Molecular analysis has allowed the definitive diagnosis of multiple acyl-CoA dehydrogenase deficiency (MADD)

Multiple acyl-CoA dehydrogenation deficiency (MADD) is a rare autosomal recessive disorder due to defects in the electron transfer flavoprotein (ETF) or in the electron transfer flavoprotein dehydrogenase (ETFDH) enzymes, involved in the mitochondrial electron transport chain. Patients with MADD fall into different clinical phenotypes, ranging from a severe neonatal presentation, with metabolic acidosis, cardiomyopathy and liver disease to a mild childhood/adult disease, with episodic metabolic decompensation, muscle weakness and respiratory failure.Nowadays, the MADD diagnosis is established by the presence of dicarboxylic organic acids and acylglycine derivatives in the urine and increased levels of medium-and long-chain acylcarnitines in the blood. Mutations in ETFA, ETFB, ETFDH genes, encoding for alpha and beta subunits of ETF and for ETF-dehydrogenase are associated with MADD. We report the case of a three years old child, affected by lethargy and asthenia associated with anorexia. Biochemical analyses showed hypoketotic hypoglycemia with remarkable increments in transaminases, lactic dehydrogenase, aldolase and creatine kinase. The chromatographic layout of urinary organic acids showed a typical dicarboxylic aciduria. Thus, based on these features, MADD was suspected. Fifteen years later, at the age of 19, MADD diagnosis was confirmed by molecular analysis, showing a compound heterozygosity for the mutations c.1074G>C (p.R358S; HGMD: CM031670 in HGMD database) and c.1073G>A (p.R358K) in the ETFDH gene. The c.1073G>A (p.R358K; rs796051959) mutation is reported in ClinVar database as pathogenic allele, although lacking link to a specific clinical condition. However, familial segregation study and in silico analysis, performed by bioinformatics tools, confirmed that this substitution is likely pathogenetic. Her parents were healthy carriers of one of the two mutations. It is known that the severity of the clinical phenotype of MADD may be related to the type of mutation in the ETFA/ETFB/ETFDH genes. Particularly, missense mutations in the ETFDH gene, leaving a detectable residual enzyme activity, may account for the milder form of the disease, as is the case here. In conclusion we suggest that molecular analysis is essential to the definitive diagnosis of MADD and to direct the adequate therapeutic management. Thus, through a close nutritional follow up, a few months ago the patient gave birth to a healthy boy. References Olsen et al. Clear relationship between ETF/ETFDH genotype and phenotype in patients with multiple acyl-CoA dehydrogenation deficiency. Hum Mutat. 2003; 22:12–23

Carcinoid Crisis: A Misunderstood and Unrecognized Oncological Emergency

Carcinoid Crisis represents a rare and extremely dangerous manifestation that can occur in patients with Neuroendocrine Tumors (NETs). It is characterized by a sudden onset of hemodynamic instability, sometimes associated with the classical symptoms of carcinoid syndrome, such as bronchospasm and flushing. Carcinoid Crisis seems to be caused by a massive release of vasoactive substances, typically produced by neuroendocrine cells, and can emerge after abdominal procedures, but also spontaneously in rare instances. To date, there are no empirically derived guidelines for the management of this cancer-related medical emergency, and the available evidence essentially comes from single-case reports or dated small retrospective series. A transfer to the Intensive Care Unit may be necessary during the acute setting, when the severe hypotension becomes unresponsive to standard practices, such as volemic filling and the infusion of vasopressor therapy. The only effective strategy is represented by prevention. The administration of octreotide, anxiolytic and antihistaminic agents represents the current treatment approach to avoid hormone release and prevent major complications. However, no standard protocols are available, resulting in great variability in terms of schedules, doses, ways of administration and timing of prophylactic treatments

Successes and failures of angiogenesis blockade in gastric and gastro-esophageal junction adenocarcinoma

Gastric and gastro-esophageal junction adenocarcinoma (GEA) remains a considerable major public health problem worldwide, being the fifth most common cancer with a fatality-to-case ratio that stands still at 70%. Angiogenesis, which is a well-established cancer hallmark, exerts a fundamental role in cancer initiation and progression and its targeting has been actively pursued as a promising therapeutic strategy in GEA. A wealth of clinical trials has been conducted, investigating anti-angiogenic agents including VEGF-directed monoclonal antibodies, small molecules tyrosine kinase inhibitors and VEGF-Trap agents both in the resectable and advanced setting, reporting controversial results. While phase III randomized trials testing the anti-VEGFR-2 antibody Ramucirumab and the selective VEGFR-2 tyrosine kinase inhibitor Apatinib demonstrated a significant survival benefit in later lines, the shift of angiogenesis inhibitors in the perioperative and first-line setting failed to improve patients’ outcome in GEAs. The molecular landscape of disease, together with novel combinatorial strategies and biomarker-selected approaches are under investigation as key elements to the success of angiogenesis blockade in GEA. In this article, we critically review the existing literature on the biological rationale and clinical development of antiangiogenic agents in GEA, discussing major achievements, limitations and future developments, aiming at fully realizing the potential of this therapeutic approach

the role of primary tumour location in the recurrence rate of metachronous metastasis of colon cancer

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Surgery versus stereotactic radiotherapy for treatment of pulmonary metastases. A systematic review of literature

It is not clear as to which is the best treatment among surgery and stereotactic radiotherapy (SBRT) for lung oligometastases. A systematic review of literature with a priori selection criteria was conducted on articles on the treatment of pulmonary metastases with surgery or SBRT. Only original articles with a population of patients of more than 50 were selected. After final selection, 61 articles on surgical treatment and 18 on SBRT were included. No difference was encountered in short-term survival between pulmonary metastasectomy and SBRT. In the long-term surgery seems to guarantee better survival rates. Mortality and morbidity after treatment are 0-4.7% and 0-23% for surgery, and 0-2% and 4-31% for SBRT. Surgical metastasectomy remains the treatment of choice for pulmonary oligometastases. Patients with metastatic cancer with a limited number of deposits may benefit from surgical removal or irradiation of tumor nodules in addiction to chemotherapy. Surgical resection has been demonstrated to improve survival and, in some cases, can be curative. Stereotactic radiotherapy is emerging as a less invasive alternative to surgery, but settings and implications of the two treatments are profoundly different. The two techniques show similar results in the short-term, with lower complications rates for radiotherapy, while in the long-term surgery seems to guarantee higher survival rates