Effect of revised organ transplant law in Japan on lung transplantation.

PURPOSE: To investigate how revision of the organ transplant law in Japan affected lung transplantation in this country. METHODS: Lung transplant candidates registered between January, 2000 and December, 2009 were designated as the pre-revision group (n = 396) and those registered between January, 2011 and December, 2020, as the post-revision group (n = 1326). Both groups were analyzed retrospectively using data collected by the Japanese Society of Lung and Heart-Lung Transplantation. RESULTS: The number of patients who underwent brain-dead donor lung transplantation (BDLT) increased significantly after the law amendment (32.2 vs. 13.8%, p < 0.01). The median waiting time for BDLT was significantly reduced (708 days vs. 1163 days, p < 0.01) and the mortality rate while waiting for BDLT improved significantly after the law amendment (33.1 vs. 42.6%, p < 0.01). In the post-revision group, 18 pediatric patients underwent BDLT. The 5-year survival rates after BDLT were comparable between the groups (73.5% in the pre-revision group vs. 73.2% in the post-revision group, p = 0.32). CONCLUSIONS: The organ transplant law revision shortened the waiting time for BDLT significantly and decreased the mortality rate while waiting for BDLT. The posttransplant outcomes in Japan remained favorable throughout the study period.

Effects of case volume on short- and long-term outcomes following cadaveric lung transplantation in Japan.

Background: Despite the low number of lung transplantations (LTs) in Japan, 10 LT facilities are accredited and good outcomes have been reported. A database review was conducted to clarify the impact of case volume at LT facilities in Japan on short- and long-term outcomes. Methods: All cadaveric LT cases treated between 2000 and 2021 in Japan were analyzed using the database of the Japanese Society of Lung and Heart-Lung Transplantation (JSLHT). The nine institutions represented were categorized into the low-volume (LV; <80 cumulative LT cases, <8 LTs/year, n=5) and high-volume (HV; ≥80 cumulative LT cases, ≥8 LTs/year, n=4) centers. Ninety-day and 1-year mortality, as well as 5- and 10-year survival data were evaluated. Results: A total of 658 cadaveric LTs were performed at the nine institutions. The 90-day rates of mortality at the HV and LV centers were 3.5% and 3.9%, respectively (P=0.801), while the 1-year mortality rates were 9.2% and 11.5%, respectively (P=0.199). Additionally, log-rank analysis of Kaplan-Meier curves showing case volume did not reveal a significant difference in long-term survival between the HV and LV centers (P=0.272), though the LV centers had wide differences for long-term outcomes (P=0.030). Conclusions: Case volume did not have effects on short- or long-term outcomes following LT in Japan, while there were large variations in long-term outcomes among the LV centers compared to those of the HV centers.

[Considerations for Perioperative Management of Patients with Complicated Respiratory Dysfunction].

This article describes the perioperative complications, perioperative risk assessment, and perioperative management of patients with chronic obstructive pulmonary disease (COPD) and interstitial lung disease, especially idiopathic pulmonary fibrosis( IPF), which are the leading diseases in respiratory dysfunction. In COPD, testing for forced expiratory volume during the first second and pulmonary diffusing capacity is important and an algorithm for testing has been presented by the Japanese Association for Chest Surgery. Acute exacerbation of IPF is the leading cause of postoperative mortality in Japan, and risk factors are being analyzed. To reduce the occurrence of postoperative complications, it is important to carry out a risk assessment, select appropriate surgical strategy, and implement a well-planned perioperative management.

Significance of micro-EGFR T790M mutations on EGFR-tyrosine kinase inhibitor efficacy in non-small cell lung cancer.

Small amounts of epidermal growth factor receptor (EGFR) T790M mutation (micro-T790M), which is detected using droplet digital PCR (ddPCR) but not conventional PCR, in formalin-fixed and paraffin-embedded (FFPE) samples have been investigated as a predictive factor for the efficacy of EGFR-tyrosine kinase inhibitors (TKIs). However, the predictive value of micro-T790M remains controversial, possibly owing to the failure to examine artificial T790M in FFPE specimens. Therefore, we examined the predictive value of micro-T790M in first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKI efficacy using a new method to exclude FFPE-derived artificial mutations in our retrospective cohort. The primary objective was time to treatment failure (TTF) of 1G, 2G, and 3G EGFR-TKIs according to micro-T790M status. In total, 315 patients with EGFR-positive non-small cell lung cancer treated with 1G, 2G, and 3G EGFR-TKIs were included in this study. The proportion of patients positive for micro-T790M in the 1G, 2G, and 3G EGFR-TKI groups was 48.2%, 47.1%, and 47.6%, respectively. In the micro-T790M-positive group, the TTF was significantly longer in the 2G and 3G EGFR-TKI groups than in the 1G TKI group. No differences in the micro-T790M-negative group were observed. Micro-T790M status detected using ddPCR, eliminating false positives, may be a valuable predictor of EGFR-TKI efficacy.

[Robot-assisted Minimally Invasive Surgery for Mediastinal Tumors].

The subxiphoid approach in thymectomy provides better visibility around the left brachiocephalic vein than the lateral thoracic approach. Robot-assisted thoracoscopic surgery is easier to parform than video- assisted thoracoscopic surgery for surgery of the upper mediastinum, because the forceps can be moved with many joints. Robot-assisted thymectomy using the subxiphoid approach may be less traumatic and less invasive than median sternotomy. We must continue to devise surgical procedures to make oncologically curative surgery more minimally invasive.

Prognostic factors for lung transplant recipients focusing on age and gender: the Japanese lung transplantation report 2022.

PURPOSE: To clarify the impact of donor and recipient characteristics on the survival of recipients before and after lung transplantation in the Japanese population. METHODS: Patients' data were collected for retrospective analysis from all authorized lung transplant centers in Japan. We included 1963 patients listed for lung transplantation by the end of December 2021, comprised of 658 deceased-donor and 270 living-donor lung transplants. RESULTS: Primary disease had a significant impact on the mortality of patients waiting for transplantation. The indications for transplant significantly affected the post-transplant survival rate of deceased-donor lung transplant recipients. The recipient's age also significantly affected the post-transplant survival rate of the deceased-donor and living-donor lung transplant recipients. The recipients of grafts transplanted from donors aged 61 years or older showed a worse post-transplant survival rate (≧60 years old). The survival rate for the combination of a female donor to a male recipient among the deceased-donor lung transplant recipients was the worst among the four combinations. CONCLUSION: The donor and recipient characteristics significantly impacted the survival of recipients after lung transplantation. The underlying mechanism of the negative impact of the gender mismatch of female donor to male recipient on post-transplant survival needs to be investigated further.

[Hemothorax].

Hemothorax is defined as blood accumulation in the pleural cavity with a hematocrit value of the effusion exceeding 50%. Symptoms and severity vary, ranging from asymptomatic to an imminent state of threatened cardiac arrest. This paper presents the etiology, initial work-up, and treatment of hemothorax, with an emphasis on massive hemothorax requiring an emergent thoracotomy for hemostasis. The etiology of hemothorax can be traumatic, iatrogenic, and non-traumatic/non-iatrogenic. Regardless of the etiology, the initial medical examination should be performed as in the initial trauma examination to evaluate the urgency, the amount of bleeding in the chest cavity, and the coexistence of pneumothorax. If massive hemothorax or tension pneumothorax is present, thoracic tube drainage should be started immediately. Contrast-enhanced computed tomography (CT) should be performed to identify the source of bleeding. Treatment includes fluid and blood transfusions to stabilize the circulation. Anticoagulants and antiplatelet agents should be neutralized, reduced, or withdrawn. Emergent thoracotomy for hemostasis is indicated for massive hemothorax with unstable circulation. Anterior-parasternal thoracotomy performed in the supine position has the advantage of rapid thoracotomy and good visualization. Endovascular therapy is effective when contrast-enhanced CT identifies the source of bleeding.

Left-to-right rotated single lung transplant.

We successfully performed left-to-right rotated single lung transplants in 2 patients. For this procedure, the left pulmonary artery of the donor undergoes a U-shaped turn with A3 at the bottom to anastomose with the recipient's right pulmonary artery in front of the bronchus. It is extremely important to avoid kinking the pulmonary artery at the site of the U-shaped turn.

[Lung Transplantation at a Low Volume Center].

The number of lung transplantation performed in Japan is extremely low compared to other countries, whereas we have 10 facilities certified as cadaveric lung transplantation in Japan, meaning that there are low volume centers. By August 2021, we performed lung transplantation in 21 cases for 12 years, therefore, our facility should be considered as low volume center. Surgical outcomes at low volume centers are generally considered poor. However, the overall five-year survival rate of total cases was 84.8%, and that of cadaveric cases was 94.4% in our hospital. It was better than the average of about 73% of all facilities in Japan. These data suggested that the accreditation system in Japan is functioning well. On the other hand, there may be a disparity between facilities. At our facility, we are actively performing inverted lung transplantation so as not to lose the opportunity for transplantation, and we have performed it in three cases so far and have achieved good results.

Current status of inhaled nitric oxide therapy for lung transplantation in Japan: a nationwide survey.

OBJECTIVES: Currently, inhaled nitric oxide (NO) therapy for lung transplantation is not covered by public health insurance in Japan. In this study, we evaluated the perioperative use and safety of inhaled NO therapy for lung transplantation. METHODS: Data regarding the duration of treatment and adverse events of inhaled NO therapy were collected for all lung transplantations performed from January 1, 2015, to December 31, 2019, at nine lung transplant facilities in Japan. RESULTS: During the study period, lung transplants were performed in 357 patients, among whom inhaled NO therapy was administered to 349 patients (98%). The median initial and median maximum inhaled NO doses were 10 and 20 ppm, respectively. Inhaled NO therapy was introduced during surgery and continued postoperatively in 313 patients (90%) for a median of 4 days. Significant improvements in oxygenation and decreases in pulmonary arterial pressure were observed in patients receiving inhaled NO therapy. Side effects of inhaled NO therapy, such as methemoglobinemia, were observed in 15 patients (4%), with a significant incidence in patients aged < 18 years. CONCLUSIONS: Inhaled NO therapy was performed in almost all patients who underwent lung transplantation in Japan and showed reasonable efficacy. Therefore, public health insurance coverage for inhaled NO therapy during lung transplantation is recommended.

Inflammatory Risk Factors for Early Recurrence of Non-Small Cell Lung Cancer Within One Year Following Curative Resection.

BACKGROUND: Several inflammation-based scoring systems and nutritional indicators have been shown to have relevance to survival of patients with non-small cell lung cancer (NSCLC).The present study examined preoperative and pathological factors in patients who underwent curative resection for non-small cell lung cancer, with the aim to elucidate risk factors for early recurrence within 1 year of surgery. METHODS: Patients with NSCLC who underwent surgery from January 2009 to December 2014 were retrospectively investigated. Routine laboratory measurements including carcinoembryonic antigen were performed before surgery, and pathological information was collected after surgery. Patients with recurrence within 1 year after surgery were considered as early recurrence group (ERG), those with recurrence after 1 year were as late recurrence group (LRG), and those without recurrence were as no recurrence group (NRG). RESULTS: Multivariate analysis between ERG and LRG revealed Glasgow prognostic score (GPS) and CRP-to-albumin ratio (CAR) as independent risk factors for early recurrence. Multivariate analysis between ERG and LRG + NRG confirmed CAR, vascular invasion, and pathological stage as risk factors for early recurrence. CONCLUSION: These findings indicated that CAR and GPS were confirmed to be risk factors for early recurrence, in addition to pathological factors.

[Surgical Treatment for Apical Invading Lung Cancer].

The apical invading lung cancer is the tumor infiltrating to the thoracic inlet, in other words, the 1st rib or the higher chest wall. Tumor arising in the posterior apex is invasive to the vertebral body, the sympathetic trunk, and the brachial plexus. Pancoast tumor is well known with typical triads, which is invasive to the sympathetic trunk and the brachial plexus in the posterior apex of the lung. Tumors originating in the anterior apex are called anterior apical tumors, and they often involve the subclavian vein and artery. Trimodality therapy is recommended to treat the apical invading lung cancer. Induction chemoradiotherapy followed by surgical resection lead to good local control and complete resection rate. Surgical approach should be selected based on the tumor location in the extreme apex. High posterolateral approach and hook approach are chosen for the tumor in the posterior apex. Anterior approaches developed by Masaoka, Dartevelle, Grunenwald, and Korst are suitable for the tumor in the anterior apex that are often invasive to the subclavian vessels. Surgical outcome depends on completeness of resection. Based on the preoperative evaluation of involved structures, appropriate surgical approach is important to achieve complete resection of the apical invading lung cancer.

Advanced Lung Cancer Inflammation Index Predicts Outcomes of Patients with Pathological Stage IA Lung Adenocarcinoma Following Surgical Resection.

PURPOSE: The correlation of advanced cancer with inflammation and/or nutrition factors is well known. Recently, the advanced lung cancer inflammation index (ALI) was developed as a new prognostic tool for patients with advanced lung cancer. In this study, we examined whether ALI results are correlated with prognosis of patients with early stage lung adenocarcinoma who undergo lung resection. METHODS: From January 2009 to December 2014, 544 patients underwent lung resection due to primary lung cancer at Dokkyo Medical University Hospital, of whom 166 with pathological stage IA lung adenocarcinoma were retrospectively investigated in this study. ALI was calculated as follows: Body Mass Index (BMI; kg/m2) × albumin (g/dL)/neutrophil-to-lymphocyte ratio (NLR). RESULTS: Multivariate analysis revealed that gender, red cell distribution width (RDW), NLR, and ALI were parameters significantly correlated with overall survival (OS). Patients with an ALI value less than 22.2 had an inferior 5-year OS rate as compared to those with a value of 22.2 or higher (p <0.001) as well as an inferior 5-year recurrence-free survival (RFS) rate (p <0.001). CONCLUSION: Low ALI was correlated with poor prognosis in patients with stage IA lung adenocarcinoma. Those with an ALI value less than 22.2 should be carefully followed regardless of cancer stage.

Impact of tumor infiltrating lymphocytes and lymphoid follicle formation on patient survival following surgery for lung squamous cell carcinoma.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are known to correlate with the prognosis of patients affected by a variety of cancer types. We evaluated TILs in patients who underwent surgery for lung squamous cell carcinoma (SCC). METHODS: Specimens obtained from patients during resection of lung SCC were examined for TIL density, lymphoid follicle formation, PD-L1 expression, and the appearance of regulatory T cells (Tregs). RESULTS: We enrolled 72 patients who underwent surgery for SCC (TIL grades 0, 1, and 2: 29, 18, and 25, respectively). Lymphoid follicles were observed in 13 (18.1%) patients and 8 were positive for Tregs, which were always observed in association with lymphoid follicles (P < 0.001). Multivariate analysis revealed that lymphoid follicle formation, the appearance of Tregs, pathological stage, and pleural invasion were independent prognostic factors related to overall survival, whereas TIL density and PD-L1 expression were not. CONCLUSION: SCC patients with lymphoid follicle formation accompanied by Tregs show poor survival following lung resection surgery.

L-Type Amino Acid Transporter 1 Immunoreactivity as a Possible Diagnostic and Prognostic Marker of Thymic Carcinoma.

L-type amino acid transporter 1 (LAT1) functions to transport large neutral amino acids, such as leucine, isoleucine, valine, phenylalanine, tyrosine, tryptophan, methionine, and histidine. These amino acids are essential for cell growth and proliferation. Many studies have demonstrated LAT1 expression in various types of cancer, and its high expression level was associated with poor prognosis. However, the significance of LAT1 expression in thymic epithelial tumors is controversial. We conducted this retrospective study to investigate the LAT1 immunoreactivity in thymic epithelial tumors and its impact on prognosis. We analyzed 32 patients with thymoma and 14 patients with thymic carcinoma who underwent surgery at our institute. Immunohistochemical analysis was performed using formalin-fixed paraffin-embedded surgical tissues and an anti-LAT1 polyclonal antibody. We thus found that LAT1 immunoreactivity was undetectable in all of the thymoma specimens, regardless of the subtypes of thymoma. By contrast, LAT1 immunoreactivity was consistently detected in the cytosol of thymic carcinoma cells; namely, all 14 thymic carcinoma specimens demonstrated LAT1 immunoreactivity in the cytosol. Among these 14 thymic carcinoma specimens, four carcinoma specimens also showed LAT1 immunoreactivity in the cell membrane. Survival analysis indicated that the thymic carcinoma with the LAT1 membrane signal was associated with poor prognosis, compared with the specimens with the LAT1 cytosol signal. We therefore propose that LAT1 is expressed in the cytosol of thymic carcinoma cells, which could be a diagnostic marker of thymic carcinoma. Moreover, LAT1 expression in the cell membrane is a prognostic marker of thymic carcinoma.

Nontuberculous mycobacterial and Aspergillus infections among cadaveric lung transplant recipients in Japan.

BACKGROUND: Lung transplantation is an effective treatment modality for respiratory failure. Chronic lung infections, including infections caused by nontuberculous mycobacteria (NTM) and Aspergillus, are difficult to control, and uncontrolled infections are relative contraindications for lung transplantation. However, few reports have documented the incidence and outcome of these infections in lung transplant recipients. METHODS: To quantify the incidence and outcomes of colonization and disease caused by NTM and aspergillosis in recipients before and after lung transplantation, we reviewed the medical records and microbiology data from 240 consecutive cadaveric lung transplant recipients between 2000 and 2014. RESULTS: Before lung transplantation, NTM and Aspergillus species were isolated from five (2.1%) and six (2.5%) patients, respectively, out of the total 240 recipients. All patients with NTM infection received treatment, resulting in culture conversion. They had no recurrence after lung transplantation. All patients with aspergillosis received treatment, one of whom had recurrence after lung transplantation. Over a median follow-up period of 3.3 years, NTM species were isolated after transplantation from eight of 240 patients (3.3%). Five of these patients met the criteria for NTM disease, and four of them received treatment. Four patients survived without a worsening of NTM disease. Over the same median follow-up period, Aspergillus species were isolated from seven of 240 patients (2.9%), six of whom received treatment. CONCLUSIONS: Isolation of NTM or Aspergillus species from lung transplant recipients is uncommon. Adequate pre-transplant control and post-transplant management of NTM and Aspergillus infections allows for safe lung transplantation.

Mitosis count and number of cancer cells in cases of primary pulmonary adenocarcinoma: Correlations among phosphorylated histone 3, number of cancer cells, nuclear grade, pathologic features and prognosis.

Immunohistochemistry findings for the phosphorylated form of histone 3 (pHH3) have been shown to be a reliable mitosis-specific marker. We evaluated the correlation between pHH3-stained mitotic figures (PHMFs) and clinical outcome, and compared the results with findings for numbers of PHMFs and cancer cells. The primary tumor was obtained from 113 patients with pulmonary adenocarcinomas (≤2 cm maximum dimension). All specimens were stained with pHH3, then the number of cancer cells in each was determined. Cases with a cancer-cell index ≥1000 showed worse recurrence-free survival as compared to those with a value <1000 (P < 0.001). Also, cases with a pHH3 index ≥0.27 showed worse recurrence-free survival as compared to <0.27 (P = 0.001) and cases with a pHH3/cancer-cell index ≥0.001 showed worse recurrence-free survival as compared to <0.001 (P = 0.002). Multivariate analysis demonstrated that pHH3/cancer-cell index was significantly correlated with prognosis, but not Ki-67 index. The number of cancer cells was also strongly correlated with progression of Noguchi's classification and WHO pathologic type. pHH3/cancer-cell index was correlated with prognosis, and those were useful for prognostic evaluation of pulmonary adenocarcinoma patients. Furthermore, cancer cell number was correlated with Noguchi's classification and WHO pathologic type.

Inflammation-Based Prognostic Score Predicts Postoperative Survival of Patients with Interstitial Pneumonia After Undergoing Lung Cancer Resection.

OBJECTIVES: Idiopathic interstitial pneumonias (IIPs) are associated with an increased risk of lung cancer. Glasgow prognostic score (GPS), which uses serum C-reactive protein (CRP) and albumin levels to indicate systemic inflammatory response and nutrition level, has been reported to be a predictor of overall survival in patients with various types of cancer. We evaluated the usefulness of GPS for prediction of survival of patients with both lung cancer and IIPs following a lung resection procedure. METHODS: Patients with IIPs who underwent lung cancer resection from January 2006 through December 2015 were investigated. Routine laboratory measurements, including serum CRP and albumin for determining GPS, were performed before the operation. Univariate and multivariate analyses with a COX proportional hazards regression model were used to identify independent risk factors for overall survival (OS), relapse-free survival (RFS), cancer-specific survival (CSS), and other disease-specific survival (ODSS). RESULTS: A total of 135 patients underwent lung resection during the study period. Multivariate analysis selected sublobar resection (p = 0.035), UIP pattern (p = 0.025), and GPS of 1-2 (p = 0.042) as predictive factors associated with OS, while GPS of 1-2 (p = 0.039) was shown to be a predictive factor associated with RFS. Multivariate analysis also revealed pTNM (p < 0.001), usual interstitial pneumonia pattern (p = 0.006), and GPS of 2 (p = 0.003) as predictive factors associated with CSS, while univariate analysis indicated pTNM (p = 0.042), GPS of 1 (p = 0.044), and %DLCO (p = 0.038) as predictive factors associated with ODSS. CONCLUSION: GPS is an independent prognostic factor of OS and RFS in lung cancer patients with IIPs undergoing a lung resection procedure. Furthermore, a GPS of 2 was found to be associated with CSS following lung cancer resection, while a score of 1 was associated with ODSS.