Chest X-ray is the most important element for lung cancer screening, and digital radiography has enjoyed increasing usage in recent years. Although the technology supporting digital radiography has rapidly developed year by year, the records regarding the recommended conditions of equipment for lung cancer screening have not been updated in a timely manner. We therefore established an annual update system describing the appropriate conditions of screening equipment on the website of the Japan Lung Cancer Society. Furthermore, we have also described the appropriate conditions of diagnostic monitors for lung cancer screening. However, as another issue of concern, the chest digital X-ray images submitted to several local interpretation centers are often of insufficient quality, due in nearly all cases to equipment problems. We have since examined the equipment to identify the reason for the low-quality radiography images and resolved the issues with the full cooperation of the equipment's manufacturing company. In this manner, we intend to continue to contribute to improving lung cancer screening efforts.

Lung cancers with epidermal growth factor receptor (EGFR) gene mutations are a common malignancy in East-Asians, including Japanese. Although there have been recent dramatic developments in cancer immunotherapy, EGFR-mutant lung cancers are reported to be relatively refractory to these immunotherapies. Thus, EGFR tyrosine kinase inhibitors (EGFR-TKIs) are still the sole key drug for those patients. After the discovery that an EGFR T790M secondary mutation is the most frequent mechanism of acquired resistance, several agents that simultaneously target this mutation are being developed, and osimertinib has already been approved in Japan. In addition, basic and translational research has revealed many mechanisms underlying resistance to EGFR-TKI. In this review, we will summarize the history of EGFR-TKIs and the detailed data for recently developed EGFR-TKIs. In addition, we discuss the possibility of combined therapies using EGFR-TKIs, based on the basic, translational, and clinical findings.

Background. Although lung cancer still has a high mortality rate, immune checkpoint inhibitors, including anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies are resulting in a paradigm shift in treatment strategy. Observation. T cells play an important role in cancer immunology; however, T cell immune activity is downregulated due to the binding of the PD-1 receptor that is expressed on T cells to its ligand, PD-L1, which is expressed on tumor cells. Anti-PD-1/PD-L1 antibodies block the binding of PD-1 to PD-L1 and thereby inhibit this downregulation of T cell activity. Nivolumab is an anti-PD-1 antibody. Phase III studies that compared nivolumab to docetaxel demonstrated the superiority of nivolumab in terms of the overall survival (OS) of previously treated squamous cell carcinoma (SQ), non-small cell lung cancer (NSCLC), and non-squamous cell carcinoma (NSQ) NSCLC patients. Pembrolizumab is another anti-PD-1 antibody, and a phase III study showed the superiority of pembrolizumab to docetaxel in terms of the OS of previously treated NSCLC patients. In addition, a phase III study that compared pembrolizumab to platinum-based combination chemotherapy showed that pembrolizumab significantly prolonged progression-free survival as well as OS in advanced NSCLC patients, and that PD-L1 was expressed on at least 50% of the tumor cells in the first line setting. Several anti-PD-L1 antibodies such as atezolizumab, durvalumab and avelumab are also being evaluated in various clinical studies. Conclusions. Anti-PD-1/PD-L1 antibodies represent key drugs for the standard therapy of NSCLC, both as a second-line and as a first-line therapy. However, other predictive biomarkers of immunotherapy are required.

The approval of nivolumab and pembrolizumab for advanced non-small cell lung cancer has allowed some patients to receive benefits such as prolonged overall survival and a long-term response with relatively mild adverse events. Meanwhile, there are patients who suffer from various disadvantages due to inappropriate patient selection, errors in evaluating treatment effects and high drug prices. We therefore need to evaluate the evidence and issues associated with nivolumab in order to better prepare any associated problems that need to be overcome in the future.

Objective. The aim of this retrospective study was to evaluate the prognostic factors for long-term survival (≥5 years) in patients with stage IV NSCLC. Methods. We reviewed 66 patients with stage IV NSCLC who were diagnosed at our hospital from 10/1/2002 to 9/30/2010. Results. In comparison to 58 patients who survived for <5 years, 8 patients who survived for ≥5 years were more likely to have an EGFR mutation positive, an early N status (N0, N1), and a single metastatic site. Age <75 years, an early N status (N0, N1), and the absence of liver metastasis were independent prognostic factors. Among the patients who survived for ≥5 years, the rate of EGFR-TKI use was higher, the rate of disease control in patients who were treated with both cytotoxic drugs and an EGFR-TKI was higher, and progression-free survival was longer in patients who were treated with cytotoxic drugs and an EGFR-TKI in comparison to patients who survived for <5 years. Conclusion. Our results suggest that age <75 years, an early N status (N0, N1), and the absence of liver metastasis may contribute to long-term survival in patients with stage IV NSCLC. We should take these results into consideration when deciding aggressive therapy.

Objective. Adverse events associated with chemoradiotherapy (CRT) include radiation-induced mucositis and esophagitis. Polaprezinc has been reported to be useful for treating these adverse events in head and neck cancer patients. We investigated the preventive effects of polaprezinc against radiation-induced esophagitis in patients with thoracic malignancies. Methods. Our subjects were 50 patients who received CRT. The patients were divided into two groups: one receiving polaprezinc dissolved in sodium alginate (AL+Zn group), and the other receiving only sodium alginate (AL group). We then used a visual analogue scale (VAS) to compare the degree of pharyngeal pain and pain caused by esophagitis experienced by these two groups. Results. Pain was classified as "none or mild" (VAS<30 mm) in 88% of subjects in the AL+Zn group, compared with 83% in the AL group (P=0.315); pain was classified as "moderate" (30 mm≤VAS<54 mm) in 11% of subjects in the AL+Zn group, compared with 4% in the AL group (P=0.060). Of note, pain was classified as "severe" (VAS≥54 mm) in only 1% of subjects in AL+Zn group, compared with 13% of subjects in the AL group, indicating a significant difference (P=0.00088). Esophagitis grade ≤2 occurred in 67% of subjects in the AL+Zn group, compared to an incidence of 84% in the AL group, a non-significant difference (P=0.196). While no grade 3 cases of esophagitis were noted in the AL+Zn group, one was noted in the AL group. Conclusion. Although polaprezinc proved effective in reducing the incidence of severe pain associated with esophagitis induced by CRT in patients with thoracic malignancies, we did not observe any general preventive effects.

Background. We herein report a case of unexpected death due to invasive pneumococcal disease during chemotherapy for small cell lung cancer. Case. A 65-year-old man was diagnosed with extensive-stage disease small cell lung cancer, cT1bN3M1b (OSS, HEP), cStage IV. He had received cisplatin and etoposide as first-line chemotherapy, amrubicin as second-line chemotherapy, and irinotecan as third-line chemotherapy. He developed a fever and expectorated purulent sputum on the 27th day of the second course of third-line chemotherapy and was hospitalized with right lower lobe pneumonia. Penicillin-sensitive Streptococcus pneumoniae was isolated from his sputum and blood. His respiratory condition rapidly worsened, and he was placed on a mechanical ventilator on the day of hospitalization. Despite antibiotic treatment and intensive care, he died due to acute renal failure and septic shock. He had never been given a pneumococcal vaccine. Conclusion. Patients treated with chemotherapy sometimes miss a chance to receive pneumococcal vaccination due to their tight chemotherapy schedule. Unvaccinated patients who receive chemotherapy should be vaccinated against pneumococcal disease proactively.

Background. Combined large cell neuroendocrine carcinoma (LCNEC) is rare, and the clinical features and therapeutic strategy have not been yet established. We report a case of combined LCNEC in a young male patient that was initially interpreted as a pulmonary abscess. Case. A 36-year-old male patient presented with fever of two months duration and an abnormal shadow of the right lung. A medical examination revealed a high inflammatory reaction. He was diagnosed with a pulmonary abscess and treated with antibiotics but the treatment proved ineffective. Fluorodeoxyglucose-positron emission tomography (FDG-PET) revealed a high uptake in the mass of the right upper lobe, and a bronchoscopic lung biopsy confirmed a diagnosis of non-small cell lung cancer. Right upper lobectomy with mediastinal lymph node dissection was performed. The postoperative pathological diagnosis was combined LCNEC and adenocarcinoma (pT3N0M0 Stage IIB). He became afebrile soon after resection and the inflammatory reaction normalized at one month after surgery. He received 4 cycles of adjuvant chemotherapy (CDDP+CPT-11). At present, he is alive without recurrence at 31 months after surgery. Conclusion. Surgery and adjuvant chemotherapy achieved a good result in the treatment of a young patient with combined LCNEC. Some studies have reported that the clinical features of combined LCNEC are similar to LCNEC; however, it is suggested that the coexisting tumor might affect the therapeutic strategy and the prognosis of combined LCNEC.

Background. Lung metastasis of breast cancer 20 years after mastectomy with an air space pattern on imaging harboring an epidermal growth factor receptor (EGFR) gene mutation is rare. Case. A 62-year-old female with a surgical history of breast cancer at 42 years of age was referred to our hospital because of a persistent cough. Chest computed tomography (CT) revealed widespread ground-glass attenuation and air space consolidation in both the middle and lower lung fields. A pathological examination of the lung specimen revealed adenocarcinoma, which was positive for an EGFR gene mutation. The patient was treated with gefitinib for 4 weeks, but her CT findings deteriorated. She underwent a re-biopsy and was diagnosed with lung metastasis from breast cancer. On switching to hormonal therapy, her CT findings improved. Conclusions. We encountered a case of lung metastasis of breast cancer with an air space pattern on imaging that harbored an EGFR gene mutation. Physicians should consider not only lung cancer but also lung metastasis in cases with an air space pattern on imaging. Our case reminds us to consider the possibility of breast cancer, especially when there is a history of breast cancer.

Background. Lymphoepithelioma-like carcinoma (LELC) is a rare tumor that has features that are similar to lymphoepithelioma of undifferentiated nasopharyngeal carcinoma. Case. A 65-year-old man had undergone radiotherapy for prostate cancer five years previously. The patient was referred to our institution after the detection of a nodule in the left lower lobe of the lung by follow-up computed tomography (CT). Since the tumor had increased in size, we performed thoracotomy and open biopsy. A frozen-section examination revealed undifferentiated carcinoma, and left lower lobectomy was performed. A histological examination revealed irregular nests of atypical cells with large nuclei, and significant lymphocytic infiltration in the stroma of the tumor. A histological examination with hematoxylin-eosin staining revealed features similar to LELC of the lung. According to the World Health Organization classification (4th edition), a diagnosis of LELC requires infection by Epstein-Barr virus (EBV). However Epstein-Barr virus-encoded RNA in situ hybridization (EBER-ISH) and immunohistochemical staining for latent membrane protein 1 (LMP1) were negative in this case. Thus, due to the lack of EBV infection, the pathological diagnosis was non-keratinizing squamous cell carcinoma with marked inflammatory cell infiltration. At the time of writing, the patient has been recurrence-free for fifteen months. Conclusion. We experienced a case of non-keratinizing squamous cell carcinoma that showed pathological features that were similar to pulmonary LELC. A careful diagnosis is required because LELC and undifferentiated carcinoma have significantly different prognoses. Further studies are warranted to determine how to diagnose and treat EBV-negative cases that show findings similar to LELC.