Emerging role of gefitinib in the treatment of non-small-cell lung cancer (NSCLC)

Most patients with non-small-cell lung cancer (NSCLC) present with advanced disease and their long-term prognosis remains poor. Epidermal growth factor receptor (EGFR)-targeted therapies, such as gefitinib, have been subjected to comprehensive clinical development. Several phase II and III trials evaluated the clinical efficacy of gefitinib as monotherapy in pretreated patients with advanced NSCLC, as well as both monotherapy and combined with chemotherapy in chemotherapy-naive patients. A phase III trial (ISEL) in heavily pretreated advanced NSCLC patients demonstrated some improvement in survival with gefitinib compared with placebo; however, the difference was not statistically significant within the overall population. A large phase III trial in pretreated patients (INTEREST) demonstrated the non-inferiority of gefitinib in comparison with docetaxel for overall survival, together with an improved quality of life and tolerability profiles. In a large phase III trial (IPASS) in Asian chemotherapy-naive, never or former light-smoker patients with adenocarcinoma, gefitinib was more effective than carboplatin–paclitaxel in prolonging progression-free survival, particularly in patients harboring EGFR gene mutations. Gefitinib was a generally well tolerated treatment, with skin rash and diarrhea being the most common treatment adverse events. As a result, gefitinib is expected to have a large impact on the management of patients with advanced NSCLC, in particular in EGFR mutated patients

PD-L1 ≥ 50% lung cancer refractory to PD-1 inhibition: The role of salvage chemo-immunotherapy combination

Novel treatment strategies incorporating PD-1/PD-L1 inhibitors in the first-line setting of advanced non-small-cell lung cancer (NSCLC) provided relevant improvements in survival outcomes. Among NSCLC patients with PD-L1 tumor proportion score ≥50%, identifying the ones to be addressed to pembrolizumab monotherapy or chemo-immunotherapy combinations is a matter of debate, taking into account the risks of overtreatment and toxicity. Here we report the clinical stories of four NSCLC patients with PD-L1 tumor proportion score ≥50% and good performance status, sharing high tumor burden including serosal involvement. After having rapidly progressed on first-line PD-1/PD-L1 inhibitors, they achieved major clinical and radiological response to pembrolizumab-chemotherapy combination. These cases prove the feasibility and effectiveness of salvage chemo-immunotherapy in pembrolizumab-refractory NSCLC patients

Lessons to be Learnt from Real-World Studies on Immune-Related Adverse Events with Checkpoint Inhibitors: A Clinical Perspective from Pharmacovigilance

The advent of immune checkpoint inhibitors (ICIs) caused a paradigm shift both in drug development and clinical practice; however, by virtue of their mechanism of action, the excessively activated immune system results in a multitude of off-target toxicities, the so-called immune-related adverse events (irAEs), requiring new skills for timely diagnosis and a multidisciplinary approach to successfully manage the patients. In the recent past, a plethora of large-scale pharmacovigilance analyses have characterized various irAEs in terms of spectrum and clinical features in the real world. This review aims to summarize and critically appraise the current landscape of pharmacovigilance studies, thus deriving take-home messages for oncologists. A brief primer to study design, conduction, and data interpretation is also offered. As of February 2020, 30 real-world postmarketing studies have characterized multiple irAEs through international spontaneous reporting systems, namely WHO Vigibase and the US FDA Adverse Event Reporting System. The majority of studies investigated a single irAE and provided new epidemiological evidence about class-specific patterns of irAEs (i.e. anti-cytotoxic T-lymphocyte antigen 4 [CTLA-4] versus anti-programmed cell death 1 [PD-1] receptor, and its ligand [PD-L1]), kinetics of appearance, co-occurrences (overlap) among irAEs, and fatality rate. Oncologists should be aware of both strengths and limitations of these pharmacovigilance analyses, especially in terms of data interpretation. Optimal management (including rechallenge), predictivity of irAEs (as potential biomarkers of effectiveness), and comparative safety of ICIs (also in terms of combination regimens) represent key research priorities for next-generation real-world studies

Open repair of type Ia endoleak in the aortic arch: three tailored approaches

Endoleaks are an important complication following hybrid thoracic endovascular aortic repair (TEVAR) with an incidence ranging from 20% to 25%. There are five different types of endoleaks, which are classified based on the source of vessels that cause the inflow into the aneurysm sac. Type I endoleaks (EL-I) occur at either the proximal (Ia) or distal (Ib) attachment sites and can be seen during insertion of the initial stent graft or during a follow-up surveillance imaging exam. EL-I may be secondary to incomplete dilatation or inaccurate sizing of the stent graft, diseased aortic wall or aortic tortuosity with angulations, leading to higher chances of rupture. However, EL-I represent a technical failure of endovascular repair that should be corrected promptly. However, endovascular EL-I repair at the level of aortic arch is not always possible due to an improper landing zone in the ascending aorta making it technically challenging. In the present paper, we describe three cases of EL-Ia following TEVAR and we address different repair techniques. Written informed consents were obtained from the patients for publication of the article and any accompanying images

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

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