Psychiatric Adverse Reactions to Anaplastic Lymphoma Kinase Inhibitors in Non-Small-Cell Lung Cancer: Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System

open7siBackground The development of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) has improved the survival outcomes of patients with advanced ALK-rearranged non-small-cell lung cancer (NSCLC). The adverse events (AEs) related to ALK inhibitors are fairly well known; notably, about 20% of patients receiving lorlatinib experienced cognitive effects and behavioral alterations in pivotal trials. Therefore, psychiatric disorders could represent AEs of special interest for all ALK TKIs, deserving careful assessment in the post-marketing setting. Objective We conducted a real-world pharmacovigilance study on psychiatric AEs with marketed ALK inhibitors in subjects with advanced NSCLC. Patients and methods We performed an observational, retrospective analysis of spontaneous reports submitted to the Food and Drug Administration Adverse Events Reporting System (FAERS, as of December 2020), selecting psychiatric AEs to ALK TKIs approved in NSCLC (crizotinib, ceritinib, alectinib, brigatinib, lorlatinib). These AEs were independently scrutinized by three oncologists applying predefined exclusion criteria, described in terms of clinical/demographic features and assessed for drug-related causality according to an adaptation of the WHO–UMC system, a standardized probabilistic algorithm. Results Among 584 reported psychiatric AEs, 95 cases were selected as potentially treatment related, with higher reporting frequency for lorlatinib (26, 2.8%), followed by brigatinib (10, 1.2%), alectinib (18, 0.7%), ceritinib (12, 0.6%), and crizo- tinib (29, 0.3%). Reported psychiatric symptoms were mood disorders (39), psychotic disorders (24), and anxiety, agitation, and irritability (25). In the majority (74%) of cases, psychiatric AEs were serious and required hospitalization in about 32% of patients; 15.8% of retained cases were considered as highly probable and 69.5% as probable. Drug discontinuation was recorded in 31.6% of the reported cases, with the highest proportion for lorlatinib (65.4%). Conclusion Notwithstanding limitations, our study found a higher proportion of psychiatric AEs with lorlatinib, but also raised the hypothesis of psychiatric reactions as a class effect of ALK TKIs.openSisi, Monia; Fusaroli, Michele; De Giglio, Andrea; Facchinetti, Francesco; Ardizzoni, Andrea; Raschi, Emanuel; Gelsomino, FrancescoSisi, Monia; Fusaroli, Michele; De Giglio, Andrea; Facchinetti, Francesco; Ardizzoni, Andrea; Raschi, Emanuel; Gelsomino, Francesc

Deep sternal infections after in situ bilateral internal thoracic artery grafting for left ventricular myocardial revascularization: predictors and influence on 20-year outcomes

Background: The incidence and potential factors influencing deep sternal wound infection (DSWI) in a cohort of patients undergoing coronary artery bypass grafting (CABG) using skeletonized bilateral internal thoracic artery (BITA) was explored. Furthermore, we studied influence of DSWI on long-term survival, major adverse cardiac events (MACEs) and repeat coronary revascularization (RCR).Methods: The study cohort consisted of 1,325 consecutive patients who were divided in two groups: patients experiencing DSWI (n=33, group 1) and those who did not have sternal infection (n=1,292, group 2). A logistic regression model was employed to find predictors of DSWI whereas Cox regression and a competing risk models were carried out to test predictors of late death, MACE and RCR, respectively. Follow up was 100% complete and ranged from 1 to 245 months. Median follow-up was 103 months (IQR, 61 to 189 months). Cumulative follow-up was 16,430 patient years.Results: The incidence of DSWI was 2.4%. Multivariable logistic regression analysis found any single independent predictor of DSWI. However, the association of peripheral vascular disease (PVD) and diabetes increased the risk by 1.4 and 1.6 times. When DM was associated with obesity the risk increased by 2.1 and 2.6 times compared to the single factors, respectively. Obese female patients were at a 1.6-fold higher risk when compared to the association of DM with obesity. DSWI was not an independent predictor of long-term survival (HR, 2.31; 95% CI: 0.59–9.12), RCR (SHR, 2.89; 95% CI: 0.65–10.12), or MACE (SHR, 1.98; 95% CI: 0.44–8.56).Conclusions: With an accurate patient selection (i.e., exclusion of obese diabetic females) and strict DM control BITA represents a first choice for most of CABG patients, even at high risk for DSWI. The occurrence of DSWI does not influence long-term survival and late outcomes. Our findings should be confirmed by further larger research.</br

IFN-γ and CD38 in Hyperprogressive Cancer Development

Immune checkpoint inhibitors (ICIs) improve the survival of patients with multiple types of cancer. However, low response rates and atypical responses limit their success in clinical applications. The paradoxical acceleration of tumor growth after treatment, defined as hyperprogressive disease (HPD), is the most difficult problem facing clinicians and patients alike. The mechanisms that underlie hyperprogression (HP) are still unclear and controversial, although different factors are associated with the phenomenon. In this review, we propose two factors that have not yet been demonstrated to be directly associated with HP, but upon which it is important to focus attention. IFN-γ is a key cytokine in antitumor response and its levels increase during ICI therapy, whereas CD38 is an alternative immune checkpoint that is involved in immunosuppressive responses. As both factors are associated with resistance to ICI therapy, we have discussed their possible involvement in HPD with the conclusion that IFN-γ may contribute to HP onset through the activation of the inflammasome pathway, immunosuppressive enzyme IDO1 and activation-induced cell death (AICD) in effector T cells, while the role of CD38 in HP may be associated with the activation of adenosine receptors, hypoxia pathways and AICD-dependent T-cell depletion

Active infective endocarditis: Clinical characteristics and factors related to hospital mortality

Background: Little information exists on the clinical characteristics and factors related to hospital mortality in patients with active infective endocarditis referred for surgery. Methods: Between January 1, 2003 and December 31, 2006, 86 patients (56 males, 30 females, mean age 59.2 years) with active infective endocarditis were referred to our Department (2.8% of overall hospitalizations). The relation of several clinical, laboratory and echocardiographic findings at admission with hospital mortality was evaluated. Results: A native valve (NVE) was involved in 50/86; the other 30 had a prosthetic valve endocarditis (PVE). Six had pacemaker endocarditis. The aortic valve was involved more frequently than the mitral valve, both in NVE and PVE. The tricuspid valve was involved in four drug addicts; 51% of patients were in NYHA class III&#8211;IV. Staphylococci and streptococci were isolated in 69% of patients (39% vs 30%). Blood cultures were negative in 24%. Overall hospital mortality has been 11.6%. Two patients died before surgery, eight in the perioperative period. Hospital mortality was closely related to age, clinical and laboratory evidence of advanced septic condition (temperature > 38°C, leukocytosis and creatinine > 2.0 mg/dL) and hemodynamic impairment. Conclusions: Active infective endocarditis is a significant cause of referral to heart surgery departments and hospital mortality is still > 10%. Clinical and laboratory parameters easily available at admission suggest that severe sepsis and/or hemodynamic impairment may be helpful in predicting the clinical outcome in this group of high risk patients. (Cardiol J 2010; 17, 6: 566-573

mTOR Pathway Expression as Potential Predictive Biomarker in Patients with Advanced Neuroendocrine Tumors Treated with Everolimus

Background: Everolimus (Eve), which is a mammalian target of Rapamicin (mTOR) inhibitor, is part of the therapeutic armamentarium of neuroendocrine tumors (NETs). Currently, there are no validated biomarkers predicting Eve efficacy in NETs. In this study, we explore whether the expression of phosphorilated (p)-mTOR and p70S6-kinase (S6K), a downstream effector of mTOR, correlates with the outcome of patients with NET that were treated with Eve. Methods: Tissue specimens that were derived from NETs treated with Eve at our Institution were examined for the expression levels of p-mTOR and p-S6K by immunohistochemistry. Response rate (RR), progression-free survival (PFS), and overall survival (OS) were analyzed in two groups: p-mTOR/p-S6K positive (group 1) and p-mTOR/p-S6K negative (group 2). Univariate and multivariate Cox regression analysis were performed. Results: Twenty-four patients with advanced NETs that were treated with Eve were included in the analysis. Eight out 24 (33.3%) patients were both p-mTOR and p-S6K positive. A better median PFS and OS in group 1 (18.2 and 39.9 months) as compared to group 2 (13 and 32.4 months) was depicted, with a toxicity profile that was comparable with data literature. Conclusions: Our study suggests that the activation of mTOR pathway can predict better outcomes in patients with NET treated with Eve. However, these results warrant further confirmation in a prospective setting

The Role of Obesity in Early and Long-Term Outcomes after Surgical Excision of Lung Oligometastases from Colorectal Cancer

Obesity correlates with better outcomes in many neoplastic conditions. The aim of this study was to assess its role in the prognosis and morbidity of patients submitted to resection of lung oligometastases from colorectal cancer. Seventy-six patients undergoing a first pulmonary metastasectomy were retrospectively included in the study. Seventeen (22.3%) were obese (body mass index (BMI) >30 kg/m(2)). Assessed outcomes were overall survival, time to recurrence, and incidence of post-operative complications. Median follow-up was 33 months (IQR 16-53). At follow-up, 37 patients (48.6%) died, whereas 39 (51.4%) were alive. A significant difference was found in the 3-year overall survival (obese 80% vs. non-obese 56.8%, p = 0.035). Competing risk analysis shows that the cumulative incidence of recurrence was not different between the two groups. Multivariate analysis reveals that the number of metastases (p = 0.028), post-operative pneumonia (p = 0.042), and DFS (p = 0.007) were significant predictors of death. Competing risk regression shows that no independent risk factor for recurrence has been identified. The complication rate was not different between the two groups (17.6% vs. 13.6%, p = 0.70). Obesity is a positive prognostic factor for survival after pulmonary metastasectomy for colorectal cancer. Overweight patients do not experience more post-operative complications. Our results need to be confirmed by large multicenter studies

The Palliative Prognostic (PaP) Score without Clinical Evaluation Predicts Early Mortality among Advanced NSCLC Patients Treated with Immunotherapy

Background: An acceptable risk-benefit ratio may encourage the prescription of immune checkpoint inhibitors (ICI) near the late stage of life. The lung immune prognostic index (LIPI) was validated in advanced non-small cell lung cancer (NSCLC) patients treated with ICIs. The palliative prognostic (PaP) score without clinical prediction of survival (PaPwCPS) predicts early mortality probability in terminal cancer patients. Methods: We performed a retrospective study including 182 deceased advanced NSCLC patients, treated with single-agent ICI at our Institution. Two prognostic categories of high and low mortality risk were identified through ROC curve analysis for PaPwCPS and LIPI scores. Results: Most were &gt;65 years of age (68.3%) and received second-line ICI (61.2%). A total of 29 (15.9%) and 131 (72.0%) patients died within 30 and 90 days from treatment start, respectively. A total of 81 patients (44.5%) received ICI during the last month of life. Baseline PaPwCPS and LIPI scores were assessable for 78 patients. The AUC of ROC curves was significantly increased for PaPwCPS as compared with LIPI score for both 30-day and 90-day mortality. A high PaPwCPS score was associated in multivariate analysis with increased 30-day (HR 2.69, p = 0.037) and 90-day (HR 4.01, p &lt; 0.001) mortality risk. A high LIPI score was associated with increased 90-day mortality risk (p &lt; 0.001). Conclusion: We found a tendency towards ICI prescription near the late stage of life. The PaPwCPS score was a reliable predictor of 30- and 90-day mortality

Lymphadenectomy during pulmonary metastasectomy: Impact on survival and recurrence

Background and Objectives: Lymphadenectomy during pulmonary metastasectomy (PM) is widely carried out. We assessed the potential benefit on patient survival and tumor recurrence of this practice. Methods: One hundred eighty‐one patients undergoing a first PM were studied. Eighty‐six patients (47.5%) underwent lymphadenectomy (L+ group) whereas 95 (52.5%) did not undergo nodal harvesting (L−group). Main outcomes were overall survival (OS) and disease‐free survival (DFS). Median follow‐up was 25 months (interquartile range [IQR], 13‐49). Results: At follow‐up 84 patients (46.4%) died, whereas 97 (53.6%) were still alive with recurrence in 78 patients (43%). There was no difference in 5‐year survival (L+ 30.0% vs L− 43.2%; P = .87) or in the 5‐year cumulative incidence of recurrence (L + 63.2% vs L−80%; P = .07) between the two groups. Multivariable analysis indicated that disease‐free interval (DFI) less than 29 months (P P = .003) were significant predictors of death. Metastases from non‐small–cell lung cancer increased the risk of lung comorbidities by a factor of 19.8, whereas the risk of DFI less than 29 months was increased nearly 11‐fold. Competing risk regression identified multiple metastases (P = .004), head/neck primary tumor (P = .009), and age less than 67 years (P = .024) as independent risk factors for recurrence. Conclusion: Associated lymphadenectomy showed not to give any additional advantage in terms of survival and recurrence after PM

Papillary muscle intervention vs mitral ring annuloplasty in ischemic mitral regurgitation

Background and Aims The main pathophysiological factor of chronic ischemic mitral regurgitation (MR) is the outward displacement of the papillary muscles (PMs) leading to leaflet tethering. For this reason, papillary muscle intervention (PMI) in combination with mitral ring annuloplasty (MRA) has recently been introduced into clinical practice to correct this displacement, and to reduce the recurrence of regurgitation. Methods A meta‐analysis was conducted comparing the outcomes of PMI and MRA performed in combination vs MRA performed alone, in terms of MR recurrence and left ventricular reverse remodeling (LVRR). A meta‐regression was carried out to investigate the impact of the type of PMI procedure on the outcomes. Results MR recurrence in patients undergoing both PMI and MRA was lower than in those who only had MRA (log incidence rate ratio, −0.66; lower‐upper limits, −1.13 to 0.20; I2 = 0.0%; p = .44; Egger's test: intercept 0.35 [−0.78 to 1.51]; p = .42). The group with both PMI and MRA and that with only MRA showed a slightly higher reduction in left ventricular diameters (−5.94%; −8.75% to 3.13%,). However, in both groups, LVRR was p = .33). Conclusions Using PMI and MRA together has a lower MR recurrence than using MRA alone. No significant LVRR was observed between the two groups nor between the PMI techniques employed