Neuroendocrine subtypes of small cell lung cancer differ in terms of immune microenvironment and checkpoint molecule distribution

Small cell lung cancer (SCLC) has recently been subcategorized into neuroendocrine (NE)-high and NE-low subtypes showing 'immune desert' and 'immune oasis' phenotypes, respectively. Here, we aimed to characterize the tumor microenvironment according to immune checkpoints and NE subtypes in human SCLC tissue samples at the protein level. In this cross-sectional study, we included 32 primary tumors and matched lymph node (LN) metastases of resected early-stage, histologically confirmed SCLC patients, which were previously clustered into NE subtypes using NE-associated key RNA genes. Immunohistochemistry (IHC) was performed on formalin-fixed paraffin-embedded TMAs with antibodies against CD45, CD3, CD8, MHCII, TIM3, immune checkpoint poliovirus receptor (PVR), and indoleamine 2,3-dioxygenase (IDO). The stroma was significantly more infiltrated by immune cells both in primary tumors and in LN metastases compared to tumor nests. Immune cell (CD45+ cell) density was significantly higher in tumor nests (P = 0.019), with increased CD8+ effector T-cell infiltration (P = 0.003) in NE-low vs NE-high tumors. The expression of IDO was confirmed on stromal and endothelial cells and was positively correlated with higher immune cell density both in primary tumors and in LN metastases, regardless of the NE pattern. Expression of IDO and PVR in tumor nests was significantly higher in NE-low primary tumors (vs NE-high, P < 0.05). We also found significantly higher MHC II expression by malignant cells in NE-low (vs NE-high, P = 0.004) tumors. TIM3 expression was significantly increased in NE-low (vs NE-high, P < 0.05) tumors and in LN metastases (vs primary tumors, P < 0.05). To our knowledge, this is the first human study that demonstrates in situ that NE-low SCLCs are associated with increased immune cell infiltration compared to NE-high tumors. PVR, IDO, MHCII, and TIM3 are emerging checkpoints in SCLC, with increased expression in the NE-low subtype, providing key insight for further prospective studies on potential biomarkers and targets for SCLC immunotherapies

From Bench to Bedside: Attempt to Evaluate Repositioning of Drugs in the Treatment of Metastatic Small Cell Lung Cancer (SCLC)

BACKGROUNDS: Based on in vitro data and results of a recent drug repositioning study, some medications approved by the FDA for the treatment of various non-malignant disorders were demonstrated to have anti-SCLC activity in preclinical models. The aim of our study is to confirm whether use of these medications is associated with survival benefit. METHODS: Consecutive patients with pathologically confirmed, stage 4 SCLC were analyzed in this retrospective study. Patients that were prescribed statins, aspirin, clomipramine (tricyclic antidepressant; TCA), selective serotonin reuptake inhibitors (SSRIs), doxazosin or prazosin (α1-adrenergic receptor antagonists; ADRA1) were identified. RESULTS: There were a total of 876 patients. Aspirin, statins, SSRIs, ADRA1, and TCA were administered in 138, 72, 20, 28, and 5 cases, respectively. A statistically significant increase in median OS was observed only in statin-treated patients when compared to those not receiving any of the aforementioned medications (OS, 8.4 vs. 6.1 months, respectively; p = 0.002). The administration of SSRIs, aspirin, and ADRA1 did not result in a statistically significant OS benefit (median OS, 8.5, 6.8, and 6.0 months, respectively). The multivariate Cox model showed that, besides age and ECOG PS, radiotherapy was an independent survival predictor (Hazard Ratio, 2.151; 95% confidence interval, 1.828-2.525; p <0.001). CONCLUSIONS: Results of drug repositioning studies using only preclinical data or small numbers of patients should be treated with caution before application in the clinic. Our data demonstrated that radiotherapy appears to be an independent survival predictor in stage 4 SCLC, therefore confirming the results of other prospective and retrospective studies

Subtype-specific KRAS mutations in advanced lung adenocarcinoma: A retrospective study of patients treated with platinum-based chemotherapy

Background: Platinum-based chemotherapy is the most common treatment in advanced-stage lung adenocarcinoma. Because the clinical significance of KRAS mutational status in this setting has not yet been clearly determined, a mutation subtype-specific analysis was performed in the so far largest cohort of Caucasian patients with KRAS mutant advanced-stage lung adenocarcinoma treated with platinum-based chemotherapy. Methods: 505 Caucasian stage III-IV lung adenocarcinoma patients with known amino acid substitution-specific KRAS mutational status and treated with platinum-based chemotherapy were included. The correlations of subtype-specific KRAS mutations with smoking status, progression-free and overall survival (PFS and OS, respectively) and therapeutic response were analysed. Results: Among 338 KRAS wild-type, 147 codon 12 mutant and 20 codon 13 mutant patients, there were no mutation-related significant differences in PFS or OS (P values were 0.534 and 0.917, respectively). Eastern Cooperative Oncology Group (ECOG) status and clinical stage were significant independent prognostic factors. KRAS mutation showed a significant correlation with smoking status (P = 0.018). Importantly, however, G12V KRAS mutant patients were significantly more frequent among never-smokers than all other codon 12 KRAS mutant (G12x) subtypes (P = 0.016). Furthermore, this subgroup tended to have a higher response rate (66% versus 47%; P = 0.077). A modestly longer median PFS was also found in the G12V mutant cohort (233 days; versus 175 days in the G12x group; P = 0.145). Conclusions: While KRAS mutation status per se is neither prognostic nor predictive in stage III-IV lung adenocarcinoma, subtype-specific analysis may indeed identify clinically relevant subgroups of patients that may ultimately influence treatment decisions. © 2014 The Authors

The Enteric Nervous System and the Microenvironment of the Gut: The Translational Aspects of the Microbiome-Gut-Brain Axis

The proper functioning of the gastrointestinal tract is essential for digestion, absorption and the elimination of waste products. It protects us against pathogens, allergens and toxins, continuously monitoring and regulating the internal environment. The vast majority of these tasks are carried out by the nervous and immune systems of the gut in close cooperation by constantly adapting to internal and external stimuli, maintaining its homeostasis. In this review, we would like to summarize the most recent findings about the cytoarchitecture and functional microanatomy of the enteric nervous system and the immune microenvironment of the gut highlighting the essential role and inevitable molecular crosstalk between these two highly organized networks. Gut neuroimmunology is a rapidly evolving field and might help us to understand the etiology of inflammatory bowel disease and the systemic consequences of chronic intestinal inflammation. Finally, we also included a brief outlook to present the most recent research depicting the multifaceted role of the gut microbiome, its contribution to the gut-brain axis and human disease

The Enteric Nervous System and the Microenvironment of the Gut: The Translational Aspects of the Microbiome-Gut-Brain Axis

The proper functioning of the gastrointestinal tract is essential for digestion, absorption and the elimination of waste products. It protects us against pathogens, allergens and toxins, continuously monitoring and regulating the internal environment. The vast majority of these tasks are carried out by the nervous and immune systems of the gut in close cooperation by constantly adapting to internal and external stimuli, maintaining its homeostasis. In this review, we would like to summarize the most recent findings about the cytoarchitecture and functional microanatomy of the enteric nervous system and the immune microenvironment of the gut highlighting the essential role and inevitable molecular crosstalk between these two highly organized networks. Gut neuroimmunology is a rapidly evolving field and might help us to understand the etiology of inflammatory bowel disease and the systemic consequences of chronic intestinal inflammation. Finally, we also included a brief outlook to present the most recent research depicting the multifaceted role of the gut microbiome, its contribution to the gut-brain axis and human disease

Implication of the Gut Microbiome and Microbial-Derived Metabolites in Immune-Related Adverse Events: Emergence of Novel Biomarkers for Cancer Immunotherapy

Immune checkpoint inhibitors (ICIs) have changed how we think about tumor management. Combinations of anti-programmed death ligand-1 (PD-L1) immunotherapy have become the standard of care in many advanced-stage cancers, including as a first-line therapy. Aside from improved anti-tumor immunity, the mechanism of action of immune checkpoint inhibitors (ICIs) exposes a new toxicity profile known as immune-related adverse effects (irAEs). This novel toxicity can damage any organ, but the skin, digestive and endocrine systems are the most frequently afflicted. Most ICI-attributed toxicity symptoms are mild, but some are severe and necessitate multidisciplinary side effect management. Obtaining knowledge on the various forms of immune-related toxicities and swiftly changing treatment techniques to lower the probability of experiencing severe irAEs has become a priority in oncological care. In recent years, there has been a growing understanding of an intriguing link between the gut microbiome and ICI outcomes. Multiple studies have demonstrated a connection between microbial metagenomic and metatranscriptomic patterns and ICI efficacy in malignant melanoma, lung and colorectal cancer. The immunomodulatory effect of the gut microbiome can have a real effect on the biological background of irAEs as well. Furthermore, specific microbial signatures and metabolites might be associated with the onset and severity of toxicity symptoms. By identifying these biological factors, novel biomarkers can be used in clinical practice to predict and manage potential irAEs. This comprehensive review aims to summarize the clinical aspects and biological background of ICI-related irAEs and their potential association with the gut microbiome and metabolome. We aim to explore the current state of knowledge on the most important and reliable irAE-related biomarkers of microbial origin and discuss the intriguing connection between ICI efficacy and toxicity

Prognostic Factors in Pseudomyxoma Peritonei with Emphasis on the Predictive Role of Peritoneal Cancer Index and Tumor Markers

Background: Pseudomyxoma peritonei (PMP) is a rare peritoneal condition where mucus-secreting tumorous cells progressively produce a thick, gelatin-like substance. The prognosis of patients with PMP is determined by the degree of cellularity within the mucin (low-grade (LAMN) vs. high-grade (HAMN) histologic features) and by the extent of the disease. Methods: Prognostic relevance of tumor markers CA19-9 and CEA, gender, Peritoneal Cancer Index (PCI), and completeness of cytoreduction (CC) after cytoreductive surgery were evaluated on 193 consecutive PMP patients, based on a retrospective analysis of prospectively gathered data from a German tertial referral center. Results: We demonstrated that low PCI, CC0 status, low-grade histology, and female gender were independent positive prognostic factors for both overall survival (OS) and progression-free survival (PFS). Furthermore, LAMN patients with achieved CC0 status show significantly better OS and PFS compared to those with CC1 status (p = 0.0353 and p = 0.0026 respectively). In contrast, the duration and drug of hyperthermic intraperitoneal chemotherapy (HIPEC) were not prognostic in any comparison. Increased CA19-9 and CEA levels were significantly associated with HAMN cases, but also predicted recurrence in patients with low-grade histologies. Conclusion: Our study confirmed the prognostic role of tumor markers and emphasized the importance of CC status and PCI in a large cohort of PMP- and LAMN patients