Spread Through Air Spaces in Stage I to III Resected Lung Adenocarcinomas: Should the Presence of Spread Through Air Spaces Lead to an Upstaging?

In recent years, the concept of spread through air spaces (STAS) has been discussed as an adverse prognostic factor for lung cancer. The aim of our study is to clarify the prognostic role of STAS in relation to the main recognized prognostic factors in a retrospective cohort of 330 European patients who underwent stages I to III lung adenocarcinoma resection. On univariate analysis, the presence of STAS was related to progression-free survival (PFS; hazard ratio [HR]: 1.48; 95% CI: 1.02-2.19; P = 0.038) and overall survival (OS; HR: 1.61; 95% CI: 1.03-2.52; P = 0.50). On multivariate analysis, STAS was related to PFS (HR: 1.51; 95% CI: 1.00-2.17; P = 0.050) and to OS (HR: 1.67; 95% CI: 1.00-2.81; P = 0.050). We showed that the presence of STAS was associated with lower PFS, equivalent to the next pathologic T stage, especially the median PFS of T3 stages without STAS was at 62.8 months while the median PFS of T3 stages with STAS was at 15.7 months, closer to the median PFS of 17.4 months in T4 stages. To conclude, STAS is an independent prognostic factor of PFS in this European cohort and is close to significance for OS. We suggest that the presence of STAS might lead to an upstaging of lung adenocarcinoma.

Value of immunohistochemistry in crushed areas of pulmonary neuroendocrine carcinoma.

Immunohistochemical demonstration of neuroendocrine differentiation is often performed in routine diagnostic practice for lung neuroendocrine carcinoma. However, these carcinomas are often crushed, especially on small specimens. The value of immunohistochemistry on crushed areas is not known. We aimed to assess the value of immunohistochemical markers in crushed areas. We performed a retrospective study of 299 patients with a diagnosis of pulmonary neuroendocrine carcinoma. We showed that the markers TTF-1, synaptophysin, chromogranin A, CD56, and INSM1 were more often negative in crushed areas compared with well-preserved areas. The proliferation index with anti-Ki67 was decreased but remained on average around 90%. For all markers, the percentage of labeled cells was lower than in the preserved areas. Finally, we show that cases without labeling in the crushed areas and maintained labeling in the non-crushed areas have a lower percentage of labeling than cases without this labeling mismatch. Finally, there were no false positives of these stains. Neuroendocrine markers are valid in crushed areas when positive. However, the percentage of labeled cells may be lower than on preserved areas and lead to false negatives. Finally, the proliferation index, although decreased, remains close to that on preserved areas.

Prognostic role of immune microenvironment in pleural metastases from breast and lung adenocarcinomas.

Background: Pleural metastatic disease is a common disease with dismal prognosis. The immune microenvironment of metastatic pleural tissue remains largely unknown. Thus, we aimed to investigate the presence of different immune cell populations, and to compare them with clinical characteristics. Methods: We included 70 patients with lung and breast adenocarcinoma (ADC) diagnosed with pleural metastasis during a 2-year period with the primary endpoint to investigate if the main immune cell populations are present in pleural metastases and if they have any prognostic role. Secondary endpoints were to detect any differences in their presence between lung and breast primaries and to search for any correlation with the macroscopic (thoracoscopic) findings. We used immunohistochemical techniques for the detection of CD4+, CD8+, CD20+, CD163+ and S100+ cells in whole tissue pleural biopsies of lung and breast metastases. Results: Primary endpoint: all these populations are present in the biopsies from lung and higher stromal and intratumoral CD4 counts, as well as higher stromal CD20 cells were positive prognostic factors for lung cancer metastases, while higher S100 intratumoral counts were positive prognostic factors in lung and marginally breast cancer metastases. Secondary endpoints: significant higher values for the stromal CD163 group (P=0.04) and for the intratumoral S100 group (P=0.006) were seen in lung compared to breast metastases. Interesting correlations were also noted between thoracoscopic findings (nodules, masses, pachypleuritis) and the different factors studied. Conclusions: Our data show that the immune microenvironment may be important in this advanced tumoral setting and that possible targets of the nowadays numerous treatment strategies implicating the immune system may merit further exploration in this poor prognosis disease.

Targeting KRAS Mutant in Non-Small Cell Lung Cancer: Novel Insights Into Therapeutic Strategies.

Although KRAS-activating mutations represent the most common oncogenic driver in non-small cell lung cancer (NSCLC), various attempts to inhibit KRAS failed in the past decade. KRAS mutations are associated with a poor prognosis and a poor response to standard therapeutic regimen. The recent development of new therapeutic agents (i.e., adagrasib, sotorasib) that target specifically KRAS G12C in its GDP-bound state has evidenced an unprecedented success in the treatment of this subgroup of patients. Despite providing pre-clinical and clinical efficacy, several mechanisms of acquired resistance to KRAS G12C inhibitors have been reported. In this setting, combined therapeutic strategies including inhibition of either SHP2, SOS1 or downstream effectors of KRAS G12C seem particularly interesting to overcome acquired resistance. In this review, we will discuss the novel therapeutic strategies targeting KRAS G12C and promising approaches of combined therapy to overcome acquired resistance to KRAS G12C inhibitors.

Adjuvant chemotherapy for completely resected IIA-IIIA non-small cell lung cancer: compliance to guidelines, safety and efficacy in real-life practice.

Background: Since randomised clinical trials demonstrated a survival benefit of adjuvant chemotherapy (AC) following curative-intent lung surgery, AC has been implemented as a standard therapeutic strategy for patients with a completely resected IIA-IIIA non-small cell lung cancer (NSCLC). Regarding the moderate benefit of AC and the lack of literature on AC use in real-life practice, we aimed to evaluate compliance to guidelines, AC safety and efficacy in a less selected population. Methods: Between January 2009 and December 2014, we retrospectively analysed 210 patients with theoretical indication of AC following curative-intent lung surgery for a completely resected IIA-IIIA NSCLC. The primary objective of this retrospective study was to evaluate compliance to AC guidelines. Secondary objectives included safety and efficacy of AC in real-life practice. Results: Among 210 patients with a theoretical indication of AC, chemotherapy administration was validated in multidisciplinary team (MDT) for 62.4% of them and 117 patients (55.7%) finally received AC. Patient's clinical conditions were the main reasons advanced in MDT for no respect to AC guidelines. Most of the patients received cisplatin-vinorelbine (86.3%) and AC was initiated within 8 weeks following lung surgery for 73.5% of patients. One-half of patients who received AC experienced side effects leading to either dose-intensity modification or treatment interruption. In real-life practice, AC was found to provide a survival benefit over surgery alone. Factors related to daily-life practice such as delayed AC initiation or incomplete AC planned dose received were not associated with an inferior survival. Conclusions: Although AC use might differ from guidelines in real-life practice, this retrospective study highlights that AC can be used safely and remains efficient among a less selected population. In the context of immunotherapy and targeted therapies development in peri-operative treatment strategies, the place of AC has to be precised in the future.

The Immune Microenvironment of Malignant Pleural Mesothelioma: A Literature Review.

Malignant pleural mesothelioma (MPM) is a rare and aggressive tumour with a poor prognosis, associated with asbestos exposure. Nowadays, treatment is based on chemotherapy with a median overall survival of less than two years. This review highlights the main characteristics of the immune microenvironment in MPM with special emphasis on recent biological advances. The MPM microenvironment is highly infiltrated by tumour-associated macrophages, mainly M2-macrophages. In line with infiltration by M2-macrophages, which contribute to immune suppression, other effectors of innate immune response are deficient in MPM, such as dendritic cells or natural killer cells. On the other hand, tumour infiltrating lymphocytes (TILs) are also found in MPM, but CD4+ and CD8+ TILs might have decreased cytotoxic effects through T-regulators and high expression of immune checkpoints. Taken together, the immune microenvironment is particularly heterogeneous and can be considered as mainly immunotolerant or immunosuppressive. Therefore, identifying molecular vulnerabilities is particularly relevant to the improvement of patient outcomes and the assessment of promising treatment approaches.

Use of adjuvant chemotherapy in resected non-small cell lung cancer in real-life practice: a systematic review of literature.

BACKGROUND: Adjuvant chemotherapy (AC) is recommended since 2004 for patients with a completely resected non-small cell lung cancer (NSCLC). Indeed, several randomized clinical trials have demonstrated an improved survival for patients treated with adjuvant cisplatin-based regimen than surgery alone. In these large clinical trials, patients were well selected and fit to receive AC. As the benefit of AC was estimated at 5.4% of 5-year overall survival (OS), it seems important to evaluate AC use in a less selected population. In particular, elderly patients were underrepresented in large randomized clinical trials. Furthermore, other confounding factors might limit AC efficacy in real-life practice such as the delay of chemotherapy initiation following lung surgery or the number of AC cycles received. Therefore, the aim of this systematic review is to summarize the state of the literature on AC use in current clinical practice. METHODS: A systematic assessment of literature articles and reviews on AC use in real-life practice was performed by searching in several relevant database including Medline, Google Scholar and Cochrane Library following PICOS (i.e., Population, Intervention, Comparison, Outcomes, Study design) eligibility criteria and PRISMA guidelines. Among the 1,957 results obtained with the request formulated on these research database, 56 relevant articles on AC use in non-trial setting were selected and included in the results section. RESULTS: This systematic literature review highlights the lack of literature on AC use in real-life practice as most of these studies were retrospective. Interestingly, a delayed AC-mostly due to postoperative complications-was better than surgery alone. Furthermore, AC was less purposed to elderly patients, despite retrospective studies outlined that this therapeutic option could be benefit in this specific population as for younger patients. In real-life practice, AC was also often incomplete due to adverse events, but dose reduction or omission was not always associated with an inferior survival. In non-trial setting, number of AC cycles delivered, dose reduction or omission is quite similar to randomized clinical trials. DISCUSSION: Nowadays, AC is part of the therapeutic strategy used in completely resected NSCLC. In a population of less selected patients, this systematic literature review shows that AC can be used safely and efficiently, especially in elderly patients. As well, delayed AC seems effective. Finally, the place of immunotherapy and targeted therapies have to be precised in the future as well as biomarkers to better select patients that would response to chemotherapy.

Vaccination and Immune Checkpoint Inhibitors: Does Vaccination Increase the Risk of Immune-related Adverse Events? A Systematic Review of Literature.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have become part of cancer treatments. Their main side effects are immune-related adverse events (irAEs). So far, there has been no recommendation regarding routine vaccinations during ICIs treatment. Clinicians are aware of the risk of irAEs increases in this specific situation. The aim of this review of literature is to summarize the main studies about vaccination and ICIs interactions. METHODS: A systematic assessment of literature articles was performed by searching in PubMed (MEDLINE), and major oncology meeting following PRISMA guidelines. RESULTS: This review highlights the lack of literature. Indeed, most of the studies published were about influenza vaccination. Vaccination for patients under ICIs causes a humoral response and seems to be associated with an increase rate of seroconversion. Interestingly vaccination may provoke irAEs in ICIs-treated patients. So far, inactivated vaccines have not been contraindicated during ICI treatment. CONCLUSION: Larger prospective studies are needed in order to define a consensus on the use of vaccines under immunotherapy.