The three RAS oncogenes with high homology, considered to be undruggable, are the most frequently (approximately 25%) mutated gene family in human cancer. Missense mutations of the KRAS gene occur predominantly at codons 12, 13 or 61 and are observed in 30% of patients with lung adenocarcinoma in North American populations and 10% of those in Japanese populations. Although comprehensive efforts to develop therapeutic strategies to block the mutant RAS function, which is involved in the growth and development of cancer, have been made, clinically effective anti-RAS therapies have remained elusive for more than 30 years since the discovery of the RAS oncogenes in the 1980s. Therefore, in 2013, the National Cancer Institute (NCI) launched an RAS initiative to develop drugs that target the cell signaling pathway controlled by the RAS oncogenes. With research in progress, there is hope that mutant RAS can finally be conquered in the near future. In the present manuscript, I will describe the history of and recent advances in these research efforts.

Objective. A small proportion of metastases are oligometastases, so a clear definition has yet to be established. Local consolidative therapy might be effective for patients with oligometastases; however, treatment analyses are insufficient. We reviewed the clinical outcomes of patients with non-small cell lung cancer (NSCLC) with oligometastases in our institution. Methods. We conducted a retrospective analysis of data for 10 patients with oligometastases among 525 patients who were diagnosed with stage IV NSCLC from April 2003 to September 2017. Results. The patient characteristics were as follows: male/female, 7/3; age, 38-72 years (median 65 years); histology, adenocarcinoma/NSCLC/large cell carcinoma/giant cell carcinoma = 6/2/1/1; gene mutations, EGFR/ALK/negative = 1/1/8; TNM classification (7th edition), T1/T2/T3 at 4/4/2; metastatic organ, brain/small intestine/adrenal gland/bone/liver/axillary lymph node at 4/2/1/1/1/1; number of metastases, 1/2/3 at 9/0/1; and performance status, 0/1/2 at 9/1/0. The following local treatments were performed in 8 patients: surgery/radiotherapy of the primary tumor and metastases/surgery and radiotherapy of metastases/radiotherapy of metastases in 4/1/1/2. Chemotherapy was performed for 8 patients. The median survival time (MST) was 35.7 months (9-55 months) for all 10 patients, 24.1 months (9-36 months) for those who were gene-mutation-negative, and 35 and 55 months for those who were EGFR- and ALK-positive, respectively. Conclusion. In our patients with oligometastases, local treatments for the primary tumor or metastases were performed in many cases, and the prognosis was relatively good.

Background. PD-1 blockade therapy is controversial in patients with unresectable stage III lung cancer and a poor performance status. Case. A 75-year-old male patient presented with hoarseness and dysphagia. Chest computed tomography demonstrated a mass of 7 cm in diameter, involving the left hilar and right mediastinal nodes, great vessels, and trachea. Bronchoscopic biopsy in the right tracheal wall revealed squamous cell carcinoma with the high expression of PD-L1 (tumor proportion score, 100%). FDG-PET and brain MRI did not show any metastatic lesions; thus, the patient was diagnosed as having stage IIIC disease. The patient seemed weakened by the symptoms due to locally advanced lung cancer. His ECOG performance status was 4. We did not consider it possible for him to tolerate chemotherapy and radiotherapy; thus, immunotherapy with PD-1 blockade was initiated. After 2 cycles of pembrolizumab, the lesion drastically shrunk; however, his systemic status did not improve. He and his family did not want to continue cancer treatment, and he was transferred to a recuperation hospital after 3 cycles. Despite receiving no other anticancer treatment, his systemic status gradually improved, and he was finally discharged 5 months after the initiation of pembrolizumab treatment. After 11 months, the tumor shrunk further and a durable anticancer response was observed. Conclusion. We reported a case of stage III lung cancer that showed a durable response and improvement of the systemic status after only 3 cycles of pembrolizumab therapy.

Background. Pulmonary pleomorphic carcinoma (PPC) is a rare and highly malignant tumor that is considered to be resistant to chemotherapy. We report the cases of two patients with PPC who were treated with pembrolizumab. Case 1. A 64-year-old man was referred to our department with right back pain. A large mass in the right lower lobe was noted and CT-guided percutaneous biopsy of the mass revealed PPC with the high expression of PD-L1 (tumor proportion score 100%), which was classified as clinical stage IVA. He was treated with pembrolizumab as an initial treatment, which led to a partial response. Case 2. A 62-year-old woman was diagnosed with pathological stage IIB (pT3N0M0) PPC after right upper resection following a diagnosis of early clinical stage non-small cell lung carcinoma. Pleural metastasis was noted two months after surgery. The expression of PD-L1 in the resected specimen was low (tumor proportion score 30%). The tumor was responsive to the first-line combined chemotherapy with carboplatin and nab-paclitaxel, but non-responsive to the second-line treatment with pembrolizumab. Conclusion. Pembrolizumab might show a degree of efficacy for PPC with the high expression of PD-L1.

Background. Minute pulmonary meningothelial-like nodule (MPMN) is incidentally detected in resected lung specimens. However, to date, its origin has remained unclear. Case. We report the case of 67-year-old woman with MPMN with deletion of the neurofibromatosis (NF)-2 gene, which was incidentally detected in a resected pulmonary adenocarcinoma specimen. She was suffering from dry cough and was referred to our hospital. CT revealed part-solid ground glass nodule (GGN) of 14 mm in size, which included a 6-mm solid part in the left S¹⁺² segment. She underwent left upper lobectomy under VATS according to intraoperative pathological diagnosis of minimally invasive adenocarcinoma. The postoperative pathological findings revealed the pulmonary lesion to be lepidic adenocarcinoma (pT1aN0M0 stage IA1). An MPMN lesion was also detected adjacent to the adenocarcinoma lesion. Postoperative immunohistochemistry revealed that the lesion was positive for epithelial membrane antigen (EMA), CD56, vimentin, and progesterone receptor (PgR). We also evaluated the status of the NF-2 gene using the FISH method, which revealed deletion of the NF-2 gene in the MPMN lesion. In the 18 months since surgery, the patient has been well without any recurrence of lung cancer, central nervous system (CNS) occurrence, or pulmonary meningioma. Conclusion. This mutational change of NF-2 in MPMN was previously reported to be similar to meningioma of the CNS. Our results are compatible with previous reports. Further studies are needed to elucidate the pathogenesis of this rare entity.

Background. Immune checkpoint inhibitors are used more frequently now for the treatment of non-small cell lung cancer than ever before. Various immune-related adverse events have been reported, and the management of these events is regarded to be important. Case. A 70-year-old man was administered nivolumab for the treatment of advanced non-small cell lung cancer. However, we did not re-administer nivolumab because severe diarrhea and vomiting occurred a few days after this administration. He began to complain of general fatigue and a poor appetite, and he also suffered from hyponatremia 10 months after the administration. Despite treatment for his hyponatremia, the symptoms did not improve. The patient reported a cold sensation, and hypotension occurred. A close examination helped us to diagnose pituitary dysfunction and secondary adrenal insufficiency. After the oral administration of hydrocortisone, these symptoms disappeared quickly. Conclusion. We always need to be alert for the immune-related adverse effects of immune checkpoint inhibitors, even after a single administration.

Background. Driver gene mutations, including epidermal growth factor receptor (EGFR) gene mutations, and immune escape mechanisms, including the programmed death-ligand 1 (PD-L1) pathway, have attracted attention as therapeutic targets for lung cancer. Case. A 57-year-old man was found to have a 35-mm mass in the right upper lobe, a 17-mm nodule in the right lower lobe, and swollen supraclavicular and mediastinal lymph nodes. A mediastinal lymph node biopsy led to the diagnosis of lung adenocarcinoma (cT4N3M0: Stage IIIC), which arose from the right upper lobe. The tumor was EGFR gene mutation (exon21 L858R)-positive and PD-L1-negative. After the initiation of afatinib treatment, the tumor in the right lower lobe and supraclavicular and mediastinal lymph nodes shrank; however, the tumor in the right upper lobe continued to grow. Another biopsy from the tumor in the right upper lobe revealed adenocarcinoma that was EGFR gene mutation-negative and PD-L1-positive (90%). Subsequently, the tumor in the right upper lobe was diagnosed as lung adenocarcinoma (cT2aN0M0: Stage IB), with strong PD-L1 positivity but no EGFR gene mutation. In contrast, the tumor in the right lower lobe was lung adenocarcinoma (cT1aN3M0: Stage IIIC), with an EGFR gene mutation (exon21 L858R) but no expression of PD-L1. This led to the diagnosis of multiple lung cancers. Conclusion. In cases in which multiple tumor sites show heterogeneous treatment responses, it is advisable to collect as many pathological specimens as possible in consideration of the possibility of multiple cancers or transformation.

Background. It has been reported that the incidence of Klinefelter syndrome is approximately 1 in 600 newborn males. However, there seem to be many people with Klinefelter syndrome who do not yet realize that they have the disease. In addition, it is often reported that Klinefelter syndrome is associated with malignancies. The incidence of malignant germ cell tumors among patients with this syndrome is also much higher than that in the general population. Case. An 18-year-old man presented with sudden-onset dyspnea and left chest pain. A massive mediastinal tumor was observed on computed tomography images, and core needle biopsies and blood test results led to a diagnosis of mixed germ cell tumor. In addition, we suspected Klinefelter syndrome in the patient because of his germ cell tumor, physical characteristics (tall and thin body, long arms and legs), and history of attention deficit hyperactivity disorder, all of which are strongly associated with the syndrome. Genetic examination results confirmed our suspicions, and the patient was diagnosed with Klinefelter syndrome. After completing his chemotherapy treatment, he underwent surgery. At the time of writing, the patient has had an uneventful postoperative course without recurrence for four years and two months. Conclusion. In males diagnosed with mediastinal germ cell tumor, an additional diagnosis of Klinefelter syndrome should be considered if the patient has the physical characteristics of said syndrome or a history of learning disability.

Background. Treatment with immune checkpoint inhibitors is associated with several immune-related adverse events (irAEs). We herein report a case report of nivolumab-induced severe neutropenia with stomatitis that was improved by steroid pulse therapy. Case. A 74-year-old man with EGFR mutation-negative adenocarcinoma (Stage IVB) was treated with nivolumab after the failure of systemic chemotherapy. Severe enteritis was experienced after 4 courses (3 months) of nivolumab treatment. Although enteritis was controlled by prednisolone, new irAEs, such as liver dysfunction and severe neutropenia with stomatitis appeared after the fifth course of nivolumab. The patient made a quick recovery from these irAEs after steroid pulse therapy. In addition, the tumor size was significantly decreased by the fifth course of nivolumab therapy. In spite of the interruption of further treatment due to adverse events, tumor progression was not observed at 27 months after the final administration of nivolumab. Conclusion. Neutropenia is rarely induced by immune checkpoint inhibitors; however, the opportunities for combination treatment with myelosuppressive chemotherapy and immune checkpoint inhibitors will increase in the very near future. The diagnosis of immune checkpoint inhibitor-induced neutropenia is important for allowing the timely administration of steroid therapy.

Background. Benign asbestos pleural effusion, diffuse pleural thickening, and rounded atelectasis are asbestos-related lung diseases. Case. A 76-year-old man who had worked in the shipbuilding industry was admitted for right pleural effusion. Chest CT showed rounded atelectasis, right pleural effusion, bilateral pleural thickening and pleural plaque in the right lower lobe. Right rounded atelectasis and collapsed fibrotic lung tissue were revealed by transbronchial lung biopsy. The right effusion was lymphocyte-predominant exudative pleural effusion. The pleural biopsy specimens obtained by VATS demonstrated fibrotic pleural thickening. As a result, diffuse pleural thickening and rounded atelectasis were diagnosed as having benign asbestos pleural effusion. One year later, the same disorder was found on the left thoracic side. Although this patient received corticosteroids and several drainage therapy treatments, the pleural effusion, pleural thickening and rounded atelectasis progressed with marked restrictive ventilatory impairment. He died of type 2 respiratory failure 3 years after his initial visit. At autopsy, extensive fibrous pleural thickening and multiple rounded atelectasis lesions were observed in both lungs. Conclusion. Because diffuse pleural thickening, rounded atelectasis lesions and benign asbestos pleural effusion can have a poor prognosis, such as this case, multilateral systemic management is desired.