[Significance and Points to Note of Perioperative Oral Care].

With the development of minimally invasive surgery for lung cancer, surgical indications for elderly patients have been increasing. However, elderly patients are at risk for aspiration pneumonia, which is accompanied by a decline in swallowing function and results in aspiration pneumonia. More than 700- 1,000 species are present in the oral microbiome, and the progression of the oral microbiome to the lung has been reported to be associated with poor prognosis. Perioperative complications include dental injuries associated with intubation for general anesthesia and postoperative pneumonia. Preoperative tooth extractions and mouth protectors are effective in preventing dental injuries. Perioperative oral care is often reported to be effective in preventing postoperative pneumonia by removing dental calculus and plaque and cleaning the tongue and stimulating saliva production. Oral care should be continued after as well as before surgery to avoid delaying adjuvant therapy. If the hospital performing the surgery has the department of dentistry and oral surgery, oral care can be completed in the hospital. However, if the hospital does not have that department, it is necessary to collaborate with a local dental clinic in various ways.

Single-cell sequencing on CD8+ TILs revealed the nature of exhausted T cells recognizing neoantigen and cancer/testis antigen in non-small cell lung cancer.

BACKGROUND: CD8+tumor infiltrating lymphocytes (TILs) are often observed in non-small cell lung cancers (NSCLC). However, the characteristics of CD8+ TILs, especially T-cell populations specific for tumor antigens, remain poorly understood. METHODS: High throughput single-cell RNA sequencing and single-cell T-cell receptor (TCR) sequencing were performed on CD8+ TILs from three surgically-resected lung cancer specimens. Dimensional reduction for clustering was performed using Uniform Manifold Approximation and Projection. CD8+ TIL TCR specific for the cancer/testis antigen KK-LC-1 and for predicted neoantigens were investigated. Differentially-expressed gene analysis, Gene Set Enrichment Analysis (GSEA) and single sample GSEA was performed to characterize antigen-specific T cells. RESULTS: A total of 6998 CD8+ T cells was analyzed, divided into 10 clusters according to their gene expression profile. An exhausted T-cell (exhausted T (Tex)) cluster characterized by the expression of ENTPD1 (CD39), TOX, PDCD1 (PD1), HAVCR2 (TIM3) and other genes, and by T-cell oligoclonality, was identified. The Tex TCR repertoire (Tex-TCRs) contained nine different TCR clonotypes recognizing five tumor antigens including a KK-LC-1 antigen and four neoantigens. By re-clustering the tumor antigen-specific T cells (n=140), it could be seen that the individual T-cell clonotypes were present on cells at different stages of differentiation and functional states even within the same Tex cluster. Stimulating these T cells with predicted cognate peptide indicated that TCR signal strength and subsequent T-cell proliferation and cytokine production was variable but always higher for neoantigens than KK-LC-1. CONCLUSIONS: Our approach focusing on T cells with an exhausted phenotype among CD8+ TILs may facilitate the identification of tumor antigens and clarify the nature of the antigen-specific T cells to specify the promising immunotherapeutic targets in patients with NSCLC.

Early chest tube removal regardless of drainage volume after anatomic pulmonary resection: A multicenter, randomized, controlled trial.

OBJECTIVES: This study aimed to evaluate the safety and feasibility of early chest tube removal after anatomic pulmonary resection, regardless of the drainage volume. METHODS: We conducted a multicenter, randomized, controlled, noninferiority trial. Patients with greater than 300 mL drainage volume during postoperative day 1 were randomly assigned to group A (tube removed on postoperative day 2) and group B (tube retained until drainage volume ≤300 mL/24 hours). The primary end point was the frequency of respiratory-related adverse events (grade 2 or higher based on the Clavien-Dindo classification) within 30 days postoperatively. RESULTS: Between April 2019 and October 2021, 175 patients were assigned to group A (N = 88) or group B (N = 87). One patient in group B who experienced chylothorax was excluded from the study. Respiratory-related adverse events were observed in 10 patients (11.4%) in group A and 12 patients (14.0%) in group B (P = .008). The frequencies of thoracentesis or chest tube reinsertion were not significantly different (8.0% and 9.3% in groups A and B, respectively, P = .752). Additionally, the duration of chest tube placement was significantly shorter in group A than in group B (median, 2 vs 3 days; P < .001). No significant difference between groups A and B was found in postoperative hospital stay (median, 6 vs 7 days, P = .231). CONCLUSIONS: Early chest tube removal, regardless of drainage volume, was safe and feasible in patients who underwent anatomic pulmonary resection.

Two-Stage Portal Vein Ligation Facilitates Liver Regeneration Safely in Rats with Liver Cirrhosis.

BACKGROUND: Portal vein (PV) embolization is performed prior to extended hepatectomy for the damaged liver to increase future remnant liver volume and prevent postoperative liver failure. This study examined whether two-stage PV ligation (PVL) increased regeneration and hypertrophy of the future remnant liver compared to conventional PVL, and whether two-stage PVL was safe for damaged liver. METHOD: We produced a cirrhotic liver rat model with perioperatively maintained fibrosis. Rats were divided into: Group A (70%PVL), ligation of left branch of PV; Group B (90%PVL), ligation of right and left branches of PV; and Group C (two-stage 90%PVL), two-stage PVL with left branch ligation of PV followed by right branch ligation 7 days later. To evaluate liver regeneration, liver weight ratios, proliferating cell nuclear antigen (PCNA) labeling index (LI), mitotic index (MI), and TdT-mediated dUTP-biotin nick end labeling (TUNEL) LI in the non-ligated caudate lobe were measured. RESULTS: Fourteen-day survival rate was 20% in Group B but 100% in Group C. TUNEL LI differed significantly between Groups A and B at 2 and 7 days postoperatively. Weight ratios were significantly higher in Group C than in Groups A and B at 14 days postoperatively. PCNA LI and MI in the non-ligated caudate lobe decreased to preoperative levels by 7 days postoperatively in Groups A and B, but remained elevated until 14 days postoperatively in Group C. CONCLUSION: In cirrhotic liver rats, two-stage PVL avoided the lethal liver failure seen with one-stage PVL, and significantly facilitated liver regeneration more than one-stage PVL.

Efficacy of preoperative inhaled LAMA/LABA combinations in patients with lung cancer and untreated COPD.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a high incidence of postoperative pulmonary complications (PPCs). When untreated COPD is found before lung cancer surgery, we have been actively intervening therapeutically with inhaled long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) combinations. We investigated the efficacy of preoperative LAMA/LABA treatment. METHODS: We reviewed data from 261 patients who underwent pulmonary resection for primary lung cancer. Of these, 59 patients showed unrecognized obstructive ventilatory impairment on respiratory function testing. We administered inhaled drugs for 38 patients, of whom 22 patients treated with LAMA/LABA combinations and diagnosed with COPD were retrospectively analyzed regarding improvement of respiratory function and postoperative course. RESULTS: Median duration of LAMA/LABA treatment was 19.5 days (interquartile range (IQR), 10.5-28.3 days). Percentage predicted vital capacity (%VC) (pretreatment: 95.6%, IQR 91.9-111.7 vs. posttreatment 102.8%, IQR 92.3-113.0), forced expiratory volume in 1 s (FEV1) (1.76 L, 1.43-2.12 vs. 2.00 L, 1.78-2.40), forced VC (FVC) (2.96 L, 2.64-3.47 vs. 3.22 L, 2.95-3.74) and percentage predicted FEV1 (80.1%, 68.4-97.0 vs. 91.6%, 80.3-101.9) were all significantly improved (P<0.05 each). FEV1/FVC tended to be improved, but not significantly. No significant difference in improvement of respiratory function was seen between short-term (≤2 weeks) and normal-term (>2 weeks) treatment. PPCs occurred in 4 of 22 patients (18.2%), showing no significant difference compared to patients with COPD previously treated with inhaled drugs (2/20; 10.0%). CONCLUSIONS: Respiratory function is improved by preoperative LAMA/LABA treatment even in the short term. Starting treatment allows even COPD patients diagnosed on preoperative screening to experience the same frequency of PPCs as previously treated patients.

Prognostic factors in pulmonary metastasectomy and efficacy of repeat pulmonary metastasectomy from colorectal cancer.

BACKGROUND: The rate of pulmonary metastasectomy from colorectal cancer (CRC) has increased with recent advances in chemotherapy, diagnostic techniques, and surgical procedures. The purpose of this study was to investigate the prognostic factors for response to pulmonary metastasectomy and the efficacy of repeat pulmonary metastasectomy. METHODS: This study was a retrospective, single-institution study of 126 CRC patients who underwent pulmonary metastasectomy between 2000 and 2019 at the Gifu University Hospital. RESULTS: The 3- and 5-year survival rates were 84.9% and 60.8%, respectively. Among the 126 patients, 26 (20.6%) underwent a second pulmonary metastasectomy for pulmonary recurrence after initial pulmonary metastasectomy. Univariate analysis of survival identified seven significant factors: (1) gender (p = 0.04), (2) past history of extra-thoracic metastasis (p = 0.04), (3) maximum tumor size (p = 0.002), (4) mediastinal lymph node metastasis (p = 0.02), (5) preoperative carcinoembryonic antigen (CEA) level (p = 0.01), (6) preoperative carbohydrate antigen 19-9 (CA19-9) level (p = 0.03), and (7) repeat pulmonary metastasectomy for pulmonary recurrence (p < 0.001). On multivariate analysis, only mediastinal lymph node metastasis (p = 0.02, risk ratio 8.206, 95% confidence interval (CI) 1.566-34.962) and repeat pulmonary metastasectomy for pulmonary recurrence (p < 0.001, risk ratio 0.054, 95% CI 0.010-0.202) were significant. Furthermore, in the evaluation of surgical outcomes, the safety of second pulmonary metastasectomy was almost the same as that of initial pulmonary metastasectomy. CONCLUSIONS: Repeat pulmonary metastasectomy is likely to be safe and effective for recurrent cases that meet the surgical criteria. However, mediastinal lymph node metastasis was a significant independent prognostic factor for worse overall survival.

Identification of Homozygous Somatic DICER1 Mutation in Pleuropulmonary Blastoma.

Pleuropulmonary blastoma (PPB) is a rare, progressive, and aggressive malignant intrathoracic tumor observed during childhood. Mutations in the DICER1 gene have been considered a major etiologic factor of PPB and cause a variety of tumor types in children and young adults. We present a 3-year-old boy with type II PPB. Multimodal treatment consisting of surgery and neoadjuvant chemotherapy was effective. DICER1 mutations were examined by Sanger sequencing, microarray comparative genomic hybridization, and microsatellite markers. The results revealed that a somatic biallelic DICER1 mutation with uniparental disomy was present in the tumor tissue.

Management of the inter-segmental plane using the "Combined Dimensional Reduction Method" is safe and viable in uniport video-assisted thoracoscopic pulmonary segmentectomy.

BACKGROUND: The management of the intersegmental plane (ISP) is challenging during uniport video-assisted thoracoscopic (VATS) pulmonary segmentectomy. Staplers and electrocautery have been used extensively in ISP management. However, both of them have their respective drawbacks. Currently, we have provided a revised technique termed as "Combined Dimensional Reduction Method" (CDR method), for managing the ISP with combined application of ultrasonic scalpel and staplers. The study aimed to review the outcomes of patients who underwent uniport VATS segmentectomy with or without the CDR method in our institute and assess the feasibility and safety of the CDR method. METHODS: From March 2017 to February 2018, 220 patients who underwent uniport VATS segmentectomy were retrospectively reviewed. By using IQQA software, pulmonary structures were reconstructed as three-dimensional (3D) images, making the targeted structures could be identified preoperatively. For the management of the ISP, in the CDR group, we firstly used the ultrasonic scalpel to trim the 3D pulmonary structure along the intersegmental demarcation, making the remaining targeted parenchyma both sufficiently thin enough and located on a 2D plane; thus, enabling easy use of staplers in managing ISP. Whereas, in the non-CDR group, we only use the staplers to manage the ISPs. The clinical characteristics, complications, and postoperative pulmonary functions were compared between the two groups. RESULTS: Propensity score analysis generated 2 well-matched pairs of 71 patients in CDR and non-CDR groups. There was no 30-day postoperative death or readmission in either group. The CDR group was significantly associated with the shorter operative time (178.3±35.8 vs. 209.2±28.7 min) (P=0.031) and postoperative stay (4.5±2.3 vs. 5.7±4.2 days) (P=0.041), compared to the non-CDR group. Moreover, no significant difference was observed in blood loss, a period of chest tube drainage, a period of ultrafine tube drainage, and postoperative pulmonary complications between the two groups. Moreover, the recovery rate of postoperative forced expiratory volume in 1 second (FEV1) or vital capacity (VC) at 1 and 3 months after segmentectomy was comparable between them. CONCLUSIONS: The CDR method could make segmentectomy easier and more accurate, and therefore has the potential to be a viable and effective technique for uniport VATS pulmonary segmentectomy.

Preoperative screening for nasal carriage of methicillin-resistant Staphylococcus aureus in patients undergoing general thoracic surgery.

Objectives: Nasal carriage of methicillin-resistant Staphylococcus aureus (MRSA) is a risk factor for surgical site infections (SSIs). However, few studies have evaluated the rate of nasal carriage of MRSA and its effect on SSIs in patients undergoing general thoracic surgery. We investigated the importance of preoperative screening for nasal carriage of MRSA in patients undergoing general thoracic surgery. Patients and Methods: We retrospectively analyzed 238 patients with thoracic diseases who underwent thoracic surgery. We reviewed the rates of nasal carriage of MRSA and SSIs. Results: Results of MRSA screening were positive in 11 of 238 patients (4.6%), and 9 of these 11 patients received nasal mupirocin. SSIs occurred in 4 patients (1.8%). All 4 patients developed pneumonia; however, MRSA pneumonia occurred in only 1 of these 4 patients. No patient developed wound infection, empyema, and/or mediastinitis. SSIs did not occur in any of the 11 patients with positive results on MRSA screening. Conclusions: The rates of nasal carriage of MRSA and SSIs were low in this case series. Surveillance is important to determine the prevalence of MRSA carriage and infection in hospitals, particularly in the intensive care unit. However, routine preoperative screening for nasal carriage of MRSA is not recommended in patients undergoing general thoracic surgery.

Division of the intersegmental plane using electrocautery for segmentectomy in clinical stage I non-small cell lung cancer.

BACKGROUND: Division of intersegmental planes is one of the important practical issues for segmentectomy to obtain feasible outcomes without relapse for clinical stage I non-small cell lung cancer. Almost all surgeons perform this procedure using a stapler. However, division of intersegmental planes for segmentectomy can also be performed by electrocautery. In this article, we demonstrate the merits and drawbacks of division of the intersegmental plane by electrocautery for segmentectomy. METHODS: Of those 125 patients who underwent segmentectomy with clinical stage I primary lung cancer, we compared cautery cases (n=50) with stapler cases (n=75). The cautery group included 29 cases (58.0%) with partial use of a staple at the end of division. RESULTS: Operative time was significantly longer in cautery cases (281±72 min) than stapler in cases (235±86 min; P=0.003). No difference in the duration of chest tube placement was evident between cautery (3.0±3.0 days) and stapler groups (2.8±1.7 days; P=0.613). However, delayed air leakage occurred significantly more frequently in cautery cases (14.0%) than in stapler cases (4.0%; P=0.048). Five-year overall survival (OS) in clinical stage I was 94.7% in cautery cases and 80.5% in stapler cases (log-rank P=0.047). Five-year disease-free survival (DFS) was 80.0% and 71.3%, respectively (log-rank P=0.075). CONCLUSIONS: The merits of cautery division include the ability to achieve meticulous division of the intersegmental plane and good preservation of the shape of residual segments. Conversely, the drawbacks include prolonged air leakage. Pleural suture or closure of residual segments may be useful to prevent delayed air leakage.

Thoracoscopic segmentectomy: hybrid approach for clinical stage I non-small cell lung cancer.

BACKGROUND: Recently, minimally invasive surgical approaches have been developed, typified by video-assisted thoracic surgery (VATS). A meticulous surgical procedure to prevent local recurrence is required during segmentectomy for clinical stage I non-small-cell primary lung cancer. In this article, we demonstrated the validity of hybrid VATS segmentectomy. METHODS: Of these 125 patients, 62 (49.6%) underwent intensively radical segmentectomy (RS). The remaining 63 (50.4%) patients underwent palliative segmentectomy (PS). We used two 2-cm ports and performed a muscle-sparing mini-thoracotomy in which a partially open metal retractor allowed direct, thoracoscopic visualization as hybrid VATS segmentectomy in 63.2% of our cases. RESULTS: The consolidation/tumor ratio obtained with thin-sliced computed tomography was significantly lower in RS cases than in PS cases (P=0.001). The proportion of pathological stage IA cases was significantly higher in RS cases (95.2%) than in PS cases (66.7%; P<0.01). Five-year overall survival (OS) for clinical stage I was 100.0% in RS cases and 73.5% in PS cases (log-rank P<0.001). Five-year disease-free survival (DFS) was 95.5% and 55.7%, respectively (log-rank P<0.001). CONCLUSIONS: During segmentectomy, the most critical consideration is establishment of sufficient surgical margins around the cancer. Our hybrid approach that includes meticulous surgical manipulations may produce sufficient surgical margins.

A multicenter, randomized, double-blind, dose-finding study of condoliase in patients with lumbar disc herniation.

OBJECTIVE Chemonucleolysis with condoliase has the potential to be a new, less invasive therapeutic option for patients with lumbar disc herniation (LDH). The aim of the present study was to determine the most suitable therapeutic dose of condoliase. METHODS Patients between 20 and 70 years of age with unilateral leg pain, positive findings on the straight leg raise test, and LDH were recruited. All eligible patients were randomly assigned to receive condoliase (1.25, 2.5, or 5 U) or placebo. The primary end point was a change in the worst leg pain from preadministration (baseline) to week 13. The secondary end points were changes from baseline in the following items: worst back pain, Oswestry Disability Index (ODI), SF-36, and neurological examination. For pharmacokinetic and pharmacodynamic analyses, plasma condoliase concentrations and serum keratan sulfate concentrations were measured. The safety end points were adverse events (AEs) and radiographic and MRI parameters. Data on leg pain, back pain, abnormal neurological findings, and imaging parameters were collected until week 52. RESULTS A total of 194 patients received an injection of condoliase or placebo. The mean change in worst leg pain from baseline to week 13 was -31.7 mm (placebo), -46.7 mm (1.25 U), -41.1 mm (2.5 U), and -47.6 mm (5 U). The differences were significant at week 13 in the 1.25-U group (-14.9 mm; 95% CI -28.4 to -1.4 mm; p = 0.03) and 5-U group (-15.9 mm; 95% CI -29.0 to -2.7 mm; p = 0.01) compared with the placebo group. The dose-response improvement in the worst leg pain at week 13 was not significant (p = 0.14). The decrease in the worst leg pain in all 3 condoliase groups was observed from week 1 through week 52. Regarding the other end points, the worst back pain and results of the straight leg raise test, ODI, and SF-36 showed a tendency for sustained improvement in each of the condoliase groups until week 52. In all patients at all time points, plasma condoliase concentrations were below the detectable limit (< 100 µU/ml). Serum keratan sulfate concentrations significantly increased from baseline to 6 hours and 6 weeks after administration in all 3 condoliase groups. No patient died or developed anaphylaxis or neurological sequelae. Five serious AEs occurred in 5 patients (3 patients in the condoliase groups and 2 patients in the placebo group), resolved, and were considered unrelated to the investigational drug. Severe AEs occurred in 10 patients in the condoliase groups and resolved or improved. In the condoliase groups, back pain was the most frequent AE. Modic type 1 change and decrease in disc height were frequent imaging findings. Dose-response relationships were observed for the incidence of adverse drug reactions and decrease in disc height. CONCLUSIONS Condoliase significantly improved clinical symptoms in patients with LDH and was well tolerated. While all 3 doses had similar efficacy, the incidence of adverse drug reactions and decrease in disc height were dose dependent, thereby suggesting that 1.25 U would be the recommended clinical dose of condoliase. Clinical trial registration no.: NCT00634946 (clinicaltrials.gov).

What factors determine the survival of patients with an acute exacerbation of interstitial lung disease after lung cancer resection?

PURPOSES: Acute exacerbation of interstitial pneumonia (AEIP) is a leading cause of death after lung cancer resection in patients with interstitial lung disease. METHODS: We retrospectively analyzed 1763 patients with non-small cell lung cancer with a clinical diagnosis of interstitial lung disease (ILD) who underwent lung cancer resection between 2000 and 2009 at 61 hospitals in Japan. AEIP occurred in 164 of 1763 (9.3%) patients with a mortality rate of 43.9% (72/164). Univariate and multivariate analyses were carried out to identify possible risk factors of fatal AEIP. We then analyzed the 164 patients who developed postoperative AEIP and identified the preoperative and postoperative risk factors. RESULTS: A multivariate regression analysis identified that the sex, percent vital capacity, neoadjuvant radiation, preoperative history of AEIP, preoperative use of steroids, usual interstitial pneumonia pattern on CT, and surgical procedures were independent preoperative risk factors for death due to AEIP. ILD patients with emphysema somehow showed a lower risk of fatal AEIP than those without emphysema in this study. CONCLUSIONS: This study revealed eight risk factors for fatal AEIP.

Suppression of aortic expansion and contractile recovery in a rat abdominal aortic aneurysm model by biodegradable gelatin hydrogel sheet incorporating basic fibroblast growth factor.

Biodegradable gelatin hydrogel sheet (BGHS) incorporating basic fibroblast growth factor (bFGF) may inhibit the progression of abdominal aortic aneurysm (AAA). We investigated whether AAA in a rat model treated with BGHS soaked with bFGF can suppress aortic expansion and recover the contractile response of aneurysmal aortic wall. Experimental AAA was induced in 10-week-old male Sprague-Dawley rats with intra-aortic elastase infusion. Aortas of these rats were assigned to 4 groups (n = 6 each) as follows: Control group, aortas infused with saline; Elastase only group, aortas infused with elastase; Hydrogel group, aortas wrapped with saline-soaked BGHS after elastase infusion; and bFGF group, aortas wrapped with bFGF (100 µg)-soaked BGHS after elastase infusion. Preoperatively and on postoperative day (POD)7 and POD14, mean aortic maximal diameter was measured ultrasonographically. Aortic expansion ratio was calculated as: (post-infusion aortic diameter on POD14/pre-infusion aortic diameter × 100). Aortas were stained with Elastica van Gieson and α-smooth muscle actin to measure the ratio of elastic fibers and α-smooth muscle actin-positive cells area to the media area. Aortas on POD14 were cut into 2-mm rings and treated with contractile agent, then tension was recorded using myography. Maximum aorta diameters were significantly greater in Elastase only group, Hydrogel group, and bFGF group than in Control group (on POD14). Maximum diameter was significantly lower in bFGF group (3.52 ± 0.4 mm) than in Elastase only group (6.21 ± 1.4 mm on POD14, P < .05). On histological analysis, ratio of the area staining positively for elastic fibers was significantly greater in bFGF group (7.43 ± 1.8%) than in Elastase only group (3.76 ± 2.9%, P < .05). The ratio for α-smooth muscle actin-positive cells was significantly lower in Elastase only group (38.3 ± 5.1%) than in Control group (49.8 ± 6.7%, P < .05). No significant differences were seen between Elastase only group and bFGF group, but ratios tended to be increased in bFGF group. Consecutive mean contractile tensions were significantly higher in bFGF group than in Elastase only group. Maximum contractile tension was significantly higher in bFGF group (1.3 ± 0.4 mN) than in Elastase only group (0.4 ± 0.2 mN, P < .05). Aortic expansion can be suppressed and contractile responses of aneurysmal aortic wall recovered using BGHS incorporating bFGF.