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Simple Summary: In the era of precision medicine and immunotherapy, the isolation and characterization of exosomes from the peripheral blood mononuclear cells (PBMC-EXs) of SCLC patients may represent a new tool to define responder (BR) from non-responder (NR) patients undergoing chemoimmunotherapy treatment. In this proof-of-concept study, we isolated PBMC-EXs from the peripheral blood of SCLC patients and investigated the potential role of such extracellular vesicles (EVs) in monitoring tumor response to drug stimuli. Interestingly, we found increased exosome levels of c-Myc and Snail along with reduced levels of the immune markers MAVS and STING in NR patients. Also, we showed that PBMC-EXs from BR patients induced an increase in apoptosis and a reduction in the cell viability of SCLC cells compared to PBMC-EXs from NR SCLC patients. Thus, we suggest that PBMC-EXs may represent an innovative strategy to be further explored for the therapy and selection of immune-responsive SCLC patients. Small cell lung cancer (SCLC) is a highly invasive and rapidly proliferating lung tumor subtype. Most patients respond well to a combination of platinum-based chemotherapy and PD-1/PDL-1 inhibitors. Unfortunately, not all patients benefit from this treatment regimen, and few alternative therapies are available. In this scenario, the identification of new biomarkers and differential therapeutic strategies to improve tumor response becomes urgent. Here, we investigated the role of exosomes (EXs) released from the peripheral blood mononuclear cells (PBMCs) of SCLC patients in mediating the functional crosstalk between the immune system and tumors in response to treatments. In this study, we showed that PBMC-EXs from SCLC patients with different responses to chemoimmunotherapy showed different levels of immune (STING and MAVS) and EMT (Snail and c-Myc) markers. We demonstrated that PBMC-EXs derived from best responder (BR) patients were able to induce a significant increase in apoptosis in SCLC cell lines in vitro compared to PBMC-EXs derived from non-responder (NR) SCLC patients. PBMC-EXs were able to affect cell viability and modulate apoptotic markers, DNA damage and the replication stress pathway, as well as the occurrence of EMT. Our work provides proof of concept that PBMC-EXs can be used as a tool to study the crosstalk between cancer cells and immune cells and that PBMC-EXs exhibit an in vitro ability to promote cancer cell death and reduce tumor aggressiveness. [ABSTRACT FROM AUTHOR]

Simple Summary: Much interest has arisen around adipose-derived stem cells (ASCs) due to their multifunctional activities in the tumor microenvironment (TME). Mitochondrial dynamics and mitochondrial transfer are critical processes that promote tumor progression through fission, fusion, and transfer from stromal cells, such as ASCs. This perspective focuses on the connection between ASCs and tumor cells, leveraging the idea that inhibiting their possible pro-tumorigenic effect can interfere with these processes and limit the ability of tumor cells to survive. Unfortunately, the use of ASC/MSCs in cancer therapy has some limitations, as many variables must be considered; however, bridging the gap between preclinical studies and clinical applications could lead to new therapeutic strategies. Adipose-derived stem cells (ASCs) significantly influence tumor progression within the tumor microenvironment (TME). This review examines the pro-tumorigenic roles of ASCs, focusing on paracrine signaling, direct cell–cell interactions, and immunomodulation. ASC-mediated mitochondrial transfer through tunneling nanotubes (TNTs) and gap junctions (GJs) plays a significant role in enhancing cancer cell survival and metabolism. Cancer cells with dysfunctional mitochondria acquire mitochondria from ASCs to meet their metabolic needs and thrive in the TME. Targeting mitochondrial transfer, modulating ASC function, and influencing metabolic pathways are potential therapeutic strategies. However, challenges like TME complexity, specificity, safety concerns, and resistance mechanisms must be addressed. Disrupting the ASC–cancer cell–mitochondria axis offers a promising approach to cancer therapy. [ABSTRACT FROM AUTHOR]

Context.--Fine-needle aspiration cytology (FNAC) of pulmonary nodules is usually guided by computed tomography (CT), whereas ultrasonography (US) is generally considered not applicable for such purposes. Objective.--To evaluate the clinical applicability and diagnostic utility of US-guided transthoracic FNAC of peripheral pulmonary nodules. Design.--Ultrasonography-guided transthoracic FNAC was obtained from 40 selected patients with peripheral, subpleural, and paravertebral pulmonary nodules. Airdried and Diff-Quik-stained smears were used for rapid on-site evaluation; additional smears were alcohol fixed for Papanicolaou staining. Cell blocks were set up for immunocytochemical and molecular studies; in 2 cases, a flow cytometry evaluation was also performed. The series was compared to 40 CT-guided pulmonary FNAC samples from patients with pleural, peripheral, and paravertebral pulmonary nodules, to evaluate differences in terms of diagnostic rate, time of execution, safety, and cost. Results.--The US-guided FNAC samples had results that were adequate and representative in 95% of cases. No significant differences were observed between the 2 groups in terms of diagnostic rate, number of passes, and cellularity of both smears and cell blocks. The mean time needed for the execution of US-guided FNAC was 13.1 minutes, whereas the mean time for CT-guided FNAC was 23.6 minutes. Thus, US-guided FNAC was significantly more rapid than CT-guided pulmonary FNAC. Because pneumothorax occurred in 1 individual who underwent US-guided FNAC and in 9 who underwent CT-guided FNAC, we might conclude that US-guided FNAC is a significantly safer procedure. Finally, comparing the costs of both procedures, US-guided FNAC is less expensive. Conclusions.--Our experience showed an elevated clinical applicability and diagnostic utility of US-guided transthoracic FNAC for selected pulmonary nodules. (Arch Pathol Lab Med. 2020;144:361-369; doi: 10.5858/arpa.2018-0346-OA), The diagnostic evaluation of peripheral pulmonary lesions is currently based on an integrated approach that includes imaging and direct sampling techniques. In this setting, computed tomography (CT) has taken the [...]

Background: Lung cancer (LC), including both non-small (NSCLC) and small (SCLC) subtypes, is currently treated with a combination of chemo- and immunotherapy. However, predictive biomarkers to identify high-risk patients are needed. Here, we explore the role of peripheral blood mononuclear cells (PBMCs) as a tool for novel biomarkers searching. Methods: We analyzed the expression of the cGAS-STING pathway, a key DNA sensor that activates during chemotherapy, in PBMCs from LC patients divided into best responders (BR), responders (R) and non-responders (NR). The PBMCs were whole exome sequenced (WES). Results: PBMCs from BR and R patients of LC cohorts showed the highest levels of STING (p < 0.0001) and CXCL10 (p < 0.0001). From WES, each subject had at least 1 germline/somatic alteration in a DDR gene and the presence of more DDR gene mutations correlated with clinical responses, suggesting novel biomarker implications. Thus, we tested the effect of the pharmacological DDR inhibitor (DDRi) in PBMCs and in three-dimensional spheroid co-culture of PBMCs and LC cell lines; we found that DDRi strongly increased cGAS-STING expression and tumor infiltration ability of immune cells in NR and R patients. Furthermore, we performed FACS analysis of PBMCs derived from LC patients from the BR, R and NR cohorts and we found that cytotoxic T cell subpopulations displayed the highest STING expression. Conclusions: cGAS-STING signaling activation in PBMCs may be a novel potential predictive biomarker for the response to immunotherapy and high levels are correlated with a better response to treatment along with an overall increased antitumor immune injury. [ABSTRACT FROM AUTHOR]

Measurable residual disease (MRD) has emerged as a relevant parameter of response to therapy in chronic lymphocytic leukemia (CLL). Although several methods have been developed, flow cytometry has emerged as the most useful and standardized approach to measure and quantify MRD. The improved sensitivity of MRD measurements has been paralleled by the development of more effective therapeutic strategies for CLL, increasing the applicability of MRD detection in this setting. Chemotherapy and chemoimmunotherapy have firstly demonstrated their ability to obtain a deep MRD. Combined targeted therapies are also demonstrating a high molecular response rate and prospective trials are exploring the role of MRD to guide the duration of treatment in this setting. In this review we briefly summarize what we have learned about MRD with emphasis on its flow cytometric detection. [ABSTRACT FROM AUTHOR]