When does a melanoma metastasize? Implications for management.

Selecting which patients with clinically-localized melanoma require treatment other than wide excision of the primary tumor is based on the risk or presence of metastatic disease. This in turn is linked to survival. Knowing if and when a melanoma is likely to metastasize is therefore of great importance. Several studies employing a range of different methodologies have suggested that many melanomas metastasize long before the primary lesion is diagnosed. Therefore, waiting for dissemination of metastatic disease to become evident before making systemic therapy available to these patients may be less effective than giving them post-operative adjuvant therapy initially if the metastatic risk is high. The identification of these high-risk patients will assist in selecting those to whom adjuvant systemic therapy can most appropriately be offered. Further studies are required to better identify high-risk patients whose primary melanoma is likely to have already metastasized.

Effect of smoking on melanoma incidence: a systematic review with meta-analysis.

BACKGROUND: There is a strong correlation between cigarette smoking and the development of many cancer types. It is therefore paradoxical that multiple reports have suggested a reduced incidence of melanoma in smokers. This study aimed to analyze all existing studies of melanoma incidence in smokers relative to non-smokers. METHODS: Searches of MEDLINE and Embase were conducted for studies reporting data on melanoma in smokers and never-smokers. No study design limitations or language restrictions were applied. The outcome examined was the association between smoking status and melanoma. Analyses focussed on risk of melanoma in smokers and never-smokers generated from multivariable analyses and these were pooled using a fixed effects model. Risk of bias was assessed using the Newcastle-Ottawa tool. FINDINGS: Forty-nine studies that included 59,429 melanoma patients were identified. Pooled analyses showed that current-smokers had a significantly-reduced risk of melanoma both in males (risk ratio (RR) 0.60, 95%CI_0.56 to0.65, p < .001) and females (RR 0.79- 95%-CI-0.73-to-0.86, p < .001). Male former-smokers had a 16% reduction in melanoma risk compared to never-smokers (RR-0.84,-95%CI-0.77-to-0.93, p < .001), but no risk reduction was observed in female former-smokers (RR-1.0-95%CI-0.92-to-1.08). INTERPRETATION: Current-smokers have a significantly-reduced risk of developing melanoma compared to never-smokers, with a reduction in melanoma risk of 40% in men and 21% in women.

Clinical management of melanocytic tumours of uncertain malignant potential (MelTUMPs), including melanocytomas: A systematic review and meta-analysis.

Little guidance is currently available for managing patients with melanocytic tumours of uncertain or low malignant potential (MelTUMPs, including melanocytomas), in particular the optimal excision margins and whether to offer sentinel node biopsy (SNB). The objective of this review was to evaluate excision margins and the prognostic utility of SNB by systematic review of the literature and meta-analysis. PRISMA guidelines were followed. Medline, EMBASE and Cochrane databases were searched to October 2021 for studies of patients with MelTUMPs reporting excision margins and/or SNB-positivity. Meta-analysis was performed on the SNB-positivity rate using a random effects model, followed by sensitivity analyses on subgroups. 111 primary studies reported excision margins and/or SNB data for 1962 patients. Follow-up was available for 1649 patients: 1561 (94.7%) were alive without disease at last review, 53 (3.2%) had developed further disease, 29 (1.8%) had died of metastatic disease (melanoma) and six (0.4%) died of unrelated causes. SNB was performed in 837 patients. The pooled positivity rate on meta-analysis was 32% (95% CI: 23-44%). Clinical outcome could be correlated with excision margin in only 171 patients (60% of those with known follow up) and was therefore not analysed further. Evidence indicating the ideal excision margins for MelTUMPs was lacking. SNB had a high positivity rate despite very low rates of recurrence or melanoma-related death. Consequently, SNB should not be offered routinely for MelTUMPs (including melanocytomas), due to its lack of prognostic utility for this tumour type (high certainty of evidence).

Radiation therapy for melanoma brain metastases: a systematic review.

BACKGROUND: Radiation therapy (RT) for melanoma brain metastases, delivered either as whole brain radiation therapy (WBRT) or as stereotactic radiosurgery (SRS), is an established component of treatment for this condition. However, evidence allowing comparison of the outcomes, advantages and disadvantages of the two RT modalities is scant, with very few randomised controlled trials having been conducted. This has led to considerable uncertainty and inconsistent guideline recommendations. The present systematic review identified 112 studies reporting outcomes for patients with melanoma brain metastases treated with RT. Three were randomised controlled trials but only one was of sufficient size to be considered informative. Most of the evidence was from non-randomised studies, either specific treatment series or disease cohorts. Criteria for determining treatment choice were reported in only 32 studies and the quality of these studies was variable. From the time of diagnosis of brain metastasis, the median survival after WBRT alone was 3.5 months (IQR 2.4-4.0 months) and for SRS alone it was 7.5 months (IQR 6.7-9.0 months). Overall patient survival increased over time (pre-1989 to 2015) but this was not apparent within specific treatment groups. CONCLUSIONS: These survival estimates provide a baseline for determining the incremental benefits of recently introduced systemic treatments using targeted therapy or immunotherapy for melanoma brain metastases.

Melanoma In Situ: A Critical Review and Re-Evaluation of Current Excision Margin Recommendations.

Most international clinical guidelines recommend 5-10 mm clinical margins for excision of melanoma in situ (MIS). While the evidence supporting this is weak, these guidelines are generally consistent. However, as a result of the high incidence of subclinical extension of MIS, especially of the lentigo maligna (LM) subtype, wider margins will often be needed to achieve complete histologic clearance. In this review, we assessed all available contemporary evidence on clearance margins for MIS. No randomized trials were identified and the 31 non-randomized studies were largely retrospective reviews of single-surgeon or single-institution experiences using Mohs micrographic surgery (MMS) for LM or staged excision (SE) for treatment of MIS on the head/neck and/or LM specifically. The available data challenge the adequacy of current international guidelines as they consistently demonstrate the need for clinical margins > 5 mm and often > 10 mm. For LM, any MIS on the head/neck, and/or ≥ 3 cm in diameter, all may require wider clinical margins because of the higher likelihood of subclinical spread. Histologic clearance should be confirmed prior to undertaking complex reconstruction. However, it is not clear whether wider margins are necessary for all MIS subtypes. Indeed, it seems that this is unlikely to be the case. Until optimal surgical margins can be better defined in a randomized trial setting, ideally controlling for MIS subtype and including correlation with histologic excision margins, techniques such as preliminary border mapping of large, ill-defined lesions and, most importantly, sound clinical judgement will be needed when planning surgical clearance margins for the treatment of MIS.

Treatment of in-transit melanoma metastases using intralesional PV-10.

Melanoma in-transit metastases (ITMs) can sometimes be difficult to manage by surgical excision due to their number, size or location. Treatment by intralesional injection of PV-10, a 10% solution of rose bengal, has been reported to be a simple, safe and effective alternative, but more outcome data are required to confirm its value in the management of ITMs. Two hundred and twenty-six melanoma ITMs in 48 patients were treated with intralesional PV-10 supplied under a special-access scheme. By 8 weeks a complete response in all injected ITMs was achieved in 22 patients (46%) and a partial response in 19 patients (40%). Of 19 patients who had uninjected metastases, 3 (16%) had a response in these. The most common adverse event was transient localised pain in injected tumours. New ITMs developed in 25 patients within 8 weeks, and later in another 8 patients. Repeat injection cycles were given to 21 patients: 13 of these received repeat injection into partially responding or nonresponding tumours, 5 had new ITMs, as well as partially-responding lesions injected, and 3 received injection into new ITMs only. Twenty-two patients received subsequent systemic therapy. At 1 year 37 of the 48 patients were alive, 28 with melanoma, and at 2 years 27 were alive, and 19 with melanoma. Injection of PV-10 was simple and safe and resulted in tumour involution in most patients and sometimes in noninjected tumours. However, many patients developed new lesions; these were treated by further PV-10 injections or with alternative therapies.

Lack of Accuracy of Body Temperature for Detecting Serious Bacterial Infection in Febrile Episodes.

BACKGROUND: Body temperature is a time-honored marker of serious bacterial infection, but there are few studies of its test performance. The aim of our study was to determine the accuracy of temperature measured on presentation to medical care for detecting serious bacterial infection. METHODS: Febrile children 0-5 years of age presenting to the emergency department of a tertiary care pediatric hospital were sampled consecutively. The accuracy of the axillary temperature measured at presentation was evaluated using logistic regression models to generate receiver operating characteristic curves. Reference standard tests for serious bacterial infection were standard microbiologic/radiologic tests and clinical follow-up. Age, clinicians' impression of appearance of the child (well versus unwell) and duration of illness were assessed as possible effect modifiers. RESULTS: Of 15,781 illness episodes 1120 (7.1%) had serious bacterial infection. The area under the receiver operating characteristic curve for temperature was 0.60 [95% confidence intervals (CI): 0.58-0.62]. A threshold of ≥ 38°C had a sensitivity of 0.67 (95% CI: 0.64-0.70), specificity of 0.45 (95% CI: 0.44-0.46), positive likelihood ratio of 1.2 (95% CI: 1.2-1.3) and negative likelihood ratio of 0.7 (95% CI: 0.7-0.8). Age and illness duration had a small but significant effect on the accuracy of temperature increasing its "rule-in" potential. CONCLUSION: Measured temperature at presentation to hospital is not an accurate marker of serious bacterial infection in febrile children. Younger age and longer duration of illness increase the rule-in potential of temperature but without substantial overall change in its test accuracy.

Republished: value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.

OBJECTIVE: The leukocyte count is frequently used to evaluate suspected bacterial infections but estimates of its test performance vary considerably. We evaluated its accuracy for the detection of serious bacterial infections in febrile children. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department. PATIENTS: Febrile 0-5-year-olds who had a leukocyte count on presentation. OUTCOME MEASURES: Accuracy of total white blood cell and absolute neutrophil counts for the detection of urinary tract infection, bacteraemia, pneumonia and a combined ('any serious bacterial infection') category. Logistic regression models were fitted for each outcome. Reference standards were microbiological/radiological tests and clinical follow-up. RESULTS: Serious bacterial infections were present in 714 (18.3%) of 3893 illness episodes. The area under the receiver operating characteristic curve for 'any serious bacterial infection' was 0.653 (95% CI 0.630 to 0.676) for the total white blood cell count and 0.638 (95% CI 0.615 to 0.662) for absolute neutrophil count. A white blood cell count threshold >15×10(9)/L had a sensitivity of 47% (95% CI 43% to 50%), specificity 76% (95% CI 74% to 77%), positive likelihood ratio 1.93 (95% CI 1.75 to 2.13) and negative likelihood ratio 0.70 (95% CI 0.65 to 0.75). An absolute neutrophil count threshold >10×10(9)/L had a sensitivity of 41% (95% CI 38% to 45%), specificity 78% (95% CI 76% to 79%), positive likelihood ratio 1.87 (95% CI 1.68 to 2.09) and negative likelihood ratio 0.75 (95% CI 0.71 to 0.80). CONCLUSIONS: The total white blood cell count and absolute neutrophil count are not sufficiently accurate triage tests for febrile children with suspected serious bacterial infection.

Value of white cell count in predicting serious bacterial infection in febrile children under 5 years of age.

OBJECTIVE: The leukocyte count is frequently used to evaluate suspected bacterial infections but estimates of its test performance vary considerably. We evaluated its accuracy for the detection of serious bacterial infections in febrile children. DESIGN: Prospective cohort study. SETTING: Paediatric emergency department. PATIENTS: Febrile 0-5-year-olds who had a leukocyte count on presentation. OUTCOME MEASURES: Accuracy of total white blood cell and absolute neutrophil counts for the detection of urinary tract infection, bacteraemia, pneumonia and a combined ('any serious bacterial infection') category. Logistic regression models were fitted for each outcome. Reference standards were microbiological/radiological tests and clinical follow-up. RESULTS: Serious bacterial infections were present in 714 (18.3%) of 3893 illness episodes. The area under the receiver operating characteristic curve for 'any serious bacterial infection' was 0.653 (95% CI 0.630 to 0.676) for the total white blood cell count and 0.638 (95% CI 0.615 to 0.662) for absolute neutrophil count. A white blood cell count threshold >15×10(9)/L had a sensitivity of 47% (95% CI 43% to 50%), specificity 76% (95% CI 74% to 77%), positive likelihood ratio 1.93 (95% CI 1.75 to 2.13) and negative likelihood ratio 0.70 (95% CI 0.65 to 0.75). An absolute neutrophil count threshold >10×10(9)/L had a sensitivity of 41% (95% CI 38% to 45%), specificity 78% (95% CI 76% to 79%), positive likelihood ratio 1.87 (95% CI 1.68 to 2.09) and negative likelihood ratio 0.75 (95% CI 0.71 to 0.80). CONCLUSIONS: The total white blood cell count and absolute neutrophil count are not sufficiently accurate triage tests for febrile children with suspected serious bacterial infection.

Variability and accuracy in interpretation of consolidation on chest radiography for diagnosing pneumonia in children under 5 years of age.

BACKGROUND: Consolidation on chest radiography is widely used as the reference standard for defining pneumonia and variability in interpretation is well known but not well explored or explained. METHODS: Three pediatric sub-specialists (infectious diseases, radiology and respiratory medicine) viewed 3,033 chest radiographs in children aged under 5 years of age who presented to one Emergency Department (ED) with a febrile illness. Radiographs were viewed blind to clinical information about the child and blind to findings of other readers. Each chest radiograph was identified as positive or negative for consolidation. Percentage agreement and kappa scores were calculated for pairs of readers. Prevalence of consolidation and reader sensitivity/specificity was estimated using latent class analysis. RESULTS: Using the majority rule, 456 (15%) chest radiographs were positive for consolidation while the latent class estimate was 17%. The radiologist was most likely (21.3%) and respiratory physician least likely (13.7%) to diagnose consolidation. Overall percentage agreement for pairs of readers was 85-90%. However, chance corrected agreement between the readers was moderate, with kappa scores 0.4-0.6 and did not vary with patient characteristics (age, gender, and presence of chronic illness). Estimated sensitivity ranged from 0.71 to 0.81 across readers, and specificity 0.91 to 0.98. CONCLUSIONS: Overall agreement for identification of consolidation on chest radiographs was good, but agreement adjusted for chance was only moderate and did not vary with patient characteristics. Clinicians need to be aware that chest radiography is an imperfect test for diagnosing pneumonia and has considerable variability in its interpretation.

Preventing urinary tract infections in early childhood.

Urinary tract infection (UTI) is common in children, causes them considerable discomfort, as well as distress to parents and has a tendency to recur. Approximately 20% of those children who experience one infection will have a repeat episode. Since 1975, 11 trials of long-term antibiotics compared with placebo or no treatment in 1,550 children have been published. Results have been heterogeneous, but the largest trial demonstrated a small reduction (6% absolute risk reduction, risk ratio 0.65) in the risk of repeat symptomatic UTI over 12 months of treatment. This effect was consistent across sub groups of children based upon age, gender, vesicoureteric reflux status and number of prior infections. Trials involving re-implantation surgery (and antibiotics compared with antibiotics alone) for the sub-group of children with vesicoureteric reflux have not shown a reduction in repeat UTI, with the possible exception of a very small benefit for febrile UTI. Systematic reviews have shown that circumcision reduces the risk of repeat infection but 111 circumcisions would need to be performed to prevent one UTI in unpredisposed boys. Given the need for anaesthesia and the risk of surgical complication, net clinical benefit is probably restricted to those who are predisposed (such as those with recurrent infection). Many small trials in complementary therapies have been published and many suggest some benefit, however inclusion of children is limited. Only three trials involving 394 children for cranberry products, two trials with a total of 252 children for probiotics and one trial with 24 children for vitamin A are published. Estimates of efficacy vary widely and imprecision is evident. Multiple interventions to prevent UTI in children exist. Of those, long-term low dose antibiotics has the strongest evidence base, but the benefit is small. Circumcision in boys reduces the risk substantially, but should be restricted to those at risk. There is little evidence of benefit of re-implantation alone, and the benefit of this procedure over antibiotics alone is very small. Cranberry concentrate is probably effective.

Accuracy of the "traffic light" clinical decision rule for serious bacterial infections in young children with fever: a retrospective cohort study.

OBJECTIVES: To determine the accuracy of a clinical decision rule (the traffic light system developed by the National Institute for Health and Clinical Excellence (NICE)) for detecting three common serious bacterial infections (urinary tract infection, pneumonia, and bacteraemia) in young febrile children. DESIGN: Retrospective analysis of data from a two year prospective cohort study SETTING: A paediatric emergency department. PARTICIPANTS: 15,781 cases of children under 5 years of age presenting with a febrile illness. MAIN OUTCOME MEASURES: Clinical features were used to categorise each febrile episodes as low, intermediate, or high probability of serious bacterial infection (green, amber, and red zones of the traffic light system); these results were checked (using standard radiological and microbiological tests) for each of the infections of interest and for any serious bacterial infection. RESULTS: After combination of the intermediate and high risk categories, the NICE traffic light system had a test sensitivity of 85.8% (95% confidence interval 83.6% to 87.7%) and specificity of 28.5% (27.8% to 29.3%) for the detection of any serious bacterial infection. Of the 1140 cases of serious bacterial infection, 157 (13.8%) were test negative (in the green zone), and, of these, 108 (68.8%) were urinary tract infections. Adding urine analysis (leucocyte esterase or nitrite positive), reported in 3653 (23.1%) episodes, to the traffic light system improved the test performance: sensitivity 92.1% (89.3% to 94.1%), specificity 22.3% (20.9% to 23.8%), and relative positive likelihood ratio 1.10 (1.06 to 1.14). CONCLUSION: The NICE traffic light system failed to identify a substantial proportion of serious bacterial infections, particularly urinary tract infections. The addition of urine analysis significantly improved test sensitivity, making the traffic light system a more useful triage tool for the detection of serious bacterial infections in young febrile children.

Diagnosis and management of urinary tract infection in children.

A young child presents to their primary health provider with fever and irritability. How likely is a urinary tract infection? How should a urine sample be collected? How accurate are urinary dipsticks and microscopy compared with culture for the diagnosis? What route and type of antibiotics should be used? What imaging is indicated? Diagnosing and treating children with urinary tract infection presents many questions. This review summarises the most relevant recent primary studies, systematic reviews and guidelines.

What nephrologists need to know about diagnostic test accuracy articles.

Systematic reviews of randomized controlled trials are well-recognized as the best evidence for an intervention and are also becoming more available for diagnostic test evaluation. In the absence of a well-conducted and well-reported systematic review clinicians must rely on primary studies to determine how best to interpret and understand diagnostic test information. Diagnostic test studies are abundant in the published literature; however, there are considerable limitations to the information provided in many of these papers and careful appraisal is required before the findings can be applied to individual patients. The current paper provides a framework for determining bias, clinical applicability and erroneous findings within a paper, allowing greater efficiency in selecting studies and deciding on the value of the information reported in them.

The accuracy of clinical symptoms and signs for the diagnosis of serious bacterial infection in young febrile children: prospective cohort study of 15 781 febrile illnesses.

OBJECTIVES: To evaluate current processes by which young children presenting with a febrile illness but suspected of having serious bacterial infection are diagnosed and treated, and to develop and test a multivariable model to distinguish serious bacterial infections from self limiting non-bacterial illnesses. Design Two year prospective cohort study. Setting The emergency department of The Children's Hospital at Westmead, Westmead, Australia. PARTICIPANTS: Children aged less than 5 years presenting with a febrile illness between 1 July 2004 and 30 June 2006. INTERVENTION: A standardised clinical evaluation that included mandatory entry of 40 clinical features into the hospital's electronic record keeping system was performed by physicians. Serious bacterial infections were confirmed or excluded using standard radiological and microbiological tests and follow-up. Main outcome measures Diagnosis of one of three key types of serious bacterial infection (urinary tract infection, pneumonia, and bacteraemia), and the accuracy of both our clinical decision making model and clinician judgment in making these diagnoses. RESULTS: We had follow-up data for 93% of the 15 781 instances of febrile illnesses recorded during the study period. The combined prevalence of any of the three infections of interest (urinary tract infection, pneumonia, or bacteraemia) was 7.2% (1120/15 781, 95% confidence interval (CI) 6.7% to 7.5%), with urinary tract infection the diagnosis in 543 (3.4%) cases of febrile illness (95% CI 3.2% to 3.7%), pneumonia in 533 (3.4%) cases (95% CI 3.1% to 3.7%), and bacteraemia in 64 (0.4%) cases (95% CI 0.3% to 0.5%). Almost all (>94%) of the children with serious bacterial infections had the appropriate test (urine culture, chest radiograph, or blood culture). Antibiotics were prescribed acutely in 66% (359/543) of children with urinary tract infection, 69% (366/533) with pneumonia, and 81% (52/64) with bacteraemia. However, 20% (2686/13 557) of children without bacterial infection were also prescribed antibiotics. On the basis of the data from the clinical evaluations and the confirmed diagnosis, a diagnostic model was developed using multinomial logistic regression methods. Physicians' diagnoses of bacterial infection had low sensitivity (10-50%) and high specificity (90-100%), whereas the clinical diagnostic model provided a broad range of values for sensitivity and specificity. CONCLUSIONS: Emergency department physicians tend to underestimate the likelihood of serious bacterial infection in young children with fever, leading to undertreatment with antibiotics. A clinical diagnostic model could improve decision making by increasing sensitivity for detecting serious bacterial infection, thereby improving early treatment.

Absolute and relative accuracy of rapid urine tests for urinary tract infection in children: a meta-analysis.

Rapid urine tests, such as microscopy, for bacteria and white cells, and dipsticks, for leucocyte esterase and nitrites, are often used in children that are unwell to guide early diagnosis and treatment of urinary tract infection. We aimed to establish whether these tests were sufficiently sensitive to avoid urine culture in children with negative results and to compare the accuracy of dipsticks with microscopy. Medline, Embase, and reference lists were searched. Studies were included if urine culture results were compared with rapid tests in children. Data were analysed to obtain absolute and relative accuracy estimates. Data from 95 studies in 95 703 children were analysed. Summary estimates for sensitivity and specificity for microscopy for Gram-stained bacteria were 91% (95% CI 80-96) and 96% (92-98), for unstained bacteria were 88% (75-94) and 92% (84-96), for urine white cells were 74% (67-80) and 86% (82-90), for leucocyte esterase or nitrite positive dipstick were 88% (82-91) and 79% (69-87), and for nitrite-only positive dipstick were 49% (41-57) and 98% (96-99). Microscopy for bacteria with Gram stain had higher accuracy than other laboratory tests with relative diagnostic odds ratio compared with bacteria without Gram stain of 8.7 (95% CI 1.8-41.1), white cells of 14.5 (4.7-44.4), and nitrite of 22.0 (0.7-746.3). Microscopy for white cells should not be used for the diagnosis of urinary tract infection because its accuracy is no better than that of dipstick, laboratory facilities are needed, and results are delayed. Rapid tests are negative in around 10% of children with a urinary tract infection and cannot replace urine culture. If resources allow, microscopy with Gram stain should be the single rapid test used.