The independent and joint risks of alcohol consumption, smoking, and excess weight on morbidity and mortality: a systematic review and meta-analysis exploring synergistic associations.

OBJECTIVE: Alcohol consumption, smoking, and excess weight independently increase the risk of morbidity/mortality. Less is known about how they interact. This research aims to quantify the independent and joint associations of these exposures across health outcomes and identify whether these associations are synergistic. STUDY DESIGN: The protocol for this systematic review and meta-analysis was pre-registered (PROSPERO CRD42021231443). METHODS: Medline and Embase were searched between 1 January 2010 and 9 February 2022. Eligible peer-reviewed observational studies had to include adult participants from Organisation for Co-Operation and Development countries and report independent and joint associations between at least two eligible exposures (alcohol, smoking, and excess weight) and an ICD-10 outcome (or equivalent). For all estimates, we calculated the synergy index (SI) to identify whether joint associations were synergistic. Meta-analyses were conducted for outcomes with sufficiently homogenous data. RESULTS: The search returned 26,290 studies, of which 98 were included. Based on 138,130 participants, the combined effect (SI) of alcohol and smoking on head and neck cancer death/disease was 3.78 times greater than the additive effect of each exposure (95% confidence interval [CI] = 2.61, 5.48). Based on 2,603,939 participants, the combined effect of alcohol and excess weight on liver disease/death was 1.55 times greater than the additive effect of each exposure (95% CI = 1.33, 1.82). CONCLUSION: Synergistic associations suggest the true population-level risk may be underestimated. In the absence of bias, individuals with multiple risks would experience a greater absolute risk reduction from an intervention that targets a single exposure than individuals with a single risk.

Effect of different durations of using a standing frame on the rate of hip migration in children with moderate to severe cerebral palsy: a feasibility study for a randomised controlled trial.

AIM: To assess the feasibility of a randomised controlled trial (RCT) to evaluate the effect of different doses of standing time on hip migration rate in children with cerebral palsy (CP). METHOD: Children aged 1-12 years with CP GMFCS levels III-V were recruited and randomised to either doubling or continuing with their usual time in their standing frame. Caregivers kept a standing time diary. The primary outcome measure was Reimers hip migration percentage, measured at baseline, 12 and 24 months. A blinded assessor measured secondary clinical outcomes at baseline, 6 and 12 months. Feasibility results are reported following CONSORT guidelines. RESULTS: Twenty-five children were recruited. Nineteen were randomised and 10 completed the 12-month intervention. The mean daily standing time in the intervention group was 49minutes (SD 39.1) (Monday-Sunday) and 58.1 (SD 44.1) minutes during weekdays. In children remaining in the trial, primary and secondary clinical outcome measures were available in 54% and 90% of children respectively. There were three serious adverse events, unrelated to standing. CONCLUSIONS: It may be feasible to conduct an RCT to assess the effect of duration of standing on hip migration in children with CP with an altered protocol. The suggested target dose is 60minutes five times per week compared to a control group standing for 30minutes three times per week, over twelve months. Use of botulinum toxin need not be a criterion for exclusion and radiography should be included as a research cost. NHS Health Research Committee, South West ethics approval (ref 13/SW/0228).

A 10-year review of surgical management of dermatofibrosarcoma protuberans.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a rare skin cancer. Standard treatment in the UK is either wide local excision (WLE) or Mohs micrographic surgery (MMS). It is unclear which approach has the lower recurrence rate. OBJECTIVES: We undertook a retrospective comparative review of surgical management of DFSP in the UK National Health Service in order to define (i) current surgical practice for primary and recurrent DFSP, (ii) local recurrence rates for primary DFSP and (iii) survival outcomes for DFSP. METHODS: A retrospective clinical case-note review of patients with histologically confirmed DFSP (January 2004 to December 2013) who have undergone surgical treatment. RESULTS: The surgical management of 483 primary and 64 recurrent DFSP in 11 plastic surgery and 15 dermatology departments was analysed. Almost 75% of primary DFSP (n = 362) were treated with WLE and 20% (n = 97) with MMS. For recurrent DFSP, 69% (n = 44) and 23% (n = 15) of patients underwent WLE and MMS, respectively. Recurrent primary DFSP occurred in six patients after WLE and none after MMS. The median follow-up time was 25·5 months (interquartile range 6·8-45·1) for new and 19·8 (IQR 4·5-44·5) for recurrent DFSP [Correction added on 1 Feb 2021, after first online publication: 4.8 years (interquartile range 3.5-5.8) was incorrect], with eight reported deaths during the follow-up analysis period (one confirmed to be DFSP related). CONCLUSIONS: WLE was the most common surgical modality used to treat DFSP across the UK. The local recurrence rate was very low, occurring only after WLE. Although a prospective randomized controlled trial may provide more definitive outcomes, in the absence of a clearly superior surgical modality, treatment decisions should be based on patient preference, clinical expertise and cost.

Current role of sentinel lymph node biopsy in the management of cutaneous melanoma: A UK consensus statement.

Sentinel node biopsy (SNB) has been at the forefront of the surgical staging of melanoma patients for the past 15 years. The high accuracy of this prognostic staging procedure is now recognised in all international guidelines for melanoma. However during this period there have been a number of important changes in the management of melanoma, many occurring within the past five years. The outcomes of five recent randomised Phase 3 trials have established the role of adjuvant targeted therapy and immunotherapy in resected Stage 3 and Stage 4 disease and have potentially changed the role of SNB. Two landmark international prospective studies have examined the benefit of performing a completion lymph node dissection (CLND) following the detection of microscopicallyinvolved sentinel nodes. Finally, the marked increase in the incidence of melanoma and the role of SNB in potentially guiding therapy has resulted in a significant increase in the pathological workload of the dermatopathology services. To address these issues a multi-disciplinary consensus meeting involving many melanoma experts from the UK was convened in May 2018. Three main areas were considered: oncology, surgery and pathology. This report is a summary of the conclusions reached, which were agreed by the clinicians attending the meeting and then externally peer reviewed. The recommendations summarised in this Consensus Statement.

Do airline pilots and cabin crew have raised risks of melanoma and other skin cancers? Systematic review and meta-analysis.

BACKGROUND: Airline pilots and cabin crew are potentially exposed to hazardous ultraviolet and cosmic radiation, which may increase their risk of melanoma and other skin cancers. OBJECTIVES: To establish precise risks of melanoma and keratinocyte cancer (KC) for airline pilots and for cabin crew based on all studies published to date. METHODS: We searched MEDLINE, ISI Science Citation Index, Embase, SCOPUS and CINAHL to June 2018. All studies of melanoma and KC risk and mortality in airline pilots and cabin crew compared with the general population were eligible. Standardized incidence ratios (SIRs) and standardized mortality ratios (SMRs) were pooled using random effects models. RESULTS: From 5866 papers retrieved, we reviewed 44 full-text articles, of which 12 studies with data collected mostly between the 1970s and 1990s were eligible for inclusion. The pooled SIR (pSIR) for melanoma in pilots was 2.03 [95% confidence interval (CI) 1.71-2.40] and in cabin crew it was 2.12 (95% CI 1.71-2.62). For pilots, the pooled SMR for melanoma was 1.99 (95% CI 1.17-3.40) and for cabin crew it was 1.18 (95% CI 0.73-1.89). For KC, the pSIR was 1.86 (95% CI 1.54-2.25) in pilots and 1.97 (95% CI 1.25-2.96) in cabin crew. There was no evidence of study heterogeneity. CONCLUSIONS: The available evidence shows that airline pilots and cabin crew have about twice the risk of melanoma and other skin cancers than the general population, with pilots more likely to die from melanoma. However, most of the evidence was collected several decades ago and their relevance to contemporary levels of risk is uncertain.

Identifying substance misuse in primary care: TAPS Tool compared to the WHO ASSIST.

BACKGROUND: There is a need for screening and brief assessment instruments to identify primary care patients with substance use problems. This study's aim was to examine the performance of a two-step screening and brief assessment instrument, the TAPS Tool, compared to the WHO ASSIST. METHODS: Two thousand adult primary care patients recruited from five primary care clinics in four Eastern US states completed the TAPS Tool followed by the ASSIST. The ability of the TAPS Tool to identify moderate- and high-risk use scores on the ASSIST was examined using sensitivity and specificity analyses. RESULTS: The interviewer and self-administered computer tablet versions of the TAPS Tool generated similar results. The interviewer-administered version (at cut-off of 2), had acceptable sensitivity and specificity for high-risk tobacco (0.90 and 0.77) and alcohol (0.87 and 0.80) use. For illicit drugs, sensitivities were >0.82 and specificities >0.92. The TAPS (at a cut-off of 1) had good sensitivity and specificity for moderate-risk tobacco use (0.83 and 0.97) and alcohol (0.83 and 0.74). Among illicit drugs, sensitivity was acceptable for moderate-risk of marijuana (0.71), while it was low for all other illicit drugs and non-medical use of prescription medications. Specificities were 0.97 or higher for all illicit drugs and prescription medications. CONCLUSIONS: The TAPS Tool identified adult primary care patients with high-risk ASSIST scores for all substances as well moderate-risk users of tobacco, alcohol, and marijuana, although it did not perform well in identifying patients with moderate-risk use of other drugs or non-medical use of prescription medications. The advantages of the TAPS Tool over the ASSIST are its more limited number of items and focus solely on substance use in the past 3months.

Initiation and growth kinetics of solidification cracking during welding of steel.

Solidification cracking is a key phenomenon associated with defect formation during welding. To elucidate the failure mechanisms, solidification cracking during arc welding of steel are investigated in situ with high-speed, high-energy synchrotron X-ray radiography. Damage initiates at relatively low true strain of about 3.1% in the form of micro-cavities at the weld subsurface where peak volumetric strain and triaxiality are localised. The initial micro-cavities, with sizes from 10 × 10-6 m to 27 × 10-6 m, are mostly formed in isolation as revealed by synchrotron X-ray micro-tomography. The growth of micro-cavities is driven by increasing strain induced to the solidifying steel. Cavities grow through coalescence of micro-cavities to form micro-cracks first and then through the propagation of micro-cracks. Cracks propagate from the core of the weld towards the free surface along the solidifying grain boundaries at a speed of 2-3 × 10-3 m s-1.

Effect of topical imiquimod as primary treatment for lentigo maligna: the LIMIT-1 study.

BACKGROUND: Topical imiquimod is sometimes used for lentigo maligna (LM) in situ melanoma instead of surgery, but frequency of cure is uncertain. Pathological complete regression (pCR) is a logical surrogate marker for cure after imiquimod, although residual LM and atypical melanocytic hyperplasia may not be reliably distinguished. A trial comparing imiquimod vs. surgery might be justified by a high imiquimod pCR rate. OBJECTIVES: Primary: to estimate the pCR rate for LM following imiquimod. Secondary: to assess the accuracy of prediction of pCR, using clinical complete regression (cCR) plus negative post-treatment biopsies, tolerability, resource use, patients' preferences and induced melanoma immunity. METHODS: This was a single-arm phase II trial of 60 imiquimod applications over 12 weeks for LM then radical resection. A pCR rate ≥ 25 out of 33 would reliably discriminate between pCR rates < 60% and ≥ 85%. Clinical response was assessed and biopsies taken after imiquimod. Patients recorded adverse events in diaries. Patient preference was measured after surgery using a standard gamble tool. RESULTS: The pCR rate was 10 of 27 (37%, 95% confidence interval 19-58%). The rate of cCR plus negative biopsies was 12 of 28, of whom seven of 11 had pCR on subsequent surgery. The median dose intensity was 86·7%. Of the 16 surveyed patients, eight preferred primary imiquimod over surgery if the cure rate for imiquimod was 80%, and four of 16 if it was ≤ 40%. CONCLUSIONS: The pCR rate was insufficient to justify phase III investigation of imiquimod vs. SURGERY: Clinical complete response and negative targeted biopsies left uncertainty regarding pathological clearance. Some patients would trade less aggressive treatment of LM against efficacy.

Retrospective review of locally set tolerances for VMAT prostate patient specific QA using the COMPASS(®) system.

PURPOSE: This study retrospectively reviewed locally set pass rates/tolerances for COMPASS(®) pre-treatment quality assurance results for RapidArc prostate plans to determine if these are appropriate. This was performed via quantifying the agreement between treatment planning system calculations and measurements based on absolute dose comparisons (3% tolerance for all dose points) and global gamma index assessment (3%/3 mm criterion for 97% of points). METHOD: Seventy-three prostate one-arc RapidArc plans, delivered by four dosimetrically matched linacs, were measured using the MatriXX Evolution two-dimensional array and analysed using COMPASS(®) (v.3, IBA Dosimetry). For the planning target volumes (PTV) considered, the D99%, D50%, D1% and DMean differences were analysed. The percentage volume with gamma greater than 1, average gamma and DMean difference were investigated for all structures. Nine plans were also assessed across the linac fleet to investigate potential linac dependence of results. RESULTS AND CONCLUSIONS: Regarding PTV DMean differences, all plans fell within the 3% tolerance and mostly within 2%, although there was a relatively small systematic difference. The absolute percentage differences of average and median doses suggested a weak linac dependence of the results which was found to be clinically insignificant. New stricter tolerances were established both for dose comparisons and gamma evaluation. Correlation between the gamma pass rates and the differences in the D99%, D50% and D1% was found to be moderate suggesting that gamma analysis in isolation has questionable clinical meaning and should only be used to indicate outliers for further analysis.

Malignant melanoma of the gastro-intestinal tract: a case series.

BACKGROUND: Resection of gastrointestinal (GI) metastases of malignant melanoma (MM) offers a significant survival benefit. No adjuvant therapy has been shown to be effective in the treatment of these metastases. METHODS: All resections of MM affecting the GI tract at a UK University teaching hospital between October 1999 and January 2013 were identified from a pathology database. Demographic, investigative, operative and outcome data were retrieved from hospital records. Survival analysis was performed. RESULTS: Thirty patients were identified (median age 62.7 years). 3 patients underwent a second operation at a later date to resect further metastases. 6 patients (20.0%) presented with no identifiable cutaneous lesion. The average time to GI metastases was 52.0 months (range 4.9-139.8 months) for those with an identified cutaneous primary (n = 24). Two patients with initial cutaneous lesions with Breslow's thickness <1 mm developed GI metastases. Common presenting symptoms included abdominal pain (n = 8, 27.6%), GI bleeding (n = 5, 17.2%) and symptoms of GI tract obstruction (n = 4, 13.8%). CT scan was the most commonly performed investigation (96.6%). Over half of resections (54.5%, n = 18) included small bowel resection. Mortality at 2 and 5 years was 66.4% and 73.1%. Of the 3 patients who underwent a second resection of GI metastases, one is still alive after 26 months of follow up; 2 patients died after 32.8 and 18.6 months. CONCLUSIONS: Clinicians should have a low threshold for investigating GI symptoms in patients with a history of malignant melanoma even in the case of early-stage primary disease. Re-resection should be considered in patients presenting with further GI metastases.

An exploratory study into the unmet supportive needs of breast cancer patients.

This study explores the unmet supportive needs of people with breast cancer attending a London NHS Foundation Trust Hospital. A mixed methods approach was used. One hundred and one patients completed a specially designed questionnaire focusing on their concerns in the previous week, and whether they felt they had been offered sufficient support from health professionals. Seven semi-structured interviews were then completed in order to gain insight into the need for future developments of services for patients with breast cancer. Pearson's chi-squared analysis was used to examine whether symptoms reported within 1 year of diagnosis differed from symptoms reported more than 1 year post diagnosis. Fatigue was the most common concern expressed (53%) with no significant difference between the two groups. Emotional concerns and pain were also highly reported (35% and 36%). Only 32% of the questionnaire participants reported that they had been offered support in dealing with their concerns. Most participants (65%) would have liked more support from the healthcare team. From the interviews it was clear that whilst there are gaps in services available, participants were not aware of the range of services already available for people with breast cancer. The results of this study have helped to inform service development, particularly around the management of fatigue.

BRAF mutation testing algorithm for vemurafenib treatment in melanoma: recommendations from an expert panel.

The incidence of melanoma has increased rapidly over the past 30 years, and the disease is now the sixth most common cancer among men and women in the U.K. Many patients are diagnosed with or develop metastatic disease, and survival is substantially reduced in these patients. Mutations in the BRAF gene have been identified as key drivers of melanoma cells and are found in around 50% of cutaneous melanomas. Vemurafenib (Zelboraf(®) ; Roche Molecular Systems Inc., Pleasanton, CA, U.S.A.) is the first licensed inhibitor of mutated BRAF, and offers a new first-line option for patients with unresectable or metastatic melanoma who harbour BRAF mutations. Vemurafenib was developed in conjunction with a companion diagnostic, the cobas(®) 4800 BRAF V600 Mutation Test. The purpose of this paper is to make evidence-based recommendations to facilitate the implementation of BRAF mutation testing and targeted therapy in patients with metastatic melanoma in the U.K. The recommendations are the result of a meeting of an expert panel and have been reviewed by melanoma specialists and representatives of the National Cancer Research Network Clinical Study Group on behalf of the wider melanoma community. This article is intended to be a starting point for practical advice and recommendations, which will no doubt be updated as we gain further experience in personalizing therapy for patients with melanoma.

Melphalan in regional chemotherapy for locally recurrent metastatic melanoma.

In-transit metastases occur in approximately 3% of melanoma patients, can be very symptomatic and survival in this group may be prolonged. Regional chemotherapy with melphalan delivered by isolated limb perfusion (ILP) or isolated limb infusion (ILI) are effective treatment options which are generally well tolerated. ILI is a less invasive and simpler alternative to ILP. ILI is tolerated better than ILP, though is probably less effective. Complete response rates are 45- 69% for ILP and 23-44% for ILI. The limb is often warmed to lower temperatures in ILI compared to ILP and the limb becomes progressively more hypoxic and acidotic during ILI, each of these parameters potentially having an effect on outcome. ILP & ILI are used primarily as palliative options when excision of in-transit metastases is unfeasible but can be used as an adjunctive procedure to surgery, for other tumour types such as merkel cell carcinoma, and can be repeated if indicated. For ILI correction of melphalan dose for ideal body weight has been shown to substantially decrease the rates of severe local toxicity while maintaining complete response rates, but overall response rate is reduced. Combination treatment with tumour necrosis factor α has been used with variable outcomes and new combinations with buthionine sulfoximine and ADH-1 are being investigated.

Phase I/II trial of a dendritic cell vaccine transfected with DNA encoding melan A and gp100 for patients with metastatic melanoma.

This trial tested a dendritic cell (DC) therapeutic cancer vaccine in which antigen is loaded using a novel non-viral transfection method enabling the uptake of plasmid DNA condensed with a cationic peptide. Proof of principle required the demonstration of diverse T lymphocyte responses following vaccination, including multiple reactivities restricted through both major histocompatibility complex (MHC) class I and II. Patients with advanced melanoma were offered four cycles of vaccination with autologous DC expressing melan A and gp100. Disease response was measured using Response Evaluation Criteria in Solid Tumours. Circulating MHC class I- and II-restricted responses were measured against peptide and whole antigen targets using interferon-γ ELIspot and enzyme-linked immunosorbent assay assays, respectively. Responses were analyzed across the trial population and presented descriptively for some individuals. Twenty-five patients received at least one cycle. Vaccination was well tolerated. Three patients had reduction in disease volume. Across the trial population, vaccination resulted in an expansion of effector responses to both antigens, to the human leukocyte antigen A2-restricted modified epitope, melan A ELAGIGILTV, and to a panel of MHC class I- and II-restricted epitopes. Vaccination with mature DC non-virally transfected with DNA encoding antigen had biological effect causing tumour regression and inducing diverse T lymphocyte responses.

Revised UK guidelines for the management of cutaneous melanoma 2010.

These guidelines for the management of cutaneous melanoma present an evidence-based guidance for treatment, with identification of the strength of evidence available at the time of preparation of the guidelines, and a brief overview of epidemiology, diagnosis, investigation, and follow-up.