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).

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.

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.

Treatment of melanoma brain metastases with radiation and immunotherapy or targeted therapy: A systematic review with meta-analysis.

BACKGROUND: Patients with melanoma brain metastases are now frequently treated with immunotherapy (IMT) or targeted therapy (TT). The aim of this systematic review was to determine relative survival outcomes after combining radiotherapy (RT) with IMT or TT. METHODS: 126 studies were identified by searching Medline, Embase and Cochrane CENTRAL (to 7Aug 2023). RESULTS: Multivariable analyses showed that the risk of death was reduced by 30 % for combined stereotactic radiosurgery (SRS)+IMT compared to IMT alone, by 65 % for patients treated with SRS+anti-PD1 and by 59 % for patients treated with SRS+anti-CTLA4 and/or anti-PD1 (HR 0.41, 95 %CI 0.31-0.54) compared to SRS alone. Four studies compared SRS+anti-CTLA4 with SRS+anti-PD1, showing a 42 % reduction in risk of death with SRS+anti-PD1 treatment. Combined treatment with SRS+TT showed a 59 % reduction in risk compared to SRS alone. CONCLUSION: The systematic review suggests a substantial survival benefit for combining SRS with IMT or TT for patients with melanoma brain metastases.

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.

Long-Term survival across breslow thickness categories: Findings from a Population-Based study of 210,042 Australian melanoma patients.

The prognosis of a patient with a primary cutaneous melanoma is known to be related to the Breslow thickness of their tumor. This study sought to determine long-term (30-year) survival rates for the four AJCC 8th Edition T-categories by analyzing Australian registry data for 210,042 melanoma patients diagnosed from 1982-2014. The 30-year incidence rates of death due to melanoma and non-melanoma causes (with 95% confidence intervals) were 7.1% (CI 6.9-7.3%) and 32.8% (CI 32.3-33.3%), respectively. For T2 melanomas, the corresponding rates were 21.6% (CI 21.0-22.3%) and 35.6% (CI 34.7-36.6%), for T3 melanomas 34.2% (CI 33.4-35.1%) and 39.6% (CI 38.5-40.8%), and for T4 melanomas 44.3% (CI 43.2-45.3%) and 39.6% (CI 38.3-41.0%). A plateau in melanoma-related deaths occurred in T4 patients after 20 years but there were ongoing melanoma-related deaths for the other T-categories beyond 30 years. A progressive rise in the risk of death from other causes occurred across all T-categories.

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.

Antibiotic prophylaxis and recurrent urinary tract infection in children.

BACKGROUND: Antibiotics are widely administered to children with the intention of preventing urinary tract infection, but adequately powered, placebo-controlled trials regarding efficacy are lacking. This study from four Australian centers examined whether low-dose, continuous oral antibiotic therapy prevents urinary tract infection in predisposed children. METHODS: We randomly assigned children under the age of 18 years who had had one or more microbiologically proven urinary tract infections to receive either daily trimethoprim-sulfamethoxazole suspension (as 2 mg of trimethoprim plus 10 mg of sulfamethoxazole per kilogram of body weight) or placebo for 12 months. The primary outcome was microbiologically confirmed symptomatic urinary tract infection. Intention-to-treat analyses were performed with the use of time-to-event data. RESULTS: From December 1998 to March 2007, a total of 576 children (of 780 planned) underwent randomization. The median age at entry was 14 months; 64% of the patients were girls, 42% had known vesicoureteral reflux (at least grade III in 53% of these patients), and 71% were enrolled after the first diagnosis of urinary tract infection. During the study, urinary tract infection developed in 36 of 288 patients (13%) in the group receiving trimethoprim-sulfamethoxazole (antibiotic group) and in 55 of 288 patients (19%) in the placebo group (hazard ratio in the antibiotic group, 0.61; 95% confidence interval, 0.40 to 0.93; P = 0.02 by the log-rank test). In the antibiotic group, the reduction in the absolute risk of urinary tract infection (6 percentage points) appeared to be consistent across all subgroups of patients (P > or = 0.20 for all interactions). CONCLUSIONS: Long-term, low-dose trimethoprim-sulfamethoxazole was associated with a decreased number of urinary tract infections in predisposed children. The treatment effect appeared to be consistent but modest across subgroups. (Australian New Zealand Clinical Trials Registry number, ACTRN12608000470392.)

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.

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.

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.

Comparative accuracy of renal duplex sonographic parameters in the diagnosis of renal artery stenosis: paired and unpaired analysis.

OBJECTIVE: The purpose of this study was to evaluate the test performance of duplex sonographic parameters in screening for hemodynamically significant renal artery stenosis, which occurs in approximately 5% of persons with hypertension. MATERIALS AND METHODS: A comprehensive literature search was conducted to find studies on the diagnosis of renal artery stenosis in which duplex sonography and intraarterial angiography were compared and in which sensitivity and specificity were calculated. MEDLINE (1966-2005), EMBASE (1988-2005), and reference lists were searched and the authors contacted. Data were subjected to meta-analysis according to the hierarchical summary receiver operating characteristic curve model. Heterogeneity in test performance relating to population and design features was investigated. RESULTS: From 1,357 titles, 88 studies involving 9,974 arteries in 8,147 patients were included. The following four parameters were evaluated: peak systolic velocity (21 studies), acceleration time (13 studies), acceleration index (13 studies), and renal-aortic ratio (13 studies). The corresponding diagnostic odds ratios (ORs) were 60.9 (95% CI, 28.3-131.2), 28.9 (95% CI, 7.1-117.2), 16.0 (95% CI, 5.1-50.6), and 29.3 (95% CI, 12.7-67.7). Results based on studies in which parameters were directly compared showed that peak systolic velocity had greater accuracy than renal-aortic ratio (relative diagnostic OR, 1.8; p = 0.03; nine studies) and acceleration index (relative diagnostic OR, 5.3; p < 0.001; five studies). Acceleration time versus acceleration index showed no evidence of a difference in accuracy (relative diagnostic OR, 1.1; p = 0.65; nine studies). Analysis of peak systolic velocity used in combination with other parameters compared with peak systolic velocity alone (seven studies) showed evidence of a shift in test positivity (p < 0.001) but only weak evidence of improvement in accuracy (relative diagnostic OR, 1.6; p = 0.09). CONCLUSION: Sonography is a moderately accurate screening test for renal artery stenosis. The single measurement, peak systolic velocity, has the highest performance characteristics, an expected sensitivity of 85% and specificity of 92%. Additional measurements do not increase accuracy.

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.

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.