[Perioperative Rehabolotation Usefulness in Preventing Complications].

The number of elderly patients in thoracic surgery is increasing. The percentage of patients over the age of 80 in surgical cases of malignant diseases such as lung cancer and mediastinal tumors is increasing every year. It is also true that the indications for surgery have been expanding as surgery itself has become less invasive, such as thoracoscopic and robotic surgery. However, it is not uncommon for patients over 80 years of age to have some organ dysfunction and many comorbidities. Therefore, when performing surgery for lung cancer and other diseases, it is important to assess the patient's ability to tolerate surgery, including respiratory and cardiac functions, and to perform risk management. To prevent postoperative complications and improve the accuracy of perioperative management, respiratory rehabilitation should be conducted before and after surgery, and not only smoking cessation instruction but also inhalation training using incentive spirometry( IS), breathing exercises, and the use of inhalers such as long-acting ß2 agonist (LABA)/long-acting muscaring antagonist (LAMA) for patients with chronic obstructive pulmonary disease( COPD) are useful.

Alpha-actinin-4 (ACTN4) gene amplification is a predictive biomarker for adjuvant chemotherapy with tegafur/uracil in stage I lung adenocarcinomas.

Although adjuvant tegafur/uracil (UFT) is recommended for patients with completely resected stage I non-small-cell lung cancer (NSCLC) in Japan, only one-third of cases has received adjuvant chemotherapy (ADJ) according to real-world data. Therefore, robust predictive biomarkers for selecting ADJ or observation (OBS) without ADJ are needed. Patients who underwent complete resection of stage I lung adenocarcinoma with or without adjuvant UFT were enrolled. The status of ACTN4 gene amplification was analyzed by FISH. Statistical analyses to determine whether the status of ACTN4 gene amplification affected recurrence-free survival (RFS) were carried out. Formalin-fixed, paraffin-embedded samples from 1136 lung adenocarcinomas were submitted for analysis of ACTN4 gene amplification. Ninety-nine (8.9%) of 1114 cases were positive for ACTN4 gene amplification. In the subgroup analysis of patients aged 65 years or older, the ADJ group had better RFS than the OBS group in the ACTN4-positive cohort (hazard ratio [HR], 0.084, 95% confidence interval [CI], 0.009-0.806; P = .032). The difference in RFS between the ADJ group and the OBS group was not significant in ACTN4-negative cases (all ages: HR, 1.214; 95% CI, 0.848-1.738; P = .289). Analyses of ACTN4 gene amplification contributed to the decision regarding postoperative ADJ for stage I lung adenocarcinomas, preventing recurrence, improving the quality of medical care, preventing the unnecessary side-effects of ADJ, and saving medical costs.

[Therapeutic Strategies for Metachronous Multiple Primary Lung Cancer].

BACKGROUNDS: It is not uncommon to encounter metachronous primary lung cancer after surgical treatment along with the increase in the elderly patients. In consideration of increasing number of such patients, it is necessary to take various treatment strategies. METHODS: In order to establish a treatment strategy for multiple lung cancer, we retrospectively examined multiple lung cancer cases operated for primary lung cancer in our department from January 2013 to December 2019, and the future treatment strategy was examined. RESULTS: Of 821 patients who underwent surgery for primary lung cancer, 61 were multiple lung cancers, 31 were synchronous multiple lung cancers, and 30 were metachronous multiple lung cancers. Among the cases of metachronous multiple lung cancer, 28 cases had undergone lobectomy or more in the first operation, 1 case of segmental resection, and 1 case of partial resection. As for the treatment of secondary lung cancer lesions, 21 lesions were performed surgery( lobectomy;2, segmental resection;2, partial resection;17), 6 lesions of photodynamic therapy (PDT), and 3 lesions of stereotactic body radiation therapy (SBRT). Among the surgical cases, there were three cases on the same side as the first cancer and 18 cases on the opposite side. The three cases underwent partial resection. Among 21 patients, postoperative home oxygen therapy was introduced in 2 patients. Regarding the prognosis, three patients who had surgical resection, died of recurrence of the first lesion. One of the six PDT patients died of recurrence of the first lung cancer and another died of other disease. All three patients who underwent SBRT are alive without recurrence. CONCLUSIONS: If early detection and early diagnosis are made as a treatment strategy for metachronous multiple lung cancer, it may be possible to preserve lung function by reducing surgery or SBRT, PDT, and to cure without damaging the quality of life.

Left upper lobectomy is a risk factor for cerebral infarction after pulmonary resection: a multicentre, retrospective, case-control study in Japan.

PURPOSE: The anatomical site of resected lobes may influence postoperative cerebral infarction. The objective of the current study was to determine if left upper pulmonary lobectomy is a risk factor for postoperative cerebral infarction. METHODS: This was a retrospective case-control study in patients undergoing pulmonary lobectomy from 2004 to 2013 in Japan. We retrospectively identified 610 patients from 153 institutions who had developed postoperative cerebral infarction following pulmonary lobectomy. The control group consisted of 773 patients who underwent lobectomy without cerebral infarction during a randomly selected single month in 2009 at the same institutions. RESULTS: Factors associated with cerebral infarction were age [10-year intervals, odds ratio (OR): 1.46; 95% confidence interval (CI): 1.23-1.73; p < 0.001], male sex (OR 1.92; 95% CI 1.29-2.86; p = 0.001), presence of comorbidities (OR 1.82; 95% CI 1.35-2.44; p < 0.001), perioperative anti-platelet or anti-coagulant drug use (OR 1.71; 95% CI 1.20-2.45; p = 0.003), and lobectomy. Subgroup analyses revealed that cerebral infarction was strongly associated with left upper lobectomy. CONCLUSIONS: Our findings suggest that left upper lobectomy is associated with a higher risk of cerebral infarction than other types of lobectomy, particularly in the early postoperative period.

Correction to: Left upper lobectomy is a risk factor for cerebral infarction after pulmonary resection: a multicentre, retrospective, case-control study in Japan.

The original article can be found online.

A combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent.

The aim of this study was to evaluate the feasibility of a combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent (gold studded stent [GSS]). Laser irradiation (664 nm, continuous wave) was performed through the GSS using a straight and cylindrical fiber 1.0 cm away from a power meter. There are two types of GSS: the TD type for the trachea and the BD type for the bronchus. Laser outputs were set to 150 mW, 180 mW, 210 mW, 240 mW, 270 mW, and 300 mW. The laser powers passing through the both types of GSS were measured three times for each outputs and the averages were calculated. Based on the results, animal experiment was performed using two female pigs. Under general anesthesia, a GSS (BD type) was inserted into trachea of pigs, and PDT using NPe6 as a photosensitizer was performed by 100 J/cm2 laser irradiation on parts of the trachea with and without a GSS. Immediately after and 1 week after PDT, pig tracheas were harvested and histological analysis was performed. Histological analysis of areas with or without the stent showed edematous changes between the cartilage and submucosal layer immediately after PDT, and necrotic changes 1 week later. The effectiveness of NPe6-PDT for pigs' trachea covered by the stent was same as trachea without the stent. The use of a GSS may enable PDT to be effective even in the area covered by the stent.

[Perspective of Uniportal Video-assisted Thoracic Surgery for Early Lung Cancer in Japan].

Uniportal video-assisted thoracic surgery (U-VATS) has become prevalent among thoracic surgeon in a part of countries including Japan. U-VATS and robotic-assisted thoracoscopic surgery( RATS) are 2 types of minimally invasive surgical techniques. Uniportal procedures are feasible although they can be technically challenging. RATS is superior to U-VATS in terms of the ability to perform procedures that require fine motor skills and to maintain wide visual fields during the procedure;however, it is not as feasible and more costly compared with U-VATS. U-VATS is also considered safer as it is easier than RATS to be converted to thoracotomy when needed. Thus, suitable procedures should be selected to meet the needs of specific cases. In the present study, we review the treatment outcomes of U-VATS for anatomical lung resection that were performed at our institution for patients with early-stage lung cancer.

[Virtual Bronchoscopic Navigation( VBN) and Electromagnetic Navigation System].

Recently small peripheral lesions have been discovered due to development of computed tomography (CT) instruments and dissemination of CT examination etc. Histological or cytological diagnosis for peripheral lesions is recommended to be performed. The diagnostic yield for peripheral pulmonary lesion depends on the size. Transbronchial lung biopsy (TBLB) was developed using techniques such as navigation system( vitual bronchoscopic navigation:VBN), endobronchial ultrasonography(EBUS) using guide sheath(GS), extremely small bronchoscope and the like for lesions of 2.0 cm or less. VBN is a method in which virtual bronchoscopy images of the bronchial path to the peripheral lesion are produced and used as a guide to navigate the bronchoscope. In the randomized controlled trial, it was reported that VBN not only improves the diagnostic rate but also shortens the total examination time. The American College of Chest Physician (ACCP) guidelines recommend the use of EBUS-GS, VBN for the bronchoscopic diagnosis of peripheral pulmonary lesions. Bronchial navigation method using a magnetic field (electromagnetic navigation:EMN) to link the navigation system and the actual bronchoscope in real time has appeared. This new technique, electromagnetic navigational bronchoscopy (ENB) promises accurate navigation to peripheral pulmonary target lesion. Bronchoscopic navigation is also used for marking in thoracoscopic surgery, and it is greatly expected not only as a tool for simply diagnosing but also as a treatment technique in the future.

[Complete Surgical Resection for Lung Cancer Invading Anterior Apex after Preoperative Chemoradiotherapy Via Transmanubrial Approach and Anterolateral Thoracotomy].

Surgical resection plays an important role as a radical treatment for lung cancers. Many lung cancer patients are found in an advanced state and it is currently in a condition that can not be operated, and the prognosis is also bad. For locally advanced lung cancer, complete resection including surrounding organs is expected by performing chemoradiotherapy before surgery. We report a case of complete surgical resection for lung cancer invading anterior apex after preoperative chemoradiotherapy via transmanubrial approach and anterolateral thoracotomy.

Safe transection of aberrant arteries associated with pulmonary sequestrations.

BACKGROUND: Video-assisted thoracoscopic surgery (VATS) lobectomy is increasingly used for pulmonary sequestration; however, there are few descriptions of safe handling of the aberrant artery. Here we clarify the safe handling of an aberrant artery using a clinical review and an experimental model. METHODS: We retrospectively reviewed the records of patients who underwent lobectomy for pulmonary sequestration with aberrant arteries at the Nippon Medical School between January 2008 and December 2010. This was supplemented by an experimental pressure test using vessels obtained from pigs. RESULTS: We identified four patients with aberrant arteries that were successfully occluded via either stapling. In the experimental model, we divided pig vessels into small-diameter (S) and large-diameter (L) groups. The 1.0-mm-high staples were stronger in the S group than in the L group (p = 0.028). In the L group, the 2.0-mm-high staples were stronger than the 1.0-mm staples (p = 0.015). Leakage from the staple line was associated with a poorer B-shape of inserted staples. CONCLUSIONS: The techniques described in this report are useful in successful minimally invasive transection of an aberrant artery (other than very thin vessels) when resecting a pulmonary sequestration by stapler only. A detailed investigation should be performed to determine the most appropriate stapler or cartridge.

Enhanced systemic antitumor efficacy of PD-1/PD-L1 blockade with immunological response induced by photodynamic therapy.

BACKGROUND: Photodynamic therapy (PDT) is an antitumor therapy and has traditionally been regarded as a localized therapy in itself. However, recent reports have shown that it not only exerts a direct cytotoxic effect on cancer cells but also enhances body's tumor immunity. We hypothesized that the immunological response induced by PDT could potentially enhance the efficacy of programmed death-1 (PD-1) / programmed death-ligand 1 (PD-L1) blockade. METHODS: The cytotoxic effects of PDT on colon 26 cells were investigated in vitro using the WST assay. We investigated whether the antitumor effect of anti-PD-1 antibodies could be amplified by the addition of PDT. We performed combination therapy by randomly allocating tumor-bearing mice to four treatment groups: control, anti-PD-1 antibodies, PDT, and a combination of anti-PD-1 antibodies and PDT. To analyze the tumor microenvironment after treatment, the tumors were resected and pathologically evaluated. RESULTS: The viability rate of colon 26 cells decreased proportionally with the laser dose. In vivo experiments for combined PDT and anti-PD-1 antibody treatment, combination therapy showed an enhanced antitumor effect compared with the control. Immunohistochemical findings of the tumor microenvironment 10 days after PDT indicated that the number of CD8+ cells, the area of Iba-1+ cells and the area expressing PD-L1 were significantly higher in tumors treated with combination therapy than in tumors treated with anti-PD-1 antibody alone, PDT alone, or the control. CONCLUSIONS: PDT increased immune cell infiltration into the tumor microenvironment. The immunological response induced by PDT may enhance the efficacy of PD-1/PD-L1 blockade.

Protein interaction networks characterizing the A549 cells Klotho transfected are associated with activated pro-apoptotic Bim and suppressed Wnt/ß-catenin signaling pathway.

Invasive assays and lung tumor-bearing mice models using a human lung adenocarcinoma cell line A549 cells transfected with the Klotho (KL) gene, A549/KL cells, have confirmed that KL suppresses invasive/metastatic potential. This study aimed to identify the co-expression protein networks and proteomic profiles associated with A549/KL cells to understand how Klotho protein expression affects molecular networks associated with lung carcinoma malignancy. A two-step application of a weighted network correlation analysis to the cells' quantitative proteome datasets of a total of 6,994 proteins, identified by mass spectrometry-based proteomic analysis with data-independent acquisition (DIA), identified one network module as most significantly associated with the A549/KL trait. Upstream analyses, confirmed by western blot, implicated the pro-apoptotic Bim (Bcl-2-like protein 11) as a master regulator of molecular networks affected by Klotho. GeneMANIA interaction networks and quantitative proteome data implicated that Klotho interacts with two signaling axes: negatively with the Wnt/ß-catenin axis, and positively by activating Bim. Our findings might contribute to the development of future therapeutic strategies.

Long-term outcomes of PDT for centrally-located early lung cancers with tumor diameters > 2.0 cm.

BACKGROUND: Photodynamic therapy (PDT) is used for the treatment of centrally-located early lung cancers (CLELCs) and is recommended for tumors ≤ 1.0 cm in diameter. We previously reported that PDT using talaporfin sodium, second-generation photosensitizer, for tumors > 1.0 cm but ≤ 2.0 cm in diameter was able to achieve a therapeutic outcome comparable to that of tumors with a diameter of ≤ 1.0 cm. However, the effectiveness of PDT using talaporfin sodium for tumors > 2.0 cm in diameter remains unclear. We conducted a retrospective analysis of cases in which PDT was performed for flat-type CLELCs with tumor diameters of > 2.0 cm. METHODS: We retrospectively analyzed seven cases (eight lesions) with tumor diameters > 2.0 cm and no evidence of extracartilaginous invasion or lymph node metastasis. RESULTS: All the patients underwent multiple PDT sessions. The PDT treatment results over the study period were partial response in one case (14.3 %), stable disease (SD) in three cases (42.9 %), and progressive disease (PD) in three cases (42.9 %). At the time of writing this report, five of seven cases (71.4 %) are still undergoing treatment. The duration of SD-the time from the start of treatment until the criteria for PD were met (SD or better maintained)-ranged from 7 to 52 months (mean, 25.3 months). CONCLUSIONS: "Maintenance PDT" for CLELCs > 2.0 cm in diameter has the potential to inhibit tumor progression in the long term while maintaining quality of life, rather than simply aiming only for a quick radical cure.

Management of thyroid carcinoma showing thymus-like differentiation (CASTLE) invading the trachea.

PURPOSE: To define the clinicopathological features and discuss the optimal management of carcinoma showing thymus-like differentiation (CASTLE). METHODS: We retrospectively analyzed six patients with CASTLE. RESULTS: The subjects comprised two men and four women (average age at initial diagnosis, 61 years, range 47-75 years). Preoperative biopsy yielded a correct diagnosis in two patients. Five patients underwent surgery and one was treated with radiation therapy alone. Four had extrathyroidal invasion and three had lymph node metastasis. During the clinical course, tracheal invasion was detected in five patients, the upper extent of the tumor being the lower half of the first tracheal ring. Two of these patients underwent tracheal sleeve resection. Two patients received postoperative radiotherapy for nodal metastasis, and one, after palliative surgery. The median follow-up period was 67 months (range 38-129). Recurrence was found 10 years post-therapy in the patient treated with radiation therapy only, resulting in death soon after. Although local recurrence was not found in the remaining five patients, new pulmonary metastases were diagnosed in the patient who underwent non-curative surgery. CONCLUSIONS: CASTLE can be diagnosed preoperatively by core needle biopsy and CD5 staining. Curative resection with neck dissection followed by radiotherapy can yield a good outcome. Larynx-sparing complete resection may be more feasible for CASTLE, even though it has a higher incidence of tracheal invasion than differentiated thyroid carcinoma.

Development of a new minimally invasive phototherapy for lung cancer using antibody-toxin conjugate.

BACKGROUND: Photodynamic therapy (PDT) is a cancer-targeted treatment that uses a photosensitizer (PS) and laser irradiation. The effectiveness of current PDT using red light for advanced cancers is limited, because red light can only reach depths within a few millimeters. To enhance the antitumor effect for lung cancers, we developed a new phototherapy, intelligent targeted antibody phototherapy (iTAP). This treatment uses a combination of immunotoxin and a PS, mono-L-aspartyl chlorin e6 (NPe6). METHODS: We examined whether cetuximab encapsulated in endosomes was released into the cytosol by PS in PDT under light irradiation. A431 cells were treated with fluorescein isothiocyanate-labeled cetuximab, NPe6, and light irradiation and were observed with fluorescence microscopy. We analyzed the cytotoxicity of saporin-conjugated cetuximab (IT-cetuximab) in A431, A549, and MCF7 cells and the antitumor effect in model A549-bearing mice in vivo using the iTAP method. RESULTS: Fluorescent microscopy analysis showed that the photodynamic effect of NPe6 (20 µM) and light irradiation (37.6 J/cm2 ) caused the release of cetuximab from the endosome into the cytosol. In vitro analysis demonstrated that the iTAP method enhanced the cytotoxicity of IT-cetuximab by the photodynamic effect. In in vivo experiments, compared with IT-cetuximab alone or PDT alone, the iTAP method using a low dose of IT-cetuximab showed the greatest enhancement of the antitumor effect. CONCLUSIONS: Our study is the first report of the iTAP method using NPe6 for lung cancer cells. The iTAP method may become a new, minimally invasive treatment superior to current PDT methods.

Prognostic role of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography with an image-based harmonization technique: A multicenter retrospective study.

Objectives: Despite the prognostic impacts of preoperative fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examination, fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography-based prognosis prediction has not been used clinically because of the disparity in data between institutions. By applying an image-based harmonized approach, we evaluated the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters in clinical stage I non-small cell lung cancer. Methods: We retrospectively examined 495 patients with clinical stage I non-small cell lung cancer who underwent fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography examinations before pulmonary resection between 2013 and 2014 at 4 institutions. Three different harmonization techniques were applied, and an image-based harmonization, which showed the best-fit results, was used in the further analyses to evaluate the prognostic roles of fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Results: Cutoff values of image-based harmonized fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters, maximum standardized uptake, metabolic tumor volume, and total lesion glycolysis were determined using receiver operating characteristic curves that distinguish pathologic high invasiveness of tumors. Among these parameters, only the maximum standardized uptake was an independent prognostic factor in recurrence-free and overall survivals in univariate and multivariate analyses. High image-based maximum standardized uptake value was associated with squamous histology or lung adenocarcinomas with higher pathologic grades. In subgroup analyses defined by ground-glass opacity status and histology or by clinical stages, the prognostic impact of image-based maximum standardized uptake value was always the highest compared with other fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography parameters. Conclusions: The image-based fluorine-18 fluorodeoxyglucose-positron emission tomography/computed tomography harmonization was the best fit, and the image-based maximum standardized uptake was the most important prognostic marker in all patients and in subgroups defined by ground-glass opacity status and histology in surgically resected clinical stage I non-small cell lung cancers.

Retrospective analysis of nodal spread patterns according to tumor location in pathological N2 non-small cell lung cancer.

BACKGROUND: The purpose of the present study was to determine the nodal spread patterns of pN2 non-small cell lung cancer (NSCLC) according to tumor location, and to attempt to evaluate the possible indications of selective lymph node dissection (SLND). METHODS: We retrospectively analyzed nodal spread patterns in 207 patients with NSCLC of less than 5 cm with N2 involvement. RESULTS: The tumor location was right upper lobe (RUL) in 79, middle lobe in 12, right lower lobe (RLL) in 40, left upper division (LUD) in 41, lingular division in 11, and left lower lobe (LLL) in 24. Both RUL and LUD tumors showed a higher incidence of upper mediastinal (UM) involvement (96 and 100%, respectively) and a lower incidence of subcarinal involvement (15 and 10%, respectively) than lower lobe tumors (UM; RLL 60%, LLL 42%; subcarinal: RLL 60%, LLL 46%, respectively). Among the patients with 24 right UM-positive RLL and 10 left UM-positive LLL tumors, 2 showed negative hilar, subcarinal, and lower mediastinal involvement, and cT1, suggesting that UM dissection may be unnecessary in lower lobe tumors with no metastasis to hilar, subcarinal, and lower mediastinal nodes on frozen sections according to the preoperative T status. Among the patients with 12 subcarinal-positive RUL and 4 subcarinal-positive LUD tumors, one showed negative hilar or UM involvement, suggesting that subcarinal dissection may be unnecessary in RUL or LUD tumors with no metastasis to hilar and UM nodes on frozen sections. CONCLUSIONS: The present study appears to provide one of the supportive results regarding the treatment strategies for tumor location-specific SLND.

An intrapericardial foregut cyst: report of a thoracoscopically resected case.

Intrapericardial foregut cysts are rare, and are usually found serendipitously. An abnormal shadow was incidentally found on a chest X-ray film of a 45-year-old asymptomatic female undergoing a regular check-up. Computed tomography revealed a smooth-walled, left mediastinal cyst (70 × 46 mm) immediately adjacent to the pericardium and left ventricle. We performed video-assisted thoracic surgery, which suggested that the lesion had macroscopically originated from the epicardium. However, the resected cyst was histologically determined to be an intrapericardial foregut cyst. This experience taught us that, while intrapericardial cysts possess the latent possibility of causing sudden death, cardiac failure, or eventual malignant changes, carefully planned and meticulously executed resection, avoiding damage to adjacent organs or vessels, is recommended.

New Technique for Introducing a Surgical Stapler during Robot-Assisted Lobectomy for Lung Cancer.

BACKGROUND: The da Vinci Si version robot lacks a vascular stapler that can be controlled by the operating surgeon at the surgical console when dividing pulmonary vessels. Therefore, to initiate and safely perform robotic anatomical lobectomy for lung cancer, it is important to develop a safe method for introducing a surgical stapler. METHODS: We performed a retrospective study of the first 42 consecutive patients who underwent robotic lobectomy for lung cancer at Nippon Medical School Hospital between January 2019 and December 2020. RESULTS: Up to case 18, we performed robot-assisted thoracoscopic surgery (RATS) lobectomy by using a four-arm approach with two assistant ports. For dividing pulmonary vessels, the surgical stapler was introduced through the assist ports. However, since this is not the port position usually used in video-assisted thoracoscopic surgery (VATS), there were many difficult situations. For RATS lobectomy case 19 and all subsequent cases, we utilized a total port approach that uses three robotic arms and two assistant ports. To resect the pulmonary vessels or bronchi with endoscopic staplers, the port for the robotic arm was removed and the endoscopic staplers were placed through a 12-mm Xcel bladeless port. This change reduced operation time, blood loss, and robotic arm interference. No patient developed intraoperative complications during RATS lobectomy. CONCLUSION: The present total port approach, with three robotic arms, appears to be feasible for introducing surgical staplers during RATS with the da Vinci Si robotic system.