Neoadjuvant treatment for stage III and IV cutaneous melanoma.

BACKGROUND: Cutaneous melanoma is amongst the most aggressive of all skin cancers. Neoadjuvant treatment is a form of induction therapy, given to shrink a cancerous tumour prior to the main treatment (usually surgery). The purpose is to improve survival and surgical outcomes. This review systematically appraises the literature investigating the use of neoadjuvant treatment for stage III and IV cutaneous melanoma. OBJECTIVES: To assess the effects of neoadjuvant treatment in adults with stage III or stage IV melanoma according to the seventh edition American Joint Committee on Cancer (AJCC) staging system. SEARCH METHODS: We searched the following databases up to 10 August 2021 inclusive: Cochrane Skin Specialised Register, CENTRAL, MEDLINE, Embase, LILACS and four trials registers, together with reference checking and contact with study authors to identify additional studies. We also handsearched proceedings from specific conferences from 2016 to 2020 inclusive. SELECTION CRITERIA: Randomised controlled trials (RCTs) of people with stage III and IV melanoma, comparing neoadjuvant treatment strategies (using targeted treatments, immunotherapies, radiotherapy, topical treatments or chemotherapy) with any of these agents or current standard of care (SOC), were eligible for inclusion. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Primary outcomes were overall survival (OS) and adverse effects (AEs). Secondary outcomes included time to recurrence (TTR), quality of life (QOL), and overall response rate (ORR). We used GRADE to evaluate the certainty of the evidence. MAIN RESULTS: We included eight RCTs involving 402 participants. Studies enrolled adults, mostly with stage III melanoma, investigated immunotherapies, chemotherapy, or targeted treatments, and compared these with surgical excision with or without adjuvant treatment. Duration of follow-up and therapeutic regimens varied, which, combined with heterogeneity in the population and definitions of the endpoints, precluded meta-analysis of all identified studies. We performed a meta-analysis including three studies. We are very uncertain if neoadjuvant treatment increases OS when compared to no neoadjuvant treatment (hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.15 to 1.21; 2 studies, 171 participants; very low-certainty evidence). Neoadjuvant treatment may increase the rate of AEs, but the evidence is very uncertain (26% versus 16%, risk ratio (RR) 1.58, 95% CI 0.97 to 2.55; 2 studies, 162 participants; very low-certainty evidence). We are very uncertain if neoadjuvant treatment increases TTR (HR 0.51, 95% CI 0.22 to 1.17; 2 studies, 171 participants; very low-certainty evidence). Studies did not report ORR as a comparative outcome or measure QOL data. We are very uncertain whether neoadjuvant targeted treatment with dabrafenib and trametinib increases OS (HR 0.28, 95% CI 0.03 to 2.25; 1 study, 21 participants; very low-certainty evidence) or TTR (HR 0.02, 95% CI 0.00 to 0.22; 1 study, 21 participants; very low-certainty evidence) when compared to surgery. The study did not report comparative rates of AEs and overall response, and did not measure QOL. We are very uncertain if neoadjuvant immunotherapy with talimogene laherparepvec increases OS when compared to no neoadjuvant treatment (HR 0.49, 95% CI 0.15 to 1.64; 1 study, 150 participants, very low-certainty evidence). It may have a higher rate of AEs, but the evidence is very uncertain (16.5% versus 5.8%, RR 2.84, 95% CI 0.96 to 8.37; 1 study, 142 participants; very low-certainty evidence). We are very uncertain if it increases TTR (HR 0.75, 95% CI 0.31 to 1.79; 1 study, 150 participants; very low-certainty evidence). The study did not report comparative ORRs or measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to the combination of ipilimumab and nivolumab as adjuvant treatment. There may be little or no difference in the rate of AEs between these treatments (9%, RR 1.0, 95% CI 0.75 to 1.34; 1 study, 20 participants; low-certainty evidence). The study did not report comparative ORRs or measure TTR and QOL. Neoadjuvant immunotherapy (combined ipilimumab and nivolumab) likely results in little to no difference in OS when compared to neoadjuvant nivolumab monotherapy (P = 0.18; 1 study, 23 participants; moderate-certainty evidence). It may increase the rate of AEs, but the certainty of this evidence is very low (72.8% versus 8.3%, RR 8.73, 95% CI 1.29 to 59; 1 study, 23 participants); this trial was halted early due to observation of disease progression preventing surgical resection in the monotherapy arm and the high rate of treatment-related AEs in the combination arm. Neoadjuvant combination treatment may lead to higher ORR, but the evidence is very uncertain (72.8% versus 25%, RR 2.91, 95% CI 1.02 to 8.27; 1 study, 23 participants; very low-certainty evidence). It likely results in little to no difference in TTR (P = 0.19; 1 study, 23 participants; low-certainty evidence). The study did not measure QOL. OS was not reported for neoadjuvant immunotherapy (combined ipilimumab and nivolumab) when compared to neoadjuvant sequential immunotherapy (ipilimumab then nivolumab). Only Grade 3 to 4 immune-related AEs were reported; fewer were reported with combination treatment, and the sequential treatment arm closed early due to a high incidence of severe AEs. The neoadjuvant combination likely results in a higher ORR compared to sequential neoadjuvant treatment (60.1% versus 42.3%, RR 1.42, 95% CI 0.87 to 2.32; 1 study, 86 participants; low-certainty evidence). The study did not measure TTR and QOL. No data were reported on OS, AEs, TTR, or QOL for the comparison of neoadjuvant interferon (HDI) plus chemotherapy versus neoadjuvant chemotherapy. Neoadjuvant HDI plus chemotherapy may have little to no effect on ORR, but the evidence is very uncertain (33% versus 22%, RR 1.75, 95% CI 0.62 to 4.95; 1 study, 36 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: We are uncertain if neoadjuvant treatment increases OS or TTR compared with no neoadjuvant treatment, and it may be associated with a slightly higher rate of AEs. There is insufficient evidence to support the use of neoadjuvant treatment in clinical practice. Priorities for research include the development of a core outcome set for neoadjuvant trials that are adequately powered, with validation of pathological and radiological responses as intermediate endpoints, to investigate the relative benefits of neoadjuvant treatment compared with adjuvant treatment with immunotherapies or targeted therapies.

Hairy Cell Leukemia Masquerading as Pancytopenia in Pregnancy.

Thrombocytopenia is one of the most common hematological abnormalities observed during pregnancy, and in rare cases, this may be the first indicator of an underlying hematological malignancy. Hairy cell leukemia (HCL) is an uncommon B-cell lymphoproliferative disorder of which thrombocytopenia is a recurrent presenting feature. A case of pancytopenia presenting in pregnancy is described in which the thrombocytopenia persisted postpartum coincidental with a vesicular, pustular rash characterised as Sweet's syndrome. Hematological, histological, immunophenotypic, and molecular investigations confirmed the presence of HCL. The patient was treated with cladribine resulting in resolution of Sweet's syndrome, hematological remission from HCL, and achievement of a normal platelet count. This case highlights the need to maintain a wide differential diagnosis for presentations of pancytopenia or thrombocytopenia in pregnancy and the requirement for follow-up investigation of unusual cases with a lack of response to steroids or immunoglobulin.

Multiple primary melanoma: a single centre retrospective review.

Prognosis has been shown to be worse for patients with multiple primary melanomas than those with a single melanoma. One recent retrospective study showed that older, white men were at higher risk of multiple primary melanomas. In our institution 2057 melanomas were diagnosed between January 1994 and March 2016. We identified 99 (4.8%) patients who had multiple primary melanomas. The average number of melanomas was 2.5 (range: 2-10). The site for first and second melanomas was similar in 30%. We found that subsequent melanomas were more likely to be in situ and thinner in terms of Breslow thickness and Clarks level. The commonest subtypes were superficial spreading and lentigo maligna. The commonest sites involved were the lower limbs. We found no significant difference in age between our total melanoma group and the multiple primary melanoma group (64 and 66 years, respectively). The average time of diagnosis between the first and second melanomas was 33.7 months. Additionally, 70% of second melanomas were diagnosed within 2 years of first diagnosis, highlighting the importance of ongoing skin surveillance in patients with a recent diagnosis of melanoma.

Bone mineral density in cystic fibrosis: benefit of exercise capacity.

The aim of this study was to evaluate the association between bone mineral density (BMD) and objective maximal exercise measurements in adults with cystic fibrosis (CF). Twenty-five CF patients (19 males, 6 females, mean age 25.5 yr, range: 17-52) underwent BMD assessment and maximal-cycle ergometer exercise testing. We examined the relationship between gas exchange (% peak-predicted O(2) uptake, CO(2) output, O(2) saturation), exercise performance (maximum power, exercise duration), and respiratory mechanics (tidal volume, rate) with lumbar spine and total proximal femur BMD. The strongest clinical correlate with BMD was forced expiratory volume at 1s (lumbar spine Z-score, r=0.36; total proximal femur Z-score, r=0.68, p<0.01). The strongest exercise correlate was % peak-predicted O(2) uptake (lumbar spine Z-score, r=0.44, p<0.01; total proximal femur Z-score, r=0.59, p<0.01). There was a closer association between exercise parameters and total proximal femur BMD (r=0.43-0.60) than with lumbar spine BMD (r=0.04-0.45). Multiple regression analysis revealed VO(2) to be the strongest independent predictor of BMD (R(2)=0.86, p<0.001) followed by petCO(2) and body mass index (R(2)=0.7 and 0.5, respectively, p<0.01). Exercise appears to influence total proximal femur BMD more than lumbar spine BMD in CF. Exercise rehabilitation programs focusing on peripheral strength training may benefit those CF patients with low total proximal femur BMD.

Treatment of lobar atelectasis with bronchoscopically administered recombinant human deoxyribonuclease in cystic fibrosis?

INTRODUCTION: Recombinant human deoxyribonuclease (rhDNase) reduces sputum viscosity and improves pulmonary function in cystic fibrosis (CF). OBJECTIVE: The objective of this study was to describe our experience in which rhDNase (Pulmozyme; Roche, Basel, Switzerland) was administered by bronchoscopic instillation into atelectatic lobes in five adults with CF. CONCLUSION: We found this method successful in treating lobar atelectasis, which was resistant to conventional therapy with antibiotics and physiotherapy. In all but one of the cases we described, administration of DNase in this manner resulted in a radiographic and clinical improvement of the atelectasis. We recommend that respiratory physicians consider this as a second line treatment in the management of atelectasis.

Thin-section CT in patients with cystic fibrosis: correlation with peak exercise capacity and body mass index.

PURPOSE: To evaluate whether thin-section chest computed tomographic (CT) findings correlate with exercise capacity, body mass index (BMI), dyspnea, and leg discomfort in patients with cystic fibrosis (CF). MATERIALS AND METHODS: Institutional ethics committee approval was obtained, and patients provided written informed consent. Twenty-two patients (13 male and nine female patients; mean age, 22 years +/- 5.9; age range, 17-41 years) with stable CF underwent thin-section CT and exercise testing on a cycle ergometer. Three radiologists blinded to the clinical severity of disease and the spirometric findings of all patients independently and randomly scored all scans with a modified Bhalla scoring system. The primary measurement of the outcome of exercise testing was percentage of predicted peak O2 uptake. Univariate (Spearman rank correlation) and multivariate analyses were used to compare thin-section CT, clinical (age, sex, spirometric data, and BMI), and exercise measurements. RESULTS: The correlation between total thin-section CT score and percentage of predicted peak O2 uptake was stronger than the correlation between the percentage of predicted peak O2 uptake and any clinical measurement (R = -0.60, P < .01). The thin-section CT structural abnormalities that had the strongest correlation with percentage of predicted peak O2 uptake were severity of bronchiectasis and presence of sacculations or abscesses (R = -0.70 and -0.71, respectively; P < .01). Multivariate analysis showed total thin-section CT score to be the only significant predictor of exercise capacity, accounting for 42% of the variance in percentage of predicted peak O2 uptake. CONCLUSION: In patients with CF, the correlation between thin-section CT score and exercise limitation is stronger than that between spirometry results or BMI and exercise limitation.