A case report of a lung cancer patient with two uncommon EGFR mutations and a review of the literature: two sides of the same coin.

Lung cancer is the malignancy with the highest morbidity and mortality worldwide. Approximately 60% of non-small cell lung cancer (NSCLC) presents driver alterations most of which are targetable. Nowadays, limited clinical data are available regarding the efficacy of epithelial growth factor receptor (EGFR) tyrosine kinase inhibitors in patients with NSCLC harboring uncommon EGFR mutations, considering their heterogeneity. Herein, we report a rare case of EGFR-mutated lung adenocarcinoma which has developed into squamous cell carcinoma with uncommon EGFR (Ex18) compound mutations and phosphatidylinositol 3-kinase mutation receiving afatinib at the forefront.

Systemic Sclerosis Association with Malignancy.

The association of systemic sclerosis (SSc) and cancer is well known from several decades suggesting common genetic and environmental risk factors involved in the development of both diseases. Immunosuppressive drugs widely used in SSc may increase the risk of cancer occurrence and different SSc clinical and serological features identify patients at major risk to develop malignancy. In this context, among serological features, presence of anti-RNA polymerase III and anti-topoisomerase I autoantibodies seems to increase cancer frequency in SSc patients (particularly lung and breast cancers). Lung fibrosis and a long standing SSc pulmonary involvement have been largely proposed as lung cancer risk factors, and the exposure to cyclophosphamide and an upper gastrointestinal involvement have been traditionally linked to bladder and oesophagus cancers, respectively. Furthermore, immune checkpoint inhibitors used for cancer therapy can induce immune-related adverse events, which are more frequent and severe in patients with pre-existing autoimmune diseases such as SSc. The strong association between SSc and cancer occurrence steers clinicians to carefully survey SSc patients performing periodical malignancy screening. In the present review, the most relevant bilateral relationships between SSc and cancer will be addressed.

Ivosidenib in IDH1-mutated cholangiocarcinoma: Clinical evaluation and future directions.

To date, treatment options for patients with chemorefractory cholangiocarcinoma (CCA) are limited. However, the advancements in molecular techniques have recently increased the opportunity to offer molecularly targeted therapies to patients with several cancer types and some targetable oncogenic alterations have been identified also in CCA. Among these potentially actionable molecular alterations, isocitrate dehydrogenase-1 (IDH1) mutations have been detected in approximately 10-20% of intrahepatic CCA (iCCA). IDH1 is responsible for the accumulation of oncometabolites inducing epigenetic changes that are involved in various signaling pathways. Ivosidenib is the first IDH1 inhibitor which significantly improved progression-free survival (PFS) (2.7 vs 1.4 months) and overall survival (OS) (10.3 vs 5.1 months [adjusted median OS]) compared with placebo in chemorefractory IDH1-mutated CCA. The very low incidence of grade (G) 3-4 adverse events (AEs) and treatment discontinuation due to toxicity, associated with a significantly less marked decline in health-related quality of life for patients in the ivosidenib group than in placebo group, facilitates patient adherence and clinician confidence. Here, we review the development of ivosidenib in CCA patients and evaluate the clinical impact of the results of the phase III ClarIDHy trial which was responsible for the Food and Drug Administration (FDA) approval for patients with IDH1-mutated CCA whose disease progressed after standard chemotherapy (CT). We also discuss the known primary and secondary resistance mechanisms, including concomitant and acquired mutations in other genes (e.g. IDH2 mutations), second-site mutation in IDH1, and enhanced activation of other pathways (e.g. PI3K/AKT/mTOR pathway). Finally we examine the future directions, as the opportunity to combine ivosidenib with other synergistic agents, including standard chemotherapy (CT), immune checkpoint inhibitors (ICIs), and IDH2 inhibitors.

Association of Systemic Steroid Treatment and Outcome in Patients Treated with Immune Checkpoint Inhibitors: A Real-World Analysis.

BACKGROUND: Immune-related adverse events (irAEs) are inflammatory side effects, which can occur during immune-checkpoint(s) inhibitors (ICIs) therapy. Steroids are the first-line agents to manage irAEs because of their immunosuppressive properties. However, it is still debated whether or when steroids can be administered without abrogating the therapeutic efforts of immunotherapy. METHODS: We retrospectively evaluated 146 patients with metastatic non-small cell lung cancer (NSCLC), melanoma and renal cell carcinoma (RCC) treated with ICIs. We assessed the progression-free survival (PFS) of patients treated with steroids due to an irAE compared to a no-steroid group. RESULTS: The early treatment with steroid (within the first 30 days from the beginning of immunotherapy) was not related to a shorter PFS (p = 0.077). Interestingly, patients who were treated with steroids after 30 days from the start of immunotherapy had significantly longer PFS (p = 0.017). In a multivariate analysis, treatment with steroids after 30 days was an independent prognostic factor for PFS (HR: 0.59 [95% CI 0.36-0.97], p = 0.037). CONCLUSIONS: This retrospective study points out that early systemic steroids administration to manage irAEs might not have a detrimental effect on patient clinical outcome in NSCLC, melanoma and RCC patients.

Tight systolic blood pressure control with combination therapy decreases type 2 endoleaks in patients undergoing endovascular aneurysm repair.

BACKGROUND: Endovascular aneurysm repair (EVAR) has revolutionized the treatment of abdominal aortic aneurysm (AAA) disease. However, the survival advantage is lost in the long term due the occurrence of endoleaks affecting the late rupture of aneurism sac. Few data are available on the role of blood pressure control in affecting the incidence of type 2 endoleaks in patients undergoing EVAR. OBJECTIVE: Aim of this study was to evaluated whether systolic blood pressure (SBP) control to target 130 mmHg reached after preoperative cardiology consultant might decrease the incidence of type II endoleak(T2E), sac expansion and related aortic reintervention after elective endovascular aneurysm repair(EVAR). METHODS: We analyzed 386 patients undergoing EVAR between 2008 and 2016. The primary endpoints were T2E, sac expansion and related aortic re-intervention or sac shrinkage during a median follow-up of 24 months [12-48]. The secondary endpoint was every cause of vascular or cardiac morbidity and mortality. RESULTS: The SBP value of 130 mmHg at the time of EVAR resulted, at ROC curve analysis, the most sensitive and specific for all the analyzed endpoints (T2E, n = 74; sac expansion n = 19; re-intervention, n = 10, sac shrinkage, n = 72). The combination antihypertensive therapy showed a significant inverse relationship with T2E occurrence. The incidence of primary endpoints was significantly higher (p < 0.001) in patients with SBP ≥ 130 mmHg. Cardiovascular death was significantly more prevalent (p < 0,001) in patients with SBP ≥130 mmHg. These findings were confirmed at the multivariable Cox regression analysis [primary endpoint HR = 0.09(0.06-0.15), p < 0.001; cardiovascular death HR = 0.33(0.12-0.85), p = 0.023]. CONCLUSIONS: Tight SBP control at the target of 130 mmHg at the time of elective EVAR significantly decreases TE2 occurrence, need of re-intervention and cardiovascular death in a prolonged follow-up of a large sample of patients.