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.
Hypothesizing that morphometric measurements are reliable markers of fitness in patients with lung cancer requiring aggressive surgical intervention, the purpose of this study was to assess their ...impact on postoperative outcome and long-term survival in patients with non-small cell lung cancer (NSCLC) requiring pneumonectomy.
Height, weight, and body mass index (BMI), as well as usual clinical, laboratory (including C-reactive protein CRP concentrations), and pathologic data were retrospectively retrieved from files of 161 consecutive patients treated by pneumonectomy for NSCLC, whose preoperative computed tomographic (CT) scans were available in the Picture Archive and Communication System (PACS) of the hospital. Cross-sectional areas of right and left psoas areas (measured by CT scan at the L3 level), perirenal fat thickness, and anterior subcutaneous tissue thickness at the left renal vein level were also assessed.
BMI and total psoas area were strongly and directly correlated (p = 0.0000001), whereas BMI was inversely related to CRP levels. Sarcopenia (total psoas area ≤33rd percentile) was associated with high CRP levels (>20 mg/L) (p = 0.010). Factors associated with 90-day mortality included older age (p = 0.000045), lower body weight (p = 0.032), and BMI less than or equal to 25 kg/m
(p = 0.013). At univariate analysis, long-term outcome was negatively affected by a nonsquamous cell histologic type (p = 0.011), pathologic stage IIIB-IV (p =0.026), CRP levels greater than 20 mg/L (p = 0.017), BMI less than or equal to 25 kg/m
(p = 0.010), and total psoas area less than or equal to the 33rd percentile (p = 0.029). Multivariate analysis showed the independent prognostic value of both BMI and total psoas area.
BMI less than or equal to 25 kg/m
and total psoas cross-sectional area less than or equal to the 33rd percentile are prognostic determinants in patients with NSCLC requiring pneumonectomy.
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.
Lower pre-surgery Body Mass Index (BMI) and low muscle mass impact negatively long-term survival of non-small cell lung cancer (NSCLC). We investigated their influence on survival after major lung ...resection for NSCLC.
A retrospective analysis of a prospectively collected database was made on 304 consecutive patients.
Underweight, normal, overweight and obese patients represented 7.6%, 51.6%, 28.6%, and 12.6% of the pre-disease population. Weight loss and gain were recorded in 5% and 44.4% of patients, respectively. Low muscle mass was more frequently associated with BMI < 25 kg/m
(
< 0.000001). Overall survival was positively affected by pre-disease (
= 0.036) and pre-surgery (
0.017) BMI > 25 kg/m
, and, even more, in case of BMI > 25 kg/m
and increasing weight (
= 0.012). Long-term outcome was negatively influenced by low muscle mass (
= 0.042) and weight loss (
0.0052) as well as age (
0.017), ASA categories (
0.025), extent of resection (
0.0001), pleural invasion (
0.0012) and higher pathologic stage (
< 0.0001). Three stepwise multivariable models confirmed the independent favorable prognostic value of higher pre-disease (RR 0.660.49-0.89,
0.006) and pre-surgery BMI (RR 0.720.54-0.98,
0.034), and the absence of low muscle mass (RR 0.560.37-0.87,
0.0091).
Body reserves assessed by simple clinical markers impact survival of surgically treated NSCLC. Strategies improving body fat and muscular mass before surgery should be considered.
•Sarcopenia is associated with short-term outcome in pneumonectomy.•Similarly, right side of pneumonectomy was associated with short-term outcome.•Muscle surface measurements after fat-suppression ...are the most distinctive factor.
Sarcopenia is associated with poor outcome in cancer-patients. However, the methods to define sarcopenia are not entirely standardized. We compared several morphometric measurements of sarcopenia and their prognostic value in short-term-outcome prediction after pneumonectomy.
Consecutive lung-cancer patients undergoing pneumonectomy from January 2007 to December 2015 and having a pre-operative computed tomography (CT) scan were retrospectively included. Sarcopenia was assessed by the following CT-based parameters measured at the level of the third lumbar vertebra: cross-sectional Total Psoas Area (TPA), cross-sectional Total Muscle Area (TMA), and Total Parietal Muscle Area (TPMA), defined as TMA without TPA. Measures were obtained for entire muscle surface, as well as by excluding fatty infiltration based on CT attenuation. Findings were stratified for gender, and a threshold of 33rd percentile was set to define sarcopenia. Acute Respiratory Failure (ARF), Acute Respiratory Distress Syndrome (ARDS), and 30-day mortality were assessed as parameters of short-term-outcome.
Two hundred thirty-four patients with pneumonectomy (right, n = 107; left, n = 127) were analysed. Postoperative mortality rate was 9.0 % (21/234), 17.1 % of patients (40/234) experienced ARF requiring re-intubation, and 10.3 % (24/234) had ARDS. All parameters describing sarcopenia gave significant results; the best discriminating parameter was TMA after excluding fat (p < 0.001). While right sided pneumonectomy and sarcopenia were independently associated to the three short-term outcome parameters, Charlson Comorbidity Index only independently predicted ARF.
Sarcopenia defined as the sex-related 33rd percentile of fat-excluded TMA at the level of the third lumbar vertebra is the most discriminating parameter to assess short-term-outcome in patients undergoing pneumonectomy.
BACKGROUND Histologic classification of lung adenocarcinoma subtype has a prognostic value in most studies. However, lung adenocarcinoma characteristics differ across countries. Here, we aimed at ...validating the prognostic value of this classification in a large French series of lung adenocarcinoma. METHODS We reviewed 407 consecutive lung adenocarcinomas operated on between 2001 and 2005 and reclassified them according to the International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) classification and subsequently graded them into low, intermediate, and high grade. We analyzed the relevance of this classification according to clinical, pathologic, and molecular analysis. RESULTS Patients (median age, 61 years; 288 men) underwent lobectomy (n = 378) or pneumonectomy (n = 29). Patients' overall survival at 5 and 10 years was 53.2% and 32.6%, respectively. Union for International Cancer Control stage distribution was 189 stage I, 104 stage II, 107 stage III, and seven stage IV. Low-grade tumor was found in one patient, intermediate grade in 275 patients, and high grade in 131 patients. KRAS and EGFR mutations were detected in 34% and 9.6%, respectively. Histologic grade was significantly correlated with extent of resection ( P = .01), thyroid transcriptional factor-1 expression ( P = .00000001), vascular emboli ( P = .03), and EGFR mutations ( P = .01). Mucinous adenocarcinomas were associated with KRAS mutations ( P = .003). At univariate analysis, age, extent of resection, histologic grade, pleural invasion, vascular emboli, pathologic T and N, and stage were predictive of survival. At multivariate analysis, age ( P = .0001), histologic grade ( P = .03), and stage ( P = .000003) were independent prognostic factors. CONCLUSIONS IASLC/ATS/ERS classification of lung adenocarcinomas predicts survival in French population. Histologic grade correlates with clinical, pathologic and molecular parameters suggesting different oncogenic pathways.
Surgery is the mainstay treatment of non-small-cell lung cancer (NSCLC), but its impact on very-long-term survival (beyond 15 years) has never been evaluated.
All patients operated on for major lung ...resection (Jun. 2001-Dec. 2002) for NSCL in the Thoracic Surgery Department at Paris-Hôtel-Dieu-University-Hospital were included. Patients' characteristics were prospectively collected. Vital status was obtained by checking INSEE database and verifying if reported as "non-death" by the hospital administrative database and direct phone interviews with patients of families.
345 patients were included. The 15- and 20-year survival rates were 12.2% and 5.7%, respectively. At univariate analysis, predictors of worse survivals were: increasing age at surgery (
= 0.0042), lower BMI (
= 0.009), weight loss (
= 0.0034), higher CRP (
= 0.049), pathological stage (
= 0.00000042), and, among patients with adenocarcinoma, higher grade (
= 0.028). Increasing age (
= 0.004), cumulative smoking (
= 0.045), lower BMI (0.046) and pathological stage (
= 0.0026), were independent predictors of long-term survival at Cox multivariate analysis. In another model, increasing age (
= 0.013), lower BMI (
= 0.02), chronic bronchitis (
= 0.03), lower FEV1% (
= 0.00019), higher GOLD class of COPD (
= 0.0079), and pathological stage (
= 0.000024), were identified as independent risk factors.
Very-long-term survivals could be achieved after surgery of NSCLC, and factors classically predicting 5- and 10-years survival also determined longer outcomes suggesting that both initial tumor aggressiveness and host's characteristics act beyond the period usually taken into account in oncology.
In spite of increasing diffusion, Enhanced Recovery Pathways (ERP) have been scarcely assessed in large scale programs of lung cancer surgery. The aim of this study was auditing our practice.
A ...two-step audit program was established: the first dealing with our initial ERP experience in patients undergoing non-extended anatomical segmentectomies and lobectomies, the second including all consecutive patients undergoing all kind of lung resections for NSCLC. The first step aimed at auditing results of ERP on occurrence of postoperative complications and at assessing which ERP components are associated with improved short-term outcomes. We also audited late results by assessing long-term survival of patients in the first step of our study. The second step aimed at auditing on large-scale short-term results of the ERP in a real-life setting.
Over a one-year period, 166 patients were included. The median number of ERP procedures per patient was three (IQR 3-4). No postoperative death occurred. The overall adverse events rate was 30%. In multivariate analyzes, the only element associated with reduced adverse postoperative events was chest tube withdrawal within POD2 (OR = 0.21, 95% CI (0.10-0.46)). The 1-, 3-, and 5-year survival rates were 97%, 86.1%, and 76.3%, respectively. In the second period, 1077 patients were included in our ERP; 11 patients died during the postoperative period or within 30 days of operation (1.02%). The overall postoperative adverse event rate was 30.3%, major complication occurring in 134 (12.4%), and minor ones in 192 (17.8%). Respiratory complications occurred in 64 (5.9%). Thoracoscore independently predicted postoperative death, the occurrence of complications (all-kind, minor, major, or respiratory ones).
Compliance to ERP procedures and early chest tube removal are associated with reduced postoperative events in patients with lung resection surgery. In a large setting scale, ERP can be applied with satisfactory results in terms of mortality and morbidity. Thoracoscore is a useful tool in predicting mortality and postoperative adverse events.
There is no standardization in methods to assess sarcopenia; in particular the prognostic significance of muscular fatty infiltration in lung cancer patients undergoing surgery has not been evaluated ...so far. We thus performed several computed tomography (CT)-based morphometric measurements of sarcopenia in 238 consecutive non-small cell lung-cancer patients undergoing pneumonectomy from 1 January 2007 to 31 December 2015. Sarcopenia was assessed by the following CT-based parameters: cross-sectional total psoas area (TPA), cross-sectional total muscle area (TMA), and total parietal muscle area (TPMA), defined as TMA without TPA. Measures were performed at the level of the third lumbar vertebra and were obtained for the entire muscle surface, as well as by excluding fatty infiltration based on CT attenuation. Findings were stratified for gender, and a threshold of the 33rd percentile was set to define sarcopenia. Furthermore, we assessed the possibility of being sarcopenic at both the TPA and TPMA level, or not, by taking into account of not fatty infiltration. Five-year survival was 39.1% for the whole population. Lower TPA, TMA, and TPA were associated with lower survival at univariate analysis; taking into account muscular fatty infiltration did not result in more powerful discrimination. Being sarcopenic at both psoas and parietal muscle level had the optimum discriminating power. At the multivariable analysis, being sarcopenic at both psoas and parietal muscles (considering the whole muscle areas, including muscular fat), male sex, increasing age, and tumor stage, as well as Charlson Comorbidity Index (CCI), were independently associated with worse long-term outcomes. We conclude that sarcopenia is a powerful negative prognostic factor in patients with lung cancer treated by pneumonectomy.
Our aim was to study the clinical, surgical, and pathological characteristic of women with homolateral recurrence of pneumothorax despite previous surgery.
This study is a retrospective analysis of ...the clinical and pathological records of all consecutive women of reproductive age hospitalized in a thoracic surgery department for surgical treatment of pneumothorax recurrence despite previous surgery between 2000 and 2009.
During the study period, 35 women were operated on. Their mean age was 37 years. Twenty-nine pneumothoraces (83%) were right sided. In 20 women, the recurrence occurred during the menstrual period. At initial surgery, 5 cases had been catamenial with evidence of thoracic endometriosis, 12 were catamenial with no evidence of endometriosis, 5 were noncatamenial with thoracic endometriosis, and 13 were idiopathic. At repeat surgery the figures were 18, 4, 5, and 8 cases, respectively. Repeat operation was carried out by video-assisted thoracoscopy in 13 cases, video-assisted minithoracotomy in 10, and standard thoracotomy in 12. Partial diaphragmatic resection was performed at repeat surgery in 16 patients (45.7%). Talc pleurodesis and pleural abrasion were carried out in 20 (57.1%) and 15 patients (42.9%), respectively. No major morbidity was observed. After repeat surgery, hormonal treatment was prescribed in 24 cases. Median follow-up was 40 months (range, 1.5 to 138 months). In 6 women, further homolateral recurrence of pneumothorax occurred (17.1%) and required surgery in 3 cases.
Repeat surgery can be safely performed in women with recurrence of pneumothorax despite previous surgery, and frequently shows initially missed endometriosis.
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