Effects of lung volume reduction surgery for emphysema on glycolipidic hormones

BACKGROUND: Pulmonary emphysema is associated with cachexia and disregulation of the hormones regulating the glycolipid metabolism, insulin resistance, and altered substrate utilization. This study aimed at identifying the effects of lung volume reduction surgery (LVRS) on glycolipidic hormones compared to respiratory rehabilitation (RR). METHODS: Thirty-three patients with moderate-to-severe emphysema who were undergoing video-assisted thoracoscopic LVRS were compared to 31 similar patients who refused the operation and followed a standardized RR program. All patients were evaluated before and 12 months after treatment for respiratory function, body composition, glycolipidic hormones, metabolic parameters, and insulin resistance, which was calculated using the homeostatic model assessment index for insulin resistance (HOMA-IR). These groups were compared to a matched healthy control population. RESULTS: Only after LVRS significant improvements were obtained in respiratory function (FEV1, +25.2%; p<0.0001; residual volume, -19.5%; p<0.0001), metabolic parameters (total cholesterol, +13.1%; p<0.01; high-density lipoprotein cholesterol, +11.2%; p<0.01; triglycerides, +18.4; p<0.001; nonesterified fatty acid, -19.7%; p<0.001), and body composition (fat-free mass [FFM], +6.5%; p<0.01; fat mass [FM], +11.9%; p<0.01). The leptin/FM ratio (-6.1%; p<0.01) and resistin/FM ratio (-5.6%; p<0.01) decreased, whereas the adiponectin/FM ratio (+6.9%; p<0.01) and ghrelin (+9.2%; p<0.01) increased, together with reductions in glycemia (-8.8%; p<0.01), insulin level (-20.4%; p<0.001), and HOMA-IR (-27.2%; p<0.0001). The decrement in residual volume was correlated with increment of FFM (rho=-0.49; p<0.02), FM (rho=-0.55; p<0.009), and ghrelin (rho=-0.52; p<0.01), and also with decreases in leptin corrected for FM (rho=0.50; p<0.02) and, marginally, HOMA-IR (rho=0.35; p=0.07). CONCLUSIONS: After LVRS, glycolipidic hormone levels and nutritional status significantly improved, along with insulin resistance reduction and more physiologic utilization of substrates. Correlations between residual volume and body composition as well as glycolipidic hormone levels suggest that postoperative recovery in respiratory dynamics may induce favorable clinical changes when compared to RR

Phylogenetic ctDNA analysis depicts early-stage lung cancer evolution.

The early detection of relapse following primary surgery for non-small-cell lung cancer and the characterization of emerging subclones, which seed metastatic sites, might offer new therapeutic approaches for limiting tumour recurrence. The ability to track the evolutionary dynamics of early-stage lung cancer non-invasively in circulating tumour DNA (ctDNA) has not yet been demonstrated. Here we use a tumour-specific phylogenetic approach to profile the ctDNA of the first 100 TRACERx (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy (Rx)) study participants, including one patient who was also recruited to the PEACE (Posthumous Evaluation of Advanced Cancer Environment) post-mortem study. We identify independent predictors of ctDNA release and analyse the tumour-volume detection limit. Through blinded profiling of postoperative plasma, we observe evidence of adjuvant chemotherapy resistance and identify patients who are very likely to experience recurrence of their lung cancer. Finally, we show that phylogenetic ctDNA profiling tracks the subclonal nature of lung cancer relapse and metastasis, providing a new approach for ctDNA-driven therapeutic studies

New predictors of response to neoadjuvant chemotherapy and survival for invasive thymoma: a retrospective analysis

BACKGROUND: Cell-cycle protein (p27, p21, and p53) expression can predict response to neoadjuvant chemotherapy and prognosis in some neoplasms. This study evaluated whether these markers could also be effective in invasive thymoma during a multimodality treatment. METHODS: Between 1989 and 2008, 33 patients with invasive thymoma underwent surgical resection after neoadjuvant chemotherapy. Expression of p27, p21, and p53 was assessed using immunohistochemistry in specimens retrieved pre and post chemotherapy. Factors influencing response to neoadjuvant chemotherapy and survival were investigated by univariate and multivariate analysis. Good response was defined as complete disappearance of tumor at imaging or necrosis >90% at pathologic studies. RESULTS: Twelve patients disclosed an imaging good response. Complete resection was possible in 17 patients, 9 of whom had presented imaging good response and 11 of whom had revealed pathologic good response. On univariate analysis both imaging and pathologic poor responses were significantly associated with incomplete resection (P = 0.04 and P = 0.03, respectively) and preneoadjuvant triple combination of p27 low, p21 low, and p53 high expressions (P = 0.001 and P < 0.0001, respectively), the last factor being the only one selected on logistic regression (P = 0.01 and P = 0.005, respectively). Long-term survival analysis was negatively influenced by triple combination of p27, p21, and p53 (P < 0.0001) and incomplete resection (P < 0.0001), which were also selected on Cox's regression (P = 0.004 and P = 0.02, respectively). CONCLUSIONS: The triple combination of p27 low, p21 low, and p53 high expressions was the most significant predictor of imaging and pathologic poor responses to neoadjuvant chemotherapy in invasive thymoma. This combination together with incomplete resection was also the most significant negative predictor of long-term survival

Might cyclooxygenase-2 (COX-2), p21 and p27 expression affect prognosis and therapeutic strategy of patients with malignant pleural mesothelioma?

Objectives: To evaluate the impact of immunohistochemical expression of cyclooxygenase-2 (COX-2) and cell-cycle proteins (p21 and p27) in specimens from malignant pleural mesothelioma. Methods: We retrospectively reviewed immunohistochemical expression of COX-2, p21 and p27 dichotomised into high and low expression from specimens of 67 consecutive patients undergoing biopsy plus pleurodesis (n=6), pleurectomy-decortication (n=44) or extrapleural pneumonectomy (n=27) operations for malignant pleural mesothelioma between 1987 and 2007. Histology was epithelioid (n=50), biphasic (n=17) and sarcomatoid (n=10) subtypes. TNM-stage was I (n=21), II (n=36) and III (n=20). Combined therapies were sole adjuvant radiotherapy (n=17), adjuvant radio-chemotherapy (n=36) and neoadjuvant chemotherapy plus adjuvant radiotherapy (n=24). Results were investigated by Kaplan–Meier survival and Cox regression analysis. Results: Median survival was 13 months. Survival was negatively influenced by nonepithelial histology (P<0.01), positive resection margins (P<0.02), metastatic mediastinal lymph nodes (P<0.01), high COX-2 (P=0.001), low p21 (P<0.0001) and p27 (P=0.001) expression. Conversely, neither the type of surgery (biopsy vs. pleurectomy-decortication vs. extrapleural pneumonectomy), nor combined therapies (sole radiotherapy vs. adjuvant radio-chemotherapy vs. neoadjuvant chemotherapy plus adjuvant radiotherapy) reached a significant level of difference. Cox regression analysis showed that only immunohistochemical triple combination of high COX-2 and low p21 and p27 expression influenced survival (P<0.0001, Odds Ratio 4.7, 95% confidence interval 3–11) regardless of kind of treatment. Conclusions: The presence of high expression COX-2 and low p21 and p27 expression significantly influences the prognosis of malignant pleural mesothelioma. Therapeutic strategy should consider these protein expressions, avoiding major operations in cases of combination of these factors

Biodegradable paclitaxel-loaded microparticles prepared from novel block copolymers: Influence of polymer composition on drug encapsulation and release

This study covers the preparation of microspheres for the controlled and targeted release of paclitaxel, using novel degradable polymers as carrier materials. Paclitaxel-loaded microspheres were prepared by oil-in-water single-emulsion solvent extraction/evaporation technique by using a series of polyurethanes and a block copolymer; the physicochemical properties of these polymers were modulated by changing nature and composition of their structural units. The obtained microparticles showed a regular morphology and properties (diameter: 1-100μm; resuspension index: 18.8-100%; encapsulation efficiency: 26.6-97.2%) depending on polymer hydrophilicity and emulsifier used. In vitro release curves showed in all cases almost zero-order kinetics after an initial low burst effect (from 1 to 8.4%), which is required to minimize the drug side effects. This work also proposes a novel strategy to combine a controlled and a targeted release through the functionalization of the polymer matrix with peptide sequences. An RGD-functionalized polyurethane was used to successfully prepare paclitaxel-loaded microparticles. Studies on the preparation of polymer microspheres are reported. © 2013 European Peptide Society and John Wiley & Sons, Ltd

Variations of inflammatory mediators and alpha1-antitrypsin levels after lung volume reduction surgery for emphysema

Rationale: In emphysema,chronic inflammation, including protease– antiprotease imbalance, is responsible for declining pulmonary function and progressive cachexia. Objectives: To evaluate variations of inflammatory mediators and a1-antitrypsin levels after lung volume reduction surgery (LVRS) compared with respiratory rehabilitation. Methods: A total of 28 patients with moderate to severe emphysema, who underwent video-assisted thoracoscopic LVRS, were compared with 26 similar patients, who refused operation and followed a standardized rehabilitation program, and to a matched healthy group. Respiratory function, body composition, circulating inflammatory mediators, and a1-antitrypsin levels were evaluated before and 12 months after treatment. Gene expression levels of inflammatory mediators and protease–antiprotease were assessed in emphysematous specimens from 17 operated patients by matching to normal tissue from resection margins. Measurements and Main Results: Significant improvements were only obtained after surgery in respiratory function (FEV1, 125.2%, P , 0.0001; residual volume [RV], 219.5%, P , 0.0001; diffusing lung capacity for carbon monoxide, 13.3%, P , 0.05) and body composition (fat-free mass, 16.5%, P , 0.01; fat mass, 111.9%, P , 0.01), with decrement of circulating inflammatory mediators (TNF-a, 222.2%, P , 0.001; IL-6, 224.5%, P , 0.001; IL-8, 220.0%, P , 0.001) and increment of antiprotease levels (a1-antitrypsin, 127.0%, P , 0.001). Supportive gene expression analysis demonstrated active inflammation and protease hyperactivity in the resected emphysematous tissue. Reduction of TNF-a and IL-6 and increment of a1-antitrypsin levels significantly correlated with reduction of RV (P 5 0.03, P 5 0.009, and P 5 0.001, respectively), and partially with increment of fat-free mass (P50.03, P50.02, and P5 0.09, respectively). Conclusions: LVRS significantly reduced circulating inflammatory mediators and increased antiprotease levels over respiratory rehabilitation, also improving respiratory function and nutritional status. Correlations of inflammatory mediators and antiprotease levels with RV and, partly, with body composition suggest that elimination of inflammatory emphysematous tissue may explain clinical improvements after surgery