Recently, therapeutics focusing on the MET exon 14 skipping mutation and MET amplification have entered the spotlight. Clinical trials of tepotinib (VISION trial) and capmatinib (GEOMETRY mono-1 trial) have demonstrated the efficacy of these agents in patients with advanced non-small-cell lung cancer (NSCLC) harboring a MET exon 14 skipping mutation. We are also developing MET inhibitors, such as savolitinib and crizotinib, and antibody-drug conjugates targeting MET, such as Sym01 and telisotuzumab vedotin. In addition, the mechanism of resistance after MET inhibitor therapy and its overcoming strategies have been investigated. In the present report, we outline the development of therapeutics for lung cancer targeting MET alterations.

Computer-aided diagnoses (CADs) of lung cancer have been studied for a long time. However, the development of a highly accurate CAD for lung cancer has been difficult due to the difficulty of determining appropriate features for various opacities. With the advent of deep learning, the core technology of the third artificial intelligence (AI) boom, it has now become possible to develop CAD systems with higher accuracy and a more general purpose, and expectations concerning the utility of CADs, such as lung cancer detection and differentiation, are increasing. In addition, research on radiomics and radiogenomics, which integrate non-imaging information with imaging information, is ramping up. Many companies are actively developing CAD systems; however, they are not yet fully practical. One issue is that AI cannot explain the diagnostic process, so research on AI that can explain the reason for the diagnosis is important. Five years ago, the possibility of AI replacing radiologists was widely discussed. However, at present, the shortage of radiologists has become a problem. In order for AI to be useful in lung cancer imaging in the future, not only the technical aspects of AI development but also the response of physicians who accept it are required.

Background/Aim. Both pembrolizumab monotherapy and PD-1/PD-L1 inhibitor plus platinum-based chemotherapy are recommended for the first-line treatment of advanced non-small-cell lung cancer (NSCLC) with a high PD-L1 expression. However, which therapy is more useful in clinical practice is unclear. We examined the efficacy and safety of each therapy based on the clinical experience at our hospital. Study Design. We retrospectively reviewed 55 NSCLC patients with a high PD-L1 expression between March 2017 and September 2020. Of these 55 patients, 34 underwent pembrolizumab monotherapy (monotherapy), and 21 underwent pembrolizumab plus platinum-based chemotherapy (combination therapy) as their initial treatment. Results. The median progression-free survival (PFS) for patients who underwent combination therapy was longer than that for patients who underwent monotherapy (median: 9.2 vs. 7.7 months) (p=0.762), but there were no significant differences between the groups. In addition, the response rate tended to be higher and the proportion of PD cases lower in the combination group than in the monotherapy group in patients with a large baseline tumor size (BTS). Conclusion. Combination therapy may be more effective than monotherapy for NSCLC with a high PD-L1 expression, especially in cases with a large BTS.

Objective. We assessed the utility of the tumor doubling time (TDT) for predicting the histological type of thymic epithelial tumors. Methods. We retrospectively reviewed 67 patients with thymic epithelial tumors who underwent surgery in our institution. Patients who underwent induction therapy or who failed to undergo serial computed tomography (CT) at least twice before surgery with an interval exceeding 20 days were excluded. The relationship between the histological type and the TDT was ultimately investigated in 38 patients. Results. The study population consisted of 16 men and 22 women (median age, 65 years old). The median preoperative tumor size was 4.0 cm. Twenty-nine tumors were diagnosed as thymoma, and 9 were diagnosed as thymic carcinoma. The median interval of the serial CT studies was 113 days. During the follow-up period, 29 patients showed an increase in tumor size (thymoma, n=20; thymic carcinoma, n=9). Tumor regression was observed in 1 patient (thymoma, n=1), while 8 patients showed no marked change in tumor size (thymoma, n=8). In 29 patients who showed tumor enlargement, the TDT in thymic carcinoma (median 164 days; range 44-2130 days) was significantly shorter than that of thymoma (median 468 days; range 138-4519 days) (p=0.0072). The area under the curve (AUC) of the receiver operating characteristic (ROC) curve for the differential diagnosis between thymoma and thymic carcinoma was 0.817. Conclusion. The TDT can be a useful parameter for differentiating between thymoma and thymic carcinoma.

Background. A successful genetic analysis by accurate and quick next generation sequencing (NGS) has become essential in decision-making in relation to the treatment strategy for patients with advanced non-small cell lung cancer (NSCLC). We report the case of a female NSCLC patient in a country in which no driver mutations had been detected. A targetable driver mutation was successfully detected through the re-evaluation of LC-SCRUM-Asia (Lung Cancer Genomic Screening Project for Individualized Medicine in Asia). Case. A 49-year-old, never-smoking woman was diagnosed with advanced lung adenocarcinoma based on the histopathological analysis of a surgical biopsy specimen of her right cervical lymph node in Vietnam. NGS, which was performed using the specimen that was resected in her country did not detect any driver mutations. She came to Japan with the hope of undergoing a re-examination with NGS. The second NGS analysis through LC-SCRUM-Asia using her pleural effusion successfully detected the SDC4-ROS1 fusion gene, leading to treatment with crizotinib. An evaluation of the quality of DNA and RNA from the surgically resected metastatic cervical lymph node revealed severe fragmentation of DNA, which seemed to be caused by formalin over-fixation. Conclusion. It is necessary to consider the storage condition when submitting samples for NGS. Global quality management is also required for the application NGS in precision medicine.

Background. Although it is widely known that lung cancer frequently metastasizes to the brain, lung, bone, and adrenal gland, ocular metastasis is extremely rare. Adenocarcinoma accounts for a large percentage of lung cancers with ocular metastasis and the prognosis of lung cancer with ocular metastasis is reported to be worse. Case. A 72-year-old woman visited our hospital with an abnormal chest shadow. Chest radiography showed a mass in the left lower lobe. A histological examination revealed adenocarcinoma. The patient underwent left lower lobectomy. She was followed-up after surgery; however, it relapsed after six months. In addition to enlargement of the mediastinal lymph nodes, computed tomography showed a left ocular tumor. Surgical resection of the ocular tumor was performed. A histological analysis of the ocular tumor revealed metastasis of lung adenocarcinoma. Conclusion. We report a case of lung adenocarcinoma, which relapsed with ocular metastasis after resection.

Background. Although various immune-related adverse events (irAEs) have been reported following the administration of immune-checkpoint inhibitors, relapsing polychondritis (RP) is an extremely rare one. Case. A 61-year-old man was diagnosed with lung squamous cell cancer (cT2bN3M0, cStage IIIB) with a high tumor expression of PD-L1 (tumor proportion score >90%). He underwent 6 courses of pembrolizumab as first-line chemotherapy and showed a partial response. However, we had to discontinue this treatment owing to the occurrence of intractable pneumothorax. After he recovered from the pneumothorax, we conducted second-line chemotherapy with carboplatin and nab-paclitaxel and third-line chemotherapy with 29 courses of nivolumab, resulting in a partial response. Subsequently, he complained of spontaneous tenderness of the bilateral ribs and dyspnea in the supine position. There were no abnormal findings on either abdominal computed tomography (CT), gastrointestinal endoscopy, or colonoscopy. However, fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT revealed the prominent accumulation of FDG in the tracheobronchial trees, costal cartilages, and nasal septum. Furthermore, we noted an increased thickness of the bronchial wall on contrast-enhanced CT. A biopsy of the costal cartilage revealed lymphocyte infiltration and granuloma reaction. Given these findings, we diagnosed him with RP. After the administration of corticosteroids, the thickness of the bronchial wall decreased, and his subjective symptoms improved. Conclusion. We experienced a rare case of RP induced by nivolumab. FDG-PET/CT was useful in its diagnosis.

Background. Certain malignancies are known to occasionally occur in patients with polymyositis. Conversely, the occurrence of polymyositis during the treatment of lung cancer is rare. Case. We herein report a case of polymyositis that occurred during the treatment of lung adenocarcinoma with an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). A 58-year-old woman who was diagnosed with stage IV lung adenocarcinoma with an EGFR mutation (exon 19 deletion) received the EGFR-TKI osimertinib. During treatment, she experienced progressive pain in the proximal muscles. Laboratory findings revealed an increase in creatine kinase (CK) levels. Upon a further examination, she was diagnosed with polymyositis as a paraneoplastic syndrome. Systemic steroids, immunosuppressive agents, and immunoglobulin were administered for polymyositis, and another EGFR-TKI, afatinib, was administered for lung adenocarcinoma. Even though the clinical courses of lung cancer and polymyositis were not parallel, both disease entities subsided. Conclusion. Polymyositis during lung adenocarcinoma treatment is rare; therefore, it should be considered as a coexisting entity when such patients exhibit elevated serum CK levels.

Background. Pulmonary spindle cell carcinoma is a rare disease with a poor prognosis; it accounts for only about 0.2% of primary lung cancer. We herein report two patients with recurrent/unresectable spindle cell carcinoma who maintained a good response for a long time. Case 1. A 70-year-old man felt chest pain, and a mass (47 mm) was identified in the left-anterior segment. We clinically suspected lung cancer with chest wall invasion (cT3N0M0) and performed left upper lobectomy combined with chest wall resection. Finally, the pathological diagnosis was pulmonary spindle cell carcinoma. Four months after surgery, chest computed tomography detected recurrent lesions in the left axillary lymph node, left adrenal gland, and pancreas. He received pembrolizumab monotherapy. He has since finished 23 courses of pembrolizumab, and his disease has remained stable. Metastatic lesions are now present only in his pancreas. Case 2. A 75-year-old woman was suspected of having ascending colon cancer due to right lower abdominal pain. A close examination revealed multiple lesions in multiple organs, including the colon and left lung. This was considered to be multiple metastases from a malignant tumor. A computed tomography-guided lung biopsy did not lead to a definitive diagnosis, and ascending colectomy was performed to improve the abdominal pain. Pathologically, the tumor in the colon was diagnosed as spindle-shaped malignant tumor, which led to suspicion of primary lung cancer. Partial resection of the left lower lobe was performed to achieve a diagnosis and as treatment, and the tumor was diagnosed as pulmonary spindle cell carcinoma (pT2N0M1c). We selected pembrolizumab monotherapy. At present, after 29 courses of pembrolizumab, no obvious lesions can be seen radiologically. Conclusion. While pulmonary spindle cell carcinoma is a histological type with a poor prognosis, in some cases, pembrolizumab is effective, and a long-term survival can be achieved.

Background. After the approval of the first-generation anaplastic lymphoma kinase (ALK) inhibitor crizotinib and the second-generation agents alectinib and ceritinib, the third-generation agent lorlatinib was approved in Japan in 2018 as a molecular-targeted drug for ALK fusion gene-positive non-small-cell lung cancer (NSCLC). We herein report an elderly patient with ALK fusion gene-positive NSCLC who experienced adverse events during second-line lorlatinib treatment and was successfully treated with reduced-dose (50 mg/day) lorlatinib every other day. Case. An 82-year-old Japanese man was diagnosed with adenocarcinoma of the lung (pT2aN2M0 stage IIIA), and 5 years after left total pneumonectomy, he showed recurrence with multiple lymph node metastases, multiple bone metastases, and pleural dissemination. He was positive for the ALK fusion gene and started treatment with alectinib as the first-line therapy but relapsed 3 years and 6 months later. We administered lorlatinib (100 mg/day) as second-line therapy. Due to the development of visual hallucinations, this treatment was discontinued. After the improvement of the hallucinations, we restarted treatment with the dose of lorlatinib reduced to 50 mg/day. The visual hallucinations recurred, and lorlatinib was stopped again. After the hallucinations improved, we initiated alternate-day treatment with 50 mg/day lorlatinib. The antitumor effect has been maintained for over 12 months with no hallucinations. Conclusion. For patients with uncontrollable visual hallucinations as an adverse event during lorlatinib treatment, alternate-day treatment with 50 mg/day lorlatinib may be effective.

Background. Transformation to small-cell lung cancer (SCLC) has been reported as one of the resistance mechanisms of EGFR-TKI-positive adenocarcinomas, and the transformed tumor has been reported to respond to chemotherapy for SCLC. EGFR gene mutations and ALK fusion gene mutations are considered to be exclusive, and co-positive cases are extremely rare. We herein report a case in which an adenocarcinoma that was co-positive for EGFR gene mutations and ALK fusion gene mutations transformed to SCLC after chemotherapy. Case. Follow-up computed tomography after treatment for Castleman's disease at a previous hospital in a 64-year-old man revealed a nodular shadow and right pleural effusion in the upper right lobe, which was staged as pT4N0M1a (pleural metastasis) stage IV adenocarcinoma. Surgery was performed, and the surgical specimen was positive for EGFR gene mutations and ALK fusion gene mutations. The administration of erlotinib was therefore started. Subsequently, since the tumor became resistant to treatment and was EGFR-T790M-positive, osimertinib was administered. The tumor responded to treatment but then recurred. Many chemotherapy agents were attempted, and he was eventually referred to our hospital for further treatment. A third bronchial lung biopsy was performed, which revealed EGFR gene mutations and ALK fusion gene mutation positivity, as well as SCLC transformation. Amrubicin was administered as the treatment for SCLC and was effective. Conclusion. Our experience suggests that EGFR gene mutation and ALK fusion gene mutation co-positive cases can transform to SCLC after chemotherapy. Co-positive cases themselves are rare, and no instances of co-positive cases that transformed to SCLC after treatment have been previously reported. We therefore reported a rare case of such a transformation.

Background. Extensive-disease small-cell lung carcinoma has a high response rate for the initial treatment; however, most cases recur and are exacerbated in the short term. Case. A 68-year-old man was referred to our hospital because of a right upper lung field mass on a chest X-ray examination. He was diagnosed with small-cell lung carcinoma in the right upper lobe, cT3N2M1b, stage IVB (7th edition of the TNM system for lung cancer). He was treated by combination chemotherapy with cisplatin and irinotecan, and the left cerebellar metastasis disappeared after two courses, with the chest and abdominal lesions disappearing after four courses. He was also treated with whole-brain irradiation because of recurrence of the left cerebellar metastasis on magnetic resonance imaging one month after the final chemotherapy session. He maintained a recurrence-free survival for seven years; however, computed tomography (CT) revealed a mass in the left adrenal gland. The new lesion was pathologically diagnosed as metastasis of small-cell lung carcinoma by laparoscopic left adrenalectomy that was performed for the diagnosis and treatment, although it was considered atypical for extensive-disease small-cell lung carcinoma to recur after a long-term recurrence-free survival. Conclusion. Extensive-disease small-cell lung carcinoma can induce distant metastasis and recurrence after a long-term recurrence-free survival. It is necessary to conduct careful observation of such patients even after a long-term recurrence-free survival is achieved.