Phacomatosis pigmentokeratotica: Exploring extracutaneous comorbidities and topical therapy.

Phacomatosis pigmentokeratotica (PPK) is a RASopathy characterized by the presence of a sebaceous nevus and a papular speckled lentiginous nevus. This case report highlights the associated extracutaneous comorbidities, including life-threatening arrhythmia, and introduces topical rapamycin as a potential therapeutic avenue for sebaceous nevus in PPK patients.

Restrospective reappraisal of the prognostic classification of spitzoid melanocytic neoplasms after BRAF and NRAS mutation characterisation: a single institution experience.

AIMS: The current WHO classification of melanocytic tumours excludes neoplasms showing BRAF or NRAS mutations from the Spitz category. This study aimed to review and reclassify atypical melanocytic tumours with spitzoid morphological features diagnosed between 2009 and 2021 in our hospital after expanding the molecular profile, including BRAF and NRAS mutations in all cases. METHODS AND RESULTS: A total of 71 neoplasms showing spitzoid features (Spitz-like) and atypia were included. The risk of progression of tumours was first studied by integrating the morphology, immunohistochemistry (p16, Ki67, HMB45 and PRAME) and fluorescence in-situ hybridisation (FISH) results (melanoma multiprobe and 9p21). In a second step, after expanding the molecular study, including BRAF and NRAS mutational status, the neoplasms were finally classified into four subgroups: atypical Spitz tumour (AST, n = 45); BRAF-mutated naevus/low-grade melanocytoma with spitzoid morphology (BAMS, n = 2); Spitz melanoma (SM, n = 14); and BRAF or NRAS mutated melanoma with spitzoid features (MSF, n = 10). Follow-up of patients revealed uneventful results for AST and BAMS. Only one SM presented lymph node metastasis after 134 months. Conversely, patients with MSF showed an unfavourable outcome: three developed lymph node metastases after a mean time of 22 months, with one patient presenting distant metastasis and dying of the disease 64 months from diagnosis. The progression-free survival showed significant differences between the four groups of spitzoid tumours (P < 0.001) and between both melanoma subtypes (P = 0.012). CONCLUSIONS: The classification and prognostication of atypical neoplasms with spitzoid features requires the integration of histomorphology with the molecular investigation of tumours, which should include BRAF and NRAS mutational status.

The onset of PI3K-related vascular malformations occurs during angiogenesis and is prevented by the AKT inhibitor miransertib.

Low-flow vascular malformations are congenital overgrowths composed of abnormal blood vessels potentially causing pain, bleeding and obstruction of different organs. These diseases are caused by oncogenic mutations in the endothelium, which result in overactivation of the PI3K/AKT pathway. Lack of robust in vivo preclinical data has prevented the development and translation into clinical trials of specific molecular therapies for these diseases. Here, we demonstrate that the Pik3caH1047R activating mutation in endothelial cells triggers a transcriptome rewiring that leads to enhanced cell proliferation. We describe a new reproducible preclinical in vivo model of PI3K-driven vascular malformations using the postnatal mouse retina. We show that active angiogenesis is required for the pathogenesis of vascular malformations caused by activating Pik3ca mutations. Using this model, we demonstrate that the AKT inhibitor miransertib both prevents and induces the regression of PI3K-driven vascular malformations. We confirmed the efficacy of miransertib in isolated human endothelial cells with genotypes spanning most of human low-flow vascular malformations.

Extra-axial sacral soft tissue giant cell ependymoma affecting a child: Case report and review of the literature.

An otherwise healthy eight-year-old girl presented with a mass in the soft tissue of the sacral region. The lesion was diagnosed as a vascular malformation on imaging studies, for which percutaneous sclerotherapy was attempted. The mass continued to grow and a complete resection was performed after four years. The pathological diagnosis was giant cell ependymoma (GCE). GCE is a term used to describe a rare histologic variant of ependymoma characterized by malignancy-like morphologic phenotype and indolent behavior. To the best of our knowledge, this is the first case of extra-axial soft tissue sacral GCE reported in a child.

Do the clinical criteria used to diagnose periodontitis affect the association with prematurity?

In recent years, several studies have examined the possible relationship between periodontal disease in pregnant women and preterm birth. One of the difficulties facing these studies is the heterogeneity of the clinical criteria used to define periodontitis. The aim of this cross-sectional study was to determine the degree of association between maternal periodontitis and preterm birth according to different consensus definitions of periodontal disease. In a study of 146 mothers (60 with preterm births and 86 with term deliveries) at the Sant Joan de Déu Maternal and Children's Hospital in Barcelona, a periodontal examination was carried out within 2 days of birth and the presence of periodontal disease was evaluated using the main clinical classifications published in the literature. The prevalence of periodontitis ranged from 25.4 to 52.1%, depending on the criteria used for its definition. Using the most restrictive criteria, pregnant women with periodontitis had a higher risk of preterm birth (OR: 7.49; p < 0.001) and premature rupture of membranes (OR: 2.49; p = 0.017). Premature infants born to mothers with periodontitis presented a tendency toward low weight, adjusted for gestational age (OR: 3.32; p = 0.065). Our findings suggest that the association between periodontitis and preterm birth is influenced by the definitions of periodontitis used.

Genome-wide postnatal changes in immunity following fetal inflammatory response.

The fetal inflammatory response (FIR) increases the risk of perinatal brain injury, particularly in extremely low gestational age newborns (ELGANs, < 28 weeks of gestation). One of the mechanisms contributing to such a risk is a postnatal intermittent or sustained systemic inflammation (ISSI) following FIR. The link between prenatal and postnatal systemic inflammation is supported by the presence of well-established inflammatory biomarkers in the umbilical cord and peripheral blood. However, the extent of molecular changes contributing to this association is unknown. Using RNA sequencing and mass spectrometry proteomics, we profiled the transcriptome and proteome of archived neonatal dried blood spot (DBS) specimens from 21 ELGANs. Comparing FIR-affected and unaffected ELGANs, we identified 782 gene and 27 protein expression changes of 50% magnitude or more, and an experiment-wide significance level below 5% false discovery rate. These expression changes confirm the robust postnatal activation of the innate immune system in FIR-affected ELGANs and reveal for the first time an impairment of their adaptive immunity. In turn, the altered pathways provide clues about the molecular mechanisms triggering ISSI after FIR, and the onset of perinatal brain injury. DATABASES: EGAS00001003635 (EGA); PXD011626 (PRIDE).

Oncological results of salvage laryngectomy in patients with laryngeal carcinoma. / Resultados oncológicos de la laringectomía de rescate en pacientes con carcinomas escamosos de laringe.

OBJECTIVE: To analyse the oncological results of a salvage total laryngectomy in patients with a laryngeal carcinoma. MATERIAL AND METHODS: Retrospective review of a cohort of 241 patients treated with a salvage laryngectomy after a local recurrence. The initial treatment received by these patients was radiotherapy (n=201, 83.4%), chemoradiotherapy (n=19, 7.9%), and partial surgery (n=21, 8.7%), RESULTS: Total laryngectomy as salvage treatment achieved local control of the disease in 81.3% of cases, with a 5-year specific survival of 65.3%. The variables related with specific survival in a univariate analysis were the location of the primary tumour, the local extension of the initial tumour and of the recurrence, the resection margins, and the pathological status of the neck dissections. According to the results of a multivariate analysis, the variables related to specific survival were the status of the resection margins, the presence of simultaneous regional recurrence, and the local extension of the recurrence. CONCLUSION: The 5-year specific survival of patients treated with a salvage laryngectomy was 65.3%. The variables related with the control of the disease were the status of the resection margins, the presence of simultaneous regional recurrence and the local extension of the recurrence.

Analysis of specific survival and local control through a recursive partitioning analysis in patients with head and neck carcinoma. / Análisis de la supervivencia específica y el control local mediante un análisis de partición recursiva en pacientes con carcinomas de cabeza y cuello.

INTRODUCTION AND OBJECTIVES: Recursive partitioning analysis (RPA) is a technique that allows prognostic classification in oncological patients. The aim of the present study is to analyse by means of an RPA a cohort of patients with squamous carcinomas of the head and neck (SCHN). METHODS: 5,226 SCHN were retrospectively analysed with an RPA, considering the specific survival and local control of the disease as dependent variables. A cohort of patients was used for the creation of the classification model, and another cohort was used to carry out its internal validation. RESULTS: Considering specific survival as a dependent variable we obtained a classification tree with 14 terminal nodes that were grouped into 5 categories, including as partition variables the local and regional extent of the tumour, and the location of the tumour. When considering the local control of the disease as a dependent variable we obtained a classification tree with 10 terminal nodes that were grouped into 4 categories, including as partition variables the local extension and location of the tumour, the type of treatment performed, the age of the patient, and if it was a first tumour or a subsequent neoplasm. The validation study confirmed the prognostic capacity of the models developed with the RPA. One of the advantages of the RPA is that it allows the identification of groups of patients with specific behaviour. CONCLUSION: RPA is shown to be an effective technique for the prognostic classification of patients with a SCHN.

Indications and results of extended total laryngectomy with en-bloc resection of overlying cervical skin.

PURPOSE: Extended total laryngectomy with en-bloc resection of overlying cervical skin (ETL) is indicated in cases with infiltration of the pre-laryngeal soft tissues. The present study analyses the surgical indications and the results of ETL in our hospital. METHODS: Retrospective review of 38 patients treated with an ETL during the period 1988-2016. RESULTS: The indications for ETL were the initial treatment of tumors with extralaryngeal extension (n = 16), salvage treatment after failure of partial surgery or radiotherapy (n = 17), and total laryngectomy in patients with infection or fibrosis of the skin over the larynx (n = 5). The surgical defect was reconstructed with local flaps in 3 cases, with pectoralis major flaps in 34 cases, and with an internal mammary artery perforator flap in one case. The rate of pharyngocutaneous fistula in the postoperative period was 16%. 5-year cancer-specific survival for patients treated with an ETL was 67.1%. The patients with positive margins and those operated as a salvage treatment after failure of previous treatments showed worse survival. CONCLUSIONS: ETL offers acceptable oncological results for patients with tumors with extralaryngeal extension. Myocutaneous or myofascial pectoralis major flaps allow for adequate reconstruction of the surgical defect with a low rate of complications.

Patients with locally advanced hypopharyngeal carcinoma. Results over a 30-year period. / Pacientes con carcinoma localmente avanzado de hipofaringe. Resultados a lo largo de un periodo de 30 años.

INTRODUCTION AND OBJECTIVES: The treatment of locally advanced carcinomas of the hypopharynx may include surgery or several combinations of radiotherapy and chemotherapy as organ preservation strategies. The objective of the present study is to analyze the results of locally advanced hypopharyngeal carcinoma patients treated in a single centre over a 30-year period. METHODS: Retrospective chart review of 278 patients with T3-T4 hypopharyngeal carcinomas treated between 1985 and 2015 at a tertiary institution. RESULTS: As much as 15.5% of the patients received only palliative treatment. Surgery, usually followed by radiotherapy or chemoradiotherapy was offered to 38.1% of the patients, and radiotherapy or chemoradiotherapy alone was offered to the remaining 46.6% of the patients. Cause-specific survival at 5 years was 39.7% (95% CI 33.7-45.7) for the whole sample. Surgery achieved better local control of the disease, but these figures did not translate into an increase of cause-specific survival for T3 tumours. Five-year survival free of laryngeal dysfunction for patients who received conservative treatment was 36.4%. In a multivariate analysis, only T4 local extension, N2-3 category, and posterior hypopharyngeal wall location related significantly with cause-specific survival. CONCLUSIONS: There were no significant differences in cause-specific survival related to treatment modality for T3 carcinomas. On the other hand, surgery achieved a significant increase in cause-specific survival for T4 hypopharyngeal carcinomas.

Study protocol for a randomised controlled trial: treatment of early intrauterine growth restriction with low molecular weight heparin (TRACIP).

INTRODUCTION: The incidence of intrauterine growth restriction (IUGR) is estimated at about 3% of pregnancies, and it is associated with 30% of all perinatal mortality and severe morbidity with adverse neurodevelopmental and cardiovascular health consequences in adult life. Early onset IUGR represents 20%-30% of all cases and is highly associated with severe placental insufficiency. The existing evidence suggests that low molecular weight heparin (LMWH) has effects beyond its antithrombotic action, improving placental microvessel structure and function of pregnant women with vascular obstetric complications by normalising proangiogenic and antiapoptotic protein levels, cytokines and inflammatory factors. The objective of our study is to demonstrate the effectiveness of LMWH in prolonging gestation in pregnancies with early-onset IUGR. METHODS AND ANALYSIS: This is a multicentre, triple-blind, parallel-arm randomised clinical trial. Singleton pregnancies qualifying for early (20-32 weeks at diagnosis) placental IUGR (according to Delphi criteria) will be randomised to subcutaneous treatment with bemiparin 3500 IU/0.2 mL/day or placebo from inclusion at diagnosis to the time of delivery. Analyses will be based on originally assigned groups (intention-to-treat). The primary objective will be analysed by comparing gestational age and prolongation of pregnancy (days) in each group with Student's t-tests for independent samples and by comparing Kaplan-Maier survival curves (from inclusion to delivery, log-rank test). A linear regression model for gestational age at birth will consider the following covariates: gestational age at inclusion (continuous) and pre-eclampsia (binary). ETHICS AND DISSEMINATION: The study will be conducted in accordance with the principles of Good Clinical Practice. This study was approved by the Clinical Research Ethics Committee (CEIC) of Sant Joan de Déu Hospital, on 13 July 2017. The trial is registered in the public registry www.clinicaltrial.gov. according to Science Law 14/2011, and the results will be published in an open access journal. TRIAL REGISTRATION NUMBER: NCT03324139; Pre-results.

Relationship between response to induction chemotherapy and disease control in patients with advanced laryngeal carcinoma included in an organ preservation protocol.

The aim of the study is to analyze the relationship between the degree of response to induction chemotherapy and the disease control in patients with locally advanced laryngeal carcinomas candidates to total laryngectomy. This retrospective study includes 389 patients with T3-T4 laryngeal tumors candidates to total laryngectomy, diagnosed between 1985 and 2013, treated with induction chemotherapy in an organ preservation protocol. Five-year local recurrence-free survival for patients receiving conservative treatment with radiotherapy after a complete response to induction chemotherapy was 75.4%; for patients with partial response greater than 50%, it was 62.0%; and for patients with the absence of response, it was 32.7%. There were significant differences in local recurrence-free survival and laryngeal dysfunction-free survival according to the response to induction chemotherapy (P = 0.0001) at the expense of patients with absence of response to induction chemotherapy. Patients with partial response greater than 50% treated with radiotherapy had a tendency to have worse local recurrence-free survival and laryngeal dysfunction-free survival than patients with complete response, but the differences did not reach statistical significance. Patients with the absence of response after induction chemotherapy had significant differences in disease-specific survival according to the second treatment: for patients treated with surgery it was 70.2%, whereas for patients treated with radiotherapy, it was 28.2% (P = 0.0001). In patients with the absence of response to induction chemotherapy, conservative treatment with radiotherapy implies a significant decrease in survival.

Epidermal Choristoma of the Tongue Mimicking a Congenital Melanotic Macule.

We report the fifth case of epidermal choristoma of the oral cavity in a Caucasian newborn with a congenital melanotic macule on the dorsum of the tongue. Epidermal choristoma is an exceedingly rare and benign condition probably caused by a developmental abnormality. It is identified according to the presence of normal skin in an abnormal location. Histologically it is identified according to areas of stratified epithelium and hyperpigmentation of the basal layer along with cutaneous adnexal structures (hair follicles, sebaceous or sweat glands). The clinical presentation is variable, but most of the cases described presented with a congenital lingual pigmented macule. These lesions should be included within the differential diagnosis of congenital lingual macules and distinguished from other entities such as congenital lingual melanotic macules and melanocytic lesions. Surgical excision is the treatment of choice. Epidermal choristoma is a benign condition that probably is underdiagnosed because it is a new and rare entity, and dermatologists should be aware of it.

Specific activation of K-RasG12D allele in the bladder urothelium results in lung alveolar and vascular defects.

K-ras is essential for embryogenesis and its mutations are involved in human developmental syndromes and cancer. To determine the consequences of K-ras activation in urothelium, we used uroplakin-II (UPK II) promoter driven Cre recombinase mice and generated mice with mutated KrasG12D allele in the urothelium (UPK II-Cre;LSL-K-rasG12D). The UPK II-Cre;LSL-K-rasG12D mice died neonatally due to lung morphogenesis defects consisting of simplification with enlargement of terminal air spaces and dysmorphic pulmonary vasculature. A significant alteration in epithelial and vascular basement membranes, together with fragmentation of laminin, points to extracellular matrix degradation as the causative mechanism of alveolar and vascular defects. Our data also suggest that altered protease activity in amniotic fluid might be associated with matrix defects in lung of UPK II-Cre;LSL-K-rasG12. These defects resemble those observed in early stage human neonatal bronchopulmonary dysplasia (BPD), although the relevance of this new mouse model for BPD study needs further investigation.