With the identification of novel driver genes and development of molecular-targeted drugs, advances in genomic testing and treatment strategies for non-small-cell lung cancer (NSCLC) are ongoing. Since the advent of genomic testing to detect driver gene abnormalities for patients with advanced or recurrent NSCLC being considered for drug therapy, thoracic surgeons have had few opportunities to perform genomic medicine in daily clinical practice. Due to recent technological advances, genomic testing for NSCLC has shifted from single-gene testing to multiplex companion diagnostics and comprehensive genome profile, so understanding genomic medicine is becoming increasingly important in terms of treatment optimization, prognosis prediction and prevention in the field of perioperative treatment, where thoracic surgeons are primarily involved. We herein review the current status, future prospects and issues regarding genomic medicine involving respiratory surgeons.

Cancer cachexia is associated with weight loss, anorexia, and fatigue, and a deteriorated life prognosis and quality of life among cancer patients. The onset of cachexia involves various factors, including inflammatory cytokines and tumor products, leading to abnormalities in energy metabolism and degradation of the skeletal muscles. Fearon et al. proposed simple diagnostic criteria based on the degree of weight loss and promoted intervention at an early stage. However, the recognition of cancer cachexia is still low, so education on the state will be necessary in the future. In 2021, anamorelin, a ghrelin agonist, was approved as a therapeutic drug in Japan for the first time globally and is currently being used in clinical practice. However, drug therapy alone is not sufficient, and comprehensive treatment combined with nutritional therapy and exercise therapy is considered necessary for proper resolution. The development of new drugs, such as GDF-15 antibody, is also progressing, with further advances in cancer cachexia treatment expected in the future.

Kirsten rat sarcoma viral oncogene homolog (KRAS) is a frequently activated oncogene in human cancer. Since its discovery over 30 years ago, efforts to develop therapies targeting KRAS have been unsuccessful. KRAS has been considered an undruggable target for several reasons: difficulty designing molecules that compete with the guanosine triphosphate (GTP) binding site because of the very high affinity between KRAS and GTP, and redundancy in post-transcriptional modifications required for membrane association and downstream signaling pathways. Inhibition of a single signaling pathway or post-transcriptional modification leads to the activation of other pathways. In addition, the patient survival of cancers with KRAS mutations is not always dependent on KRAS. However, a small molecule that covalently binds cysteine of the G12C mutant form of KRAS and that locks KRAS in its guanosine diphosphate (GDP)-bound inactive state was reported in 2013. Since then, several companies have developed KRAS^G12C-specific small-molecule inhibitors, such as sotorasib and adagrasib. The United States Food and Drug Administration granted accelerated approval to sotorasib in 2021 as a second-line and subsequent therapy for non-small-cell lung cancer (NSCLC) harboring a KRAS^G12C mutation. Further research, including the development of direct inhibitors targeting sites other than G12C in KRAS, combination strategies with KRAS^G12C inhibitors, countermeasures after resistance acquisition, and biomarkers for effective patient selection, are awaited.

Objective. We herein report the comprehensive genome profiles obtained by next-generation sequencing (MINtS) using cytological samples (following cell samples) in our hospital. Method. After having registered various kinds of cell samples gathered by examinations performed for cases suspected of being lung cancer at our hospital with the North East Japan Study Group 021A study, we sent the samples to a genetic testing facility. Analyses of EGFR, KRAS, BRAF, and HER2 gene mutations were performed, and ALK, RET, and ROS1 fusion was done. Results. The 1298 samples sent to the facility from December 2015 to June 2019 were all cell samples. The most common EGFR gene mutation was lung adenocarcinoma, which was found in 164 (27.2%) out of 602 samples. The EGFR mutation was more found in 97 (48%) samples with never smoker and in 97 (47%) samples with female, significantly (P<0.01). The KRAS gene mutation was found in 89 samples (15%), and 1 was more found in 72 samples (20%), significantly (P<0.01). The Cobas^® EGFR Mutation Test version 2.0 of the available EGFR genetic test was performed in 380 patients with lung adenocarcinoma, and the positive conformity ratio was 82.6%, with a negative coincidence rate of 95.2% for MINtS. Conclusion. These findings suggest that MINtS performed using cell samples, which are easier to acquire than tumor tissue, is a promising comprehensive gene variation laboratory procedure for next-generation sequencing in lung cancer patients.

Background. Primary malignant pericardial mesothelioma is an extremely rare disease. We herein report an autopsy case and review cases reported in the last 20 years in Japan. Case. A 58-year-old woman with dyspnea was referred to our hospital for an abnormal chest shadow under suspicion of a mediastinal tumor. Chest computed tomography showed a giant mediastinal tumor (100×95 mm) and a small amount of pericardial effusion. The tumor was located in the base of heart and compressed the main blood vessels and main bronchi. Based on the findings of a transthoracic ultrasound-guided biopsy and imaging, we diagnosed her with primary malignant pericardial mesothelioma. She received chemotherapy (cisplatin and pemetrexed) and palliative radiotherapy at the same time but ultimately died of cardiac tamponade and tumor disseminated intravascular coagulation two months later. An autopsy revealed that the cardiac tamponade had been caused by mucinous pericardial fluid and a hematoma in the pericardial cavity. The histologic subtype was epithelial type. Conclusion. The most common symptom of primary malignant pericardial mesothelioma is heart failure with pericardial effusion. A pericardial fluid sample frequently shows negative cytology, so we should perform a pericardial biopsy for a definitive diagnosis. Chemotherapy with a platinum agent and pemetrexed is effective.

Background. Most lung cancer patients with bilateral adrenal metastases are asymptomatic. However, bilateral adrenal metastases may infrequently result in Addison's disease. These cases mainly occur during lung cancer treatment and Addison's disease is rarely found as an initial symptom. Case. The patient was a man in his seventies who had experienced general fatigue for approximately five months. Because he complained of sweating and abnormal behavior (including a strange voice on waking up), he was emergently admitted to our hospital. At admission, he presented hypoglycemic symptoms and pigmentation of the whole-body skin was observed. Chest computed tomography revealed a nodule in the left upper lung lobe. Abdominal computed tomography showed bilateral adrenal tumors that contained a low-density area and which showed heterogeneous enhancement. Blood tests showed a marked increase in adrenocorticotropic hormone and carcinoembryonic antigen and a marked decrease in cortisol. Based on these findings, he was diagnosed with Addison's disease due to bilateral adrenal tumors, and steroid replacement therapy rapidly improved his condition. Laparoscopic biopsy of the right adrenal tumor allowed us to finally diagnose primary lung adenocarcinoma based on the findings of immunohistochemical staining. At present, combination therapy with nivolumab and ipilimumab is being performed and has been effective for reducing the tumors. Conclusion. Since Addison's disease is a fatal but treatable disease, we should keep in mind that it may occur as a complication in lung cancer patients with bilateral adrenal metastases.

Background. Immune checkpoint inhibitors are the standard of care for non-small cell lung cancer; however, immune-related adverse events have been reported, and appropriate management is important. Immune-related renal failure is one such adverse event. Most patients with immune-related renal failure respond well to steroids. However, some patients develop steroid resistance, and residual renal dysfunction is associated with a worse prognosis. There is no consensus on additional treatment for steroid resistance. Case. The patient was a 72-year-old man diagnosed with cT3N2M0 stage IIIB squamous cell carcinoma of the lung. He had received carboplatin, nab-paclitaxel, and pembrolizumab as initial therapy. The best observed response was a partial response, and he was admitted to the hospital for further investigation because of worsening type 2 diabetes mellitus during the third course of treatment. His blood glucose control was relatively good; however, on the eighth day, he developed increased fatigue and elevated serum creatinine (S-Cr). Although fluid replacement and antimicrobial therapy were started, his renal function worsened. Under the suspicion of immune-related renal failure, steroid therapy was started on the 11th day; however, his renal function did not improve. On the 13th day, hemodialysis (HD) was started. His renal function improved and HD could be withdrawn, with his S-Cr level improving to the baseline level on the 27th day; thereafter, the steroid dosage was tapered. The patient's renal function has not worsened again. Conclusion. We experienced a relatively early onset of immune-related renal failure. Early treatment with steroids and temporary HD may improve a patient's renal function.

Background. Nuclear protein in testis (NUT) carcinoma is an aggressive malignant tumor associated with chromosomal rearrangement of the NUT midline carcinoma family member 1 (NUTM1) gene. Reports of NUT carcinoma have been increasing in recent years. Case. A 26-year-old man presented to our hospital for the evaluation of bloody sputum and chest pain. Radiological imaging revealed an anterior mediastinal tumor. A computed tomography-guided needle biopsy detected thymic squamous cell carcinoma. The patient was administered four cycles of carboplatin/paclitaxel chemotherapy. Although the primary lesion responded to chemotherapy, the mediastinal lymph node showed continuous rapid growth, resulting in left recurrent nerve paralysis. Radiotherapy was initiated at the mediastinal lymph node. However, the patient subsequently developed pleural dissemination as well as liver and retroperitoneal metastasis and died seven months after his first visit. An autopsy evaluation revealed bilateral lung, liver, lymph node (lung hilum, mediastinal, and celiac), pleural, diaphragm, and retroperitoneal cancer. A histopathological evaluation of the tumor tissues showed mixed features of keratinized and undifferentiated cell components; an immunohistochemistry revealed that both components had immunopositivity for NUT and p63. The patient was ultimately diagnosed with NUT carcinoma. Conclusion. NUT carcinoma was diagnosed in this case following an autopsy. Some young patients diagnosed with thoracic squamous carcinoma may have NUT carcinoma.

Background. Thrombotic complications associated with coronavirus disease 2019 (COVID-19) vaccination have been reported. We herein report a resected case of lung cancer with pulmonary thromboembolism after COVID-19 vaccination. Case. A 74-year-old man visited our hospital three days after his second COVID-19 vaccination due to breathlessness. Plain chest CT showed only a mass in the left upper lobe. Nine days after vaccination, his symptom worsened and he visited our hospital again. His saturation of percutaneous oxygenation (SpO₂) was 89%, and his D-dimer level was 25.9 μg/ml. Contrast-enhanced CT revealed thrombosis of the bilateral pulmonary arteries and left popliteal vein. Apixaban was administered, and his symptom improved. His D-dimer level decreased to 7.4 μg/ml. The left upper lobe nodule was diagnosed as lung cancer. After the disappearance of thrombus and normalization of the D-dimer value, we performed thoracoscopic resection of the left upper lobe. The vessel sheath of the pulmonary artery had thickened and was difficult to peel off. The patient is currently alive without relapse of thrombosis. Conclusion. Although thrombotic events after COVID-19 vaccination are rare, high rates of severe disease and mortality have been reported. The number of cases involving lung cancer patients with adverse events related to COVID-19 vaccines will increase in the future. Thus, the elucidation of the pathophysiological mechanism and establishment of effective treatment policies are expected.

Background. Few reports have described salvage surgery for locally recurrent non-small cell lung cancer after chemoradiotherapy and consolidation therapy using immune checkpoint inhibitors. Case. A 65-year-old man received chemoradiotherapy (CRT) followed by consolidation therapy using durvalumab for unresectable cStage IIIA adenocarcinoma of the left upper lung. The tumor regressed at 3 months after chemoradiotherapy, with the disappearance of a mediastinal hot spot observed on fluorodeoxyglucose (FDG)-positron emission tomography. Although tumor regrowth occurred 8 months after CRT, the mediastinal lymph node did not show the uptake of FDG. Therefore, we concluded that the tumor was downstaged to ycStage IB following treatment. At 10 months after chemoradiotherapy, we performed left lung upper lobectomy as salvage surgery. Histopathological evaluation of the resected tumor confirmed the diagnosis of low-grade adenocarcinoma ypStage IA3, with viable cells and lymphocytic infiltration. The scarred lymph nodes did not show any tumor cells. The resectability status was determined to be R0. The patient's postoperative course was uneventful, and he was discharged to home on postoperative day 10. He did not receive adjuvant chemotherapy and no recurrence has been detected in 14 months of postoperative follow-up.