MNK-driven eIF4E phosphorylation regulates the fibrogenic transformation of mesenchymal cells and chronic lung allograft dysfunction.

Tissue fibrosis remains unamenable to meaningful therapeutic interventions and is the primary cause of chronic graft failure after organ transplantation. Eukaryotic translation initiation factor (eIF4E), a key translational regulator, serves as convergent target of multiple upstream profibrotic signaling pathways that contribute to mesenchymal cell (MC) activation. Here, we investigate the role of MAP kinase-interacting serine/threonine kinase-induced (MNK-induced) direct phosphorylation of eIF4E at serine 209 (Ser209) in maintaining fibrotic transformation of MCs and determine the contribution of the MNK/eIF4E pathway to the pathogenesis of chronic lung allograft dysfunction (CLAD). MCs from patients with CLAD demonstrated constitutively higher eIF4E phosphorylation at Ser209, and eIF4E phospho-Ser209 was found to be critical in regulating key fibrogenic protein autotaxin, leading to sustained ß-catenin activation and profibrotic functions of CLAD MCs. MNK1 signaling was upregulated in CLAD MCs, and genetic or pharmacologic targeting of MNK1 activity inhibited eIF4E phospho-Ser209 and profibrotic functions of CLAD MCs in vitro. Treatment with an MNK1/2 inhibitor (eFT-508) abrogated allograft fibrosis in an orthotopic murine lung-transplant model. Together these studies identify what we believe is a previously unrecognized MNK/eIF4E/ATX/ß-catenin signaling pathway of fibrotic transformation of MCs and present the first evidence, to our knowledge, for the utility of MNK inhibitors in fibrosis.

Pulmonary tuberculoma-induced cyst formation leading to repeated pneumothorax: a case report.

Most cases of secondary spontaneous pneumothorax in patients with active pulmonary tuberculosis are caused by rupturing of the visceral pleura caused by Mycobacterium tuberculosis. The check-valve airway mechanism in the lungs is generally involved in the formation of pulmonary cysts, which often cause spontaneous pneumothorax. Herein, we describe a rare case of repeated spontaneous pneumothorax suspected to have been caused by pulmonary cyst formation as a result of a tuberculoma. The patient was a man with a family history of pulmonary tuberculosis. Pulmonary cysts were gradually enlarged on the peripheral side of a lung mass in the upper lobe of the patient's right lung, who experienced two spontaneous pneumothoraxes in the area. Exploratory surgery was performed to diagnose the lung mass and treat the pneumothorax, resulting in a final diagnosis of pulmonary tuberculoma. A check-valve mechanism caused by the pulmonary tuberculoma was suspected based on the patient's clinical course.

Genetic deficiency of the transcription factor NFAT1 confers protection against fibrogenic responses independent of immune influx.

Idiopathic pulmonary fibrosis (IPF) is marked by unremitting matrix deposition and architectural distortion. Multiple profibrotic pathways contribute to the persistent activation of mesenchymal cells (MCs) in fibrosis, highlighting the need to identify and target common signaling pathways. The transcription factor nuclear factor of activated T cells 1 (NFAT1) lies downstream of second messenger calcium signaling and has been recently shown to regulate key profibrotic mediator autotaxin (ATX) in lung MCs. Herein, we investigate the role of NFAT1 in regulating fibroproliferative responses during the development of lung fibrosis. Nfat1-/--deficient mice subjected to bleomycin injury demonstrated improved survival and protection from lung fibrosis and collagen deposition as compared with bleomycin-injured wild-type (WT) mice. Chimera mice, generated by reconstituting bone marrow cells from WT or Nfat1-/- mice into irradiated WT mice (WT→WT and Nfat1-/-→WT), demonstrated no difference in bleomycin-induced fibrosis, suggesting immune influx-independent fibroprotection in Nfat1-/- mice. Examination of lung tissue and flow sorted lineageneg/platelet-derived growth factor receptor alpha (PDGFRα)pos MCs demonstrated decreased MC numbers, proliferation [↓ cyclin D1 and 5-ethynyl-2'-deoxyuridine (EdU) incorporation], myofibroblast differentiation [↓ α-smooth muscle actin (α-SMA)], and survival (↓ Birc5) in Nfat1-/- mice. Nfat1 deficiency abrogated ATX expression in response to bleomycin in vivo and MCs derived from Nfat1-/- mice demonstrated decreased ATX expression and migration in vitro. Human IPF MCs demonstrated constitutive NFAT1 activation, and regulation of ATX in these cells by NFAT1 was confirmed using pharmacological and genetic inhibition. Our findings identify NFAT1 as a critical mediator of profibrotic processes, contributing to dysregulated lung remodeling and suggest its targeting in MCs as a potential therapeutic strategy in IPF.NEW & NOTEWORTHY Idiopathic pulmonary fibrosis (IPF) is a fatal disease with hallmarks of fibroblastic foci and exuberant matrix deposition, unknown etiology, and ineffective therapies. Several profibrotic/proinflammatory pathways are implicated in accelerating tissue remodeling toward a honeycombed end-stage disease. NFAT1 is a transcriptional factor activated in IPF tissues. Nfat1-deficient mice subjected to chronic injury are protected against fibrosis independent of immune influxes, with suppression of profibrotic mesenchymal phenotypes including proliferation, differentiation, resistance to apoptosis, and autotaxin-related migration.

The mitigating effect of exogenous carbon monoxide on chronic allograft rejection and fibrosis post-lung transplantation.

BACKGROUND: Small airway inflammation and fibrosis or bronchiolitis obliterans (BO) is the predominant presentation of chronic lung allograft dysfunction (CLAD) post-lung transplantation. Carbon monoxide (CO) is a critical endogenous signaling transducer with known anti-inflammatory and anti-fibrotic effects but its therapeutic potential in CLAD remains to be fully elucidated. METHODS: Here we investigate the effect of inhaled CO in modulating chronic lung allograft rejection pathology in a murine orthotopic lung transplant model of BO (B6D2F1/J→DBA/2J). Additionally, the effects of CO on the activated phenotype of mesenchymal cells isolated from human lung transplant recipients with CLAD were studied. RESULTS: Murine lung allografts treated with CO (250 ppm × 30 minutes twice daily from days 7 to 40 post-transplantation) demonstrated decreased immune cell infiltration, fibrosis, and airway obliteration by flow cytometry, trichrome staining, and morphometric analysis, respectively. Decreased total collagen, with levels comparable to isografts, was noted in CO-treated allografts by quantitative hydroxyproline assay. In vitro, CO (250 ppm × 16h) was effective in reversing the fibrotic phenotype of human CLAD mesenchymal cells with decreased collagen I and ß-catenin expression as well as an inhibitory effect on ERK1/2 MAPK, and mTORC1/2 signaling. Sildenafil, a phosphodiesterase 5 inhibitor, partially mimicked the effects of CO on CLAD mesenchymal cells and was partially effective in decreasing collagen deposition in murine allografts, suggesting the contribution of cGMP-dependent and -independent mechanisms in mediating the effect of CO. CONCLUSION: These results suggest a potential role for CO in alleviating allograft fibrosis and mitigating chronic rejection pathology post-lung transplant.

Transcription factor FOXF1 identifies compartmentally distinct mesenchymal cells with a role in lung allograft fibrogenesis.

In this study, we demonstrate that forkhead box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, was retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as key players in lung allograft remodeling and fibrosis. Using Foxf1-tdTomato BAC (Foxf1-tdTomato) and Foxf1-tdTomato Col1a1-GFP mice, we show that Lin-Foxf1+ cells encompassed the stem cell antigen 1+CD34+ (Sca1+CD34+) subset of collagen 1-expressing mesenchymal cells (MCs) with a capacity to generate CFU and lung epithelial organoids. Histologically, FOXF1-expressing MCs formed a 3D network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA-Seq confirmed distinct transcriptional signatures of Foxf1+ and Foxf1- MCs, with Foxf1-expressing cells delineated by their high expression of the transcription factor glioma-associated oncogene 1 (Gli1) and low expression of integrin α8 (Itga), versus other collagen-expressing MCs. FOXF1+Gli1+ MCs showed proximity to Sonic hedgehog-expressing (Shh-expressing) bronchial epithelium, and mesenchymal expression of Foxf1 and Gli1 was found to be dependent on paracrine Shh signaling in epithelial organoids. Using a murine lung transplant model, we show dysregulation of epithelial-mesenchymal SHH/GLI1/FOXF1 crosstalk and expansion of this specific peribronchial MC population in chronically rejecting fibrotic lung allografts.

Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis.

Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.

Loss of FOXF1 expression promotes human lung-resident mesenchymal stromal cell migration via ATX/LPA/LPA1 signaling axis.

Forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-associated transcription factor that demonstrates persistent expression into adulthood in mesenchymal stromal cells. However, its biologic function in human adult lung-resident mesenchymal stromal cells (LR-MSCs) remain to be elucidated. Here, we demonstrate that FOXF1 expression acts as a restraint on the migratory function of LR-MSCs via its role as a novel transcriptional repressor of autocrine motility-stimulating factor Autotaxin (ATX). Fibrotic human LR-MSCs demonstrated lower expression of FOXF1 mRNA and protein, compared to non-fibrotic controls. RNAi-mediated FOXF1 silencing in LR-MSCs was associated with upregulation of key genes regulating proliferation, migration, and inflammatory responses and significantly higher migration were confirmed in FOXF1-silenced LR-MSCs by Boyden chamber. ATX is a secreted lysophospholipase D largely responsible for extracellular lysophosphatidic acid (LPA) production, and was among the top ten upregulated genes upon Affymetrix analysis. FOXF1-silenced LR-MSCs demonstrated increased ATX activity, while mFoxf1 overexpression diminished ATX expression and activity. The FOXF1 silencing-induced increase in LR-MSC migration was abrogated by genetic and pharmacologic targeting of ATX and LPA1 receptor. Chromatin immunoprecipitation analyses identified three putative FOXF1 binding sites in the 1.5 kb ATX promoter which demonstrated transcriptional repression of ATX expression. Together these findings identify FOXF1 as a novel transcriptional repressor of ATX and demonstrate that loss of FOXF1 promotes LR-MSC migration via the ATX/LPA/LPA1 signaling axis.

Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction.

Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into µMt-/- (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory µ-chain (µs) double-KO (AID-/-µs-/-) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.

Segmentectomy Versus Lobectomy for Radiologically Pure Solid Clinical T1a-bN0M0 Lung Cancer.

BACKGROUND: Segmentectomy for radiologically pure solid tumors is still controversial because these tumors are more aggressive in malignancy than those with ground-glass opacity. This study aimed to determine the feasibility of intentional segmentectomy for pure solid small-sized lung cancer. METHODS: We retrospectively analyzed 96 radiologically pure solid tumors in clinical T1a-bN0M0 lung cancer. Patients whose tumor was located at a central region or right middle lobe were excluded. Forty-four patients who underwent lobectomy were compared with 52 those who underwent segmentectomy. Segmentectomy got converted to lobectomy if lymph node metastases or inadequate surgical margin was confirmed. Factors affecting survival were assessed using Cox regression. Propensity score stratification analysis was also performed. RESULTS: Eight patients (8%) were identified as a histological type other than adenocarcinoma or squamous cell carcinoma. Moreover, 14 patients (14%) displayed lymph node metastasis. Among those who underwent segmentectomy, nine patients (16%) were converted to lobectomy due to lymph node metastasis or inadequate surgical margin. The 3-year recurrence-free survival rates were 84.1 and 82.2% in patients who underwent segmentectomy and lobectomy, respectively (P = 0.745). In addition, the recurrence-free survival was not statistically significant between segmentectomy and lobectomy, as determined via multivariable Cox regression analysis (hazard ratio 1.11; 95% confidence interval 0.40-3.06), even after propensity score stratification (hazard ratio 1.17; 95% confidence interval 0.38-3.65). CONCLUSIONS: Segmentectomy with intraoperative assessment of lymph node metastasis and adequate surgical margin may be a feasible surgical procedure for pure solid tumors in clinical T1a-bN0M0 lung cancer.

Postoperative complications and prognosis after lobar resection versus sublobar resection in elderly patients with clinical Stage I non-small-cell lung cancer.

OBJECTIVES: The study aimed to investigate the outcomes of sublobar resection in elderly patients with non-small-cell lung cancer. METHODS: A total of 205 patients aged ≥75 years were identified from 794 consecutive patients who underwent complete surgical resection for clinical Stage I non-small-cell lung cancer. The outcomes of lobectomy and sublobar resection were compared. Propensity scores were estimated for multivariable analyses and matching. RESULTS: Sublobar resection (n = 99) was more frequently performed than lobectomy (n = 106) in older patients (P = 0.027) and those with lower maximum standardized uptake on positron emission tomography (P < 0.001), lower T stage (P < 0.001), lower %vital capacity (P = 0.007) and lower %diffusing capacity of the lungs for carbon monoxide (P = 0.025). Severe (≥Grade IIIa) postoperative complications occurred more frequently with lobectomy (11 of 106 procedures, 10.4%) than with sublobar resection (5 of 99, 5.1%; P = 0.16). In propensity score-adjusted multivariable analysis, lobectomy was an independent predictive factor for severe postoperative complications (odds ratio 3.49, 95% confidence interval 1.01-12.05; P = 0.048). Overall survival (OS) was not significantly different following lobectomy (5-year OS 67.2%) or sublobar resection (5-year OS 73.9%; P = 0.93). In multivariable analysis, the surgical procedure was not an independent predictive factor for OS (lobectomy: hazard ratio 1.03, 95% confidence interval 0.49-2.16; P = 0.94). CONCLUSIONS: Sublobar resection may be the optimal procedure in elderly patients with clinical Stage I non-small-cell lung cancer and is associated with less severe postoperative complications than lobectomy and similar OS.

Clinical Prognosis of Superior Versus Basal Segment Stage I Non-Small Cell Lung Cancer.

BACKGROUND: Despite its extensive size, variations in the clinicopathologic features of tumors in the lower lobe have been little studied. The present study investigated the prognostic differences in tumors originating from the superior and basal segments of the lower lobe in patients with non-small cell lung cancer. METHODS: Data of 134 patients who underwent lobectomy or segmentectomy with systematic nodal dissection for clinical stage I, radiologically solid-dominant, non-small cell lung cancer in the superior segment (n = 60) or basal segment (n = 74) between April 2007 and December 2015 were retrospectively reviewed. Factors affecting survival were assessed by the Kaplan-Meier method and Cox regression analyses. RESULTS: Prognosis in the superior segment group was worse than that in the basal segment group (5-year overall survival rates 62.6% versus 89.9%, p = 0.0072; and 5-year recurrence-free survival rates 54.4% versus 75.7%, p = 0.032). In multivariable Cox regression analysis, a superior segment tumor was an independent factor for poor overall survival (hazard ratio 3.33, 95% confidence interval: 1.22 to 13.5, p = 0.010) and recurrence-free survival (hazard ratio 2.90, 95% confidence interval: 1.20 to 7.00, p = 0.008). The superior segment group tended to have more pathologic mediastinal lymph node metastases than the basal segment group (15.0% versus 5.4%, p = 0.080). CONCLUSIONS: Tumor location was a prognostic factor for clinical stage I non-small cell lung cancer in the lower lobe. Patients with superior segment tumors had worse prognosis than patients with basal segment tumors, with more metastases in mediastinal lymph nodes.

Outcomes after lobar versus sublobar resection for clinical stage I non-small cell lung cancer in patients with interstitial lung disease.

OBJECTIVE: Since the prognosis after standard lobectomy for non-small cell lung cancer (NSCLC) in patients with interstitial lung disease (ILD) is poor, we investigated the possibility of sublobar resection for the improvement of the surgical results in such patients. METHODS: Of 796 consecutive patients with clinical stage I NSCLC who underwent pulmonary resection, 107 were diagnosed with ILD using high-resolution computed tomography (HRCT). Overall survivals (OS) were compared between patients with non-ILD and those with ILD or between patients with ILD who underwent lobectomy and those who underwent sublobar resection. ILD patterns consisted of usual interstitial pneumonia (UIP), possible UIP, and inconsistent with UIP. The log-rank statistics and Cox proportional hazard models were used to test for survival differences. RESULTS: OS was significantly lower in patients with "ILD inconsistent with UIP" pattern (hazard ratio [HR], 2.66; 95% confidence interval [CI], 1.19-5.97; P = .014), or "ILD with possible UIP or UIP" patterns (HR, 2.38; 95% CI, 1.76-3.21; P < .001) compared with patients with non-ILD. No significant difference in OS was observed between patients with ILD who underwent either lobectomy or sublobar resection (HR, 1.82; 95% CI, 0.81-4.06; P = .19). Multivariable Cox analysis demonstrated diffusing capacity of the lung for carbon monoxide (HR, 0.95; 95% CI, 0.91-0.99; P = .009) and not surgical procedure (HR, 2.76; 95% CI, 0.83-9.16; P = .099), as an independent prognostic factor for OS. CONCLUSIONS: Sublobar resection may be a potential alternative choice for clinical stage I NSCLC with ILD on HRCT.

Clinical benefit of neoadjuvant chemoradiotherapy for the avoidance of pneumonectomy; assessment in 12 consecutive centrally located non-small cell lung cancers.

BACKGROUND: Considering that pneumonectomy itself is a disease, avoidance of pneumonectomy needs to be deliberated. Herein, we evaluated the role of neoadjuvant chemoradiotherapy for avoidance of pneumonectomy in patients with centrally located locally advanced non-small cell lung cancer. METHODS: Patients who underwent neoadjuvant chemoradiotherapy after being judged to require pneumonectomy by cancer board between 1997 and 2011 were retrospectively evaluated. RESULTS: Twelve patients, including 10 males and 2 females with median age 63.5 years, were referred. Clinical stage was IB (1 patient), IIB (2 patients), IIIA (8 patients), and IIIB (1 patient). There were no disease progression after neoadjuvant chemoradiotherapy, and all patients underwent curative resection. For 8 patients, pneumonectomy was avoided, with 3 bronchoplasties and 3 pulmonary arterial angioplasties. We had 4 pneumonectomies: three cases of metastatic enlarged lymph nodes invading either the carina or a more central portion of the pulmonary artery than the left A3 branch or vein which needs incision of the inner pericardium and 1 case with a tumor involving the upper lobe bronchus to the inferior lobe bronchus. There were no postoperative deaths and 1 case of bronchopleural fistula. The 5-year disease-free and overall survival rates were 55.6 and 72.7% without stump or anastomotic recurrence. CONCLUSIONS: Neoadjuvant chemoradiotherapy for centrally located NSCLC appeared to be a useful treatment option for avoiding pneumonectomy without impairing curability and safety, especially in highly selected cases without invasion to carina or right-or-left main trunk of pulmonary artery or vein at pretreatment.

Enhanced gefitinib-induced repression of the epidermal growth factor receptor pathway by ataxia telangiectasia-mutated kinase inhibition in non-small-cell lung cancer cells.

The epidermal growth factor receptor (EGFR) tyrosine kinase signaling pathways regulate cellular activities. The EGFR tyrosine kinase inhibitors (EGFR-TKIs) repress the EGFR pathway constitutively activated by somatic EGFR gene mutations and have drastically improved the prognosis of non-small-cell lung cancer (NSCLC) patients. However, some problems, including resistance, remain to be solved. Recently, combination therapy with EGFR-TKIs and cytotoxic agents has been shown to improve the prognosis of NSCLC patients. To enhance the anticancer effects of EGFR-TKIs, we examined the cross-talk of the EGFR pathways with ataxia telangiectasia-mutated (ATM) signaling pathways. ATM is a key protein kinase in the DNA damage response and is known to phosphorylate Akt, an EGFR downstream factor. We found that the combination of an ATM inhibitor, KU55933, and an EGFR-TKI, gefitinib, resulted in synergistic cell growth inhibition and induction of apoptosis in NSCLC cell lines carrying the sensitive EGFR mutation. We also found that KU55933 enhanced the gefitinib-dependent repression of the phosphorylation of EGFR and/or its downstream factors. ATM inhibition may facilitate the gefitinib-dependent repression of the phosphorylation of EGFR and/or its downstream factors, to exert anticancer effects against NSCLC cells with the sensitive EGFR mutation.

[Assessment of Feasibility of Early Ambulation and Food-intake on the Operative Day after Lung Resection].

To decrease the risk of morbidity, we have started an early ambulation and food-intake program conducted on the same day as pulmonary resection. This protocol was developed with consideration of the characteristics of lung surgery and conducted through an interdisciplinary team-approach. The assessment of feasibility and clinical effectiveness of this protocol was evaluated in 64 consecutive patients. No apparent adverse effect relating to this protocol was recorded. Fifty-five of 64 patients( 80%) were able to accomplish ambulation to the up-right standing position. Thirty-four of 64 patients( 53%) were able to consume more than half the amount of their hospital supper. No patients, including 5 patients who had had a past-history of postoperative delirium after their previous surgery, developed postoperative delirium after conducting this protocol. This protocol, which consisted of extraordinary early ambulation and food-intake on the operative day, was done safely and is expected to have some benefit as a postoperative management protocol for lung surgery.

Comparison of Postoperative Pain after Different Thoracic Surgery Approaches as Measured by Electrical Stimulation.

BACKGROUND: Postoperative pain is commonly evaluated using the numerous rating scale (NRS), visual analogue scale, or pain scale; however, these assessments are easily affected by various subjective factors. We measured the degree of postoperative chest pain among different thoracic surgery approaches using NRS and electrical stimulation measurements. METHODS: Seventy patients who underwent lobectomy or segmentectomy were enrolled. Concomitant with NRS, pain scores were quantitatively measured on postoperative day 2 using an electrical neurostimulator to compare the degree of pain among three different surgical approaches: pure video-assisted thoracic surgery (VATS), hybrid VATS, and conventional thoracotomy. The risk factors associated with postoperative pain were also analyzed. RESULTS: Thirty patients underwent lung resection with pure VATS, while 30 had hybrid VATS, and 10 had conventional thoracotomy. Among the three surgical approaches, analyzing the pain score indicated statistically significant differences (pure, 159.50 ± 26.22; hybrid, 269.36 ± 30.49; thoracotomy, 589.40 ± 141.11; p = 0.003); however, NRS did not obtain a statistically significant difference between the three approaches (pure, 4.26 ± 0.27; hybrid, 4.96 ± 0.30; thoracotomy, 5.50 ± 0.68; p = 0.105). A multivariate analysis showed that the surgical approach was an independent risk factor for postoperative pain as determined by the pain score (pure vs. hybrid, p = 0.076; pure vs. thoracotomy, p < 0.001). CONCLUSION: For lung surgery, the differences in surgical approach were an independent risk factor for postoperative pain. In the early postoperative period, pure VATS was shown to be the least painful of the three surgical approaches.

Prediction for prognosis of resected pT1a-1bN0M0 adenocarcinoma based on tumor size and histological status: relationship of TNM and IASLC/ATS/ERS classifications.

OBJECTIVES: This study aimed to estimate the relationship between 7th TNM classification and IASLC/ATS/ERS classification with regard to tumor size and pathological status and to determine the utility of these classifications for predicting prognosis in resected node-negative adenocarcinoma with tumor size ≤2.0 cm and >2.0-3.0 cm. MATERIALS AND METHODS: We reviewed 321 pN0M0 lung adenocarcinoma cases resected at Hiroshima University Hospital from January 1991 to December 2010. Histological differences between T1a and T1b based on the IASLC/ATS/ERS classification were estimated and followed by evaluation of overall survival (OS) and recurrence-free interval (RFI) based on differences in tumor size and histological features. RESULTS: We found 188 cases of pT1a-1bN0M0 (135 T1a, 53 T1b). Pathological T1a tumors included significantly more adenocarcinoma in situ (AIS) cases and minimally invasive adenocarcinoma (MIA) cases than T1b tumors (60.7% vs 18.8%, respectively; p<0.0001), while more invasive adenocarcinoma cases were included in pT1b. By considering the two classifications simultaneously, the 5-year OS rates of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 97.5%, 87.5%, 95.8%, and 86.8%, respectively. The 5-year RFIs of T1a AIS/MIA, T1b AIS/MIA, T1a invasive adenocarcinoma, and T1b invasive adenocarcinoma were 100%, 100%, 91.3%, and 72.5%, respectively. T1a AIS/MIA and T1b AIS/MIA could be separated as good prognostic cases with a 100% RFI. Multivariate analysis indicated that only T1b invasive adenocarcinoma was an independent factor for predicting recurrence (p=0.001). CONCLUSION: Compared to a single classification, combining TNM and IASLC/ATS/ERS classifications could provide more detail information concerning disease recurrence. AIS and MIA should be handled equally, regardless of tumor size, because their non-/less invasive status is more useful for predicting prognosis than their tumor size classification. In contrast, the T descriptors based on TNM classification are important for predicting prognosis in invasive adenocarcinoma.

Classifications of n2 non-small-cell lung cancer based on the number and rate of metastatic mediastinal lymph nodes.

BACKGROUND: Subdivisions of N2 non-small-cell lung cancer (NSCLC) cases based on metastatic status of mediastinal and non-mediastinal lymph nodes have been proposed. This study aimed to evaluate N2 disease classification by mediastinal lymph nodes alone. PATIENTS AND METHODS: We reviewed 187 patients with NSCLC pN1-N2 who were surgically treated to evaluate the proposed classifications: number, rate, nodal zone of metastatic lymph nodes. We evaluated N2 disease classification based on mediastinal lymph nodes alone in 136 pN2 cases. RESULTS: The number (1-2, 3-5, and 6 ≤) or rate (15%≥, 15%< to 40%>, and 40%≤) classification based on all metastatic lymph nodes was validated by the log-rank test and Cox proportional hazards model. After reclassification by number or rate of metastatic mediastinal lymph nodes alone, a significant difference was maintained among all groups except between the 3-5 and 6 ≤ groups. The 5-year survival rates of the 1-2, 3-5, and 6 ≤ groups were 63.4%, 32.4%, and 18.2%, respectively (1-2 vs. 3-5, P = .015; 3-5 vs. 6 ≤, P = .134). With rate classification, the 5-year survival rates of the 15%≥, 15%-40% (15%< to 40%>), and 40%≤ groups were 56.0%, 27.3%, and 5.04%, respectively (15%≥ vs. 15%-40%, P = .011; 15-40% vs. 40%≤, P = .011). The Spearman's rank correlation coefficient showed a highly significant correlation of metastatic status between mediastinal lymph nodes and all lymph nodes (both P < .001). CONCLUSION: Classification by number and rate of mediastinal lymph nodes alone enabled subdivision of N2 NSCLC cases. Metastatic status of mediastinal lymph nodes reflects that of all lymph nodes and is prognostic indicators.

Involvement of homologous recombination in the synergism between cisplatin and poly (ADP-ribose) polymerase inhibition.

Poly (ADP-ribose) polymerase (PARP) plays a critical role in responding to DNA damage, by activating DNA repair pathways responsible for cellular survival. Inhibition of PARP is used to treat certain solid cancers, such as breast and ovarian cancers. However, its effectiveness with other solid cancers, such as esophageal squamous cell carcinoma (ESCC), has not been clarified. We evaluated the effects of PARP inhibition on the survival of human esophageal cancer cells, with a special focus on the induction and repair of DNA double-strand breaks. The effects were monitored by colony formation assays and DNA damage responses, with immunofluorescence staining of γH2AX and RAD51. We found that PARP inhibition synergized with cisplatin, and the cells were highly sensitive, in a similar manner to the combination of cisplatin and 5-fluorouracil (5-FU). Comparable increases in RAD51 foci formation were observed after each combined treatment with cisplatin and either 3-aminobenzamide (3-AB) or 5-FU in three human esophageal cancer cell lines, TE11, TE14, and TE15. In addition, decreasing the amount of RAD51 by RNA interference rendered the TE11 cells even more hypersensitive to these treatments. Our findings suggested that the homologous recombinational repair pathway may be involved in the synergism between cisplatin and either 3-AB or 5-FU, and that 3-AB and 5-FU may similarly modify the cisplatin-induced DNA damage to types requiring the recruitment of RAD51 proteins for their repair. Understanding these mechanisms could be useful for improving the clinical outcome of ESCC patients who suffer from aggressive disease that presently lacks effective treatment options.

Multidisciplinary team-based approach for comprehensive preoperative pulmonary rehabilitation including intensive nutritional support for lung cancer patients.

BACKGROUND: To decrease the risk of postoperative complication, improving general and pulmonary conditioning preoperatively should be considered essential for patients scheduled to undergo lung surgery. OBJECTIVE: The aim of this study is to develop a short-term beneficial program of preoperative pulmonary rehabilitation for lung cancer patients. METHODS: From June 2009, comprehensive preoperative pulmonary rehabilitation (CHPR) including intensive nutritional support was performed prospectively using a multidisciplinary team-based approach. Postoperative complication rate and the transitions of pulmonary function in CHPR were compared with historical data of conventional preoperative pulmonary rehabilitation (CVPR) conducted since June 2006. The study population was limited to patients who underwent standard lobectomy. RESULTS: Postoperative complication rate in the CVPR (n = 29) and CHPR (n = 21) were 48.3% and 28.6% (p = 0.2428), respectively. Those in patients with Charlson Comorbidity Index scores ≥2 were 68.8% (n = 16) and 27.3% (n = 11), respectively (p = 0.0341) and those in patients with preoperative risk score in Estimation of Physiologic Ability and Surgical Stress scores >0.3 were 57.9% (n = 19) and 21.4% (n = 14), respectively (p = 0.0362). Vital capacities of pre- and post intervention before surgery in the CHPR group were 2.63±0.65 L and 2.75±0.63 L (p = 0.0043), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6815). Forced expiratory volumes in one second of pre- and post intervention before surgery in the CHPR group were 1.73±0.46 L and 1.87±0.46 L (p = 0.0012), respectively; however, their transition in the CVPR group was not statistically significant (p = 0.6424). CONCLUSIONS: CHPR appeared to be a beneficial and effective short-term preoperative rehabilitation protocol, especially in patients with poor preoperative conditions.