Survival after surgery for lung cancer among patients with autoimmune diseases.

PURPOSE: While patients with autoimmune diseases (ADs) are at high risk for developing specific malignancies, including lung cancer, ADs may protect against the development of cancer through increased immune cell activity in tumors. This study aimed to investigate whether the presence of ADs affects surgical outcomes and survival after surgery for lung cancer. METHODS: The medical records of 1236 patients who underwent surgery for non-small cell lung cancer between 2007 and 2018 were retrospectively reviewed. Perioperative and long-term outcomes were compared between patients with and without ADs using propensity score matching. RESULTS: Among the included patients, 115 with ADs and 1121 without ADs underwent surgery. Using 1-to-1 propensity score matching, 114 pairs were selected. Although there were no significant differences in the perioperative outcomes of the two groups, the overall and relapse-free survival rates were significantly lower in the group with ADs than in the group without ADs. CONCLUSIONS: Surgery for lung cancer can be performed without increasing the complications in patients with ADs. However, the long-term outcomes were significantly worse in patients with ADs than in those without ADs, suggesting that close follow-up for lung cancer and careful whole-body examination might be needed for patients with ADs.

[Development of Virtual-assisted Lung Mapping].

The Japan Clinical Oncology Group (JCOG) 0802/West Japan Oncology Group (WJOG) 4607L trial has recently reported that in small lung cancer, segmentectomy has a higher overall survival rate than lobectomy, increasing the significance of sublobar resection. However, local recurrence is a major concern after sublobar resection, and an insufficient surgical margin is a significant risk factor for locoregional recurrence. Therefore, since 2014, we have performed virtual-assisted lung mapping (VALMAP), a preoperative bronchoscopic multiple-spot dye-marking technique, using indigo carmine as a preoperative localization technique to identify hardly detectable pulmonary nodules and confirm the adequacy of the surgical margin. However, conventional VAL-MAP (VAL-MAP 1.0) faced some chal-lenges. One issue is that approximately 10% marks were invisible and unidentifiable due to patient factors or technical issues. Another problem was that, in some cases requiring large resection depth, VAL-MAP did not lead to successful resection with adequate surgical margin. Thus, we have invented several novel techniques to solve these issues. VAL-MAP dual staining is a technique using indocyanine green (ICG) as well as indigo carmine that has improved the success rate of marking detection during surgery without causing additional complications. VAL-MAP 2.0 is a proximal mapping technique that involves the use of a coil, enabling three-dimensional mapping and making sublobar resection more accurate, particularly for a deeply located tumor.

Effect of intraoperative needle biopsy on the survival of nonsmall cell lung cancer patients: a propensity score matching analysis.

PURPOSE: It is unknown whether intraoperative needle biopsy (INB) predisposes to the postoperative recurrence of lung cancer and compromises the prognosis of these patients. We conducted this study to identify the effect of INB before lobectomy on the postoperative recurrence rate and prognosis of patients with nonsmall cell lung cancer (NSCLC). METHODS: The subjects of this retrospective study were 953 patients with pathological stage I-III NSCLC who underwent lobectomy between 2001 and 2016. The patients were divided into two groups: the INB group (n = 94) and the non-INB group (n = 859). After propensity score matching (PSM), we compared the postoperative cumulative recurrence rate, recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS) between the two groups. RESULTS: After PSM, 94 patient pairs were matched. The cumulative recurrence rate was significantly higher in the INB group than in the non-INB group (P = 0.01). The 5-year RFS rate was significantly lower in the INB group than in non-INB group (48% vs 68%), as were the 5-year DSS (76% vs 92%) and 5-year OS rates (67% vs 84%) (all P < 0.05). CONCLUSIONS: The findings of this analysis suggest that INB before lobectomy may increase the cumulative recurrence rate and worsen the prognosis of patients with resectable NSCLC. Thus, we believe that INB should be avoided unless a lung lesion cannot be diagnosed by another type of biopsy.

Dietary Fructooligosaccharides Reduce Mercury Levels in the Brain of Mice Exposed to Methylmercury.

Methylmercury (MeHg) exposure during pregnancy is a concern because of its potential health risks to fetuses. Intestinal microbiota has important roles in the decomposition and fecal excretion of MeHg. We investigated the effect of nondigestible saccharides on the accumulation and excretion of Hg after MeHg exposure. Female BALB/cByJ mice were fed a basal diet or the same diet supplemented with 5% fructooligosaccharides (FOS) or 2.5% glucomannan. Six weeks after feeding, mice were administered MeHg chloride (4 mg Hg/kg, per os (p.o.)), and urine and feces were collected for 28 d. FOS-fed mice had lower total Hg levels in all tissues (including the brain) compared with that of controls. The glucomannan diet had no effect on tissue Hg levels. No differences in tissue concentrations of inorganic Hg among groups were found. Fecal Hg excretion was markedly higher in FOS-fed mice than that in controls, but urinary Hg excretion was similar. FOS-fed mice had a higher proportion of inorganic Hg in feces than that of controls, with a significant increase in fecal Hg excretion. Analysis of fecal bacterial population showed the relative abundance of Bacteroides in FOS-fed mice to be higher than that in controls. The results suggest that FOS enhanced fecal Hg excretion and decreased tissue Hg levels after MeHg administration, possibly by accelerating MeHg demethylation by intestinal bacteria (the candidate genus Bacteroides). This demethylation also reduces MeHg absorption in the large intestine. In conclusion, daily FOS intake may decrease tissue Hg levels in animals and humans exposed to MeHg.

Comprehensive assay for the molecular profiling of cancer by target enrichment from formalin-fixed paraffin-embedded specimens.

Tumor molecular profiling is becoming a standard of care for patients with cancer, but the optimal platform for cancer sequencing remains undetermined. We established a comprehensive assay, the Todai OncoPanel (TOP), which consists of DNA and RNA hybridization capture-based next-generation sequencing panels. A novel method for target enrichment, named the junction capture method, was developed for the RNA panel to accurately and cost-effectively detect 365 fusion genes as well as aberrantly spliced transcripts. The TOP RNA panel can also measure the expression profiles of an additional 109 genes. The TOP DNA panel was developed to detect single nucleotide variants and insertions/deletions for 464 genes, to calculate tumor mutation burden and microsatellite instability status, and to infer chromosomal copy number. Clinically relevant somatic mutations were identified in 32.2% (59/183) of patients by prospective TOP testing, signifying the clinical utility of TOP for providing personalized medicine to cancer patients.

[A Surgical Case of Intrapulmonary Bronchogenic Cyst Treated by Left Lower Lobectomy for Hemopneumothorax and Repeated Hemoptysis].

A 79-year-old female visited a hospital because of high fever and computed tomography(CT)showed a cystic lesion with fluid accumulation in her left lung. She had hemoptysis and left chest pain 3 days after antibiotic therapy was started. Chest CT demonstrated the cystic lesion rupturing and causing hemopneumothorax. Then she was referred to our department and thoracic drainage was performed. However, a week after the drainage, she had hemoptysis and chest pain again, and the left lower lobectomy was performed. Histopathological findings showed the cystic lesion was intrapulmonary bronchogenic cyst. We describe a rare case of the hemopneumothorax due to the hemorrhage in the bronchogenic cyst.

Baseline lung allograft dysfunction after bilateral deceased-donor lung transplantation: A single-center experience in Japan.

BACKGROUND: Baseline lung allograft dysfunction (BLAD) refers to a condition in which a lung transplant recipient does not achieve normal pulmonary function (i.e., forced expiratory volume in 1 s or forced vital capacity of <80% of predicted values). Although BLAD is reportedly associated with a poor prognosis, the condition has not been examined in Japanese patients. METHODS: In this study, we retrospectively examined 38 Japanese adults who underwent bilateral lung transplantation from 2015 to 2022 in a single center. RESULTS: Twenty-one (55%) patients met the criteria for BLAD. No significant differences were found in recipient or donor factors between the BLAD and non-BLAD groups, but the donor-recipient ratio of the predicted vital capacity was lower in the BLAD group (p = 0.009). The intensive care unit length of stay, ventilator duration, and blood loss during transplant surgery were significantly higher in the BLAD group (p < 0.05). No significant difference was found in survival. The median observation period was significantly shorter in the BLAD than non-BLAD group (744 vs.1192 days, respectively; p = 0.031). The time to reach the normal threshold of pulmonary function after lung transplantation varied among the patients, ranging from 6 months to 4 years. CONCLUSIONS: The characteristics of these Japanese patients with BLAD were similar to those of other patients in previous reports. The effects of the observation period and donor-recipient age discrepancy on BLAD require further exploration.

Impact of surgical margin after sublobar resection of lung cancer: a narrative review.

Background and Objective: The use of low-dose computed tomography for screening has improved the detection of early-stage lung cancers. In addition, two large clinical studies have recently reported good outcomes of sublobar resection for early-stage lung cancers, increasing the need for limited resection. However, locoregional recurrence is an important issue in sublobar resection, and R0-resection with sufficient surgical margin is essential to prevent recurrences. This study aimed to investigate the suitable surgical margin distance after sublobar resection of lung cancers with a review of the literature. Methods: We used the PubMed interface to search the Medline database for retrieving literature related to surgical margin after sublobar resection published between 2003 and 2023. Key Content and Findings: Overall, 175 papers were found; of them, we investigated the outcomes of 18 selected papers. The correlation between the actual surgical margin distances and recurrences was evaluated in seven articles. All the articles, except one, indicated that an increased margin distance was associated with survival and a lower risk of locoregional recurrence. Further, a surgical margin of 9-15 mm was reported to be sufficient. The correlation between the margin-tumor ratio (M/T) and recurrences was investigated in six articles, most of which demonstrated that the ratio of <1 would be a remarkable predictor of recurrence or poor survival. Although the correlation between surgical margin and spread through air spaces (STAS) was discussed in four articles, their findings remain debatable. Conclusions: A surgical margin of >10 mm or M/T of ≥1 would be necessary for sublobar resection for STAS-negative early-stage non-small cell lung cancer, although it is difficult to draw a definite conclusion about the appropriate surgical margin because of the characteristics of available literature (mainly retrospective, with different inclusion criteria and surgical margin measurement methods).

Ten-Year Outcome and Development of Virtual-Assisted Lung Mapping in Thoracic Surgery.

Virtual-assisted lung mapping (VAL-MAP) is a preoperative bronchoscopic multispot dye-marking technique used in sublobar lung resection of barely palpable lung nodules. This review summarizes the history and outcomes of the VAL-MAP procedure. VAL-MAP was developed in 2012, and long-term outcomes of lung resection using VAL-MAP have recently been verified. Problems associated with conventional VAL-MAP include a prerequisite of post-mapping computed tomography (CT), occasional inability to see dye marks during surgery, and infrequent resection failure due to deep resection margins; various techniques have been developed to address these issues. VAL-MAP using electromagnetic navigation bronchoscopy with on-site adjustment can omit post-mapping CT. The use of indocyanine green in VAL-MAP has increased the success rate of marking detection during surgery without causing additional complications. VAL-MAP 2.0-a three-dimensional mapping technique that involves the intrabronchial placement of a microcoil-has increased the accuracy of sublobar resection, particularly for deeply located tumors. Although these promising new techniques have some limitations, they are beneficial for sublobar lung resection.

Fissureless technique of robotic left lingular segmentectomy for primary lung cancer with incomplete fissure: a case report.

BACKGROUND: Pulmonary segmentectomy for a lung with an incomplete interlobar fissure may complicate persistent air leakage. The fissureless technique is often used in lobectomy to prevent persistent air leakage. We herein describe successful use of the fissureless technique for segmentectomy with the aid of a robotic surgical system. CASE PRESENTATION: A 63-year-old man was clinically diagnosed with early-stage lung cancer for which lingular segmentectomy was indicated. A preoperative image revealed a lung with an incomplete fissure. Based on three-dimensional reconstruction imaging, we planned to divide the hilum structures in the order of the pulmonary vein, bronchus, and pulmonary artery and finally resect the lung parenchyma by dividing the intersegmental plane and interlobar fissure. This fissureless technique was successfully conducted using a robotic surgical system. The patient did not develop persistent air leakage and was alive without recurrence 1 year after segmentectomy. CONCLUSIONS: The fissureless technique may be a useful option in segmentectomy for a lung with an incomplete interlobar fissure.

Successful step-by-step diagnosis and management of expiratory central airway collapse.

A 45-year-old woman with recurrent dyspnea for 40 years was previously diagnosed with bronchial asthma and spasmodic dysphonia. On admission, the patient was diagnosed with expiratory central airway collapse (ECAC) due to expiratory dynamic airway collapse based on radiographic examination, chest computed tomography, and bronchoscopy. After continuous positive airway pressure and temporal airway stenting, surgical tracheobronchoplasty and tracheal membranous portion reinforcement using polypropylene mesh successfully relieved the respiratory symptoms. In patients with airway obstructive disease refractory to conventional therapies, ECAC should be considered.

Number of dye marks required in virtual-assisted lung mapping.

OBJECTIVES: Virtual-assisted lung mapping is a preoperative bronchoscopic multi-spot dye-marking technique used in sublobar lung resection for hardly palpable lung nodules. However, the number of marks required per nodule remains unknown. Therefore, we examined the correlation between the number of intraoperative visible marks and the successful resection rate. METHODS: We retrospectively examined 210 consecutive patients with 256 lesions who underwent virtual-assisted lung mapping during January 2014-December 2020 at our hospital. When a nodule was not resected at the initial attempt, or when a nodule was very close to the cut margin in the resected specimen and required additional resection, we categorized it as unsuccessful resection. We divided 256 lesions into successful and unsuccessful groups and compared the numbers of intraoperative visible marks between the two groups. RESULTS: Of 797 attempted marks, 738 (92.4%) were visible during the surgery. Fourteen (5.4%) of 256 lesions were determined to be unsuccessful according to the study criteria. There was a remarkable difference in the average numbers of intraoperative visible marks between both groups (3 [interquartile range: 2-4] vs. 2 [interquartile range: 1-2.8]; p < 0.01). Multivariable logistic analysis revealed a significant difference in the number of intraoperative visible marks (odds ratio: 0.28, 95% confidence interval: 0.14-0.57; p < 0.001) between both groups. CONCLUSIONS: Successful sublobar lung resection requires three or more intraoperative visible marks established using virtual-assisted lung mapping per lung nodule.

Virtual-assisted lung mapping using dual staining with indocyanine green and indigo carmine enhanced marking detectability.

Background: Virtual-assisted lung mapping (VAL-MAP) is a preoperative bronchoscopic multispot dye-marking procedure to facilitate sublobar lung resection for unidentifiable lung nodules. To increase detectable markings, we performed VAL-MAP using dual staining (VAL-MAP DS) with indocyanine green (ICG) and indigo carmine. This study was designed to evaluate the efficacy and safety of the modified technique. Methods: We retrospectively reviewed the records of patients who underwent VAL-MAP DS. Twenty patients with 27 lesions underwent 72 VAL-MAP DS markings. We investigated the overall detectable marking rate, visible marking rate, successful resection rate, and complications. Results: The overall detectable marking rate, thanks to both ICG and indigo carmine, tended to be higher than the indigo carmine visible marking rate (95.7% vs. 85.5%, P=0.08). The successful resection rate with sufficient margins was 92.0%. There were no adverse events related to the use of ICG. ICG markings of the lungs of patients with a history of smoking more than 50 pack-years tended to be visible, but the staining was too extensive compared with the staining in patients who smoked less or not at all (58.8% vs. 0.0%, P<0.001). Conclusions: VAL-MAP DS is likely be efficacious and safe in enhancing the detectability of markings. This bronchoscopic technique should be considered as one of the optimal preoperative marking methods in thoracic surgery.

Successful transcatheter arterial embolization for a massive hemothorax caused by acupuncture.

Acupuncture is an alternative treatment for a variety of diseases, and serious complications are rare. We report a case of transcatheter arterial embolization performed in a patient with a massive hemothorax after acupuncture treatment. A 36-year-old woman with no previous medical history was admitted to our hospital with left back pain and respiratory distress after acupuncture treatment. Contrast-enhanced computed tomography showed a left hemothorax and leakage of contrast medium, which was considered to result from an injury to the second intercostal artery, caused by acupuncture treatment. Transcatheter arterial embolization successfully stopped the bleeding, and the hematoma was thoracoscopically removed. No rebleeding was observed 6 months after treatment.

Rapid imaging of lung cancer using a red fluorescent probe to detect dipeptidyl peptidase 4 and puromycin-sensitive aminopeptidase activities.

Rapid identification of lung-cancer micro-lesions is becoming increasingly important to improve the outcome of surgery by accurately defining the tumor/normal tissue margins and detecting tiny tumors, especially for patients with low lung function and early-stage cancer. The purpose of this study is to select and validate the best red fluorescent probe for rapid diagnosis of lung cancer by screening a library of 400 red fluorescent probes based on 2-methyl silicon rhodamine (2MeSiR) as the fluorescent scaffold, as well as to identify the target enzymes that activate the selected probe, and to confirm their expression in cancer cells. The selected probe, glutamine-alanine-2-methyl silicon rhodamine (QA-2MeSiR), showed 96.3% sensitivity and 85.2% specificity for visualization of lung cancer in surgically resected specimens within 10 min. In order to further reduce the background fluorescence while retaining the same side-chain structure, we modified QA-2MeSiR to obtain glutamine-alanine-2-methoxy silicon rhodamine (QA-2OMeSiR). This probe rapidly visualized even borderline lesions. Dipeptidyl peptidase 4 and puromycin-sensitive aminopeptidase were identified as enzymes mediating the cleavage and consequent fluorescence activation of QA-2OMeSiR, and it was confirmed that both enzymes are expressed in lung cancer. QA-2OMeSiR is a promising candidate for clinical application.

Outcomes of Video-Assisted Thoracic Surgical Lung Biopsy for Interstitial Lung Diseases.

PURPOSE: Surgical lung biopsy (SLB) is an important diagnostic tool for interstitial lung disease (ILD), yet the risk factors for SLB are still debatable and long-term outcomes remain unknown. METHODS: We retrospectively reviewed the records of 85 consecutive patients with ILD who underwent SLB by video-assisted thoracic surgery (VATS) from 2008 to 2019. Risk factors for complications and differences of outcomes between idiopathic pulmonary fibrosis (IPF) and other ILDs were examined. RESULTS: All patients who underwent VATS had no mortality or acute exacerbation of ILD within 90 days of SLB. The rate of complication was 9.4%, and there were no statistically significant risk factors for complications. While the IPF group was not significantly different from the non-IPF group with regard to surgical parameters or complications, patients with IPF had significantly higher rates of mortality (50% vs. 9% in 5 years; p <0.001) and readmission due to acute exacerbation (75% vs. 8% in 5 years; p <0.001). CONCLUSION: VATS lung biopsy for ILD can be a safe approach regardless of underlying phenotypes. An accurate diagnosis of IPF via SLB may be beneficial for correct patient management.

Comprehensive molecular profiling of pulmonary pleomorphic carcinoma.

Information regarding the molecular features of pulmonary pleomorphic carcinoma (PPC) is insufficient. Here, we performed next-generation sequencing to determine the genomic and transcriptomic profiles of PPC. We sequenced the DNAs and RNAs of 78 specimens from 52 patients with PPC. We analyzed 15 PPC cases to identify intratumoral differences in gene alterations, tumor mutation burden (TMB), RNA expression, and PD-L1 expression between epithelial and sarcomatoid components. The genomic alterations of six cases of primary tumors and corresponding metastatic tumors were analyzed. KRAS mutations (27%) were the most common driver mutations, followed by EGFR (8%), and MET (8%) mutations. Epithelial and sarcomatoid components shared activating driver mutations, and there were no significant differences in CD274 expression or TMB between the two components. However, PD-L1 was highly expressed in the sarcomatoid component of several cases compared with the epithelial component. Primary and metastatic tumors shared oncogenic mutations among genes such as KRAS and TP53, and additional alterations including NOTCH4 mutations were specifically identified in the metastatic regions. Our data suggest that therapies targeting activating driver mutations may be effective for patients with PPC and that immune checkpoint inhibitors of PPC may be recommended after careful assessment of PD-L1 expression in each epithelial and sarcomatoid component.

Identification of Novel CD74-NRG2α Fusion From Comprehensive Profiling of Lung Adenocarcinoma in Japanese Never or Light Smokers.

INTRODUCTION: Studies are yet to characterize the differences in molecular profiles of lung adenocarcinoma (LUAD) among divergent ethnic groups. Herein, we conducted comprehensive molecular profiling of LUAD in never or light smokers from Asia to discover novel targetable mutations and prognostic biomarkers of this distinct disease entity. METHODS: We analyzed 996 cases of Japanese LUAD and performed whole-exome sequencing and RNA-seq in 125 cases of Japanese LUAD negative for the driver oncogenes defined by conventional laboratory testing. We also investigated the clinical and pathologic characteristics among the 996 cases. RESULTS: Driver oncogenes were identified in 88 cases (70.4%) with specific hotspot mutations differing from those in The Cancer Genome Atlas study. Two actionable novel fusions of FGFR2 and NRG2α were also identified. Clustering on the basis of mRNA expression profiles, but not genetic mutational ones, could predict patient prognosis. The risk score generated by the expression of a three-gene set was a strong prognostic marker for overall survival and progression-free survival in our cohort, and was further validated using The Cancer Genome Atlas cohort. Among the 996 cases, each driver alteration is distributed across all histologic subtypes. Adenocarcinoma in situ was identified to harbor driver mutations, suggesting that these alterations are early events in the pathogenesis of LUAD. ERBB2 mutations were over-represented in young adults. CONCLUSIONS: This study indicates the value of applying gene expression profiling for predicting the prognosis after a surgical operation, and that the identification of actionable mutations is important for optimizing targeted drugs in Japanese LUAD.

Strain difference of cadmium-induced testicular toxicity in inbred Wistar-Imamichi and Fischer 344 rats.

Previously, we reported that Wistar-Imamichi (WI) rats are highly resistant to cadmium (Cd)-induced lethality and hepatotoxicity compared to Fischer 344 (F344) rats. Since the testes are one of the most sensitive organs to acute Cd toxicity, we examined possible strain-related differences in Cd-induced testicular toxicity between inbred WI and F344 rats. Rats were treated with a single dose of 0.5, 1.0 or 2.0 mg Cd/kg, as CdCl(2), sc and killed 24 h later. Cd at doses of 1.0 and 2.0 mg/kg induced severe testicular hemorrhage, as assessed by pathological and testis hemoglobin content, in F344 rats, but not WI rats. After Cd treatment (2.0 mg/kg), the testicular Cd content was significantly lower in WI rats than in the F344 rats, indicating a toxiokinetic mechanism for the observed strain difference. Thus, the remarkable resistance to Cd-induced testicular toxicity in WI rats is associated, at least in part, with lower testicular accumulation of Cd. When zinc (Zn; 10 mg/kg, sc) was administered in combination with Cd (2.0 mg/kg) to F344 rats, the Cd-induced increase in testicular hemoglobin content, indicative of hemorrhage, was significantly reduced. Similarly, the testicular Cd content was significantly decreased with Zn co-treatment compared to Cd treatment alone. Thus, it can be concluded that the testicular Cd accumulation partly competes with Zn transport systems and that these systems may play an important role in the strain-related differences in Cd-induced testicular toxicity between WI and F344 rats.