 September 2018. We searched trial registries and conference proceedings on 28 October 2018. Further searches included reference lists of recent reviews and relevant articles as well as contacting experts in the field. There were no limits on publication year or language. SELECTION CRITERIA: Randomised controlled trials evaluating anti-GD2 antibody-containing immunotherapy after HDCT and autologous HSCT in people with high-risk neuroblastoma. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, abstracted data on study and participant characteristics, and assessed risk of bias and GRADE. Any differences were resolved by discussion, with third-party arbitration unnecessary. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, that is study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. MAIN RESULTS: We identified one randomised controlled trial that included 226 people with high-risk neuroblastoma who were pre-treated with autologous HSCT. The study randomised 113 participants to receive immunotherapy including isotretinoin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2, and ch14.18, a type of anti-GD2 antibody also known as dinutuximab. The study randomised another 113 participants to receive standard therapy including isotretinoin.The results on overall survival favoured the dinutuximab-containing immunotherapy group (hazard ratio (HR) 0.50, 95% confidence interval (CI) 0.31 to 0.80; P = 0.004). The results on event-free survival also favoured the dinutuximab-containing immunotherapy group (HR 0.61, 95% CI 0.41 to 0.92; P = 0.020). Randomised data on adverse events were not reported separately. The study did not report progression-free survival, late non-haematological toxicity, and health-related quality of life as separate endpoints. We graded the quality of the evidence as moderate. AUTHORS' CONCLUSIONS: The evidence base favours dinutuximab-containing immunotherapy compared to standard therapy concerning overall survival and event-free survival in people with high-risk neuroblastoma pre-treated with autologous HSCT. Randomised data on adverse events are lacking, therefore more research is needed before definitive conclusions can be made regarding this outcome.

Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus.

BACKGROUND: Foot wounds in people with diabetes mellitus (DM) are a common and serious global health issue. People with DM are prone to developing foot ulcers and, if these do not heal, they may also undergo foot amputation surgery resulting in postoperative wounds. Negative pressure wound therapy (NPWT) is a technology that is currently used widely in wound care. NPWT involves the application of a wound dressing attached to a vacuum suction machine. A carefully controlled negative pressure (or vacuum) sucks wound and tissue fluid away from the treated area into a canister. A clear and current overview of current evidence is required to facilitate decision-making regarding its use. OBJECTIVES: To assess the effects of negative pressure wound therapy compared with standard care or other therapies in the treatment of foot wounds in people with DM in any care setting. SEARCH METHODS: In January 2018, for this first update of this review, we searched the Cochrane Wounds Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE (including In-Process & Other Non-Indexed Citations); Ovid Embase and EBSCO CINAHL Plus. We also searched clinical trials registries for ongoing and unpublished studies, and scanned reference lists of relevant included studies, reviews, meta-analyses and health technology reports to identify additional studies. There were no restrictions with respect to language, date of publication or study setting. We identified six additional studies for inclusion in the review. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) that evaluated the effects of any brand of NPWT in the treatment of foot wounds in people with DM, irrespective of date or language of publication. Particular effort was made to identify unpublished studies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. Initial disagreements were resolved by discussion, or by including a third review author when necessary. We presented and analysed data separately for foot ulcers and postoperative wounds. MAIN RESULTS: Eleven RCTs (972 participants) met the inclusion criteria. Study sample sizes ranged from 15 to 341 participants. One study had three arms, which were all included in the review. The remaining 10 studies had two arms. Two studies focused on postamputation wounds and all other studies included foot ulcers in people with DM. Ten studies compared NPWT with dressings; and one study compared NPWT delivered at 75 mmHg with NPWT delivered at 125 mmHg. Our primary outcome measures were the number of wounds healed and time to wound healing.NPWT compared with dressings for postoperative woundsTwo studies (292 participants) compared NPWT with moist wound dressings in postoperative wounds (postamputation wounds). Only one study specified a follow-up time, which was 16 weeks. This study (162 participants) reported an increased number of healed wounds in the NPWT group compared with the dressings group (risk ratio (RR) 1.44, 95% confidence interval (CI) 1.03 to 2.01; low-certainty evidence, downgraded for risk of bias and imprecision). This study also reported that median time to healing was 21 days shorter with NPWT compared with moist dressings (hazard ratio (HR) calculated by review authors 1.91, 95% CI 1.21 to 2.99; low-certainty evidence, downgraded for risk of bias and imprecision). Data from the two studies suggest that it is uncertain whether there is a difference between groups in amputation risk (RR 0.38, 95% CI 0.14 to 1.02; 292 participants; very low-certainty evidence, downgraded once for risk of bias and twice for imprecision).NPWT compared with dressings for foot ulcersThere were eight studies (640 participants) in this analysis and follow-up times varied between studies. Six studies (513 participants) reported the proportion of wounds healed and data could be pooled for five studies. Pooled data (486 participants) suggest that NPWT may increase the number of healed wounds compared with dressings (RR 1.40, 95% CI 1.14 to 1.72; I² = 0%; low-certainty evidence, downgraded once for risk of bias and once for imprecision). Three studies assessed time to healing, but only one study reported usable data. This study reported that NPWT reduced the time to healing compared with dressings (hazard ratio (HR) calculated by review authors 1.82, 95% CI 1.27 to 2.60; 341 participants; low-certainty evidence, downgraded once for risk of bias and once for imprecision).Data from three studies (441 participants) suggest that people allocated to NPWT may be at reduced risk of amputation compared with people allocated to dressings (RR 0.33, 95% CI 0.15 to 0.70; I² = 0%; low-certainty evidence; downgraded once for risk of bias and once for imprecision).Low-pressure compared with high-pressure NPWT for foot ulcersOne study (40 participants) compared NPWT 75 mmHg and NPWT 125 mmHg. Follow-up time was four weeks. There were no data on primary outcomes. There was no clear difference in the number of wounds closed or covered with surgery between groups (RR 0.83, 95% CI 0.47 to 1.47; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision) and adverse events (RR 1.50, 95% CI 0.28 to 8.04; very low-certainty evidence, downgraded once for risk of bias and twice for serious imprecision). AUTHORS' CONCLUSIONS: There is low-certainty evidence to suggest that NPWT, when compared with wound dressings, may increase the proportion of wounds healed and reduce the time to healing for postoperative foot wounds and ulcers of the foot in people with DM. For the comparisons of different pressures of NPWT for treating foot ulcers in people with DM, it is uncertain whether there is a difference in the number of wounds closed or covered with surgery, and adverse events. None of the included studies provided evidence on time to closure or coverage surgery, health-related quality of life or cost-effectiveness. The limitations in current RCT evidence suggest that further trials are required to reduce uncertainty around decision-making regarding the use of NPWT to treat foot wounds in people with DM.

Autologous hematopoietic stem cell transplantation following high-dose chemotherapy for nonrhabdomyosarcoma soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In people with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage. OBJECTIVES: To assess the efficacy and safety of high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (HSCT) for all stages of nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults. SEARCH METHODS: For this update, we revised the search strategy to improve the precision and reduce the number of irrelevant hits. We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 8), PubMed from 2012 to 6 September 2016, and Embase from 2012 to 26 September 2016. We searched online trial registries and congress proceedings from 2012 to 26 September 2016. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title or abstract. We restricted the study design to RCTs. We included studies if at least 80% of participants had a diagnosis listed in any version of the World Health Organization (WHO) classification and classified as malignant. The search included children and adults with no age limits. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. The primary outcomes were overall survival and treatment-related mortality. MAIN RESULTS: We identified 1549 records; 85 items from electronic databases, 45 from study registries, and 1419 from congress proceedings. The revised search strategy did not identify any additional RCTs. In the previous version of the review, we identified one RCT comparing HDCT followed by autologous HSCT versus standard-dose chemotherapy (SDCT). The trial randomized 87 participants who were considerably heterogeneous with respect to 19 different tumor entities. The data from 83 participants were available for analysis.In the single included trial, overall survival at three years was 32.7% in the HDCT arm versus 49.4% in the SDCT arm and there was no difference between the treatment groups (hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.70 to 2.29, P = 0.44; 1 study, 83 participants; high quality evidence). In a subgroup of participants who had a complete response before HDCT, overall survival was higher in both treatment groups and overall survival at three years was 42.8% in the HDCT arm versus 83.9% in the SDCT arm and favored the SDCT group (HR 2.92, 95% CI 1.1 to 7.6, P = 0.028; 1 study, 39 participants).In the single included trial, the authors reported one treatment-related leukemia death two years after HDCT. They also evaluated severe adverse events WHO grade 3 to 4 in 22 participants in the HDCT arm and in 51 participants in the SDCT arm. The authors reported 11 events concerning digestive-, infection-, pain-, or asthenia-related toxicity in the HDCT arm and one event in the SDCT arm (moderate quality evidence). The development of secondary neoplasia was not addressed. We judged the study to have an overall unclear risk of bias as three of seven items had unclear and four items had low risk of bias. For GRADE, we judged three items as high quality and three items were not reported. AUTHORS' CONCLUSIONS: The limited data of a single RCT with an unclear risk of bias and moderate to high quality evidence showed no survival advantage for HDCT. If this treatment is offered it should only be given after careful consideration on an individual person basis and possibly only as part of a well-designed RCT.

Retinoic acid postconsolidation therapy for high-risk neuroblastoma patients treated with autologous haematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumours mainly develop in the adrenal medullary tissue, with an abdominal mass as the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterised by metastasis and other features that increase the risk of an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. This review is an update of a previously published Cochrane Review. OBJECTIVES: To evaluate the efficacy and safety of additional retinoic acid as part of a postconsolidation therapy after high-dose chemotherapy (HDCT) followed by autologous haematopoietic stem cell transplantation (HSCT), compared to placebo retinoic acid or to no additional retinoic acid in people with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library (2016, Issue 11), MEDLINE in PubMed (1946 to 24 November 2016), and Embase in Ovid (1947 to 24 November 2016). Further searches included trial registries (on 22 December 2016), conference proceedings (on 23 March 2017) and reference lists of recent reviews and relevant studies. We did not apply limits by publication year or languages. SELECTION CRITERIA: Randomised controlled trials (RCTs) evaluating additional retinoic acid after HDCT followed by HSCT for people with high-risk neuroblastoma compared to placebo retinoic acid or to no additional retinoic acid. Primary outcomes were overall survival and treatment-related mortality. Secondary outcomes were progression-free survival, event-free survival, early toxicity, late toxicity, and health-related quality of life. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: The update search did not identify any additional studies. We identified one RCT that included people with high-risk neuroblastoma who received HDCT followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a second random allocation. These 98 participants had no progressive disease after HDCT followed by autologous HSCT. There was no clear evidence of difference between the treatment groups either in overall survival (hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.46 to 1.63; one trial; P = 0.66) or in event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59). We calculated the HR values using the complete follow-up period of the trial. The study also reported overall survival estimates at a fixed point in time. At the time point of five years, the survival estimate was reported to be 59% for the retinoic acid group and 41% for the no-further-therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. We could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. We judged the evidence to be of low quality for overall survival and event-free survival, downgraded because of study limitations and imprecision. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated additional retinoic acid as part of a postconsolidation therapy after HDCT followed by autologous HSCT versus no further therapy in people with high-risk neuroblastoma. There was no clear evidence of a difference in overall survival and event-free survival between the treatment alternatives. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since when many changes in treatment and risk classification have occurred. Based on the currently available evidence, we are therefore uncertain about the effects of retinoic acid in people with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Immunotherapy for metastatic renal cell carcinoma.

BACKGROUND: Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both.Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients.In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. OBJECTIVES: To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. SEARCH METHODS: We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. SELECTION CRITERIA: We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC. DATA COLLECTION AND ANALYSIS: We collected and analyzed studies according to the published protocol. Summary statistics for the primary endpoints were risk ratios (RRs) and mean differences (MD) with their 95% confidence intervals (CIs). We rated the quality of evidence using GRADE methodology and summarized the quality and magnitude of relative and absolute effects for each primary outcome in our 'Summary of findings' tables. MAIN RESULTS: We identified eight studies with 4732 eligible participants and an additional 13 ongoing studies. We categorized studies into comparisons, all against standard therapy accordingly as first-line (five comparisons) or second-line therapy (one comparison) for mRCC.Interferon (IFN)-α monotherapy probably increases one-year overall mortality compared to standard targeted therapies with temsirolimus or sunitinib (RR 1.30, 95% CI 1.13 to 1.51; 2 studies; 1166 participants; moderate-quality evidence), may lead to similar quality of life (QoL) (e.g. MD -5.58 points, 95% CI -7.25 to -3.91 for Functional Assessment of Cancer - General (FACT-G); 1 study; 730 participants; low-quality evidence) and may slightly increase the incidence of adverse events (AEs) grade 3 or greater (RR 1.17, 95% CI 1.03 to 1.32; 1 study; 408 participants; low-quality evidence).There is probably no difference between IFN-α plus temsirolimus and temsirolimus alone for one-year overall mortality (RR 1.13, 95% CI 0.95 to 1.34; 1 study; 419 participants; moderate-quality evidence), but the incidence of AEs of 3 or greater may be increased (RR 1.30, 95% CI 1.17 to 1.45; 1 study; 416 participants; low-quality evidence). There was no information on QoL.IFN-α alone may slightly increase one-year overall mortality compared to IFN-α plus bevacizumab (RR 1.17, 95% CI 1.00 to 1.36; 2 studies; 1381 participants; low-quality evidence). This effect is probably accompanied by a lower incidence of AEs of grade 3 or greater (RR 0.77, 95% CI 0.71 to 0.84; 2 studies; 1350 participants; moderate-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with IFN-α plus bevacizumab or standard targeted therapy (sunitinib) may lead to similar one-year overall mortality (RR 0.37, 95% CI 0.13 to 1.08; 1 study; 83 participants; low-quality evidence) and AEs of grade 3 or greater (RR 1.18, 95% CI 0.85 to 1.62; 1 study; 82 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.Treatment with vaccines (e.g. MVA-5T4 or IMA901) or standard therapy may lead to similar one-year overall mortality (RR 1.10, 95% CI 0.91 to 1.32; low-quality evidence) and AEs of grade 3 or greater (RR 1.16, 95% CI 0.97 to 1.39; 2 studies; 1065 participants; low-quality evidence). QoL could not be evaluated due to insufficient data.In previously treated patients, targeted immunotherapy (nivolumab) probably reduces one-year overall mortality compared to standard targeted therapy with everolimus (RR 0.70, 95% CI 0.56 to 0.87; 1 study; 821 participants; moderate-quality evidence), probably improves QoL (e.g. RR 1.51, 95% CI 1.28 to 1.78 for clinically relevant improvement of the FACT-Kidney Symptom Index Disease Related Symptoms (FKSI-DRS); 1 study, 704 participants; moderate-quality evidence) and probably reduces the incidence of AEs grade 3 or greater (RR 0.51, 95% CI 0.40 to 0.65; 1 study; 803 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS: Evidence of moderate quality demonstrates that IFN-α monotherapy increases mortality compared to standard targeted therapies alone, whereas there is no difference if IFN is combined with standard targeted therapies. Evidence of low quality demonstrates that QoL is worse with IFN alone and that severe AEs are increased with IFN alone or in combination. There is low-quality evidence that IFN-α alone increases mortality but moderate-quality evidence on decreased AEs compared to IFN-α plus bevacizumab. Low-quality evidence shows no difference for IFN-α plus bevacizumab compared to sunitinib with respect to mortality and severe AEs. Low-quality evidence demonstrates no difference of vaccine treatment compared to standard targeted therapies in mortality and AEs, whereas there is moderate-quality evidence that targeted immunotherapies reduce mortality and AEs and improve QoL.

[Negative Pressure Wound Therapy: Randomised Controlled Trials from 2000 to 2015]. / Vakuumversiegelungstherapie von Wunden: randomisierte Studien von 2000 bis 2015.

Background Negative pressure wound therapy is believed to promote wound healing. However, the results from randomised controlled trials (RCTs) are inconsistent. Systematic reviews indicate unclear evidence, due in part to low-quality RCTs, calling for more RCTs of higher quality. Methods This study aimed to ascertain the number of RCTs as well as systematic reviews on RCTs published during the time period from 2000 to 2015. Various search strategies were used to identify studies in PubMed, Cochrane Library, Google, references lists of retrieved articles, and institutions that issue evidence reports. The study also aimed to investigate the quality of included RCTs. It evaluated whether or not the randomisation methodology was comprehensibly described and conclusions were based on acceptable endpoints. Results The search for studies resulted in 456 different references, which included a total of 49 RCTs and 81 systematic reviews. Randomisation was comprehensibly described in 37% (18 out of 49 RCTs) and concealment of allocation in 10% (5’out of 49 RCTs). Conclusions were based on acceptable endpoints in 55% (27 out of 49 RCTs). A superior efficacy of NPWT versus standard was stated in 65% (32 out of 49 RCTs). In studies based on acceptable endpoints, this proportion was 16% (8 out of 49 RCTs). Systematic reviews repeatedly included identical study data. Conclusion The published literature, reviewed over a period of more than 16 years, contains more systematic reviews incorporating secondary data from other RCTs than actual RCTs reporting primary clinical data. Many RCTs seem to be of low quality, which considerably limits the validity of the corresponding conclusions. The ongoing production of potentially unreliable RCTs and redundant systematic reviews does not seem to provide convincing answers to crucial clinical research questions. Therefore, a change in strategy should be contemplated to observe individual characteristics of the respective persons and the wounds in question.

Preclinical good laboratory practice-compliant safety study to evaluate biodistribution and tumorigenicity of a cartilage advanced therapy medicinal product (ATMP).

BACKGROUND: The clinical development of advanced therapy medicinal products (ATMPs), a new class of drugs, requires initial safety studies that deviate from standard non-clinical safety protocols. The study provides a strategy to address the safety aspects of biodistribution and tumorigenicity of ATMPs under good laboratory practice (GLP) conditions avoiding cell product manipulation. Moreover, the strategy was applied on a human ATMP for cartilage repair. METHODS: The testing strategy addresses biodistribution and tumorigenicity using a multi-step analysis without any cell manipulation to exclude changes of test item characteristics. As a safeguard measurement for meeting regulatory expectations, the project design and goals were discussed continuously with the regulatory authority using a staggered scientific advice concept. Subsequently, the strategy was applied to co.don chondrosphere® (huChon spheroid), a tissue-engineered matrix-free ATMP of human normal chondrocytes. In both the biodistribution and tumorigenicity studies, huChon spheroids were implanted subcutaneously into 40 immunodeficient mice. Biodistribution was studied 1 month after implantation. A skin disc containing the huChon spheroid, two surrounding skin rings and selected organs were analyzed by validated, gender-specific, highly-sensitive triplex qPCR and by immunohistochemistry (IHC). RESULTS: No human DNA was detected in distant skin rings and analyzed organs. IHC revealed no direct or indirect indications of cell migration. Tumorigenicity was assessed 6 months after huChon spheroid implantation by palpation, macroscopic inspection, histology and IHC. No mice from the huChon spheroid group developed a tumor at the implantation site. In two mice, benign tumors were detected that were negative for HLA-ABC, suggesting that they were of spontaneous murine origin. CONCLUSIONS: In summary, the presented strategy using a multi-step analysis was confirmed to be suitable for safety studies of ATMPs.

Negative pressure wound therapy for treating leg ulcers.

BACKGROUND: Leg ulcers are open skin wounds that occur between the ankle and the knee that can last weeks, months or even years and are a consequence of arterial or venous valvular insufficiency. Negative pressure wound therapy (NPWT) is a technology that is currently used widely in wound care and is promoted for use on wounds. NPWT involves the application of a wound dressing to the wound, to which a machine is attached. The machine applies a carefully controlled negative pressure (or vacuum), which sucks any wound and tissue fluid away from the treated area into a canister. OBJECTIVES: To assess the effects of negative pressure wound therapy (NPWT) for treating leg ulcers in any care setting. SEARCH METHODS: For this review, in May 2015 we searched the following databases: the Cochrane Wounds Group Specialised Register (searched 21 May 2015); the Cochrane Central Register of Controlled Trials (CENTRAL; The Cochrane Library 2015, Issue 4); Ovid MEDLINE (1946 to 20 May 2015); Ovid MEDLINE (In-Process & Other Non-Indexed Citations 20 May 2015); Ovid EMBASE (1974 to 20 May 2015); EBSCO CINAHL (1982 to 21 May 2015). There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomized controlled trials (RCTs) comparing the effects of NPWT with alternative treatments or different types of NPWT in the treatment of leg ulcers. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included one study, with 60 randomized participants, in the review. The study population had a range of ulcer types that were venous arteriolosclerotic and venous/arterial in origin. Study participants had recalcitrant ulcers that had not healed after treatment over a six-month period. Participants allocated to NPWT received continuous negative pressure until they achieved 100% granulation (wound preparation stage). A punch skin-graft transplantation was conducted and the wound then exposed to further NPWT for four days followed by standard care. Participants allocated to the control arm received standard care with dressings and compression until 100% granulation was achieved. These participants also received a punch skin-graft transplant and then further treatment with standard care. All participants were treated as in-patients until healing occurred.There was low quality evidence of a difference in time to healing that favoured the NPWT group: the study reported an adjusted hazard ratio of 3.2, with 95% confidence intervals (CI) 1.7 to 6.2. The follow-up period of the study was a minimum of 12 months. There was no evidence of a difference in the total number of ulcers healed (29/30 in each group) over the follow-up period; this finding was also low quality evidence.There was low quality evidence of a difference in time to wound preparation for surgery that favoured NPWT (hazard ratio 2.4, 95% CI 1.2 to 4.7).Limited data on adverse events were collected: these provided low quality evidence of no difference in pain scores and Euroqol (EQ-5D) scores at eight weeks after surgery. AUTHORS' CONCLUSIONS: There is limited rigorous RCT evidence available concerning the clinical effectiveness of NPWT in the treatment of leg ulcers. There is some evidence that the treatment may reduce time to healing as part of a treatment that includes a punch skin graft transplant, however, the applicability of this finding may be limited by the very specific context in which NPWT was evaluated. There is no RCT evidence on the effectiveness of NPWT as a primary treatment for leg ulcers.

Treatment for superficial infusion thrombophlebitis of the upper extremity.

BACKGROUND: Although superficial thrombophlebitis of the upper extremity represents a frequent complication of intravenous catheters inserted into the peripheral veins of the forearm or hand, no consensus exists on the optimal management of this condition in clinical practice. OBJECTIVES: To summarise the evidence from randomised clinical trials (RCTs) concerning the efficacy and safety of (topical, oral or parenteral) medical therapy of superficial thrombophlebitis of the upper extremity. SEARCH METHODS: The Cochrane Vascular Group Trials Search Co-ordinator searched the Specialised Register (last searched April 2015) and the Cochrane Register of Studies (2015, Issue 3). Clinical trials registries were searched up to April 2015. SELECTION CRITERIA: RCTs comparing any (topical, oral or parenteral) medical treatment to no intervention or placebo, or comparing two different medical interventions (e.g. a different variant scheme or regimen of the same intervention or a different pharmacological type of treatment). DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, patient characteristics, interventions and outcomes, including improvement of signs and symptoms as the primary effectiveness outcome, and number of participants experiencing side effects of the study treatments as the primary safety outcome. MAIN RESULTS: We identified 13 studies (917 participants). The evaluated treatment modalities consisted of a topical treatment (11 studies), an oral treatment (2 studies) and a parenteral treatment (2 studies). Seven studies used a placebo or no intervention control group, whereas all others also or solely compared active treatment groups. No study evaluated the effects of ice or the application of cold or hot bandages. Overall, the risk of bias in individual trials was moderate to high, although poor reporting hampered a full appreciation of the risk in most studies. The overall quality of the evidence for each of the outcomes varied from low to moderate mainly due to risk of bias and imprecision, with only single trials contributing to most comparisons. Data on primary outcomes improvement of signs and symptoms and side effects attributed to the study treatment could not be statistically pooled because of the between-study differences in comparisons, outcomes and type of instruments to measure outcomes.An array of topical treatments, such as heparinoid or diclofenac gels, improved pain compared to placebo or no intervention. Compared to placebo, oral non-steroidal anti-inflammatory drugs reduced signs and symptoms intensity. Safety issues were reported sparsely and were not available for some interventions, such as notoginseny creams, parenteral low-molecular-weight heparin or defibrotide. Although several trials reported on adverse events with topical heparinoid creams, Essaven gel or phlebolan versus control, the trials were underpowered to adequately measure any differences between treatment modalities. Where reported, adverse events with topical treatments consisted mainly of local allergic reactions. Only one study of 15 participants assessed thrombus extension and symptomatic venous thromboembolism with either oral non-steroidal anti-inflammatory drugs or low-molecular-weight heparin, and it reported no cases of either. No study reported on the development of suppurative phlebitis, catheter-related bloodstream infections or quality of life. AUTHORS' CONCLUSIONS: The evidence about the treatment of acute infusion superficial thrombophlebitis is limited and of low quality. Data appear too preliminary to assess the effectiveness and safety of topical treatments, systemic anticoagulation or oral non-steroidal anti-inflammatory drugs.

Negative pressure wound therapy for treating surgical wounds healing by secondary intention.

BACKGROUND: Following surgery, incisions are usually closed by fixing the edges together with sutures (stitches), staples, adhesive glue or clips. This process helps the cut edges heal together and is called 'healing by primary intention'. However, not all incised wounds are closed in this way: where there is high risk of infection, or when there has been significant tissue loss, wounds may be left open to heal from the 'bottom up'. This delayed healing is known as 'healing by secondary intention'. Negative pressure wound therapy (NPWT) is one treatment option for surgical wounds that are healing by secondary intention. OBJECTIVES: To assess the effects of negative pressure wound therapy (NPWT) on the healing of surgical wounds healing by secondary intention (SWHSI) in any care setting. SEARCH METHODS: For this review, in May 2015 we searched the following databases: the Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations; Ovid EMBASE; and EBSCO CINAHL. There were no restrictions based on language or date of publication. SELECTION CRITERIA: Published or unpublished randomised controlled trials (RCTs) comparing the effects of NPWT with alternative treatments or different types of NPWT in the treatment of SWHSI. We excluded open abdominal wounds from this review as they are the subject of a separate Cochrane review that is in draft. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We located two studies (69 participants) for inclusion in this review. One study compared NPWT with an alginate dressing in the treatment of open, infected groin wounds. and one study compared NPWT with a silicone dressing in the treatment of excised pilonidal sinus. The trials reported limited outcome data on healing, adverse events and resource use. AUTHORS' CONCLUSIONS: There is currently no rigorous RCT evidence available regarding the clinical effectiveness of NPWT in the treatment of surgical wounds healing by secondary intention as defined in this review. The potential benefits and harms of using this treatment for this wound type remain largely uncertain.

Rapid COJEC versus standard induction therapies for high-risk neuroblastoma.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. The high-risk group is characterized by metastasis and other characteristics that increase the risk for an adverse outcome. In the rapid COJEC induction schedule, higher single doses of selected drugs than standard induction schedules are administered over a substantially shorter treatment period, with shorter intervals between cycles. Shorter intervals and higher doses increase the dose intensity of chemotherapy and might improve survival. OBJECTIVES: The aim of this study was to evaluate the efficacy and adverse events of the rapid COJEC induction schedule as compared to standard induction schedules in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Outcomes of interest were complete response, early toxicity and treatment-related mortality as primary endpoints and overall survival, progression- and event-free survival, late non-hematological toxicity, and health-related quality of life as secondary endpoints. SEARCH METHODS: We searched the electronic databases CENTRAL (2014, Issue 11), MEDLINE (PubMed), and EMBASE (Ovid) for articles from inception to 11 November 2014. Further searches included trial registries, conference proceedings, and reference lists of recent reviews and relevant articles. We did not apply limits on publication year or languages. SELECTION CRITERIA: Randomized controlled trials evaluating the rapid COJEC induction schedule for high-risk neuroblastoma patients compared to standard induction schedules. DATA COLLECTION AND ANALYSIS: Two review authors performed study selection, abstracted data on study and patient characteristics, and assessed risk of bias independently. We resolved differences by discussion or by appeal to a third review author. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. We used the five GRADE considerations, study limitations, consistency of effect, imprecision, indirectness, and publication bias, to judge the quality of the evidence. We downgraded for risk of bias and imprecision MAIN RESULTS: We identified one randomized controlled trial (CCLG-ENSG-5) that included 262 patients with high-risk neuroblastoma who were randomized to receive either rapid COJEC (N = 130) or standard OPEC/COJEC (N = 132) induction chemotherapy. We graded the evidence as low quality; we downgraded for risk of bias and imprecision.There was no clear evidence of a difference between the treatment groups in complete response (risk ratio (RR) 0.99, 95% confidence interval (CI) 0.71 to 1.38), treatment-related mortality (RR 1.21, 95% CI 0.33 to 4.39), overall survival (hazard ratio (HR) 0.83, 95% CI 0.63 to 1.10), and event-free survival (HR 0.86, 95% CI 0.65 to 1.13). We calculated the HRs using the complete follow-up period of the trial.Febrile neutropenia (two or more episodes), proven fungal infections, septicemia (one or more episodes), gastrointestinal toxicity (grade 3 or 4), renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73 m(2)), neurological toxicity (grade 3 or 4), and ototoxicity (Brock grade 2 to 4) were addressed as early toxicities (during pre-operative chemotherapy). For febrile neutropenia, septicemia, and renal toxicity, a statistically significant difference in favor of the standard treatment arm was identified; for all other early toxicities no clear evidence of a difference between treatment groups was identified. With regard to late non-hematological toxicities (median follow-up 12.7 years; range 6.9 to 16.5 years), the study provided data on any complication, renal toxicity (glomerular filtration rate < 80 ml/min per body surface area of 1.73m(2)), ototoxicity (Brock grade 1 to 4), endocrine complications, neurocognitive complications (i.e. behavioral, speech, or learning difficulties), and second malignancies. For endocrine complications and neurocognitive complications, a statistically significant difference in favor of the rapid COJEC arm was found; for all other late non-hematological toxicities no clear evidence of a difference between treatment groups was identified.Data on progression-free survival and health-related quality of life were not reported. AUTHORS' CONCLUSIONS: We identified one randomized controlled trial that evaluated rapid COJEC versus standard induction therapy in patients with high-risk neuroblastoma. No clear evidence of a difference in complete response, treatment-related mortality, overall survival, and event-free survival between the treatment alternatives was found. This could be the result of low power or too short a follow-up period. Results of both early and late toxicities were ambiguous. Information on progression-free survival and health-related quality of life were not available. This trial was performed in the 1990s. Since then, many changes in, for example, treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of rapid COJEC and standard induction therapy in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

Primary prophylaxis for venous thromboembolism in patients undergoing cardiac or thoracic surgery.

BACKGROUND: Cardiac and thoracic surgery are associated with an increased risk of venous thromboembolism (VTE). The safety and efficacy of primary thromboprophylaxis in patients undergoing these types of surgery is uncertain. OBJECTIVES: To assess the effects of primary thromboprophylaxis on the incidence of symptomatic VTE and major bleeding in patients undergoing cardiac or thoracic surgery. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator searched the Specialised Register (last searched May 2014) and CENTRAL (2014, Issue 4). The authors searched the reference lists of relevant studies, conference proceedings, and clinical trial registries. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs comparing any oral or parenteral anticoagulant or mechanical intervention to no intervention or placebo, or comparing two different anticoagulants. DATA COLLECTION AND ANALYSIS: We extracted data on methodological quality, participant characteristics, interventions, and outcomes including symptomatic VTE and major bleeding as the primary effectiveness and safety outcomes, respectively. MAIN RESULTS: We identified 12 RCTs and one quasi-RCT (6923 participants), six for cardiac surgery (3359 participants) and seven for thoracic surgery (3564 participants). No study evaluated fondaparinux, the new oral direct thrombin, direct factor Xa inhibitors, or caval filters. All studies had major study design flaws and most lacked a placebo or no treatment control group. We typically graded the quality of the overall body of evidence for the various outcomes and comparisons as low, due to imprecise estimates of effect and risk of bias. We could not pool data because of the different comparisons and the lack of data. In cardiac surgery, 71 symptomatic VTEs occurred in 3040 participants from four studies. In a study of 2551 participants, representing 85% of the review population in cardiac surgery, the combination of unfractionated heparin with pneumatic compression stockings was associated with a 61% reduction of symptomatic VTE compared to unfractionated heparin alone (1.5% versus 4.0%; risk ratio (RR) 0.39; 95% confidence interval (CI) 0.23 to 0.64). Major bleeding was only reported in one study, which found a higher incidence with vitamin K antagonists compared to platelet inhibitors (11.3% versus 1.6%, RR 7.06; 95% CI 1.64 to 30.40). In thoracic surgery, 15 symptomatic VTEs occurred in 2890 participants from six studies. In the largest study evaluating unfractionated heparin versus an inactive control the rates of symptomatic VTE were 0.7% versus 0%, respectively, giving a RR of 6.71 (95% CI 0.40 to 112.65). There was insufficient evidence to determine if there was a difference in the risk of major bleeding from two studies evaluating fixed-dose versus weight-adjusted low molecular weight heparin (2.7% versus 8.1%, RR 0.33; 95% CI 0.07 to 1.60) and unfractionated heparin versus low molecular weight heparin (6% and 4%, RR 1.50; 95% CI 0.26 to 8.60). AUTHORS' CONCLUSIONS: The evidence regarding the efficacy and safety of thromboprophylaxis in cardiac and thoracic surgery is limited. Data for important outcomes such as pulmonary embolism or major bleeding were often lacking. Given the uncertainties around the benefit-to-risk balance, no conclusions can be drawn and a case-by-case risk evaluation of VTE and bleeding remains preferable.

Retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation.

BACKGROUND: Neuroblastoma is a rare malignant disease and mainly affects infants and very young children. The tumors mainly develop in the adrenal medullary tissue and an abdominal mass is the most common presentation. About 50% of patients have metastatic disease at diagnosis. The high-risk group is characterized by metastasis and other characteristics that increase the risk for an adverse outcome. High-risk patients have a five-year event-free survival of less than 50%. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome of patients with high-risk neuroblastoma. OBJECTIVES: To evaluate efficacy and adverse events of retinoic acid after consolidation with high-dose chemotherapy followed by bone marrow transplantation as compared to placebo or no therapy in patients with high-risk neuroblastoma (as defined by the International Neuroblastoma Risk Group (INRG) classification system). Our outcomes of interest were overall survival and treatment-related mortality as primary outcomes; and progression- and event-free survival, early and late toxicity, and health-related quality of life as secondary outcomes. SEARCH METHODS: We searched the electronic databases CENTRAL (2014, Issue 8) on The Cochrane Library, MEDLINE (1946 to October 2014), and EMBASE (1947 to October 2014). Further searches included trial registries, conference proceedings, and reference lists of recent reviews and relevant articles. We did not apply limits on publication year or languages. SELECTION CRITERIA: Randomized controlled trials (RCTs) evaluating retinoic acid post consolidation therapy for high-risk neuroblastoma patients treated with autologous hematopoietic stem cell transplantation (HSCT) compared to placebo or no further treatment. DATA COLLECTION AND ANALYSIS: Two review authors performed the study selection, extracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. We performed analyses according to the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The authors of the included study did not report the results specifically for the treatment groups relevant to this Cochrane Review. Therefore, we deduced the appropriate survival data from the published survival curves and calculated a hazard ratio (HR) based on the deduced data. MAIN RESULTS: We identified one RCT (CCG-3891) that included patients with high-risk neuroblastoma who received high-dose chemotherapy followed by autologous HSCT (N = 98) after a first random allocation and who received retinoic acid (13-cis-retinoic acid; N = 50) or no further therapy (N = 48) after a subsequent second random allocation. These patients had no progressive disease after consolidation therapy. There was no clear evidence of difference between the treatment groups in both overall survival (HR 0.87, 95% CI 0.46 to 1.63; one trial; P = 0.66, low quality of evidence) and event-free survival (HR 0.86, 95% CI 0.50 to 1.49; one trial; P = 0.59, low quality of evidence). We calculated these HR values using the complete follow-up period of the trial. The study also reported five-year overall survival rates: 59% for the retinoic acid group and 41% for the no further therapy group (P value not reported). We did not identify results for treatment-related mortality, progression-free survival, early or late toxicity, or health-related quality of life. Also, we could not rule out the possible presence of selection bias, performance bias, attrition bias, and other bias. AUTHORS' CONCLUSIONS: We identified one RCT that evaluated retinoic acid as a consolidation therapy versus no further therapy after high-dose chemotherapy followed by bone-marrow transplantation in patients with high-risk neuroblastoma. The difference in overall survival and event-free survival between both treatment alternatives was not statistically significantly different. This could be the result of low power. Information on other outcomes was not available. This trial was performed in the 1990s, since then many changes in for example treatment and risk classification have occurred. Therefore, based on the currently available evidence, we are uncertain about the effects of retinoic acid in patients with high-risk neuroblastoma. More research is needed for a definitive conclusion.

First-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared with first-line ciclosporin and/or antithymocyte or antilymphocyte globulin for acquired severe aplastic anemia.

BACKGROUND: Acquired severe aplastic anemia is a rare and potentially fatal disease, which is characterized by hypocellular bone marrow and pancytopenia. The major signs and symptoms are severe infections, bleeding, and exhaustion. First-line allogeneic hematopoietic stem cell transplantation (HSCT) of a human leukocyte antigen (HLA)-matched sibling donor (MSD) is a treatment for newly diagnosed patients with severe aplastic anemia. First-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy) is an alternative to MSD-HSCT and is indicated for patients where no MSD is found. OBJECTIVES: To evaluate the effectiveness and adverse events of first-line allogeneic hematopoietic stem cell transplantation of HLA-matched sibling donors compared to first-line immunosuppressive therapy including ciclosporin and/or antithymocyte or antilymphocyte globulin in patients with acquired severe aplastic anemia. SEARCH METHODS: We searched the electronic databases MEDLINE (Ovid), EMBASE (Ovid), and The Cochrane Library CENTRAL (Wiley) for published articles from 1946 to 22 April 2013. Further searches included trial registries, reference lists of recent reviews, and author contacts. SELECTION CRITERIA: The following prospective study designs were eligible for inclusion: randomized controlled trials (RCTs) and non-randomized controlled trials if the allocation of patients to treatment groups was consistent with 'Mendelian randomization'. We included participants with newly diagnosed severe aplastic anemia who received MSD-HSCT or immunosuppressive therapy without prior HSCT or immunosuppressive therapy, and with a minimum of five participants per treatment group. We did not apply limits on publication year or languages. DATA COLLECTION AND ANALYSIS: Two review authors abstracted the data on study and patient characteristics and assessed the risk of bias independently. We resolved differences by discussion or by appeal to a third review author. The primary outcome was overall mortality. Secondary outcomes were treatment-related mortality, graft failure, no response to first-line immunosuppressive therapy, graft-versus-host-disease (GVHD), relapse after initial successful treatment, secondary clonal and malignant disease, health-related quality of life, and performance score. MAIN RESULTS: We identified three trials that met the inclusion criteria. None of these trials was a RCT. 302 participants are included in this review. The three included studies were prospectively conducted and had features consistent with the principle of 'Mendelian randomization' as defined in the present review. All studies had a high risk of bias due to the study design. All studies were conducted more than 10 years ago and may not be applicable to the standard of care of today. Primary and secondary outcome data showed no statistically significant difference between treatment groups. We present results for first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor, which we denote as the MSD-HSCT group, versus first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin, which we denote as the immunosuppressive therapy group in the following section.The pooled hazard ratio for overall mortality for the MSD-HSCT group versus the immunosuppressive therapy group was 0.95 (95% confidence interval 0.43 to 2.12, P = 0.90, low quality evidence). Therefore, overall mortality was not statistically significantly different between the groups. Treatment-related mortality ranged from 20% to 42% for the MSD-HSCT group and was not reported for the immunosuppressive therapy group (very low quality evidence). The authors reported graft failure from 3% to 16% for the MSD-HSCT group and GVHD from 26% to 51% (both endpoints not applicable for the immunosuppressive therapy group, very low quality evidence). The authors did not report any data on response and relapse for the MSD-HSCT group. For the immunosuppressive therapy group, the studies reported no response from 15% (not time point stated) to 64% (three months) and relapse in one of eight responders after immunosuppressive therapy at 5.5 years (very low quality evidence). The authors reported secondary clonal disease or malignancies for the MSD-HSCT group versus the immunosuppressive therapy group in 1 of 34 versus 0 of 22 patients in one study and in 0 of 28 versus 4 of 86 patients in the other study (low quality evidence). None of the included studies addressed health-related quality of life. The percentage of the evaluated patients with a Karnofsky performance status score in the range of 71% to 100% was 92% in the MSD-HSCT group and 46% in the immunosuppressive therapy group. AUTHORS' CONCLUSIONS: There are insufficient and biased data that do not allow any conclusions to be made about the comparative effectiveness of first-line allogeneic hematopoietic stem cell transplantation of an HLA-matched sibling donor and first-line treatment with ciclosporin and/or antithymocyte or antilymphocyte globulin (as first-line immunosuppressive therapy). We are unable to make firm recommendations regarding the choice of intervention for treatment of acquired severe aplastic anemia.

Autologous hematopoietic stem cell transplantation following high dose chemotherapy for non-rhabdomyosarcoma soft tissue sarcomas.

BACKGROUND: Soft tissue sarcomas (STS) are a highly heterogeneous group of rare malignant solid tumors. Non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) comprise all STS except rhabdomyosarcoma. In patients with advanced local or metastatic disease, autologous hematopoietic stem cell transplantation (HSCT) applied after high-dose chemotherapy (HDCT) is a planned rescue therapy for HDCT-related severe hematologic toxicity. The rationale for this update is to determine whether any randomized controlled trials (RCTs) have been conducted and to clarify whether HDCT followed by autologous HSCT has a survival advantage. OBJECTIVES: To assess the effectiveness and safety of HDCT followed by autologous HSCT for all stages of non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) in children and adults. SEARCH METHODS: For this update we modified the search strategy to improve the precision and reduce the number of irrelevant hits. All studies included in the original review were considered for re-evaluation in the update. We searched the electronic databases CENTRAL (2012, Issue 11) in The Cochrane Library , MEDLINE and EMBASE (05 December 2012) from their inception using the newly developed search strategy. Online trials registers and reference lists of systematic reviews were searched. SELECTION CRITERIA: Terms representing STS and autologous HSCT were required in the title or abstract. In studies with aggregated data, participants with NRSTS and autologous HSCT had to constitute at least 80% of the data. Single-arm studies were included in addition to studies with a control arm because the number of comparative studies was expected to be very low. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study data. Some studies identified in the original review were re-examined and found not to meet the inclusion criteria and were excluded in this update. For studies with no comparator group, we synthesized the results for studies reporting aggregate data and conducted a pooled analysis of individual participant data using the Kaplan-Meyer method. The primary outcomes were overall survival (OS) and treatment-related mortality (TRM). MAIN RESULTS: The selection process was carried out from the start of the search dates for the update. We included 57 studies, from 260 full text articles screened, reporting on 275 participants that were allocated to HDCT followed by autologous HSCT. All studies were not comparable due to various subtypes. We identified a single comparative study, an RCT comparing HDCT followed by autologous HSCT versus standard chemotherapy (SDCT). The overall survival (OS) at three years was 32.7% versus 49.4% with a hazard ratio (HR) of 1.26 (95% confidence interval (CI) 0.70 to 2.29, P value 0.44) and thus not significantly different between the treatment groups. In a subgroup of patients that had a complete response before treatment, OS was higher in both treatment groups and OS at three years was 42.8% versus 83.9% with a HR of 2.92 (95% CI 1.1 to 7.6, P value 0.028) and thus was statistically significantly better in the SDCT group. We did not identify any other comparative studies. We included six single-arm studies reporting aggregate data of cases; three reported the OS at two years as 20%, 48%, and 51.4%. One other study reported the OS at three years as 40% and one further study reported a median OS of 13 months (range 3 to 19 months). In two of the single-arm studies with aggregate data, subgroup analysis showed a better OS in patients with versus without a complete response before treatment. In a survival analysis of pooled individual data of 80 participants, OS at two years was estimated as 50.6% (95% CI 38.7 to 62.5) and at three years as 36.7% (95% CI 24.4 to 49.0). Data on TRM, secondary neoplasia and severe toxicity grade 3 to 4 after transplantation were sparse. The one included RCT had a low risk of bias and the remaining 56 studies had a high risk of bias. AUTHORS' CONCLUSIONS: A single RCT with a low risk of bias shows that OS after HDCT followed by autologous HSCT is not statistically significantly different from standard-dose chemotherapy. Therefore, HDCT followed by autologous HSCT for patients with NRSTS may not improve the survival of patients and should only be used within controlled trials if ever considered.

Negative pressure wound therapy for treating foot wounds in people with diabetes mellitus.

BACKGROUND: Foot wounds in people with diabetes mellitus (DM) are a common and serious global health issue. Negative pressure wound therapy can be used to treat these wounds and a clear and current overview of current evidence is required to facilitate decision-making regarding its use. OBJECTIVES: To assess the effects of negative pressure wound therapy compared with standard care or other adjuvant therapies in the healing of foot wounds in people with DM. SEARCH METHODS: In July 2013, we searched the following databases to identify reports of relevant randomised controlled trials (RCTs): Cochrane Wounds Group Specialised Register; The Cochrane Central Register of Controlled Trials (CENTRAL); The Database of Abstracts of Reviews of Effects (DARE); The NHS Economic Evaluation Database; Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid EMBASE; and EBSCO CINAHL. SELECTION CRITERIA: Published or unpublished RCTs that evaluate the effects of any brand of negative pressure wound therapy in the treatment of foot wounds in people with diabetes, irrespective of publication date or language of publication. Particular effort was made to identify unpublished studies. DATA COLLECTION AND ANALYSIS: Two review authors independently performed study selection, risk of bias assessment and data extraction. MAIN RESULTS: We included five studies in this review randomising 605 participants. Two studies (total of 502 participants) compared negative pressure wound therapy with standard moist wound dressings. The first of these was conducted in people with DM and post-amputation wounds and reported that significantly more people healed in the negative pressure wound therapy group compared with the moist dressing group: (risk ratio 1.44; 95% CI 1.03 to 2.01). The second study, conducted in people with debrided foot ulcers, also reported a statistically significant increase in the proportion of ulcers healed in the negative pressure wound therapy group compared with the moist dressing group: (risk ratio 1.49; 95% CI 1.11 to 2.01). However, these studies were noted to be at risk of performance bias, so caution is required in their interpretation. Findings from the remaining three studies provided limited data, as they were small, with limited reporting, as well as being at unclear risk of bias. AUTHORS' CONCLUSIONS: There is some evidence to suggest that negative pressure wound therapy is more effective in healing post-operative foot wounds and ulcers of the foot in people with DM compared with moist wound dressings. However, these findings are uncertain due to the possible risk of bias in the original studies. The limitations in current RCT evidence suggests that further trials are required to reduce uncertainty around decision making regarding the use of NPWT to treat foot wounds in people with DM.