52-Week Mid-term Efficacy of Tildrakizumab in Moderate-to-severe Psoriasis: A Real-life Multicenter Experience.

Tildrakizumab is an IL-23-inhibitor that has been approved to treat plaque psoriasis. However, few reports have become available on its efficacy profile in the real-world. Our objective was to study the mid-term efficacy of tildrakizumab in patients with moderate-to-severe psoriasis in the Spanish routine clinical practice setting. This was a retrospective multicenter study that included a total of 91 psoriatic patients on tildrakizumab. The mean Psoriasis Area and Severity Index (PASI) was 9.09 (SD, 5.30). The overall tildrakizumab survival rate was 93.47% for a mean treatment exposure of 30.18 weeks (SD, 16.57). No drug discontinuation was associated with drug tolerability, or adverse reactions. Absolute PASI ≤3 was reached by 91.3% and 96.5% of the patients on weeks 28 and 52, respectively. Response was not impacted by weight, age (>65), metabolic syndrome, presence of arthritis, or previous number of biological therapies used. Based on our own experience tildrakizumab is an effective strategy to treat plaque psoriasis and difficult-to-treat-areas.

Determinant Factors of Disease Severity for Patients With Hidradenitis Suppurativa Evaluated in a Spanish Hospital Over a 5-Year Period.

It is necessary to identify which factors or comorbidities are associated with more severe hidradenitis suppurativa, aiming to identify which patients may benefit more from early systemic treatment or a more aggressive approach. A retrospective study was conducted, including patients diagnosed with HS at the dermatology department of a Spanish hospital over a 5-year period. A total of 322 patients were included. A relationship was found between diagnostic delay, the presence of acne conglobata, pilonidal sinus, cardiovascular risk factors (hypertension, dyslipidemia, and/or diabetes mellitus) and more severe HS. No significant relationship was found between psychiatric comorbidities and the severity of the HS. The presence of perianal or truncal involvement was significantly associated with severe HS. Female sex and the presence of a family history of HS were associated with an earlier onset of the disease.

Congenital and Infantile Hemangiomas: Epidemiological, Clinical, and Treatment Characteristics Based on 3 Years' Experience at a Tertiary Care Hospital - A Retrospective Case Comparison and Review of the Literature. / Características clínico-epidemiológicas y consideraciones terapéuticas de los hemangiomas congénitos e infantiles de un hospital de tercer nivel durante un periodo de 3 años: estudio comparativo y revisión de la literatura.

Distinguishing between congenital and infantile hemangiomas is challenging, but essential for appropriate treatment. The immunohistochemical marker glucose transporter type 1 is helpful, but biopsies are uncommon in this setting. The aim of this retrospective study was to describe and compare epidemiological, clinical, and treatment characteristics of congenital and infantile hemangiomas diagnosed at a tertiary care hospital over 3 years. We studied 107 hemangiomas: 34 congenital hemangiomas (rapidly involuting, partially involuting, and noninvoluting), 70 infantile hemangiomas, and 3 hemangiomas pending classification. Superficial infantile hemangiomas of the head and neck were the most prevalent tumors. Congenital hemangiomas were most often located on the trunk. Studied risk factors were more common in patients with infantile hemangiomas. In this group of patients, treatment response was independent of sex, in vitro fertilization, lesion depth and location, and type of treatment.

Expanding the clinical spectrum of the 'HDAC8-phenotype' - implications for molecular diagnostics, counseling and risk prediction.

Cornelia de Lange syndrome (CdLS) is a clinically heterogeneous disorder characterized by typical facial dysmorphism, cognitive impairment and multiple congenital anomalies. Approximately 75% of patients carry a variant in one of the five cohesin-related genes NIPBL, SMC1A, SMC3, RAD21 and HDAC8. Herein we report on the clinical and molecular characterization of 11 patients carrying 10 distinct variants in HDAC8. Given the high number of variants identified so far, we advise sequencing of HDAC8 as an indispensable part of the routine molecular diagnostic for patients with CdLS or CdLS-overlapping features. The phenotype of our patients is very broad, whereas males tend to be more severely affected than females, who instead often present with less canonical CdLS features. The extensive clinical variability observed in the heterozygous females might be at least partially associated with a completely skewed X-inactivation, observed in seven out of eight female patients. Our cohort also includes two affected siblings whose unaffected mother was found to be mosaic for the causative mutation inherited to both affected children. This further supports the urgent need for an integration of highly sensitive sequencing technology to allow an appropriate molecular diagnostic, genetic counseling and risk prediction.

Clinical onset and course, response to treatment and outcome in 24 patients with the cblE or cblG remethylation defect complemented by genetic and in vitro enzyme study data.

BACKGROUND: The cobalamin E (cblE) (MTRR, methionine synthase reductase) and cobalamin G (cblG) (MTR, methionine synthase) defects are rare inborn errors of cobalamin metabolism leading to impairment of the remethylation of homocysteine to methionine. METHODS: Information on clinical and laboratory data at initial full assessment and during the course of the disease, treatment, outcome and quality of life was obtained in a survey-based, retrospective study from physicians caring for patients with the CblE or CblG defect. In addition, data on enzyme studies in cultured skin fibroblasts and mutations in the MTRR and MTR gene were analysed. RESULTS: In 11 cblE and 13 cblG patients, failure to thrive, feeding problems, delayed milestones, muscular hypotonia, cognitive impairment and macrocytic anaemia were the most frequent symptoms. Delay in diagnosis depended on age at first symptom and clinical pattern at presentation and correlated significantly with impaired communication abilities at follow-up. Eighteen/22 patients presented with brain atrophy or white matter disease. Biochemical response to treatment with variable combinations of betaine, cobalamin, folate was significant. The overall course was considered improving (n = 8) or stable (n = 15) in 96% of patients, however the average number of CNS symptoms per patient increased significantly over time and 16 of 23 patients were classified as developmentally delayed or severely handicapped. In vitro enzyme analysis data showed no correlation with outcome. Predominantly private mutations were detected and no genotype- phenotype correlations evident. CONCLUSIONS: The majority of patients with the cblE and cblG defect show limited clinical response to treatment and have neurocognitive impairment.

Could a patient with SMC1A duplication be classified as a human cohesinopathy?

The disorders caused by mutations in genes encoding subunits and accessory proteins of cohesin complex are collectively termed as cohesinopathies. The best known cohesinopathy is Cornelia de Lange Syndrome (CdLS), which is a multisystem developmental disorder characterized by facial dysmorphism, limb malformations, growth and cognitive impairment. Mutations in five genes, encoding subunits of the cohesin complex (SMC1A, SMC3, RAD21) and its regulators (NIPBL, HDAC8), are responsible for ∼ 70% of CdLS cases. We describe a 16-year-old boy with facial dysmorphism, growth retardation, intellectual disability, hirsutism and small hands, who has a small Supernumerary Marker Chromosome (sSMC) present in mosaic form. sSMC is composed of two duplicated segments encompassing 17 genes including SMC1A gene, at the regions Xp11.22 and Xp11.21q11.1. Clinical comparison between our patient with a previously reported individual with a SMC1A duplication and four male carriers of similar sSMC reported in databases, suggest that they all share clinical features related to cohesinopathies. Although our patient does not have the classical CdLS craniofacial phenotype, he has pre and postnatal growth retardation, intellectual disability and mild musculoskeletal anomalies, features commonly seen in patients with cohesinopathies.

A randomized phase II study of PEP02 (MM-398), irinotecan or docetaxel as a second-line therapy in patients with locally advanced or metastatic gastric or gastro-oesophageal junction adenocarcinoma.

BACKGROUND: PEP02 is a novel highly stable liposomal nanocarrier formulation of irinotecan. This randomized phase II study evaluated the efficacy and safety of single agent PEP02 compared with irinotecan or docetaxel in the second-line treatment of advanced oesophago-gastric (OG) cancer. PATIENTS AND METHODS: Patients with locally advanced/metastatic disease who had failed one prior chemotherapy regimen were randomly assigned to PEP02 120 mg/m(2), irinotecan 300 mg/m(2) or docetaxel (Taxotere) 75 mg/m(2) every 3 weeks. The primary end point was objective response rate (ORR). Simon's two-stage design was used and the ORR of interest was 20% (α = 0.05, type II error ß = 0.10, null hypothesis of ORR was 5%). RESULTS: Forty-four patients per arm received treatment, and 124 were assessable for response. The ORR statistical threshold for the first stage was reached in all arms. In the intent-to-treat (ITT) population, ORRs were 13.6% (6/44), 6.8% (3/44) and 15.9% (7/44) in the PEP02, irinotecan and docetaxel arms, respectively. The median progression-free survival (PFS) and overall survival were similar between the trial arms. Commonest grade 3-4 adverse event reported was diarrhoea in the PEP02 and irinotecan groups (27.3% versus 18.2%). CONCLUSION: The ORR associated with PEP02 was comparable with docetaxel and numerically greater than that of irinotecan. PEP02 warrants further evaluation in the advanced gastric cancer setting.

Longitudinal study of in-hospital consultations with neurology in a tertiary hospital. A health care activity on the increase.

OBJECTIVE: In-hospital consultation (IHC) is a service that some medical specialties provide to others with the aim of resolving complications in patients admitted to different hospital units. The aim of this study is to perform a descriptive analysis and longitudinal study of IHCs received in our department during the last 5 years. METHOD: A retrospective study was conducted on the IHCs made within the period 2005-2009. The data analysed were as follows: department of origin of the IHC, reason for consult, date, priority of care, definitive diagnosis, need for follow-up, need for transfer, and the demographic data of the patients. RESULTS: There were a total of 1458 IHCs in the period studied. The mean age of the patients was 58.2 ± 19.10 years, and 837 (57.6%) were males. The number of IHCs per year was: 2005: 263; 2006: 226; 2007: 239; 2007: 239, 2008: 329 and 2009: 401. The majority (86.8%) had normal priority, 8.5% high priority, and 4.7% were urgent. The Emergency Department (12%), Cardiology (10.9%), General Medicine (9.8%) and Psychiatry (8.9%) were the services with the highest demand. The most frequent reasons for consulting were loss of consciousness and epileptic seizures (24.6%), cerebral vascular disease (21.1%), and confusional states and cognitive impairment (13.4%). Over one third (36.8%) were resolved in the first consultation, and the remainder (63.8%) required follow up. Of all the cases assessed, 8.4% required transfer to Neurology. CONCLUSIONS: IHC is a complex activity that may not resolve all questions in a single visit. It involves a health care burden which is increasing annually. The increasing diagnostic complexity of the neurology, as well as the increasingly more specific treatments are the factors that lead to this higher demand.

Validation of a short useful questionnaire in Spanish for the epidemiological screening of epilepsy in Spain. EPIBERIA Questionnaire.

INTRODUCTION: There is a major gap in knowledge about the epidemiology of epilepsy in Mediterranean countries. The EPIBERIA group was formed with the aim of promoting the conducting of epidemiological studies in this region in order to improve this situation. This paper deals with the validation of a brief questionnaire for screening patients with epilepsy in the general population. METHODS: We selected an English-language questionnaire previously validated by the Ottman group. It was translated, modified to suit the characteristics of the Spanish population, and administered to a sample of 200 patients (93 epileptics and 107 non-epileptic patient controls) sampled consecutively from 5 epilepsy units in different cities in Spain. Both groups were homogeneous in demographic variables and the control group was representative of the general population. RESULTS: We obtained a sensitivity of 100% and a specificity of 74.77% for the least rigorous correction model for the questionnaire, with a sensitivity of 94.62% and a specificity of 99.07% for the most stringent correction model. The PPV ranged from 7.48% for the first case to 69.49% in the second, assuming an epilepsy prevalence of 2%. CONCLUSIONS: The questionnaire EPIBERIA is a valid Spanish tool for epilepsy screening in the general population in Spain.

[Cryptogenic new-onset super-refractory status epilepticus following SARS-CoV-2 vaccination. A case report]. / Estado epiléptico superrefractario de nueva aparición criptógeno tras vacunación contra el SARS-CoV-2. A propósito de un caso.

INTRODUCTION: New-onset super-refractory status epilepticus (NOSRSE) is a neurological emergency characterised by the development of status epilepticus in a patient without epilepsy or any known prior neurological disease and with no clear structural, toxic or metabolic cause, which recurs after 24 hours of induced coma. The most common identifiable cause is inflammatory-autoimmune. Consequently, we present a case of NOSRSE related to SARS-CoV-2 vaccination as an opportunity to investigate the dysimmune origin of this pathology. CASE REPORT: We report the case of a 40-year-old male who presented at the emergency department with fever and headache with no clear source of infection. His personal history included bacterial meningitis in childhood without any sequelae and protein S deficiency without treatment at the time, as well as vaccination with ChAdOx1 nCoV-19 21 days earlier. He was initially diagnosed with a urinary tract infection and treated with cefuroxime. Two days later, he was taken back to the emergency department with confusional symptoms and tonic-clonic seizures. He did not respond to midazolam and finally required sedation and orotracheal intubation for refractory status epilepticus. While in hospital, he required a number of lines of antiepileptic drugs, ketamine, a ketogenic diet, immunotherapy and plasmapheresis in order to successfully limit NOSRSE. The aetiological study offered normal results for serology, antineuronal antibodies in serum and cerebrospinal fluid, transthoracic echocardiography, testicular ultrasound and computed tomographic angiography. Only the control MRI scan showed a diffuse and bilateral alteration of the right hemispheric cortex and thalamic pulvinar as the only finding. CONCLUSION: It is crucial to report suspected adverse reactions associated with SARS-CoV-2 vaccination, thereby allowing continued monitoring of the risk/benefit ratio of vaccination.

TITLE: Estado epiléptico superrefractario de nueva aparición criptógeno tras vacunación contra el SARS-CoV-2. A propósito de un caso.Introducción. El estado epiléptico superrefractario de nueva aparición (NOSRSE) es una emergencia neurológica caracterizada por el desarrollo de estado epiléptico en un paciente sin epilepsia ni enfermedad neurológica previa conocida y sin clara causa estructural, tóxica o metabólica, que recurre tras 24 horas del coma inducido. La causa identificable más frecuente es la inflamatoria-autoinmune. En consecuencia, planteamos un caso de NOSRSE relacionado con la vacunación para el SARS-CoV-2 como una oportunidad de indagar el origen disinmune de esta patología. Caso clínico. Varón de 40 años que acude al servicio de urgencias refiriendo fiebre y cefalea sin claro foco infeccioso. Entre sus antecedentes personales destacamos una meningitis bacteriana en la infancia sin secuelas y un déficit de proteína S sin tratamiento en ese momento, así como vacunación con ChAdOx1 nCoV-19 21 días antes. Fue inicialmente diagnosticado de infección del tracto urinario y tratado con cefuroxima. Dos días después, se le llevó de nuevo a urgencias con cuadro confusional y crisis tonicoclónicas, sin respuesta al midazolam, y requirió finalmente sedación e intubación orotraqueal por estado epiléptico refractario. Durante su ingreso requirió múltiples líneas de antiepilépticos, quetamina, dieta cetógena, inmunoterapia y plasmaféresis para conseguir limitar el NOSRSE. El estudio etiológico ofrecía normalidad de los resultados de serología, anticuerpos antineuronales en el suero y líquido cefalorraquídeo, ecocardiografía transtorácica, ecografía testicular y angiotomografía computarizada. Únicamente la resonancia magnética de control mostró una alteración difusa y bilateral de la corteza hemisférica y pulvinar talámica derecha como único hallazgo. Conclusión. Es crucial notificar las sospechas de reacciones adversas asociadas a la vacunación frente al SARS-CoV-2, permitiendo así una supervisión continuada de la relación riesgo/beneficio de ésta.

A phase I study of sunitinib in combination with FOLFIRI in patients with untreated metastatic colorectal cancer.

BACKGROUND: This study evaluated the maximum tolerated dose (MTD) of sunitinib, a multitargeted tyrosine kinase inhibitor, combined with FOLFIRI (irinotecan 180 mg/m2 given over 90 min i.v. and l-leucovorin 200 mg/m2 given over 120 min on day 1, followed by 5-FU 400 mg/m2 bolus and then 2400 mg/m2 infused over 46 h) in untreated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: In this multicentre, phase I, open-label, dose-finding trial, FOLFIRI was administered every 2 weeks. Two sunitinib regimens were explored: Schedule 4/2 (4 weeks on, 2 weeks off; 37.5 and 50 mg/day) and continuous daily dosing (CDD; 37.5 and 25 mg/day). Dose-limiting toxic toxicities (DLTs) were evaluated during weeks 1-6. Efficacy was a secondary objective. RESULTS: Thirty-seven patients were enrolled. The 37.5 mg/day Schedule 4/2 cohort had zero of six DLTs, was expanded by 15 patients and declared the MTD. The MTD was exceeded at all other sunitinib doses and schedules; DLTs included febrile neutropenia (n=1), grade 4 neutropenia (n=4) and grade 3 deep vein thrombosis with grade 4 neutropenia (n=1). At the MTD, non-haematologic grade 3/4 adverse events with a frequency of >10% were diarrhoea, vomiting and lethargy, and the objective response rate was 57.9% (95% confidence interval 33.5-79.7). CONCLUSIONS: The MTD of sunitinib combined with FOLFIRI in chemotherapy-naive mCRC was 37.5 mg/day on Schedule 4/2. CDD of sunitinib at 37.5 or 25 mg/day plus FOLFIRI was not feasible.

Heart-lung interactions with different ventilatory settings during acute lung injury and hypovolaemia: an experimental study.

BACKGROUND: The functional haemodynamic variables pulse pressure variation (PPV), stroke volume variation (SVV), and systolic pressure variation (SPV) are widely used to assess haemodynamic status. However, it is not known how these perform during acute lung injury (ALI). This study evaluated the effects of different ventilatory strategies on haemodynamic parameters in pigs with ALI during normovolaemia and hypovolaemia. METHODS: Eight anaesthetized Agroceres pigs [40 (1.9) kg] were instrumented with pulmonary artery, PiCCO, and arterial catheters and ventilated. Three ventilatory settings were randomly assigned for 10 min each: tidal volume (VT) 15 ml kg(-1) and PEEP 5 cm H(2)O, VT 8 ml kg(-1) and PEEP 13 cm H(2)O, or VT 6 ml kg(-1) and PEEP 13 cm H(2)O. Data were collected at each setting at baseline, after ALI (lung lavage+Tween 1.5%), and ALI with hypovolaemia (haemorrhage to 30% of estimated blood volume). RESULTS: At baseline, high VT increased PPV, SVV, and SPV (P<0.05 for all). During ALI, high VT significantly increased PPV and SVV [(P = 0.002 and P = 0.008) respectively.]. After ALI with hypovolaemia, ventilation at VT 6 ml kg(-1) and PEEP 13 cm H(2)O decreased the accuracy of functional haemodynamic variables to predict hypovolaemia, with the exception of PPV (area under the curve 0.875). The parameters obtained by PiCCO were less influenced by ventilatory changes. CONCLUSIONS: VT is the ventilatory parameter which influences functional haemodynamics the most. During ventilation with low VT and high PEEP, most functional variables are less able to accurately predict hypovolaemia secondary to haemorrhage, with the exception of PPV.