Increasing monocytes after lung cancer surgery triggers the outgrowth of distant metastases, causing recurrence.

Patients with lung cancer have a high incidence of tumor recurrence even after curative surgical resection. Some reports indicated that immunosuppressive cells induced by surgical stress could contribute to tumor recurrence after surgery; however, the underlying mechanisms are not fully understood. In this study, we found that increased postoperative blood monocytes served as a risk factor for tumor recurrence in 192 patients with non-small cell lung cancer (NSCLC). We established the lung cancer recurrent mouse model after tumor resection and showed that the surgical stress immediately increased the level of serum monocyte chemoattractant protein-1 (MCP-1), which subsequently increased blood monocytes. These blood monocytes were rapidly recruited into distant micrometastases and became tumor growth-promoting tumor associated macrophages (TAMs). Furthermore, even after the blood MCP-1 and monocytes decreased enough 72 h after tumor resection, TAMs in micrometastases remained rich because the MCP-1 secreted by micrometastases themselves continued to recruit monocytes around the tumor. Consequently, tumor resection triggered the outgrowth of distant metastases via the MCP-1-Monocyte-TAM axis. When we administered the MCP-1 inhibitor to the lung cancer recurrent model mice, blood monocytes decreased after tumor resection, and TAMs in micrometastases also dramatically decreased. Finally, peri- and postoperative treatment with the MCP-1 inhibitor suppressed distant metastases after surgery. Targeting the MCP-1-Monocyte-TAM axis may inhibit surgical stress-induced NSCLC recurrence by attenuating postoperative immunosuppressive monocytes in micrometastases.

Myostatin expression in lung cancer induces sarcopenia and promotes cancer progression.

OBJECTIVES: Many studies have demonstrated that sarcopenia among lung cancer predicts poor prognosis due to cancer progression. However, the cytokines that link sarcopenia and lung cancer progression remain unidentified. This study aimed to investigate whether lung cancer producing myostatin, which induces skeletal muscle atrophy, leads to sarcopenia and promotes cancer progression in patients with resected lung cancer. METHODS: Tumor tissues were obtained from 148 patients who underwent curative resection for lung cancer. Tumor cells were stained with myostatin and tumor-associated macrophages (TAM) in the tumor microenvironment were stained with CD68. We assessed the association between myostatin expression and the clinicopathological features. RESULTS: High myostatin expression in lung cancer was significantly associated with low skeletal muscle mass. The 5-year overall survival and relapse-free survival were significantly worse among patients with high myostatin expression than those with low expression. A multivariate analysis showed that TAM count was positively correlated with high myostatin expression. CONCLUSION: Sarcopenia may be induced by myostatin secreted by lung cancer cells. Moreover, myostatin may promote TAM migration into the tumor microenvironment, leading to advance lung cancer. As a result, patients with high myostatin expression had poor prognosis.

Relationship between pulmonary blood flow and volume following lung resection using dynamic perfusion digital radiography.

Background: Surgical intervention for lung resection can cause ventilation-perfusion mismatches and affect gas exchange; however, minimally invasive assessment of blood flow is difficult. This study aimed to evaluate changes in pulmonary blood flow after radical lung cancer surgery using a minimally invasive dynamic digital chest radiography system. Methods: We evaluated 64 patients who underwent radical lobectomies. Postoperative changes in pulmonary blood flow, assessed using dynamic chest radiography-based blood flow ratios (BFRs), were compared with the temporal evolution of both functional lung volumes (FLVs) and estimated lung weight (ELW) derived from computed tomography (CT) volumetry. Results: FLVs on the affected side gradually recovered over time from the lowest value observed 3 months after surgery in all procedures. BFRs on the affected side also showed a gradual recovery from the lowest value 1 month after surgery, except for left upper lobectomies (LULs). In LULs, FLVs and ELWs increased proportionally up to 3 months after surgery, with lung volumes continuing to increase thereafter. The recovery of BFRs differed depending on the resected lobe. Conclusions: A relationship between pulmonary blood flow and FLV was observed in the postoperative period. Despite varying compensatory responses depending on the surgical procedure, FLV recovery coincided with increased pulmonary blood flow.

Depletion of tumor-associated macrophages inhibits lung cancer growth and enhances the antitumor effect of cisplatin.

In lung cancer, tumor-associated macrophages (TAMs), especially M2-like TAMs, represent the main tumor progression components in the tumor microenvironment (TME). Therefore, M2-like TAMs may serve as a therapeutic target. The purpose of this study was to investigate the effect of M2-like TAM depletion in the TME on tumor growth and chemotherapy response in lung cancer. The levels of secreted monocyte chemoattractant protein (MCP-1) and prostaglandin E2 (PGE2) in the supernatants of lung cancer cell lines A549 and LLC were evaluated via ELISA. Cell migration assays were performed to assess the recruitment ability of macrophage cell lines THP-1 and J774-1 cells. Differentiation of macrophages was assessed via flow cytometry. Immunohistochemical staining was performed to visualize M2-like TAMs in transplanted lung cancer in mouse. We used the COX-2 inhibitor nimesulide to inhibit the secretion of MCP-1 and PGE2, which promotes macrophage migration and M2-like differentiation. Nimesulide treatment decreased the secretion of MCP-1 and PGE2 from lung cancer cells. Nimesulide treatment suppressed the migration of macrophages by blocking MCP-1. Lung cancer supernatant induced the differentiation of macrophages toward the M2-like phenotype, and nimesulide treatment inhibited M2-like differentiation by blocking MCP-1 and PGE2. In the lung cancer mouse model, treatment with nimesulide depleted M2-like TAMs in the TME and enhanced the tumor inhibitory effect of cisplatin. Our results indicated that blocking the secretion of MCP-1 and PGE2 from tumor cells depleted M2-like TAMs in the TME and the combination therapy with cisplatin considerably suppressed tumor growth in the LLC mouse model.

A comparative analysis of segmentectomy-aswere medicated withinsociated factors influencing bronchial tortuosity in early-stage left upper lung cancer.

BACKGROUND: Several studies of early-stage non-small cell lung cancer (NSCLC) have reported a notable therapeutic effect of segmentectomy. However, the secondary benefits of lung volume preservation remain unclear. This study aimed to investigate the potential benefits of segmentectomy, in terms of its impact on postoperative bronchial change. METHODS: Patients who underwent left-sided upper lobectomy and upper division segmentectomy for pStage 0-IA2 NSCLC, were retrospectively analyzed. Degree of the left main bronchial deviation was measured by the curvature index (CI), determined using computed tomography. Variables, including CI value and postoperative rate of change in CI were compared for postoperative cough management the lobectomy and segmentectomy groups. RESULTS: Sixty-seven patients were reviewed. Thirty-seven and 30 patients underwent lobectomy and segmentectomy, respectively, without any significant differences in baseline and surgical variables. The 5-year overall survival rates in the lobectomy and segmentectomy groups were 86.7 and 95.2%, respectively (p = 0.437). While there was no significant difference in postoperative complications, the rate of change in CI was significantly higher in the lobectomy group than in the segmentectomy group (113 vs. 106%, p = 0.005). In addition, the analysis based on postoperative cough reveals the rate of change in CI to be significantly higher in patients requiring medical treatment (p = 0.005). Conclusions Left upper division segmentectomy provides satisfactory treatment and relief of postoperative bronchial tortuosity. Our study suggests that there is a possibility the mitigation of environmental changes in the thoracic cavity may reduce symptoms, thus contributing to an improved quality of life.

Reliability of dynamic perfusion digital radiography as an alternative to pulmonary perfusion scintigraphy in predicting postoperative lung function and complications.

Background: Accurate perioperative risk assessment can enhance the perioperative management of patients undergoing radical surgery for lung cancer. In this study, we compared the accuracy of predicting perioperative complications by lung function values, estimated by blood flow ratios (BFRs), to determine whether dynamic perfusion digital radiography (DPDR) could substitute for pulmonary perfusion scintigraphy (PPS). Methods: Patients scheduled for radical surgery for lung cancer who underwent simultaneous dynamic chest radiography (DCR) and lung perfusion scintigraphy were assessed. We confirmed the agreement between two methods in the assessment of the BFR and its predicted postoperative (ppo) value. Besides, the best spirometry thresholds for the risk of perioperative respiratory or cardiovascular complications were calculated from a receiver operating characteristic (ROC) analysis. The imaging methods were compared for sensitivity and specificity. Results: Among the 44 cases enrolled, DPDR and PPS showed high correlations in BFR (r=0.868, P<0.01) and its postoperative value (r=0.975, P<0.01) and between the predicted and measured spirometry values. In both imaging modalities, the estimated postoperative diffusing capacity test for carbon monoxide (DLco) had the best prediction [area under the curve (AUC) >0.7] for respiratory complications within 1 month (with different cut-offs for same target cases). For predicting, respiratory complications within 1-3 months after surgery, these values were similar between two modalities. Furthermore, the ppoDLco values from both imaging methods were excellent indicators of the induction of postoperative long term oxygen therapy, with the AUC greater than 0.8. Conclusions: This study showed that simple and less invasive DPDR can be a good alternative to PPS for predicting postoperative pulmonary function values and the risk of postoperative respiratory complications. This new imaging modality will offer new insights and possible functional analyses of pulmonary circulation.

Sarcopenia increases the risk of post-operative recurrence in patients with non-small cell lung cancer.

BACKGROUND: Sarcopenia is among the most prevalent and serious cancer-related symptom, and is strongly correlated with a poor prognosis. Moreover, it reportedly predicts poor prognosis after surgery in patients with lung cancer. However, it is unclear whether sarcopenia directly affects post-operative recurrence. The purpose of this study was to evaluate whether sarcopenia can be a risk indicator for post-operative recurrence, and whether it suppresses anti-tumor immunity, in a cohort of patients with resected non-small cell lung cancer. METHODS: This study retrospectively reviewed the data of 256 consecutive patients who underwent curative lobectomy and lymph node dissection for non-small cell lung cancer at our institution. The psoas muscle mass index was calculated as the total psoas muscle area at the third lumbar vertebral level/height2 (cm2/m2). Sarcopenia was defined by a psoas muscle mass index of under 5.03 cm2/m2 and 3.17 cm2/m2 in male and female patients, respectively. Post-operative prognosis and cumulative incidence of recurrence rates were calculated. RESULTS: The 5-year overall survival and disease-free survival rates post-surgery were 59.5% and 38.6%, respectively, in patients with sarcopenia versus 81.1% and 72.1%, respectively, in patients without sarcopenia (p < 0.001). The 5-year cumulative incidence of recurrence rate in patients with sarcopenia was significantly higher than those without sarcopenia (49.9% versus 22.4%, respectively) in every pathological stage. Pathological stages II and III (hazard ratio, 3.36; p = 0.004), histological type (hazard ratio, 2.31; p = 0.025), and sarcopenia (hazard ratio, 2.52; p = 0.001) were independent risk factors for post-operative recurrence according to multivariate analysis. CONCLUSION: Sarcopenia is a risk indicator for post-operative recurrence in patients with non-small cell lung cancer.

A reliable fistula closure technique for refractory pneumothorax unresponsive to pleurodesis.

An 86-year-old man, who had undergone pleurodesis several times for intractable pneumothorax due to severe emphysema was referred to our department in order to treat for recurrent pneumothorax. Computed tomography after chest tube drainage revealed incomplete re-expansion right lung and giant cyst. Because the air leakage continued, we performed surgery. Thoracotomy revealed extensive intrathoracic adhesions due to chemical pleurodesis with OK-432. There was a fistula at the base of the giant cyst in the upper right lobe, which was firmly adhered to the superior vena cava and other mediastinal organs. It was not feasible to staple the lesion cyst, and covering the fistula was ineffective. Therefore, we tried to suture the fragile bulla manually to close the fistula. Adhesion was peeled off carefully to relieve tension of the bulla from mediastinum. The thin wall was folded and reinforced with polytetrafluoroethylene pledget, and then this thickened tissue was sutured to the lung with U-stitches to close the fistula. After the operation, pneumothorax improved. He was discharged without complications.

Anatomical lung resection for left lung cancer after thoracic aortic replacement.

After thoracic aortic replacement, extensive adhesions are expected to develop between the prosthesis and the lung. There have been no definitive reports on anatomical lung resection performed in patients with left lung cancer after thoracic aortic replacement. Herein, we report a series of five such cases. Our findings showed that severe adhesions were encountered after aortic arch and descending aortic replacement, but not after ascending aortic replacement. We think that these adhesions started developing in the early postoperative period and were particularly severe in the case of left upper lobe lung cancer after arch replacement. However, anatomical lobectomy and systematic lymph node dissection could still be performed safely by devising a surgical technique. In addition, there was a possibility that a new aortic aneurysm may have occurred at the time of surgery. Therefore, it is important to perform a thorough preoperative evaluation and coordinate with the cardiovascular surgery department.

Locoregional recurrence via mucus-mediated extension following lung resection for mucinous tumors.

BACKGROUND: Clinically, locoregional recurrences following mucinous tumor resection are often experienced. However, it remains unclear whether mucinous tumors directly affect local recurrence or not, and if so, the mechanism is not known. Therefore, we investigated whether mucinous tumors are associated with locoregional recurrence after pulmonary resection and whether mucus extension is a risk factor for locoregional recurrence. METHODS: The data of 152 patients who underwent pulmonary resection for metastases were reviewed. When mucus was partially or wholly present in the tumor based on macro- or microscopic identification, we assigned the tumor as mucinous. In mucinous tumors, when mucus was identified within the air spaces in the normal lung parenchyma, beyond the edge of the tumor, we assigned the tumor as positive for "mucus extension." RESULTS: The 5-year cumulative incidence of locoregional recurrence in patients with mucinous tumors was 48.1%, which was significantly higher than that observed in those with non-mucinous tumors (14.9%). Within the mucinous tumor, the presence of mucus extension beyond the tumor edge was an independent risk factor for locoregional recurrence after pulmonary resection (hazard ratio, 5.52; P = 0.019). CONCLUSIONS: During the resection of mucinous cancer, surgeons should maintain sufficient distance from the tumor edge to prevent locoregional recurrences.

Perioperative changes in respiratory impedance in lobectomy and their clinical impact.

BACKGROUND: Respiratory function declines after lung resection. However, perioperative changes in respiratory impedance and their clinical significance are unclear. The forced oscillation technique can measure respiratory impedance during quiet breathing and possibly early after surgery. We investigated respiratory impedance changes before and after lung lobectomy and examined the correlation of impedance with clinical factors. METHODS: We prospectively included patients who underwent lobectomy between February 2018 and March 2020 and measured respiratory impedance by forced oscillation preoperatively and postoperative days 1 and 7. We statistically analyzed changes in perioperative forced oscillation measurements and their correlation with clinical factors, including subjective symptoms. The modified British Medical Research Council scale and the chronic obstructive pulmonary disease (COPD) assessment test were used for scoring subjective symptoms. RESULTS: Forty-four subjects were included, in whom respiratory impedance could be measured from postoperative day 1. The respective mean values for forced oscillation measurements preoperatively and at postoperative days 1 and 7 were as follows: respiratory resistance, 5 Hz: 2.28, 2.77, and 2.75; respiratory resistance, 20 Hz: 2.00, 2.36, and 2.32; difference in respiratory resistance at 5 and 20 Hz: 0.28, 0.40, and 0.43; respiratory reactance, 5 Hz: -0.31, -0.65, and -0.56; resonant frequency: 7.45, 10.41, and 9.81; and low-frequency reactance area: 1.33, 3.27, and 2.84. These changes were statistically significant (P<0.01). Besides the difference in respiratory resistance at 5 and 20 Hz, all other measurements on postoperative day 7 were relatively weakly correlated with the modified Medical Research Council scale score at this time point (all P<0.05). Respiratory complications correlated with the respiratory resistance difference, respiratory reactance, and resonant frequency on day 7 (R =0.415, -0.421, and 0.441), while the latter also correlated with postoperative hypoxemia on day 1 (R =0.433). CONCLUSIONS: Respiratory impedance was measurable even early after surgery and significantly changed postoperatively. As the sample size was small and appeared to be biased, assessing respiratory impedance and clinical factors in detail was difficult. Since respiratory impedance is suggested to be associated with clinical factors that affect the postoperative course, it is necessary to accumulate cases and observe them over longer periods.

Does sarcopenia affect postoperative short- and long-term outcomes in patients with lung cancer?-a systematic review and meta-analysis.

BACKGROUND: Lung cancer patients frequently suffer from sarcopenia, and reports on the association of resectable lung cancer and their postoperative outcomes are increasing. Information on whether sarcopenia has any impact on short- and long-term postoperative outcomes in patients surgically treated for non-small cell lung cancer remains insufficient. Furthermore, reports vary regarding the pathological stage, surgical procedure, diagnostic tool of sarcopenia, cut-off value, prognosis, and postoperative complications. We believe that sarcopenia assessment should be included as one of the factors which affect the surgical outcomes of lung cancer. Thus, we conducted a review and meta-analysis to ascertain the association between sarcopenia and postoperative outcomes. METHODS: We performed a systematic literature search in PubMed/MEDLINE. Studies included cases defined sarcopenia, received lung cancer surgery, assessed postoperative complications, and prognosis. The pooled odds ratios for survival and postoperative complications, with 95% confidence intervals, were generated using Review manager 5.3. RESULTS: A total of ten retrospective studies were eligible for this meta-analysis, including a total of 2,643 non-small cell lung cancer patients. All reviews used skeletal muscle mass as a diagnostic tool for sarcopenia. Sarcopenia was associated with worse survival outcomes and increased postoperative complications in patients with resected lung cancer. CONCLUSIONS: Sarcopenia is an independent risk factor for postoperative death and postoperative complications in patients who have undergone surgery. It is necessary to explore the mechanism of sarcopenia and optimal intervention, such as exercise, nutrition, or drug therapy.

Dynamic perfusion digital radiography for predicting pulmonary function after lung cancer resection.

BACKGROUND: Accurate prediction of postoperative pulmonary function is important for ensuring the safety of patients undergoing radical resection for lung cancer. Dynamic perfusion digital radiography is an excellent and easy imaging method for detecting blood flow in the lung compared with the less-convenient conventional lung perfusion scintigraphy. As such, the present study aimed to confirm whether dynamic perfusion digital radiography can be evaluated in comparison with pulmonary perfusion scintigraphy in predicting early postoperative pulmonary function and complications. METHODS: Dynamic perfusion digital radiography and spirometry were performed before and 1 and 3 months after radical resection for lung cancer. Correlation coefficients between blood flow ratios calculated using dynamic perfusion digital radiography and pulmonary perfusion scintigraphy were then confirmed in the same cases. In all patients who underwent dynamic perfusion digital radiography, the correlation predicted values calculated from the blood flow ratio, and measured values were examined. Furthermore, ppo%FEV1 or ppo%DLco values, which indicated the risk for perioperative complications, were examined. RESULTS: A total of 52 participants who satisfied the inclusion criteria were analyzed. Blood flow ratios measured using pulmonary perfusion scintigraphy and dynamic perfusion digital radiography showed excellent correlation and acceptable predictive accuracy. Correlation coefficients between predicted FEV1 values obtained from dynamic perfusion digital radiography or pulmonary perfusion scintigraphy and actual measured values were similar. All patients who underwent dynamic perfusion digital radiography showed excellent correlation between predicted values and those measured using spirometry. A significant difference in ppo%DLco was observed for respiratory complications but not cardiovascular complications. CONCLUSIONS: Our study demonstrated that dynamic perfusion digital radiography can be a suitable alternative to pulmonary perfusion scintigraphy given its ability for predicting postoperative values and the risk for postoperative respiratory complications. Furthermore, it seemed to be an excellent modality because of its advantages, such as simplicity, low cost, and ease in obtaining in-depth respiratory functional information. TRIAL REGISTRATION: Registered at UMIN on October 25, 2017. https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_his_list.cgi?recptno=R000033957 Registration number: UMIN000029716.

Survival and prognostic factors in patients undergoing extended pulmonary metastasectomy.

Extended pulmonary metastasectomy has become feasible in patients with extrapulmonary metastases and multiple or bilateral pulmonary metastases. Even peritoneal dissemination is considered to be curable in modern medicine. Therefore, it is necessary to analyze the prognosis of patients undergoing complete pulmonary metastasectomy. A total of 80 patients who underwent pulmonary resection for lung metastases were retrospectively analyzed. The eligibility criteria for the present study were as follows: i) the primary tumor was controlled; ii) if extrapulmonary metastases (including peritoneal dissemination) existed, these were controlled by local treatment or such treatment was planned; iii) the one to three months follow-up computed tomography (CT) following the first assessment revealed no increase of pulmonary metastatic disease; iv) pulmonary metastases could be resected completely. The overall 5- and 10-year survival rates were 71.7 and 41.5%, respectively. Applying the extended criteria for surgery, the present study demonstrated that pulmonary metastasectomy resulted in a good patient prognosis.

Sarcopenia predicts poor postoperative outcome in elderly patients with lung cancer.

PURPOSE: Sarcopenia gradually progress with age; hence, it is necessary to define sarcopenia to predict postoperative outcomes in elderly patients with lung cancer. The purpose of this study is to propose a definition of sarcopenia in elderly patients with lung cancer, and to demonstrate the post operative outcomes. METHODS: Using computed tomography scans, the cross-sectional area (cm2) of the psoas muscle at the third lumbar vertebral level was measured. The psoas area was normalized for height. The psoas muscle mass index was calculated as total psoas muscle area at L3 level/height2 (cm2/m2). RESULTS: A total of 173 patients aged > 75 years of age received lobectomy for non-small cell lung cancer in our hospital. We defined sarcopenia as the psoas muscle mass index under 3.70 cm2/m2 in males and 2.50 cm2/m2 in females, based on the morbidity rate. The postoperative complication rate was significantly higher in patients with sarcopenia (62.5%) than in those without sarcopenia (22.7%). The 5-year survival rate was 26.5% in patients with sarcopenia, and 66.3% in patients without sarcopenia. CONCLUSIONS: In elderly lung cancer patients, sarcopenia was observed to be a high risk for morbidity and predicted poor prognosis.

Patient Survival after Surgical Management in Intrathoracic Pseudomyxoma peritonei.

BACKGROUND: Pseudomyxoma peritonei (PMP) is a rare disease, characterized by mucinous ascites and deposits diffusely present on the peritoneal surfaces. However, extension of PMP to the thoracic cavity is extremely rare. Although there are a few case reports on the long-term postoperative prognosis of intrathoracic lesions, whether surgical resection of these lesions can improve patient prognosis remains unclear. METHODS: We reviewed 17 patients with PMP who underwent resection of intrathoracic lesions after abdominal cytoreductive surgery and examined their clinical outcome after surgery. RESULTS: Direct extension into the pleural cavity was identified in 11 patients. Extrapleural pneumonectomy of the lesions followed by hyperthermic intrathoracic chemotherapy (HITOC) was performed in four patients, parietal pleurectomy and visceral tumor resection followed by HITOC in four patients, resection of all disseminated pleural and visceral lesions followed by HITOC in one patient, resection of a single disseminated lesion in one patient, and composite resection of basal segment with the diaphragm in one patient. Pulmonary metastases were found in six patients. Partial resection was performed in four patients, segmentectomy in one patient, and lobectomy in one patient. We could perform macroscopic resection of the tumor in all the cases. The 5-year overall survival rate after thoracic surgery for the 17 patients was 46.1% and relapse-free survival was 34.9%. CONCLUSIONS: Resection of intrathoracic lesions of PMP after abdominal cytoreductive surgery achieved 5 years survival in at least 46.1% of the patients. Aggressive tumor resection should be considered for patients with PMP extending to thoracic cavity.

[Resection of double bronchogenic cysts within the anterior mediastinum; report of a case].

We reported a case of surgically resected double bronchogenic cysts within the anterior mediastinum. An anterior mediastinal tumor had been found at medical examination 6 years ago in a 66-year-old man, but has been followed up without treatment. After the treatment of another disease, he was referred to our hospital for evaluation of the mediastinal tumor. A chest computed tomography showed 2 anterior mediastinal nodules. Nodules in the thymus were resected with video-assisted thoracic surgery. The tumors were both pathologically diagnosed as bronchogenic cysts.