Radiation pneumonitis (RP) is one of the most common dose-limiting adverse effects in the treatment of thoracic malignancies, including lung cancer. In cases of concurrent chemoradiotherapy for locally advanced lung cancer, symptomatic RP occurs in 5-50% of all patients and becomes severe or even fatal in some cases. Moreover, recently many patients also receive molecular targeted agents and/or immune checkpoint inhibitors. Thus, we should pay more attention to the occurrence of RP and the accurate prediction and prevention of severe RP is essential for safe and efficacious treatment. This manuscript provides an overview of the definition, classification, etiology, symptoms, diagnosis, grading system, risk factors, and management of RP. In particular, radiotherapy-related risk factors, such as dose-volume parameters, and the methods for the prediction and prevention using these factors are reviewed in detail from the perspective of radiation oncologist.

Objective. When we reported a case in which a complete response was observed in a patient treated with nivolumab, we hypothesized that eosinophils are involved in the tumor immune response to nivolumab. In the present study, we retrospectively analyzed the relationship between tumor tissue-infiltrating eosinophils before the administration of an immune checkpoint inhibitor (ICI) and the effect of ICIs. Methods. We reviewed the cases of 53 patients with a history of ICI treatment at our hospital between February 2016 and June 2018. We divided the cases into a tumor-associated tissue eosinophilia (TATE)-negative group (n=32) and a TATE-positive group (n=21) based on a tumor tissue-infiltrating eosinophil count of 7 per 10 high-power fields. Results. The median progression-free survival (PFS) in the TATE-positive group was significantly longer than that in the TATE-negative group (12.0 months [95%CI 3.8-20.2] vs. 3.0 months [95%CI 0.9-5.1]; p=0.035). A significant correlation was observed between the blood eosinophil count and the tumor tissue-infiltrating eosinophil count (p=0.001; correlation coefficient 0.429). The changes in the blood eosinophil count between the first and second ICI administrations did not differ between the two groups (p=0.381). Conclusion. Tumor tissue-infiltrating eosinophils before the administration of ICI were related to an increase in the blood eosinophil count, which may improve the effect of ICIs.

Objective. The death rate due to lung cancer in Nagano Prefecture has been the lowest in Japan for over 20 years. Using data from the regional cancer registry and hospital-based cancer registry, we examined the incidence of lung cancer in Nagano Prefecture and analyzed the reasons for the low mortality rate. Methods. We analyzed 1,759 cases of lung cancer diagnosed in 2013 and registered in the Nagano regional cancer registry, and 3,087 cases treated for lung cancer in cancer hospitals in Nagano Prefecture from 2012 to 2014. The data were compared with the national data in order to assess the characteristics of lung cancer in Nagano Prefecture. Results. The age-adjusted incidence rate of lung cancer in Nagano Prefecture was 35.4 per 100,000, while the national rate was 41.4 per 100,000. Among the lung cancer cases in Nagano Prefecture, 36.2% were found in the localized stage, which was greater than the national value of 32.5%. A comparison of the clinical stages of cases in both the regional and hospital-based registries indicated that a greater proportion of cases were found in the localized stage, while the proportion of cases found with metastases tended to be lower in Nagano Prefecture than was observed nationally. The incidence/mortality rate of lung cancer in Nagano Prefecture was 1.71, which was the second highest among all prefectures in Japan. This was much higher than the national value of 1.54. Conclusion. It is suggested that the low incidence rate and high early detection rate may contribute to the low mortality rate of lung cancer in Nagano Prefecture.

Background. Alectinib has high efficacy for anaplastic lymphoma kinase (ALK)-positive lung cancer, and severe liver dysfunction due to alectinib is rare. Acute hepatitis due to hepatitis C virus (HCV) is also rare compared to that induced by hepatitis B virus. Case. A 51-year-old man presented to our hospital with an abnormal shadow on chest radiography. The patient was diagnosed with stage IIB (cT1bN1M0) lung adenocarcinoma via a transbronchial lung biopsy. He received left pneumonectomy performed via video-assisted thoracic surgery. A biomarker analysis revealed strong immunohistochemical staining for ALK protein. However, fluorescent in situ hybridization (FISH) did not show ALK translocation. He was prescribed alectinib for the relapse of lung adenocarcinoma. However, on day 5 after administration of alectinib, blood tests showed liver dysfunction, and alectinib administration was discontinued. Blood test results for hepatitis B surface (HBs) antigen, HBs antibody, and HCV antibody were not remarkable. After discontinuation, the liver function results worsened. He was administered steroid pulse therapy due to the possibility of an adverse drug event or autoimmune hepatitis. On day 27 after the administration of alectinib, blood samples tested positive for HCV antibody and HCV-RNA. He was diagnosed with acute hepatitis due to HCV infection. His liver function gradually improved. Conclusion. We should consider the possibility of acute hepatitis by HCV during the treatment of lung cancer.

Background. Stiff person syndrome is a rare neurological syndrome characterized by fluctuating muscle rigidity and painful spasms. About 5-8% of stiff person syndrome cases are associated with malignant tumors, and the symptoms can manifest as a paraneoplastic disorder. Case. We herein report a 68-year-old man who was referred to our hospital with a chief complaint of gait disturbance due to painful muscle rigidity in both legs. Examinations of the head and spine showed no abnormalities. However, on chest computed tomography, an anterior mediastinal tumor was seen, and blood tests showed a high titer of anti-glutamic acid decarboxylase antibody. These findings suggested that his symptoms could be attributed to paraneoplastic neurological syndrome associated with the mediastinal tumor. Furthermore, characteristic symptoms and laboratory findings also indicated stiff person syndrome. These symptoms were not affected by initial treatment with steroids, but they were improved by benzodiazepine and baclofen treatment. The pathological diagnosis after radical thymectomy was type B2 thymoma. The patient's postoperative course was uneventful. His medications were decreased, and his symptoms gradually improved. Conclusion. Thymectomy might offer symptomatic relief for stiff person syndrome associated with thymoma.

Background. Although drug-induced interstitial pneumonitis caused by epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is well recognized, reports of alveolar hemorrhage caused by EGFR-TKIs are very rare. Case. The patient was a 75-year-old woman who was diagnosed with lung adenocarcinoma (cT2bN0M0, stage IIA) in December 2015. An EGFR L858R mutation in Exon21 and the EGFR T790M mutation in Exon20 were identified before the start of therapy. She chose to undergo chemotherapy without surgery or radiotherapy. She started gefitinib treatment in February 2016. In October 2016, the primary tumor grew and metastasized within the same lobe. Gefitinib was thus discontinued, and osimertinib was started at 80 mg/day in November 2016. Tumor regression was immediately achieved, but bloody sputum was observed 2 months later. Chest computed tomography revealed diffuse ground-glass opacities in the bilateral lung fields. Bronchoscopy was performed, and the patient's bronchoalveolar lavage (BAL) fluid was bloody and showed hemosiderin-laden macrophages. Based on these findings, we diagnosed alveolar hemorrhage. Osimertinib was discontinued, and oral prednisolone was started at a dose of 25 mg/day, out of concern in relation to possible drug-induced alveolar hemorrhage. The patient's symptoms immediately improved. Conclusion. If osimertinib-treated patients show alveolar hemorrhage, the withdrawal of osimertinib and start of steroid therapy should be considered due to the possibility of drug-induced alveolar hemorrhage.

Background. Multiple primary lung cancers are rarely reported and account for only around 0.6-1.3% of all lung cancers. There are few case reports in the literature of multiple lung cancers harboring different mutations. Case. A 74-year-old woman was referred to Hoshigaoka Medical Center for a further diagnosis and management owing to the finding of a right tumor shadow on chest X-ray at another hospital. Chest computed tomography (CT) revealed a mass in the S⁴ and the S⁶ in the right lung associated with right pleural effusion. We confirmed that the tumor in the right S⁴ was an EML4-ALK-positive adenocarcinoma of stage IVB (cT2bN2M1b), and alectinib was administered. After a year, the lesions remained well controlled, but right pleural effusion and pleural dissemination emerged. A transbronchial lung biopsy of S⁶ revealed that the adenocarcinoma was positive for EGFR. Conclusion. We herein report this rare case of multiple lung cancers harboring different mutations involving ALK and EGFR.

Background. Preoperative marking is often required before limited pulmonary resection for early-stage lung cancer. CT-guided marking has often been performed; however, there have been reports about air embolism as a potentially fatal complication. Thus, the introduction of virtual-assisted lung mapping (VAL-MAP) has increased. We herein report a case in which thoracoscopic extended segmentectomy was performed with good results using VAL-MAP with indocyanine green (ICG) and infrared thoracoscopy with intravenous ICG. Case. The patient was a 72-year-old woman. Chest computed tomography showed a 16-mm part-solid nodule and we planned extended lingular segmentectomy. On the day before the operation, VAL-MAP with ICG was performed. Under usual thoracoscopy, indigo carmine was recognized and the fluorescent region was more widely visible under infrared light. After dissection of the pulmonary artery, vein and bronchus, ICG was injected intravenously. It was easily distinguished from the ICG injected for VAL-MAP by the intensity of the fluorescence, which enabled radical limited resection with an adequate surgical margin. Conclusion. The combination of VAL-MAP with ICG and infrared thoracoscopy with intravenous ICG may be applicable in various operative procedures.

Background. The prognosis of malignant tumor associated with Trousseau syndrome has been said to be very poor. Recently, there have been reports of cases of advanced epidermal growth factor receptor (EGFR)-positive lung adenocarcinoma treated successfully with the molecular-targeted drug gefitinib. However, there are few reports regarding advanced ALK-positive lung adenocarcinoma with Trousseau syndrome. We herein report a case of effective treatment with alectinib and a direct oral anticoagulant (DOAC). Case. A 57-year-old man suffered a multi-cerebral infarction associated with Trousseau syndrome that progressed before the diagnosis of lung adenocarcinoma (cT1aN3M0 Stage IIIB). Upon admission, his performance status (PS) was 3, and computed tomography revealed multiple arteriovenous thrombosis. Administering systemic chemotherapy seemed difficult due to the patient's poor PS. However, the ALK fusion gene was found to be positive by endobronchial ultrasound-guided transbronchial needle aspiration, allowing us to treat the patient with the molecular-targeted drug alectinib. In addition, we administered a DOAC as anticoagulant therapy because the international normalized ratio of prothrombin time (PT-INR) was not well controlled with warfarin. Thereafter, the tumor shrank in size, and most of the multiple arteriovenous thromboses vanished by five weeks after administering the medication. Furthermore, his PS improved to 2 from 3. Conclusion. If patients with Trousseau syndrome have an oncogenic driver gene mutation, treatment with a molecular-targeted drug and DOAC as anticoagulant therapy is effective.

Background. We herein report a case of invasive mucinous adenocarcinoma (IMA) that displayed cavitary nodular shadow scattering to the adjacent areas in the right lower lobe S⁶. As differentiation from inflammatory lesions was required, the tumor was diagnosed by surgical resection. Case. A 71-year-old man was referred to our hospital for a comprehensive examination of abnormal shadows detected at a lung cancer screening. Computed tomography (CT) revealed a nodular shadow with cavity scattering to the adjacent areas in the right S⁶. Furthermore, CT images obtained about a year later revealed a growing trend in the cavity nodule in the right S⁶. Bronchoscopy was performed; however, no definitive diagnosis was obtained. Although inflammatory lesions were suggested, malignancy could not be denied. Finally, IMA was diagnosed by a surgical biopsy. Accordingly, right lower lobectomy was performed. All shadows scattered to the adjacent areas were metastatic lesions within the same lobe of the primary tumor. Conclusions. Imaging findings of IMA are widely known to be similar to those of pneumonia; however, clinicians should be cautious when making a diagnosis based on imaging, as IMA can exhibit cavity nodules, as in the present case.

Background. Immune checkpoint inhibitors (ICIs), such as Pembrolizumab, can cause immune-related adverse events (irAEs). We herein report a 49-year-old woman who developed refractory colitis after Pembrolizumab administration. Case. The patient had a left upper lobe lung adenocarcinoma that had been treated with Pembrolizumab as the fifth-line treatment. After the sixth administration of Pembrolizumab, she developed colitis as an irAE, complaining of abdominal pain, diarrhea and bloody stool. As the colitis did not respond to Prednisolone or anti-TNFα antibody, Cyclosporine was administered. The colitis was substantially improved after sufficient dosing of Cyclosporine. Some patients treated with ICIs die of colitis as an irAE. However, this is not well documented in the literature, and no consensus has been reached regarding appropriate treatment. Conclusion. The accumulation of a sufficient number of cases will reveal the efficacy of Cyclosporine in treating intractable colitis induced by Pembrolizumab.

Background. Localized malignant pleural mesothelioma is a very rare tumor, and its standard treatment has not been established. Case. A 55-year-old woman with no history of asbestos exposure visited our hospital because of pain in her right lateral chest. Computed tomography revealed a mass of 57×33 mm in the post-mediastinum. A computed tomography-guided biopsy revealed the possibility of localized malignant pleural mesothelioma. The patient underwent complete tumor resection through thoracoscopic surgery. Immunohistologically, poorly differentiated epithelium-like atypical cells were found to have proliferated with a high degree of cellularity. The tumor was located between the visceral pleura and parietal pleura. No invasion was observed in the lung parenchyma. Immunohistochemically, the tumor cells were positive for calretinin and D2-40 but negative for CEA and TTF-1. The pathologic diagnosis was epithelioid-type localized malignant pleural mesothelioma. Abdominal computed tomography that had been performed at another hospital 2 years earlier had revealed the tumor as pleural thickening of only 15×5 mm. The tumor had subsequently rapidly increased in size, although only at that lesion, with no progression to the diffuse pleural mass or metastasis to other organs. With the addition of adjuvant chemotherapy, the patient remains well with no relapse at 10 months after surgery. Conclusion. Localized malignant pleural mesothelioma may show a different pathogenesis from diffuse malignant pleural mesothelioma. Further studies are warranted to establish the standard treatment of the disease.

Background. Previous reports on limbic encephalitis as a paraneoplastic syndrome have indicated that in many cases the neurological symptoms do not improve even if the tumor shrinks. We report a case of limbic encephalitis due to small cell lung cancer in which the patient was rescued and his Performance Status (PS) was significantly improved by the performance of antitumor therapy with artificial respiration. Case. A 60-year-old man was transported to our hospital by ambulance due to convulsions. He had repeated spasms and was unable to communicate or walk. Based on the results of our examination, the patient was diagnosed with small cell lung cancer stage IIIB. Head MRI (FLAIR) showed a high signal intensity in the hippocampus and limbic system, and was diagnosed with paraneoplastic limbic encephalitis (PLE). CBDCA+VP-16 was initiated. On the fourth day of treatment he became convulsive, and artificial respiration was initiated to stop his convulsions. He was extubated on the 12th day after the disappearance of spasm and shrinkage of the tumor. No further attacks occurred. A test for anti-Hu antibodies was negative. Head MRI showed improvement of the high signal intensity of the limbic system. Thus, we continued chemotherapy. Thereafter, his consciousness and communication improved, and he was discharged alone, and subsequently returned to work. Conclusion. Although paraneoplastic neurologic symptoms do not generally improve, it is reported that therapeutic effects may be expected for neurological symptoms in patients who are negative for anti-Hu antibodies. Since small cell lung cancer is a tumor with a high temporary treatment response rate, we considered that an antitumor effect could be expected in a patient with a poor performance status before treatment. In this case, treatment could not be delayed until the result of the anti-Hu antibody test were available, and antitumor treatment was provided with artificial respiration control. As a result, we were able to rescue the patient because his neurological symptoms of paraneoplastic limbic encephalitis improved along with the antitumor effect. We believe that among patients with paraneoplastic limbic encephalitis who are anti-Hu antibody-negative and who have a tumor with a high treatment response rate, even cases with a poor PS may be rescued by antitumor therapy.