Next-generation sequencing of uveal melanoma with clinical and histological correlations: Prognostic value of new mutations in the PI3K/AKT/mTOR pathway.

BACKGROUND: Uveal melanoma (UM) is the eye's most common primary malignancy and there are no effective therapies for disseminated disease. It is important to try to know the patient's prognosis. The aim of this study was to reflect genetic variants, studied using NGS, of a series of 69 cases of UM and its correlation with histopathology and clinical progression. METHODS: We performed targeted NGS using a 519-gene panel. RESULTS: There were selected 28 different mutated genes, showing a total of 231 genetic variants that affected the function of the protein. The most common secondary mutations occurred in SF3B1 (in 26%), followed by BAP1 (in 23%), LRP1B (22%) and FGFR4 (20%). BAP1 mutation was associated with a greater likelihood of metastases and with greater presence of epithelioid cells. LRP1B was also associated with presence of epithelioid cells SF3B1 mutation was significantly associated with a spindle morphology. We found variants in the RAD51B, TOP2A, PTPRD, TSC2, DHX9, PDK1 and MTOR that have not been previously reported in consulted databases. The presence of a mutation in: CHEK2, DHX9 and PDK1 was associated with metastases. CONCLUSIONS: BAP1 is the most solid biomarker of a poor prognosis in UM and mutations can be detected using NGS. SF3B1 is associated with the spindle cell subtype of UM, which gives it probably a favourable prognostic value. Our study suggests that mutations in DHX9 and PDK1 can have prognostic value. These potential biomarkers are related to the PI3K/AKT/mTOR pathway and makes them candidates for developing new directed therapies.

Three Cases of Clear Cell Hidradenoma With "Benign" Lymph Node Involvement.

ABSTRACT: The malignant counterpart of cutaneous clear cell hidradenoma (CCH), hidradenocarcinoma, is an aggressive neoplasm that may have a fatal outcome. However, some cases of benign looking CCH with isolated lymph node involvement and excellent prognosis have been described. "CCH-like neoplasm of uncertain malignant potential" or "atypical hidradenoma" have been proposed as designations for these lesions. We report 3 cases of CCH with lymph node involvement. Ages ranged from 29 to 51 years old. All cases involved the inguinal lymph nodes: 2 of them presented with an isolated lymph node lesion, and the third case had lymph node and cutaneous involvement following the resection of a previous cutaneous lesion. Imaging studies showed no systemic involvement. None of the lesions exhibited histopathologic features of malignancy. All neoplasms were well circumscribed, had cystic spaces, did not display atypia or necrosis, and had less than 4 mitoses per high power field. No recurrence has been observed at follow-up after resection in all cases. All published cases of CCH with lymph node involvement so far affected a single lymph node in the axillary or inguinal regions, lacked features of malignancy, and had excellent long-term prognosis. Some cases previously reported as hidradenocarcinoma probably fit into this category. Our series adds more evidence to this rare phenomenon of "benign metastasis." Aggressive treatment should be avoided in these cases, and a long-term follow-up is warranted.

Genetic Imbalance Is Associated With Functional Outcome After Ischemic Stroke.

Background and Purpose- We sought to explore the effect of genetic imbalance on functional outcome after ischemic stroke (IS). Methods- Copy number variation was identified in high-density single-nucleotide polymorphism microarray data of IS patients from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) and SiGN (Stroke Genetics Network)/GISCOME (Genetics of Ischaemic Stroke Functional Outcome) networks. Genetic imbalance, defined as total number of protein-coding genes affected by copy number variations in an individual, was compared between patients with favorable (modified Rankin Scale score of 0-2) and unfavorable (modified Rankin Scale score of ≥3) outcome after 3 months. Subgroup analyses were confined to patients with imbalance affecting ohnologs-a class of dose-sensitive genes, or to those with imbalance not affecting ohnologs. The association of imbalance with outcome was analyzed by logistic regression analysis, adjusted for age, sex, stroke subtype, stroke severity, and ancestry. Results- The study sample comprised 816 CADISP patients (age 44.2±10.3 years) and 2498 SiGN/GISCOME patients (age 67.7±14.2 years). Outcome was unfavorable in 122 CADISP and 889 SiGN/GISCOME patients. Multivariate logistic regression analysis revealed that increased genetic imbalance was associated with less favorable outcome in both samples (CADISP: P=0.0007; odds ratio=0.89; 95% CI, 0.82-0.95 and SiGN/GISCOME: P=0.0036; odds ratio=0.94; 95% CI, 0.91-0.98). The association was independent of age, sex, stroke severity on admission, stroke subtype, and ancestry. On subgroup analysis, imbalance affecting ohnologs was associated with outcome (CADISP: odds ratio=0.88; 95% CI, 0.80-0.95 and SiGN/GISCOME: odds ratio=0.93; 95% CI, 0.89-0.98) whereas imbalance without ohnologs lacked such an association. Conclusions- Increased genetic imbalance was associated with poorer functional outcome after IS in both study populations. Subgroup analysis revealed that this association was driven by presence of ohnologs in the respective copy number variations, suggesting a causal role of the deleterious effects of genetic imbalance.

Recurrent Cutaneous Angiosarcoma of the Scalp With Aberrant Expression of S100: A Case Report.

Angiosarcoma (AS) is a malignant mesenchymal neoplasm of endothelial origin with a predominantly lymphatic immunophenotype, which accounts for less than 1% of all sarcomas. Cutaneous AS of the scalp is associated with high rates of local recurrence and a poor prognosis. Histologically, poorly differentiated AS often comprises solid epithelioid cells, although rare variants involving spindle cells have been reported; diagnosis requires immunohistochemical analysis using vascular cell markers. We report on a cutaneous spindle-cell AS of the scalp in a female patient; key features included spontaneous regression after biopsy, local recurrence 2 years later, and aberrant nuclear staining for S100 protein in an area of the tumor not expressing CD34 or D2-40. Tumor cells exhibited positivity for vascular markers CD31, CD34, D2-40, ERG and FLI-1 and were negative for myoid markers (αSMA and desmin), epithelial (EMA and cytokeratin AE1/AE3) and melanocyte markers (HMB45 and melan-A). Cutaneous spindle-cell AS of the scalp is a rare variant with a poor prognosis. Diagnosis of spindle-cell AS was confirmed by immunohistochemical analysis using CD31, CD34, ERG, FLI-1, podoplanin (D2-40), and claudin-5. Although a number of authors have noted aberrant expression of cytokeratins, CD30, CD117 and neuroendocrine markers (synaptophysin and chromogranin A) in AS, intense positive nuclear staining for S100 protein in neoplastic cells has not hitherto been observed. This article reports on a spindle-cell AS of the scalp notable for aberrant expression of S100, spontaneous regression and recurrence 2 years later at the same site and displaying identical histological and immunohistochemical features.

Controversies in Intrapatient Melanoma BRAFV600E Mutation Status.

Therapies targeting the BRAF oncogene have improved the overall and disease-free survival of patients with advanced melanomas. An unresolved issue in clinical practice is the existence (or not) of BRAF-mutated and BRAF-nonmutated tumors in individual patients (intrapatient BRAF mutation heterogeneity), which may serve as a mechanism of resistance to BRAF inhibitors or lead to diagnostic problems. Different research groups have reported differing results after analyzing the BRAF mutation statuses of multiple melanoma tumors. Herein, we present a brief revision of the literature on this controversial topic and propose a theory to justify the divergence of the results found in the literature.

Role of age and sex in the diagnosis of early-stage malignant melanoma: a cross-sectional study.

Age and sex have been identified as predictors of outcome in malignant melanoma (MM). This aim of this multicentre, cross-sectional study was to analyse the role of age and sex as explanatory variables for the diagnosis of thin MM. A total of 2430 patients with MM were recruited. Cases of in situ-T1 MM were more frequent than T2-T4 MM (56.26% vs. 43.74%). Breslow thickness increased throughout decades of life (analysis of variance (ANOVA) p < 0.001), with a weak correlation between Breslow thickness and patient's age (r = 0.202, p < 0.001). Breslow thickness was significantly less in women (1.79 vs. 2.38 mm, p = 0.0001). Binary logistic regression showed a significant (p < 0.001) odds ratio for age 0-29 years (1.18), and 30-59 years (1.16), and for women (1.09). Age and sex explained 3.64% of the variation observed in Tis-T1 frequency (R2 = 0.0364). Age and sex appear to explain a low percentage of the variation in the early detection of MM.

The role of accessibility policies and other determinants of health care provision in the initial prognosis of malignant melanoma: a cross-sectional study.

BACKGROUND: The prognostic benefit of health care service provision and delivery policies for patients with malignant melanoma (MM) is not yet clear. OBJECTIVE: To analyze the role of health care provision determinants in the initial prognosis of MM. METHODS: A multicenter cross-sectional study was conducted at 14 public hospitals and recruited 3550 patients with MM between 2000 and 2009. The study variables were analyzed using univariate and multivariate models to identify their role in the variations observed. RESULTS: In a 10-year period, the number of patients with MM increased by 78.54%, with primary in situ MM (Tis) or MMs with a Breslow thickness <1 mm (T1) representing 51.72% of the total number of MMs in 2000, increasing to 62.23% by the end of the study period (P = .005). Among the variables that explained the variation in MM frequency the year of diagnosis after 2004 (univariate odds ratio [OR], 1.43 [P < .001]; multivariate OR, 1.36 [P = .005]) and diagnosis in centers with specific fast-track referral systems (univariate OR, 1.24 [P = .01]; multivariate OR, 1.59 [P = .025]) were shown to explain the increasing frequency of Tis-T1 MM. LIMITATIONS: The primary potential limitation of this study is its retrospective nature. CONCLUSION: Health care provision policies and interventions aimed at improving accessibility to specialized care appear to explain the increasing frequency of Tis-T1 MM.

High serum retinol and lung function in young patients with cystic fibrosis.

OBJECTIVE: The aim of the present study was to explore the relation between lung function and serum retinol (SR) in cystic fibrosis (CF) patients. METHODS: This was a cross-sectional study conducted in a group of 98 young patients with CF (6.8-22.3 years), after the exclusion of those with pulmonary exacerbation, vitamin A deficiency, or other risks, from an initial group of 124 cases. RESULTS: Data of forced expiratory volume in 1 second (FEV1) were widely scattered (87.7% ± 16.9%). These were similar in the 78 pancreatic insufficient and 11 pancreatic sufficient patients. SR (56.6 ± 18.4 µg/dL) was >2.5th percentile of healthy people in the whole group, although 31 patients were situated above the 97.5th percentile (higher value: 110 µg/dL). The FEV1 was noticeably higher in these than in those within the normal range (93.6 ± 14.0 vs 85.0 ± 17.6 µg/dL; P < 0.05). The z score of SR correlated positively with FEV1 (r = 0.364; P = 0.000), after adjusting data for sex, age, body mass index, and pancreatic function. The odds ratio for a FEV1 >80% is 3.78 in patients with SR above the 97.5th percentile, versus only 0.26 in those within the normal range. There were no cases with retinol toxicity. CONCLUSIONS: FEV1 of young patients with CF correlates positively with SR, regardless of age, pancreatic function, or nutritional condition. Those with a moderately high retinol (up to 110 µg/dL) maintain the best respiratory function (FEV1 ≥80% in >90% of them) without any signs of toxicity.

Purple urine in Berdon syndrome: a rare finding in the clinic laboratory.

INTRODUCTION: Purple Urine Bag Syndrome (PUBS) is a rare disorder seen in elderly persons, wherein the urinary bag and the tubing turn in to purple colour. It is usually seen in patients who are on urinary catheters for a long time. It consists of a change in the colour of the urine that turns purple in a very specific context. CASE REPORT: We report the case of a paediatric female patient with Berdon Syndrome with symptoms consistent with urinary tract infection and purple urine discolouration. Urine test revealed leukocyturia and bacteriuria. DISCUSSION: Several risk factors have been proposed regarding this syndrome. Among them the commonest are female gender, advanced age, kind of diet (increased dietary tryptophan), alkaline urine and diverse situations that leads to urinary retentions which allows bacteria to work on their substrate for a longer time. Although it is a process that is not associated with gravity, recognizing it is important as treatment is simple and can minimize patient and family distress.

Impact of the COVID-19 pandemic on the digitization of routine pediatric practice in Spain: A nationwide survey study.

Introduction: The COVID-19 pandemic forced a change in the working dynamics of all healthcare professionals, leading to the sudden introduction of telemedicine. Although until that moment telemedicine applications had been described in the paediatric age, their use was anecdotal. Objective: To analyse the experience of Spanish paediatricians after the forced digitization of consultations due to the pandemic. Methods: A cross-sectional survey-type study was designed to obtain information from Spanish paediatricians about the changes that took place in the usual clinical practice. Results: 306 health professionals participated in the study Most of them agreed on the use of the internet and social networks during the pandemic, referring to mail or WhatsApp® as usual channels of communication with their patients' families. There was a great agreement among paediatricians that the evaluation of newborns after hospital discharge and establishing methodologies that allow childhood vaccination and the identification of subsidiary patients for face-to-face evaluation were necessary although the limitations of the lockdown. The idea that telephone and digital consultations have optimized the consultation time and that they will probably continue after the end of the pandemic was generally accepted. No changes in adherence to breastfeeding or the start of complementary feeding were referred to, but an increase in the duration of breastfeeding and the appearance of frequent hoaxes in social networks concerning infant feeding were found. Conclusions: It is necessary to analyse the impact of telemedicine in paediatric consultations during the pandemic to evaluate its effectiveness and quality to maintain it in routine paediatric practice.

The use of amino acid formulas in pediatric patients with allergy to cow's milk proteins: Recommendations from a group of experts.

One of the most common food allergies in children is cow's milk allergy (CMA). In breast-fed infants with CMA, the mother is encouraged to avoid dairy products. If this is not possible, or in formula fed infants, use of hypoallergenic replacement formulas such as extensively hydrolyzed formulas (EHF) is recommended. However, in ∼5% of patients EHFs are not tolerated and/or allergy symptoms can persist. When EHFs are ineffective and in severe forms of CMA, amino acid-based formulas (AAF) should be considered. Six pediatric gastroenterologists with extensive experience in food allergy management reviewed scientific publications and international clinical practice guidelines to provide practical recommendations on AAF. The guidelines reviewed had discrepancies and ambiguities around the specific indications for using formulas as a milk substitute. The panel recommends AAFs as the first therapeutic option in anaphylaxis due to CMA, in acute and chronic severe food protein-induced enterocolitis syndrome, in CMA associated with multiple food allergy, and in cases of eosinophilic esophagitis not responding to an extended exclusion diet or not eating solids. The main benefit of AAF is its absence of residual allergenicity, making it a safe treatment option in severe CMA patients who do not tolerate or respond to an EHF.

Difficult to Diagnose Cutaneous Melanoma in a Patient with BAP1 Tumor Predisposition Syndrome.

BRCA1-associated protein 1 (BAP1)-inactivated melanomas can occur sporadically or in germline contexts, particularly in recently recognized BAP1-tumor predisposition syndrome. Diagnosis represents a clinical and histopathological challenge, requiring comprehensive analysis of morphology and sometimes molecular analysis in addition to immunohistochemistry. We report a BAP1-inactivated cutaneous melanoma initially diagnosed as an atypical Spitz tumor on the auricle in a patient with BAP1-tumor predisposition syndrome. Immunohistochemistry, fluorescence in situ hybridization, and comparative genomic hybridization allowed diagnosis. Cutaneous BAP1-inactivated melanocytic tumors, previously classified as atypical Spitz Nevi, may have a dermal mitotic activity that can resemble melanoma and on the other hand, atypical Spitz tumors are sometimes difficult to differentiate from BAP1-inactivated melanoma. Specific criteria, requiring molecular diagnosis have been proposed in order to support melanoma diagnosis.

An Unusual Case of Desmoplastic Melanoma With Monster Cells Imitating an Atypical Fibroxanthoma.

Numerous cells with very large and irregular nuclei ("monster" cells) have not hitherto been reported in desmoplastic melanoma (DM). Their prognostic significance in melanomas is a matter of debate, although some authors have associated them with more aggressive tumor behavior. We report a mixed DM on the scalp of an 88-year-old woman imitating an atypical fibroxanthoma. Tumor cells stained positive for SOX10, S100, and cyclin D1; BRAF mutation status was negative, and fluorescence in situ hybridization analysis showed copy number gains in 11q13 (cyclin D1) and 6p25 (RREB1), and loss in 6q23 (MYB). Cyclin D1 amplification is associated with poor prognosis in melanoma.

Localized argyria secondary to acupuncture mimicking blue nevus.

The typical clinical manifestation of localized cutaneous argyria is a blue-grayish asymptomatic macule, which may be caused by occupational exposure, topical treatment, dental amalgams and alternative medicine therapies. The lesions often are clinically indistinguishable from blue nevi and metastatic melanoma. The authors present a case of localized cutaneous argyria secondary to an acupuncture needle, emphasizing the importance of keeping this entity in mind in the differential diagnosis of blue-grayish pigmented lesion in a body area that could have been treated with acupuncture.

COVID-19 Gastrointestinal Manifestations Are Independent Predictors of PICU Admission in Hospitalized Pediatric Patients.

Multicenter study conducted in 15 hospitals including 101 COVID-19 pediatric inpatients aiming to describe associated gastrointestinal (GI) manifestations. GI symptoms were present in 57% and were the first manifestation in 14%. Adjusted by confounding factors, those with GI symptoms had higher risk of pediatric intensive care unit admission. GI symptoms are predictive of severity in COVID-19 children admitted to hospitals.

Assessment of Two Nutritional Screening Tools in Hospitalized Children.

AIM: to evaluate validity and concordance of Screening Tool for the Assessment of Malnutrition in Pediatrics (STAMP) and Screening Tool for Risk On Nutritional status and Growth (STRONGkids) screening tools for assessment of nutritional risk in pediatric inpatients. METHODS: Prospective longitudinal observational multicenter study in children aged 1 month or older admitted as inpatients. Weight, height, cause of admission, demographic data, length of stay, and nutritional interventions were recorded. STAMP and STRONGkids were applied within the first 72 h of admission. Anthropometric measurements were recorded again 12-18 months after admission. RESULTS: Eighty-one patients with median age of 4.1 years completed the study. Agreement between tools was moderate (κ = 0.47). STAMP had a greater tendency to classify patients as high risk (12.3% vs. 2.5%). Both tools showed very weak correlation with height for age. All undernourished patients at the beginning and the end of the study were classified as medium or high risk by STAMP and STRONGkids (100% sensitivity), although specificity was below 50% in all cases. There were no differences in length of stay based on nutritional risk with any of the tools. CONCLUSIONS: STAMP and STRONGkids demonstrated moderate agreement, with high sensitivity but low specificity for the diagnosis of undernutrition. Further studies are required to analyze cost-effectiveness of these tools and nutritional interventions derived from them.