Immune checkpoint inhibitors (ICIs), such as anti-programmed death receptor-1/programmed death ligand 1 (PD/PD-L1) antibody monotherapy and in combination with chemotherapy, have shown favorable efficacy compared with chemotherapy alone in several phase III trials for advanced non-small cell lung cancer (NSCLC) and have become the standard of care. Recently, the indication for ICIs has expanded to include the perioperative treatment for early-stage NSCLC cancer and first-line treatment for small cell lung cancer. However, there are still many cases in which ICIs are not effective, or where resistance is observed after an initial response to ICIs. In addition, the PD-L1 expression on tumor cells, which has been a biomarker of ICIs susceptibility, cannot reliably predict the therapeutic efficacy of immunotherapy. Thus, the further development of novel immunotherapies and identification of biomarkers of ICI susceptibility are warranted. In this article, we review the current status of and issues associated with cancer immunotherapy in lung cancer, the potential utility of novel immunotherapies, such as novel ICIs and bispecific T-cell engager, and the future direction of the development of biomarkers for immunotherapy in lung cancer patients.

Objective. Perioperative treatment of non-small cell lung cancer is becoming more precise, and multiplex genetic analyses using next generation sequencing will inevitably be required even for surgical cases. Appropriate specimen processing is important for successful multiplex genetic analyses of surgical specimens. We therefore validated the specimen processing method for lung surgery at our hospital and obtained indicators that should be observed for successful multiplex genetic analyses from surgical specimens. Methods. Thirty patients with clinical stage IA3-IIIA non-small cell lung cancer scheduled for surgery were prospectively enrolled. Rapid intraoperative specimens were fixed in 10% formalin and surgical specimens in 20% formalin, and each was submitted to the Oncomine™ Dx Target Test^® Multi-CDx System (ODxTT). The success rate of the ODxTT analysis of each specimen and the quantity of nucleic acids extracted from each specimen were compared. The correlation between the quantity of nucleic acids extracted from the surgical specimens and the time required for the specimen processing process was also evaluated. Results. The success rate of the ODxTT analysis was 100% for both specimens. The extracted quantities of nucleic acids of both DNA and RNA were significantly higher in the surgical specimens than the rapid intraoperative specimens. No significant correlation was observed between the quantity of nucleic acids and the time required for specimen processing. Conclusion. The success rate of the ODxTT analysis was 100% for lung surgical specimens fixed in 20% formalin. The use of 20% formalin may be considered in institutions where it is difficult to process surgical specimens as recommended.

Background. Uveitis induced by immune checkpoint inhibitors (ICIs) is a rare immune-related adverse event (irAE). We herein report a patient who presented with unilateral uveitis complicated with a nodular lesion mimicking metastasis of lung cancer to the retina and with opposite-eye uveitis one month after the initiation of corticosteroid therapy. Case. A 59-year-old woman suffered recurrence of lung adenocarcinoma after right upper lobectomy and started nivolumab plus ipilimumab therapy combined with pemetrexed plus carboplatin. The patient presented with sudden visual impairment in the left eye seven weeks after the initiation of chemotherapy. She was diagnosed with optic neuritis and posterior uveitis. Optical coherence tomography showed that the uveitis was unilateral and complicated with not only serous detachment of the retina but also a nodular lesion. These findings raised the possibility that the uveitis had been induced by metastasis of lung cancer to the retina, although it might also have been an irAE due to ICI therapy. To restore her vision, we started treatment with corticosteroids. The serous detachment and nodular lesion disappeared, but the patient developed vision impairment in the right eye after the dose of corticosteroids had been tapered. The vision in the right eye was restored after the dosage of corticosteroids was increased, but the vision in the left eye was only partly recovered. The patient consequently used an occluder lens for the left eye, with her visual capability left entirely to the right eye. Conclusion. Uveitis induced by ICIs can occur laterally or be complicated with a nodular lesion, making a diagnosis challenging. Uveitis induced by ICIs can cause severe vision impairment and affect the quality of life.

Background. Thoracic SMARCA4-deficient undifferentiated tumors have been newly classified in the World Health Organization's fifth edition classification of thoracic cancers and have attracted much attention. Notably, SMARCA4 deficiency occurs in 10% of non-small cell lung cancers (NSCLC); however, its clinical significance has not been elucidated. Case. An 87-year-old man was referred to our hospital for suspected lung cancer in the right lower lobe, based on the computed tomography (CT) scan results. He was diagnosed with SMARCA4-deficient NSCLC (cT2aN3M1c, stage IVB) which was strongly positive for PD-L1; he was started on pembrolizumab. However, he developed respiratory failure and died on the 15^th day of treatment. Chest and abdominal CT performed on the 13^th day of treatment showed growth of the primary cancer, bilateral pleural effusion, and thickening of the broad interstitium, suggesting lymphangitic spread. Based on a pathological examination at autopsy, he was diagnosed with SMARCA4-deficient large cell lung cancer (yaT4N3M1c, stage IVB). He had advanced lymph node metastasis, and a microscopic examination revealed lymphatic invasion in the bilateral adrenal glands, thyroid, and intrapulmonary nodes. Conclusion. We conducted an autopsy of a patient with SMARCA4-deficient lung cancer who died of rapidly progressing disease after treatment using pembrolizumab, and a review of the relevant literature.

Background. ROS1 fusion gene-positive lung cancer is a rare genetic mutation that accounts for 1-2% of non-small-cell lung cancer (NSCLC) cases. ROS1-positive lung cancer is more common in younger patients, women, nonsmokers, and pathological adenocarcinoma with mucus than in others. NSCLC is associated with an increased incidence of thromboembolism, and NSCLC with ROS1 fusion gene mutations is associated with an elevated risk of thrombosis. We encountered a patient diagnosed with ROS1-positive lung adenocarcinoma after pulmonary thromboembolism. Case. A 46-year-old man visited our hospital with shortness of breath and pain in both lower legs. Contrast-enhanced computed tomography (CT) revealed a thrombus in the pulmonary artery and left femoral vein, nodular shadow in the right middle lobe, and mediastinal lymphadenopathy. The patient was admitted to the hospital and diagnosed with pulmonary thromboembolism based on CT findings. Continuous heparin injections were administered immediately. We diagnosed the patient with ROS1-positive lung adenocarcinoma cStage IVA after performing endoscopic ultrasound with bronchoscopy-guided fine-needle aspiration from a mediastinal lymph node. We switched the patient from continuous heparin injection to apixaban and started additional treatment with crizotinib. After three months, the thrombus resolved, and the primary tumor and lymph nodes shrank. Thrombus resolution and tumor shrinkage persisted for over 12 months. Conclusions. Patients with NSCLC and thrombotic events should be promptly scrutinized and anticoagulated, considering the possibility of rare genetic mutations.

Background. We herein report a case of granulocyte colony-stimulating factor (G-CSF) -producing lung cancer in an elderly patient who showed improvement in her performance status after surgery. Case. An 89-year-old woman had difficulty walking outside due to fatigue and dyspnea on exertion, and her activities of daily living had declined to a performance status of 2. A 7.9×5.0-cm mass lesion was found in the lower lobe of the right lung, and blood tests showed a high white blood cell count of 17810/μl and serum G-CSF level of 211 pg/ml, leading to suspicion of G-CSF-producing lung cancer. The operation was performed under thoracotomy. It was determined that the tumor had spread to the intermediate bronchus and that preservation of the middle lobe was not possible, so the middle and lower lobes were resected. G-CSF staining of the resected specimen showed positive findings in the cytoplasm of some tumor cells. Although the patient was elderly, complete resection resulted in resolution of her fever and improvement in her postoperative activities of daily living to a performance status of 1. Conclusion. G-CSF-producing lung cancer has a poor prognosis, and no standard treatment has yet been established; however, surgical resection should be attempted whenever possible, as it may improve symptoms associated with the tumor and prolong the survival.

Background. Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome is a condition characterized by symmetrical synovitis and pitting edema in the extremities. It is often associated with malignant tumors. While there have been several reported cases of RS3PE syndrome associated with lung cancer, few have described the extent or nature of the improvement in RS3PE syndrome symptoms following treatment for lung cancer. Case. A 63-year-old man presented with bilateral peripheral edema and pain and was diagnosed with RS3PE syndrome. Although he was initially independent in his activities of daily living (ADL), he had been experiencing poor grip strength and difficulty walking due to arthralgia. A CT scan conducted to screen for malignant tumors revealed a mass in the right upper lobe of the lung that was suspected to be lung cancer. The patient underwent surgery to remove the lung adenocarcinoma. A pathological examination revealed that the cancer was stage IIB, with no lymph node involvement or metastasis. The edema improved on the day after surgery, and the arthralgia improved on the third postoperative day. On the eighth postoperative day, the patient's grip strength and six-minute walking distance had remarkably improved in comparison to the pre-operative measurements. His ADL had also improved. Conclusion. In cases of RS3PE syndrome associated with surgically resectable lung cancer, surgery may improve the symptoms of RS3PE syndrome.

Background. Granulocyte colony-stimulating factor (G-CSF)-producing tumors are known to have a poor prognosis, and the efficacy of ROS1 tyrosine kinase inhibitors (ROS1-TKIs) in treating ROS1 fusion gene-positive G-CSF-producing non-small-cell lung cancer has not been reported. Case. A 56-year-old male patient presented with a rapidly progressing mediastinal tumor and an abnormally high white blood cell count. The diagnosis was lung adenocarcinoma (cTXN3M1c, stage IVB). Serum G-CSF levels were elevated. Due to the rapid progression, we started carboplatin, paclitaxel, bevacizumab, and atezolizumab without awaiting the results of gene mutation testing. However, he experienced progressive disease (PD) after two courses. Subsequently, he was administered cisplatin, pemetrexed, and bevacizumab, but PD occurred again after two courses. After confirming ROS1 fusion gene positivity and starting entrectinib, the dyspnea improved the next day, and 1.5 months later, computed tomography showed shrinkage of the tumor. PD occurred three months after starting entrectinib, and we switched to crizotinib. The tumor shrank rapidly again. Conclusion. ROS1-TKIs may be effective, even for ROS1 fusion gene-positive G-CSF-producing tumors with a poor prognosis.

Background. Good's syndrome is a rare immunodeficiency condition that develops in association with thymoma. It has been reported to occur in 0.2-0.3% of thymoma patients in Japan. Case. A 52-year-old male underwent an extended thymo-thymectomy at our institution and received a pathological diagnosis of invasive thymoma. After 11 years, follow-up computed tomography results showed signs of pleural dissemination, which was treated with chemotherapy. The disseminated tumor was resected 15 years after the initial diagnosis, and the pathological diagnosis was dissemination of invasive thymoma. There were no postoperative complications. At four months after the second surgery, the patient developed diarrhea, accompanied by weight loss of 5 kg/month. The cause was unclear. The diarrhea remained intractable despite treatment with probiotics and antidiarrheal drugs. During an examination to investigate the patient's condition, early esophageal cancer was incidentally found, for which an endoscopic submucosal dissection procedure was performed. During hospitalization, the patient developed aspiration pneumonia, which led to sepsis. Test results indicated hypogammaglobulinemia, along with a decrease in B cells and CD4-positive T cells, and the patient was diagnosed with Good's syndrome. The patient was diagnosed with Good's syndrome 16 years after the initial diagnosis of thymoma. Immunoglobulin therapy was introduced, but the patient developed sepsis due to pneumonia and died five months later. Conclusion. Chronic diarrhea is known to occur in approximately half of patients with Good's syndrome, and should be kept in mind to avoid delaying the diagnosis.