Authors' response to Letter to the Editor.

Authors' response to Letter to the Editor from Yongliang Wang and Zheng Bao.

Impact of partial pressure of arterial oxygen and radiologic findings on postoperative acute exacerbation of idiopathic interstitial pneumonia in patients with lung cancer.

PURPOSE: To establish accurate diagnostic criteria and predictors of treatment response for postoperative acute exacerbation (AE) in patients with lung cancer and idiopathic interstitial pneumonia (IIP). METHODS: Among 93 patients with IIP who underwent surgery for lung cancer, suspected postoperative AE developed in 20 (21.5%). Patients were divided into a progressive AE group, comprising patients with bilateral alveolar opacities and decreasing PaO2 ≥ 10 mmHg (n = 5); an incipient AE group, comprising patients with unilateral alveolar opacities and decreasing PaO2 ≥ 10 mmHg (n = 10); and an indeterminate AE group, comprising patients with alveolar opacities but decreasing PaO2 < 10 mmHg (n = 5). RESULTS: The progressive AE group had significantly higher 90-day mortality (80%) than the incipient AE group (10%, P = 0.017) or the indeterminate AE group (0%, P = 0.048). Bilateral opacities may indicate advanced AE and poor prognosis, whereas unilateral opacities may indicate an early stage of AE and a good prognosis. PaO2 < 10 mmHg may indicate conditions other than AE. CONCLUSIONS: In patients with lung cancer and IIP, decreasing PaO2 and HRCT findings may allow for the initiation of rapid and accurate treatment strategies for postoperative AE.

[Outcomes of Surgical Treatment for Chest Trauma].

BACKGROUND: Intra-thoracic organ bleeding and chest wall injury following chest trauma can easily lead to life-threatening emergencies and a delay in treatment may lead to fatal outcomes. Interestingly, the optimal timing, indications, and surgical techniques have not been standardized. METHOD: We retrospectively analyzed 35 patients who underwent surgical treatment for chest trauma. RESULTS: All patients with penetrating trauma (n=4) underwent emergency surgery for a hemothorax. There were no postoperative complications or hospital deaths. All patients with blunt trauma( n= 31) had multiple rib fractures;rib fixation was performed in 29 patients( 94%). Eight patients( 26%) had flail chest. The duration from injury to surgery averaged 7.5 days. The prognosis was generally favorable with no postoperative complications, but two patients died in the hospital due to multiple organ failure caused by high-energy trauma. Patients with flail chest or multiple organ injury had prolonged postoperative hospital stays. CONCLUSIONS: Patients who sustain chest trauma follow various clinical courses. Appropriate timing of surgical intervention at an early stage after injury can be life saving and hasten a functional recovery.

Guidelines for Handling of Cytological Specimens in Cancer Genomic Medicine.

Rapid advances are being made in cancer drug therapy. Since molecularly targeted therapy has been introduced, personalized medicine is being practiced, pathological tissue from malignant tumors obtained during routine practice is frequently used for genomic testing. Whereas cytological specimens fixed mainly in alcohol are considered to be more advantageous in terms of preservation of the nucleic acid quality and quantity. This article is aimed to share the information for the proper handling of cytological specimens in practice for genomic medicine based on the findings established in "Guidelines for Handling of Cytological Specimens in Cancer Genomic Medicine (in Japanese)" published by the Japanese Society of Clinical Cytology in 2021. The three-part practical guidelines are based on empirical data analyses; Part 1 describes general remarks on the use of cytological specimens in cancer genomic medicine, then Part 2 describes proper handling of cytological specimens, and Part 3 describes the empirical data related to handling of cytological specimens. The guidelines indicated proper handling of specimens in each fixation, preparation, and evaluation.

[Validity of Video-assisted Thoracic Surgery for Thymoma].

OBJECTIVES: This study aimed to identify the validity of video-assisted thoracic surgery (VATS) for thymoma, including myasthenia gravis( MG). METHODS: A total of 20 patients who underwent VATS for thymoma at our institution between 2011 and 2019 were included in the study. Preoperative complications and prognosis were analyzed to detect the safety and efficiency of VATS thymectomy. MG improvement after VATS extended thymectomy was evaluated using a quantitative myasthenia gravis score( QMGS) and Myasthenia Gravis Foundation of America post-intervention status( MGFA-PIS). RESULTS: The median tumor size was 2.6 cm (range, 1.0-8.0 cm). All thymomas were classified as TNM stageⅠ. Two patients had type A thymoma, five had type AB, six had type B1, six had type B2, and one had type B3. Postoperative complications were only observed in one patient with pneumonia. The median follow-up period was 5.1 years;no recurrence and disease-related deaths were observed. However, three patients died of other diseases. In patients with MG, postoperative crisis was not observed, and the symptoms improved in all the patients as evaluated by QMGS and MGFA-PIS. CONCLUSIONS: VATS thymectomy and VATS extended thymectomy for patients with thymoma may be effective methods to improve not only prognosis but also MG, provided the range of resections are comparable to that of conventional open surgery.

[Surgical Technique and Prognosis of Limited Resection in High-risk Patients with Primary Lung Cancer].

OBJECTIVES: To identify adaptations of limited resection for poor-risk patients with primary lung cancer and the efficacy of ensuring an adequate surgical margin. METHODS: A total of 139 poor-risk patients who underwent limited resection for their primary lung cancer in our institution between 2005 and 2020 were included. The efficacy of ensuring a surgical margin was determined by analyzing the rate of recurrence, and the prognosis was analyzed via the Kaplan-Meier method. RESULTS: Wedge resection was performed for 105 patients, and segmentectomy was performed for 34 patients. Recurrence was observed in 29 (20.8%) patients, while stump recurrence was observed in only 4( 3.8%) patients with wedge resection. The median surgical margin was 15 mm, which was equal to the median tumor size, and all histopathological margins were negative. An analysis of the 68 patients excluding those with multiple lung cancer showed that the pathological stage was not related to the prognosis. Surgical death and severe complications were not observed, and only 3 patients died of lung cancer during the observational period of 3.4 years. CONCLUSIONS: Limited resection improves the patient's prognosis and ensures an adequate surgical margin to control recurrence.

Surgical treatment for patients with idiopathic pulmonary fibrosis and lung cancer: postoperative acute exacerbation of idiopathic pulmonary fibrosis and outcomes.

Postoperative exacerbation of interstitial pneumonia in patients with interstitial lung disease and lung cancer has emerged as a serious problem. Therefore, we need to determine the risk factors for the development of postoperative exacerbation of interstitial pneumonia in this population. There are several subtypes of interstitial lung disease, which may lead to confusion about the treatment of patients with interstitial lung disease and lung cancer. Among the idiopathic forms of interstitial lung disease, we focused on idiopathic pulmonary fibrosis (IPF) and reviewed the surgical treatments used for patients with IPF and lung cancer.

[Chest Wall Injury].

A traumatic chest wall injury is a condition that is often encountered in medical practice, but the underlying pathophysiology varies widely depending on the circumstances of the injury and the patient's background. The chest wall, which protects vital organs and provides respiratory movement, can be a life-threatening emergency when injured, thus it is important to respond promptly and appropriately. Because a penetrating chest wall trauma is often associated with intra-thoracic organ damage, it is important to consider an emergency thoracotomy in cases involving massive hemorrhage or air leakage. The ribs and sternum are primarily injured in patients with blunt wall trauma. Flail chest, which is defined as multiple bifocal fractures of the ribs or multiple rib fractures with a sternal fracture, causes respiratory failure secondary to paradoxical respiration. The main treatment for flail chest is ventilatory care and surgical treatment, although early rib fixation has been reported to improve prognosis in recent years. There are several types of devices to fix the ribs and sternum, but selection criteria have yet to be established.

A novel finding related to bulla and bleb formation in patients with primary spontaneous pneumothorax.

BACKGROUND: Spontaneous pneumothorax is a common problem globally. Bullas and blebs have been implicated in this problem, but the etiology of their formation is unknown. We aim to show the relation between a novel clinical finding, the pulmonary delayed inflation (PDI) sign, and the etiology of bulla and bleb formation in young patients. METHODS: We retrospectively analyzed data from 111 patients with pneumothorax and a control group of 27 patients. We evaluated the relation between the PDI sign and other clinical factors. RESULTS: The PDI sign was observed in 78 patients. Of these, 75 exhibited the PDI sign in only the upper lobe. Regardless of smoking status, patients 34 years of age or younger had a significantly higher incidence of the PDI sign than, patients 55 years of age or older and control patients. The inflation time in patients 34 years of age or younger, regardless of smoking status, was significantly longer than in patients 55 years of age or older and patients in the control group. There was no significant association between inflation time and the presence of asthma. CONCLUSIONS: The novel PDI sign is seen in patients 34 years of age or younger. Because this sign may indicate a peripheral bronchial abnormality and may be related to the formation of blebs and bullae in young patients with spontaneous pneumothorax, it is possible that it can be used to develop effective treatments for pneumothorax in young patients.

Prognostic and functional impact of perioperative LAMA/LABA inhaled therapy in patients with lung cancer and chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an important risk factor for postoperative complications and mortality. To determine the effects of perioperative combination therapy, using a long-acting muscarinic antagonist (LAMA) and a long-acting ß2 agonist (LABA), on preoperative lung function, postoperative morbidity and mortality, and long-term outcome in COPD patients. METHODS: Between January 2005 and October 2019, 130 consecutive patients with newly diagnosed COPD underwent surgery for lung cancer. We conducted a retrospective review of their medical record to evaluate that LAMA/LABA might be an optimal regimen for patients with COPD undergoing surgery for lung cancer. All patients were received perioperative rehabilitation and divided into 3 groups according to the type of perioperative inhaled therapy and management: LAMA/LABA (n = 64), LAMA (n = 23) and rehabilitation only (no bronchodilator) (n = 43). We conducted a retrospective review of their medical records. RESULTS: Patients who received preoperative LAMA/LABA therapy showed significant improvement in lung function before surgery (p < 0.001 for both forced expiratory volume in 1 s (FEV1) and percentage of predicted forced expiratory volume in 1 s (FEV1%pred). Compared with patients who received preoperative LAMA therapy, patients with LAMA/LABA therapy had significantly improved lung function (ΔFEV1, LAMA/LABA 223.1 mL vs. LAMA 130.0 mL, ΔFEV1%pred, LAMA/LABA 10.8% vs. LAMA 6.8%; both p < 0.05). Postoperative complications were lower frequent in the LAMA/LABA group than in the LAMA group (p = 0.007). In patients with moderate to severe air flow limitation (n = 61), those who received LAMA/LABA therapy had significantly longer overall survival and disease-free survival compared with the LAMA (p = 0.049, p = 0.026) and rehabilitation-only groups (p = 0.001, p < 0.001). Perioperative LAMA/LABA therapy was also associated with lower recurrence rates (vs. LAMA p = 0.006, vs. rehabilitation-only p = 0.008). CONCLUSIONS: We believe this treatment combination is optimal for patients with lung cancer and COPD.

Neuroendocrine tumors of the lung: clinicopathological and molecular features.

In 1970, neuroendocrine tumors of the lung were classified into three categories: typical carcinoid (TC), atypical carcinoid (AC), and small cell lung carcinoma (SCLC). The third edition of the World Health Organization (WHO) classification in 1999 defined large cell neuroendocrine carcinoma (LCNEC) as a variant of large cell carcinomas, whereas the fourth edition of the WHO classification redefined LCNEC as a neuroendocrine tumor. Currently, neuroendocrine tumors of the lung are classified into four main categories: TC, AC, LCNEC, and SCLC. Although the treatments for TC, AC, and SCLC have not changed remarkably, the treatment strategy for LCNEC is not yet established because of its reclassification from a variant of "large cell carcinoma" to a new category of "neuroendocrine tumor". In this review article, we discuss the pathological findings, biological behavior, and treatment of neuroendocrine tumors of the lung.

The Utility of Virtual Bronchoscopy Using a Computed Tomography Workstation for Conducting Conventional Bronchoscopy: A Retrospective Analysis of Clinical Practice.

BACKGROUND: Recent clinical trials demonstrated the benefits of several guided-bronchoscopy technologies for the diagnosis of peripheral pulmonary lesions (PPLs). However, introduction of these technologies is expensive. Therefore, in clinical practice, these are unavailable in many hospitals. In contrast, virtual bronchoscopy (VB) using the computed tomography (CT) workstation can be made available immediately without additional cost as many hospitals already have the CT scan facility. However, the effectiveness of VB alone remains to be shown. OBJECTIVES: The aim of this study was to investigate the effect of VB using the CT workstation in hospitals performing conventional bronchoscopy. METHODS: Results from consecutive patients who underwent bronchoscopy for small PPLs (major diameter ≤30 mm) were retrospectively reviewed. Sixty-nine patients who underwent bronchoscopy without VB from April 2014 to March 2015 and 56 patients who underwent bronchoscopy with VB from April 2015 to December 2015 were assigned to non-VB and VB groups, respectively. We compared the two groups and analyzed the factors affecting the diagnostic yield. RESULTS: The VB group had a significantly higher diagnostic yield than the non-VB group (57.1 vs. 33.3%; p = 0.008). In the multivariate analysis, VB was identified as a significant factor affecting the diagnostic yield (odds ratio: 3.30, p = 0.011). CONCLUSIONS: In the conventional bronchoscopy settings, VB using the CT workstation is efficient for the diagnosis of PPLs when other guided-bronchoscopy techniques are unavailable.

[Sublobar Resection for Patients with a Metachronous Second Primary Lung Cancer Following Curative Resection of a Primary Lung Cancer].

BACKGROUND: Surgical methods for patients with a metachronous 2nd primary lung cancer following curative resection of a primary lung cancer remain controversial. The purpose of this study was to evaluate the outcomes of patients who underwent sublobar resection for a metachronous 2nd primary lung cancer. METHODS: We retrospectively analyzed 10 patients who underwent sublobar resection for a metachronous 2nd primary lung cancer occurring 5 years or more after the initial surgery for primary lung cancer. RESULTS: The 5-year overall survival rate after the 2nd surgery was 68.6%. There was no operative mortality. A postoperative recurrence developed in 4 patients, 3 of whom had pathological stage ⅠA3 cancer. Moreover, patients with a stage ⅠA3 metachronous 2nd primary lung cancer had significantly lower 5-year disease-free and overall survival rates than patients with a stage ⅠA1 or ⅠA2 cancer( disease-free survival rate, p=0.022;overall survival rate, p=0.023). CONCLUSIONS: For patients with a stage ⅠA1 or ⅠA2 metachronous 2nd primary lung cancer, sublobar resection may be acceptable because those patients had a good prognosis in this study. Early detection of a metachronous 2nd primary lung cancer following the initial surgery may be very important for improving the patient's prognosis.

[Energy Device and Soft Coagulation System in Thoracic Surgery].

While the recent emergence of energy-based surgical techniques and soft coagulation has made surgical procedures less invasive, the safety and proper use of such advances have yet to be investigated. Herein we review the experimental and clinical use of ultrasonically-activated coagulating shears, a vessel sealing system, incorporating ultrasonic and vessel sealing technology, and a soft coagulation system in thoracic surgery. All energy devices have been reported to be safe for use on pulmonary vessels, and use in combination with a ligature appears to be adequate. The thoracic duct has been reported to be sealed with sufficient pressure using energy devices, which are expected to prevent chylothorax formation. Bipolar scissors can be safely and efficiently applied for dissection of pulmonary vessels without damage to the vessel wall. Monopolar soft coagulation can be applied to shrink bullous changes and stop air leakage or bleeding within the lung.

Adherence and feasibility of 2 treatment schedules of S-1 as adjuvant chemotherapy for patients with completely resected advanced lung cancer: a multicenter randomized controlled trial.

BACKGROUND: We conducted a multicenter randomized study of adjuvant S-1 administration schedules for surgically treated pathological stage IB-IIIA non-small cell lung cancer patients. METHODS: Patients receiving curative surgical resection were centrally randomized to arm A (4 weeks of oral S-1 and a 2-week rest over 12 months) or arm B (2 weeks of S-1 and a 1-week rest over 12 months). The primary endpoints were completion of the scheduled adjuvant chemotherapy over 12 months, and the secondary endpoints were relative total administration dose, toxicity, and 3-year disease-free survival. RESULTS: From April 2005 to January 2012, 80 patients were enrolled, of whom 78 patients were eligible and assessable. The planned S-1 administration over 12 months was accomplished to 28 patients in 38 arm A patients (73.7%) and to 18 patients in 40 arm B patients (45.0%, p = 0.01). The average relative dose intensity was 77.2% for arm A and 58.4% for arm B (p = 0.01). Drug-related grade 3 adverse events were recorded for 11% of arm A and 5% of arm B (p = 0.43). Grade 1-3 elevation of bilirubin, alkaline phosphatase, aspartate aminotransferase, and alanine transaminase were more frequently recorded in arm A than in arm B. The 3-year disease-free survival rate was 79.0% for arm A and 79.3% for arm B (p = 0.94). CONCLUSIONS: The superiority of feasibility of the shorter schedule was not recognized in the present study. The conventional schedule showed higher completion rates over 12 months (p = 0.01) and relative dose intensity of S-1 (p = 0.01). Toxicity showed no significant difference among the shorter schedule and the conventional schedule, except for grade 1-3 elevation of bilirubin. TRIAL REGISTRATION: This randomized multicenter study was retrospectively registered with the UMIN-CTR (UMIN000016086, registration date December 30, 2014).

[Perioperative Management and Minimally Invasive Pulmonary Resection-early Stage Rehabilitation, Postoperative Early Ambulation].

In chest surgery, minimal invasiveness is an important topic. Video-assisted thoracic surgery and a less radical resection may be effective for decreasing postoperative complications or postoperative mortality rates. Respiratory rehabilitation is useful for preventing postoperative complications, and it is used pre- and postoperatively for patients with lung cancer and chronic obstructive pulmonary disease (COPD) in most hospitals. Although it is well adapted to patients with a lower forced expiratory volume in 1 second, higher stages of COPD, severe emphysematous changes on computed tomography, and performance status ≥2, there are no definitive criteria for rehabilitation. Before initiating respiratory rehabilitation for patients, it is important to evaluate their risk factors, such as sputum production, articular disturbances, or activities. There are many kinds of rehabilitation, but preoperative respiratory rehabilitation is especially effective in inoperable cases to improve respiratory function, to change their status to operable, and to decrease periods of chest-tube drainage or hospital admission. It should be used for minimally invasive chest surgery from now on.

The role of vascular endothelial growth factor receptor-1 signaling in compensatory contralateral lung growth following unilateral pneumonectomy.

Compensatory lung growth models have been widely used to investigate alveolization because the remaining lung can be kept intact and volume loss can be controlled. Vascular endothelial growth factor (VEGF) plays an important role in blood formation during lung growth and repair, but the precise mechanisms involved are poorly understood; therefore, the aim of this study was to investigate the role of VEGF signaling in compensatory lung growth. After left pneumonectomy, the right lung weight was higher in VEGF transgenic mice than wild-type (WT) mice. Compensatory lung growth was suppressed significantly in mice injected with a VEGF neutralizing antibody and in VEGF receptor-1 tyrosine kinase-deficient mice (TK(-/-) mice). The mobilization of progenitor cells expressing VEGFR1(+) cells from bone marrow and the recruitment of these cells to lung tissue were also suppressed in the TK(-/-) mice. WT mice transplanted with bone marrow from TK(-/-)transgenic GFP(+) mice had significantly lower numbers of GFP(+)/aquaporin 5(+), GFP(+)/surfactant protein A(+), and GFP(+)/VEGFR1(+) cells than WT mice transplanted with bone marrow from WTGFP(+) mice. The GFP(+)/VEGFR1(+) cells also co-stained for aquaporin 5 and surfactant protein A. Overall, these results suggest that VEGF signaling contributes to compensatory lung growth by mobilizing VEGFR1(+) cells.

Clinical impact of lung age on postoperative readmission in non-small cell lung cancer.

BACKGROUND: Recently, the Japanese Respiratory Society (JRS) proposed using lung age (LA) as an indicator of lung function; however, reports regarding the association of LA with the risk of postoperative readmission within 90 d after surgical treatment for non-small cell lung cancer (NSCLC) are limited. Here, we analyze the clinical relationship between LA and readmission within 90 d after surgical treatment for NSCLC. METHODS: A total of 979 patients underwent curative resections for NSCLC from January 2000-September 2012 at the Kitasato University Hospital. We selected patients who required readmission because of surgical complications within 90 d of surgery and retrospectively analyzed various clinical data. LA was calculated based on the formula given by the Japanese Respiratory Society, which relies on preoperative respiratory function. We also calculated the age gap (AG) between the calculated LA and the true age (TA). RESULTS: There were 216 patients who needed to be readmitted within 90 d of surgery, 33 (3%) of whom were hospitalized for surgical complications. Twenty-four patients (73%) had respiratory complications, and 7 patients (21%) died. There were significant differences between the readmitted and no readmitted patients in terms of preoperative factors, such as gender, LA, AG, smoking status, and smoking index (P < 0.05). In addition, there were significant differences in intraoperative blood loss, postoperative complications, histologic type, duration of hospitalization, and hospitalization after surgery (P < 0.05). Multivariate analysis using logistic regression indicated that LA, AG, blood loss, and postoperative complications were independent factors that predicted readmission. Additionally, the 5-y survival rates were 78% and 44% for the no readmitted and readmitted groups, respectively (P < 0.001). CONCLUSIONS: The AG between TA and LA was significantly associated with postoperative complications and remained an independent predictive factor after multiple regressions. LA was shown to be a useful factor for predicting the risk of surgery-related readmission within 90 d after surgery for NSCLC.

Clinical impact of lung age on postoperative complications in non-small cell lung cancer patients aged >70 y.

BACKGROUND: Surgery for elderly patients with primary lung neoplasms has become relatively common as populations age; however, the high frequency of postoperative complications has prevented its broad application. Recently, the Japanese Respiratory Society proposed lung age (LA) as an index of lung function, but reports on the association between LA and the risk factors for postoperative complications with non-small cell lung cancer (NSCLC) surgery have been limited. In this study, we analyzed the clinical applicability of LA for elderly patients with NSCLC. MATERIALS AND METHODS: We studied 320 patients aged >70 y underwent curative resections for NSCLC. LA was calculated based on the formula provided by the Japanese Respiratory Society, which depended on the patient's preoperative respiratory function and was divided into four age gap (AG) groups between the LA and the true age (TA). The categorical data were compared among the four groups. RESULTS: The numbers of patients in groups A, B, C, and D were 80, 77, 79, and 84, respectively. For the univariate analysis, the preoperative factors for postoperative complications were gender, AG, and smoking (P < 0.05). In a multivariate analysis, AG proved to be an independent factor. Although we found no significant differences, there was a tendency for the prognosis to worsen with an increase in the AG (P = 0.06). CONCLUSIONS: The AG was significantly associated with and an independent predictive factor for postoperative complications. We conclude that LA and AG are useful factors for predicting the risk of postoperative complications.

[Ultrasonically activated coagulating shears and the vessel sealing system in thoracic surgery].

While the recent emergence of energy-based surgical techniques has made surgical procedures less invasive, the safety and proper usage have yet to be investigated. Here we review the experimental and clinical use of ultrasonically activated coagulating shears and a vessel sealing system in thoracic surgery. Both energy devices have been reported to be safe for use with the pulmonary artery and vein, with a burst pressure above 100 mmHg. Although their combined use with a ligature at a central site appeared to be adequate, the long-term durability has yet to be verified. The thoracic duct was reported to be sealed with sufficient burst pressure using these energy devices, which are expected to provide an alternative treatment for chylothorax. There have also been a few reports of their usage with the lung parenchyma, but their clinical adaptation is seemingly limited.