The number of clinical protocols testing combined therapies including immune check-point inhibitors and platinum salts is currently increasing in lung cancer treatment, however preclinical studies ...and rationale are often lacking. Here, we evaluated the impact of cisplatin treatment on PD-L1 expression analyzing the clinicopathological characteristics of patients who received cisplatin-based neoadjuvant chemotherapy followed by surgery and showed that cisplatin-based induction treatment significantly increased PD-L1 staining in both tumor and immune cells from the microenvironment. Twenty-two patients exhibited positive PD-L1 staining variation after neoadjuvant chemotherapy; including 9 (23.1%) patients switching from <50% to ≥50% of stained tumor-cells. We also confirmed the up-regulation of PD-L1 by cisplatin, at both RNA and protein levels, in nude and immunocompetent mice bearing tumors grafted with A549, LNM-R, or LLC1 lung cancer cell lines. The combined administration of anti-PD-L1 antibodies (3 mg/kg) and cisplatin (1 mg/kg) to mice harboring lung carcinoma significantly reduced tumor growth compared to single agent treatments and controls. Overall, these results suggest that cisplatin treatment could synergize with PD-1/PD-L1 blockade to increase the clinical response, in particular through early and sustainable enhancement of PD-L1 expression.
•Cisplatin-based induction chemotherapy increases PD-L1 expression by tumor cells.•PD-L1 staining of microenvironment immune cells was higher after neoadjuvant treatment.•Cisplatin rapidly increases PD-L1 mRNA and protein levels in lung cancer cell lines.•In tumor bearing mice injection of cisplatin significantly enhances PD-L1 expression.•The combined treatment associating cisplatin and anti-PD-L1 improves tumor response.
Objectives
To evaluate the clinico-radiological findings of acute fibrinous and organizing pneumonia (AFOP) in the literature according to whether a surgical or non-surgical biopsy was performed, as ...well as to identify prognostic predictors.
Methods
We searched the Embase and OVID-MEDLINE databases to identify studies that presented CT findings of AFOP and had extractable individual patient data. We compared the clinical and CT findings of the patients depending on whether a surgical or non-surgical biopsy was performed and identified survival predictors using a multivariate logistic regression analysis.
Results
Eighty-one patients (surgical biopsy,
n
= 52; non-surgical biopsy,
n
= 29) from 63 studies were included. The surgical biopsy group frequently experienced an acute fulminant presentation (
p
= .011) and dyspnea (
p
= .001) and less frequently had a fever (
p
= .006) than the non-surgical biopsy group. The surgical biopsy group had a worse prognosis than the non-surgical biopsy group in terms of mechanical ventilation and mortality (both,
p
= .023). For survival analysis, the patients with the predominant CT finding of patchy or mass-like air-space consolidation survived more frequently (
p
< .001) than those with other CT findings. For prognostic predictors, subacute indolent presentation (
p
= .001) and patchy or mass-like air-space consolidation on CT images (
p
= .002) were independently associated with good survival.
Conclusions
Approximately one-third of alleged AFOP cases in the literature were diagnosed via non-surgical biopsy, but those cases had different symptomatic presentations and prognosis from surgically proven AFOP. Subacute indolent presentation and patchy or mass-like air-space consolidation at the presentation on CT images indicated a good prognosis in patients with AFOP.
Key Points
• Acute fibrinous and organizing pneumonia (AFOP) cases diagnosed via non-surgical biopsy had different symptomatic presentations and prognosis from surgically proven AFOP.
• Subacute indolent presentation and patchy or mass-like air-space consolidation on CT images indicated a good prognosis in patients with acute fibrinous and organizing pneumonia.
Animal models are currently used in several fields of biomedical research as useful alternatives to human-based studies. However, the obtained results do not always effectively translate into ...clinical applications, due to interspecies anatomical and physiological differences. Detailed comparability studies are therefore required to verify whether the selected animal species could be a representative model for the disease or for cellular process under investigation. This has proven to be fundamental to obtaining reliable data from preclinical studies. Among the different species, swine is deemed an excellent animal model in many fields of biological research, and has been largely used in respiratory medicine, considering the high homology between human and swine airways. In the context of in vitro studies, the validation of porcine airway epithelial cells as an alternative to human epithelial cells is crucial. In this paper, porcine and human tracheal and bronchial epithelial cells are compared in terms of in vivo tissue architecture and in vitro cell behaviour under standard and airlifted conditions, analyzing the regenerative, proliferative and differentiative potentials of these cells. We report multiple analogies between the two species, validating the employment of porcine airway epithelial cells for most in vitro preclinical studies, although with some limitations due to species-related divergences.
Hypothesizing that nutritional status, systemic inflammation and tumoral immune microenvironment play a role as determinants of lung cancer evolution, the purpose of this study was to assess their ...respective impact on long-term survival in resected non-small cell lung cancers (NSCLC).
Clinical, pathological and laboratory data of 303 patients surgically treated for NSCLC were retrospectively analyzed. C-reactive protein (CRP) and prealbumin levels were recorded, and tumoral infiltration by CD8+ lymphocytes and mature dendritic cells was assessed. We observed that factors related to nutritional status, systemic inflammation and tumoral immune microenvironment were correlated; significant correlations were also found between these factors and other relevant clinical-pathological parameters. With respect to outcome, at univariate analysis we found statistically significant associations between survival and the following variables: Karnofsky index, American Society of Anesthesiologists (ASA) class, CRP levels, prealbumin concentrations, extent of resection, pathologic stage, pT and pN parameters, presence of vascular emboli, and tumoral infiltration by either CD8+ lymphocytes or mature dendritic cells and, among adenocarcinoma type, tumor grade (all p<0.05). In multivariate analysis, prealbumin levels (Relative Risk (RR): 0.34 0.16-0.73, p = 0.0056), CD8+ cell count in tumor tissue (RR = 0.37 0.16-0.83, p = 0.0162), and disease stage (RR 1.73 1.03-2.89; 2.991.07-8.37, p = 0.0374- stage I vs II vs III-IV) were independent prognostic markers. When taken together, parameters related to systemic inflammation, nutrition and tumoral immune microenvironment allowed robust prognostic discrimination; indeed patients with undetectable CRP, high (>285 mg/L) prealbumin levels and high (>96/mm2) CD8+ cell count had a 5-year survival rate of 80% 60.9-91.1 as compared to 18% 7.9-35.6 in patients with an opposite pattern of values. When stages I-II were considered alone, the prognostic significance of these factors was even more pronounced.
Our data show that nutrition, systemic inflammation and tumoral immune contexture are prognostic determinants that, taken together, may predict outcome.
Non-small-cell lung carcinoma (NSCLC) is the most common lung cancer and one of the pioneer tumors in which immunotherapy has radically changed patients' outcomes. However, several issues are ...emerging and their implementation is required to optimize immunotherapy-based protocols. In this work, we investigate the ability of the Bromodomain and Extra-Terminal protein inhibitors (BETi) to stimulate a proficient anti-tumor immune response toward NSCLC. By using in vitro, ex-vivo, and in vivo models, we demonstrate that these epigenetic drugs specifically enhance Natural Killer (NK) cell cytotoxicity. BETi down-regulate a large set of NK inhibitory receptors, including several immune checkpoints (ICs), that are direct targets of the transcriptional cooperation between the BET protein BRD4 and the transcription factor SMAD3. Overall, BETi orchestrate an epigenetic reprogramming that leads to increased recognition of tumor cells and the killing ability of NK cells. Our results unveil the opportunity to exploit and repurpose these drugs in combination with immunotherapy.
Abstract
OBJECTIVES
The prognostic role of the number of resected and metastatic lymph nodes in non-small-cell lung cancer (NSCLC) is still being debated. The aim of this study was to evaluate the ...impact of lymphadenectomy in addition to the already validated variables in NSCLC survival.
METHODS
From January 2002 to December 2012, data on 4858 patients with NSCLC undergoing anatomical lung resection and hilomediastinal lymphadenectomy in 6 institutions were analysed retrospectively. Established prognostic factors in addition to the number of resected lymph nodes and the ratio between the number of metastatic lymph nodes and the number of resected lymph nodes (NR) were correlated to overall survival (OS) and disease-free survival (DFS) using the multivariable Cox regression model. Harrell’s C-statistic with the 95% confidence interval (CI) was determined. Analysis by means of maximally selected log-rank statistics was performed to find optimal cut-off points in order to split patients into groups with different outcome probabilities.
RESULTS
The median numbers of resected lymph nodes and of metastatic lymph nodes were 17 (range 6–85) and 2 (1–36), respectively. Hilar (N1) and mediastinal (N2) metastases were identified in 21.3% and 20.0% of cases, respectively. Overall, the 5-year OS and DFS rates were 54.6% and 44.8%, respectively. At multivariable analysis, age, gender, pathological stage, R0 resection, type of surgery and NR correlated with longer OS rates; the same variables plus tumour grading were further related to DFS. C-statistics were 66.0 (95% CI 62.7–69.4) for DFS and 60.5 (95% CI 58.3–62.6) for OS. An NR <40% significantly correlated with a higher 5-year survival rate in the total sample (OS 57.6% vs 23.8%, P < 0.001; DFS 48.2% vs 11.4, P < 0.001) and in patients with N1 (OS 47.9% vs 36.1%, P = 0.03; DFS 39% vs 24.2%, P = 0.02) and N2 (OS 36.9% vs 21.8%, P < 0.001 DFS 23.9% vs 9.1%, P < 0.001).
CONCLUSIONS
Our study confirms that the number of resected lymph nodes is a strong prognostic indicator in NSCLC. In particular, an NR cut-off value of 40% may predict both OS and DFS.
•Pulmonary Sarcomatoid Carcinoma (PSC) is a rare and aggressive subset of NSCLC.•PCS presented a high mutational burden provides a rationale for immunotherapy.•We herein show a significant PD-L1 ...expression (>10% of tumor cells) in 25% of PSCs.•We found a strong association between PD-L1 expression and KRAS mutations.•We distinct 2 immunological subtypes in PCS: PD-L1+/KRAS-mut vs PD-L1-/KRAS-wild.
Pulmonary Sarcomatoid Carcinoma (PSC) is a rare subset of NSCLC, associated with worse prognosis and resistant to platinum-based regimens. Recent investigations have shown high levels of PD-L1 expression in PSC, providing a rationale for the potential use of immunotherapy. In this study, we investigated whether the PD-L1 expression was related to clinico-pathologic and molecular characteristics.
Fortythree surgically-resected PSCs were selected from 2006 to 2014 and clinical information retrieved. PD-L1 expression was analyzed by immunohistochemistry and correlated with the clinic-pathologic features and driver gene mutations analyzed by Next-Generation-Sequencing. Correlation of clinical, pathological and genetic variants with PD-L1 expression positivity were tested by Fisher’s exact test analysis.
About 25% of PSCs showed a significant expression of PD-L1 (positive staining defined as staining in ≥10% of tumor cells). PD-L1 expression was associated with aggressive pathological features of PSCs including N2-involvement (PD-L1 positive in 83.3% of N2-PSCs vs in 16.2% of N0/N1-PSCs, p=0.003) and presence of either local (p=0.038) and distant metastases (p=0.022). Furthermore, PD-L1 expression was significantly associated with the overall mutational load of the tumors (PD-L1 positivity only in PSCs with at least one mutational event) and in particular with the presence of KRAS mutation (PD-L1 positive in 44.4% of KRAS-Mut PSCs vs 12.0% in KRAS-Wild PSCs). The correlation between PD-L1 expression and KRAS-mutation were found at univariate analysis (p=0.031), even considering PD-L1 as a continuous variable (p=0.018), and confirmed at multivariate analysis (p=0.035). The mutational status of the other genes explored in the NGS-panel (EGFR, APC, PTEN, PIK3CA, TP53 and STK11) did not correlate with PD-L1 expression.
PD-L1 expression significantly correlates with overall mutational load and KRAS mutational status in pulmonary sarcomatoid carcinomas.
The diagnosis of malignant mesothelioma (MPM) does not pose difficulties when presenting with usual clinico-radiologic features and morphology. Pathology textbooks and national/international ...guidelines generally describe the findings of classic MPM, underlining common clinical presentation, the gold standard of sampling techniques, usual morphologic variants, immunohistochemical results of several positive and negative primary antibodies in the differential diagnosis, and the role of novel molecular markers. Nevertheless, MPM often does not follow the golden rules in routine practice, while the literature generally does not sufficiently emphasize unusual features of its manifestation. This gap may potentially create problems for patients in sustaining a difficult diagnosis of MPM in clinical practice and during legal disputes. Indeed, the guidelines accidentally tend to favor the job of lawyers and pathologists defending asbestos-producing industries against patients suffering from MPM characterized by uncommon features. The current review is aimed at underlining the wide spectrum of clinical and radiological presentation of MPM, the possibility to consistently use cytology for diagnostic intent, the aberrant immunohistochemical expression using so-called specific negative and positive primary antibodies, and finally proposing some alternative and more unbiased approaches to the diagnosis of MPM.
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