Analysis of mismatch repair (MMR) proteins expression in a series of malignant pleural mesothelioma (MPM) patients.

BACKGROUND: Promising results have been reported with immune checkpoint inhibitors (ICI) in a small proportion of MPM patients. MMR deficiency (dMMR) has been well described in several malignancies and was approved as a biomarker for anti-PD-1 inhibitors. Next generation sequencing (NGS) data demonstrated that 2% of MPM harbor microsatellite instability. The aim of this study is to characterize MMR by immunohistochemistry (IHC) in a series of MPM including a subset of patients treated with immunotherapy. METHODS: Tumors of 159 MPM p diagnosed between 2002 and 2017 were reviewed. Formalin-fixed, paraffin-embedded tissue was stained for MLH1, MSH2, MSH6 and PMS2 and tumors were classified as dMMR (MMR protein expression negative) and MMR intact (all MMR proteins positively expressed). We retrospectively collected clinical outcomes under standard chemotherapy and experimental immunotherapy in the entire cohort. RESULTS: MMR protein expression was analyzed in 158 samples with enough tissue and was positive in all of the cases. Twenty two patients received ICI with anti-CTLA4 or anti-PD-1 blockade in clinical trials, 58% had a response or stable disease for more than 6 m, with median progression-free survival (PFS) of 5.7 m (2.1-26.1 m). The median overall survival (mOS) in all population was 15 months (m) (13.5-18.8 m). In a multivariable model factors associated to improved mOS were PS 0, neutrophil-lymphocyte ratio (NLR) < 5 and epithelioid histology (p < 0.001). CONCLUSIONS: In our series we were unable to identify any MPM patient with dMMR by IHC. Further studies are needed to elucidate potential predictive biomarkers of ICI benefit in MPM.

Porfirias agudas en la unidad de cuidados intensivos / Acute porphyria in an intensive care unit

Las porfirias son enfermedades metabólicas hereditarias muy raras, causadas por la hipoactividad de determinadas enzimas implicadas en la síntesis del grupo hemo. Presentamos tres casos de pacientes jóvenes que debutaron con crisis de porfiria aguda, y en los que, como es frecuente, se retrasó el diagnóstico y llegaron a precisar ingreso en la unidad de cuidados intensivos (UCI) por encefalopatía grave. Tras realizar el tratamiento con hemina, la clínica mejoró rápidamente, pero en un paciente persistió una polineuropatía periférica grave como secuela durante meses. Además, comunicamos el primer caso de desencadenamiento de crisis porfírica por el uso de la "píldora del día después" (levonorgestrel) (AU)

Porphyrias are rare hereditary metabolic disorders caused by the inactivity of certain enzymes that participate in hemesynthesis. We report 3 cases in which porphyria debuted with acute episodes in young patients. As is often the case, diagnosis was delayed, and intensive care was required for severe encephalopathy. Symptoms improved rapidly after hemintherapy was started, but peripheral polyneuropathy persisted for several months in 1 patient. We report the first case of aporphyria-related seizure triggered by use of the morning-after pill (levonorgestrel) (AU)

Identification and characterization of HMBS gene mutations in Spanish patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal dominant disorder with low penetrance that results from a partial deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. The disease is clinically characterized by acute neurovisceral attacks that are precipitated by several factors including certain drugs, steroid hormones, alcohol and fasting. Early diagnosis and counselling are essential to prevent attacks, being mutation analysis the most reliable method to identify asymptomatic carriers in AIP families. In this study we have investigated the molecular defect in 15 unrelated Spanish AIP patients. Mutation analysis of the HMBS gene revealed a total of fourteen mutations including six novel ones, two of them were on the same allele in one patient. The novel mutations were three missense (R26L, R173G and D178H), two frameshift (c.749_765dup and c.874insC) and one intronic deletion (IVS12+3_+11delAGGGCCTGT). RT-PCR and sequencing demonstrated that the intronic mutation caused abnormal splicing and exon 12 skipping. Prokaryotic expression of the novel missense mutations showed that only D178H had significant residual activity. These findings will facilitate the accurate identification of presymptomatic AIP carriers in these families and they further emphasize the molecular heterogeneity of AIP in Spain.