PICO questions and DELPHI methodology for improving the management of patients with acute hepatic porphyria.

BACKGROUND: Acute hepatic porphyrias (AHPs) are a group of rare diseases that encompasses acute intermittent porphyria, variegate porphyria, hereditary coproporphyria, and 5-aminolaevulinic acid dehydratase deficiency porphyria. Symptoms of AHP are nonspecific which, together with its low prevalence, difficult the diagnosis and follow-up of these patients. MATERIAL AND METHODS: This project used DELPHI methodology to answer PICO questions related to management of patients with AHPs. The objective was to reach a consensus among multidisciplinary porhyria experts providing answers to those PICO questions for improving diagnosis and follow-up of patients with AHP. RESULTS: Ten PICO questions were defined and grouped in four domains: 1. Biochemical diagnosis of patients with AHP. 2. Molecular tests for patients with AHP. 3. Follow-up of patients with AHP. 4. Screening for long-term complications of patients with AHP. CONCLUSIONS: PICO questions and DELPHI methodology have provided a consensus on relevant and controversial issues for improving the management of patients with AHP.

Diagnostic and follow-up protocol for adult patients with neurofibromatosis type 1 in a Spanish reference unit.

Neurofibromatosis type 1 (NF1) is one of the most common genetic neurocutaneous disorders. The hallmark of this disease is skin lesions in the form of café-au-lait spots, ephelides, and the characteristic cutaneous neurofibromas. Other common manifestations include bone abnormalities, "NF1 vasculopathy," and neurocognitive disorders. In addition, patients are at an increased risk for a wide variety of malignant neoplasms, including the malignant transformation of plexiform neurofibromas. It is necessary to know the various clinical characteristics of this disorder and to provide an early, multidisciplinary follow-up and treatment approach in order to provide optimal care to these patients, who present with a multisystemic disease that is potentially severe. This review summarizes the diagnosis and main clinical characteristics and suggests a protocol for screening and follow-up of adult patients with NF1.

Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review.

Neurofibromatosis type 1 (NF1) is a genetic disorder that carries a higher risk of tumor development. Plexiform neurofibromas (PNs) are present in 50% of NF1 and cause significant morbidity when surgery is not feasible. Systemic therapies had not succeeded to reduce PN tumor volume until 2016 when the first trial with an MAPK/extracellular-signal-regulated kinase (MEK) inhibitor was published. We performed a systematic research on novel targeted therapies for patients with NF1 and PNs in PubMed, EMBASE, and conference abstracts with the last update in February 2021. Since 2016, seven trials have reported positive results with MEK inhibitors and other molecular targeted therapies (cabozantinib). Selumetinib has shown an overall response rate of 68% in children with NF1 and symptomatic inoperable PNs, and was associated with pain improvement and a manageable adverse events profile. This led to Food and Drug Administration (FDA) approval of selumetinib in May 2020. Recently, cabozantinib and mirdametinib have also proven their efficacy in adult population. Other MEK inhibitors such as trametinib and binimetinib have also communicated promising preliminary results. Ongoing trials in different populations and with intermittent dosing strategies are underway.

Protocol For Patients With Suspected Acute Porphyria. / Protocolo de actuación en pacientes con sospecha de porfiria aguda.

Porphyrias are a group of congenital errors in porphyrin metabolism and in the heme biosynthetic pathway. Accumulation of porphyrin precursors (delta-aminolaevulinic acid and porphobilinogen) is responsible for the neurovisceral crises of acute porphyria, which, when expressed clinically, start with intense abdominal pain. During crises, the urinary elimination of porphobilinogen and delta-aminolaevulinic acid is always very high. Excessive porphobilinogen concentration in urine is easily identified using the simple Hoesch test. A negative test rules out a current porphyric crisis. The clinical protocol for patients with acute abdominal pain of unknown origin in whom a positive Hoesch test leads to the suspicion of acute porphyria is based on the following aspects: initial clinical assessment in the emergency department, suppression of potential triggers, specific treatment for the crisis with hemin and/or glucose overload and symptomatic treatment.

Efficacy of Idursulfase therapy in patients with Mucopolysaccharidosis type II who initiated enzyme replacement therapy in adult age. A systematic review of the literature.

BACKGROUND: Enzyme replacement therapy (ERT) has been shown to decrease urine glycosaminoglycans (uGAGs) and liver and spleen volumes, and to improve clinical symptoms in mucopolysaccharidosis type II (MPS-II) patients. METHODS: A systematic search of the literature, from inception to August 2017, was conducted to identify randomized trials or observational studies including ≥1 MPS-II patients with ERT initiated in adult age (≥16 years) and evaluating ERT efficacy. Evidence was rated according to GRADE criteria. Common efficacy outcomes of the clinical studies were analyzed. Case reports were separately evaluated. RESULTS: One randomized clinical trial, 4 observational studies and 5 case reports were selected. ERT decreased uGAG levels and liver and spleen size with moderate evidence level and led to anti-ERT antibody and IRRS development in a significant proportion of patients with moderate evidence level. There were no conclusive results for beneficial effects on 6MWT, respiratory, cardiac and neurological function, joint mobility, sleep disorders of respiratory origin, and quality of life. LIMITATIONS: Excluding one observational study, all others were not conducted specifically in the target population (ERT ≥16 years). Data were from subgroup analyses of selected studies. There was a great heterogeneity between study designs and clinical outcomes evaluated. CONCLUSIONS: ERT improves uGAGs and liver/spleen volume with a moderate evidence level in MPS-II patients initiating therapy as adults, although the putative associated clinical benefit is unclear.

Clinical characteristics of adult patients with inborn errors of metabolism in Spain: A review of 500 cases from university hospitals.

Patients with inborn errors of metabolism (IEMs) have become an emerging and challenging group in the adult healthcare system whose needs should be known in order to implement appropriate policies and to adapt adult clinical departments. We aimed to analyze the clinical characteristics of adult patients with IEMs who attend the most important Spanish hospitals caring for these conditions. A cohort study was conducted in 500 patients, categorized by metabolic subtype according to pathophysiological classification. The most prevalent group of IEMs was amino acid disorders, with 108 (21.6%) patients diagnosed with phenylketonuria. Lysosomal storage disorders were the second group, in which 32 (6.4%) and 25 (5%) patients had Fabry disease and Gaucher disease respectively. The great clinical heterogeneity, the significant delay in diagnosis after symptom onset, the existence of some degree of physical dependence in a great number of patients, the need for a multidisciplinary and coordinated approach, and the lack of specific drug treatment are common features in this group of conditions.

[New CCR5 inhibitor antiretroviral drugs and integrase inhibitors]. / Nuevos fármacos antirretrovirales: inhibidores del CCR5 y de la integrasa.

Two new antiretroviral drugs belonging to a new drug family have recently been marketed in Spain. These are maraviroc (CCR5 correceptor inhibitor) and raltegravir (integrase inhibitor). These have the advantage of not presenting crossed resistance with other previously administered antiretroviral drugs, converting them into the cornerstone of the rescue treatment in the patient infected by a multiresistant viral strain. The scientific evidence available on these two drugs is reviewed in this work and its indications in the HIV infected patient are discussed.

[Serious adverse events derived from the drug interactions of antiretroviral therapy]. / Efectos secundarios graves derivados de las interacciones medicamentosas del tratamiento antirretroviral.

BACKGROUND AND AIM: Antiretroviral drugs can cause drug interactions. MATERIAL AND METHODS: Three clinical cases are described regarding HIV-infected patients in which a clinically relevant adverse effect occurred due to a pharmacokinetic interaction. RESULTS: Case 1: A 43-year old woman being treated with tenofovir DF, emtricitabine and lopinavir/ritonavir who presents ischemia in both upper extremities following an ergotamine syndrome. Case 2: A 54-year old man being treated with zidovudine, lamivudine and lopinavir/ritonavir who presents Cushing syndrome following to use of inhaled fluticasone. Case 3: A 45-year old man being treated with tenofovir DF, emtricitabine and atazanavir/ritonavir who presents a virological failure as consequence of concomitant use of omeprazole. CONCLUSIONS: Potential drug interactions must be considered when other concomitant drugs are used with antiretroviral therapy especially when one of these is a P 450 cytochrome enzymatic inductor or inhibitor.

[Tuberculosis in the autopsy. Clinical and pathological study: an analysis of 92 cases of active tuberculosis found in 2,180 autopsies]. / Tuberculosis en la autopsia. Estudio anatomoclínico: análisis de 92 casos encontrados entre 2.180 autopsias.

BACKGROUND AND OBJECTIVE: Tuberculosis is an infectious disease currently having great importance in the daily clinical practice in Spain. Some cases of active tuberculosis are not identified until after the patient had died and an autopsy has been performed. This study has analyzed the clinical and pathological characteristics of patients diagnosed with active tuberculosis in the autopsy. MATERIAL AND METHOD: We reviewed all the autopsies performed in the University Hospital 12 de Octubre of Madrid between 1974 and 2002. The autopsy reports and clinical records were examined in those cases in which active tuberculosis was found. RESULTS: We found 92 cases of active tuberculosis, 57% corresponding to men. Mean age of this group was 64 years. A total of 20% of the patients died within 48 hours after admission. Predisposing factors were identified in 90% of the cases. Dyspnea (24% of cases) and wasting syndrome (23%) were the main symptoms that motivated patients to request medical attention. Up to 30% of cases had normal chest X-ray. Tuberculosis was suspected in only 46% of patients before death. Principal cause of death was tuberculosis in 61% of patients, 52% of patients had pulmonary tuberculosis, 28% suffered from miliary tuberculosis and 20% from extra-pulmonary tuberculosis. The lungs were the most frequently affected organ. Epithelioid granulomas were found in all patients. CONCLUSIONS: Tuberculosis is an uncommon finding in the autopsy as the cause of death. The presence of unspecific symptomatology, insufficient cost-effectiveness of the diagnostic tests and precocious death, are identified as the most frequent causes of undiagnosed tuberculosis.