Background. To compare lung cancer detection rate by sputum cytology, we need some assurance that the estimates do not vary widely if the different observers evaluate the same specimens. The aim of this study was to determine interrater agreement of sputum cytology diagnoses. Methods. Slides of sputum cytology from 150 subjects were selected from a pool of slides held by six of the laboratories that had participated in a population-based lung cancer screening program over the last ten years in Japan. The cytotechnologists in these laboratories had considerable experience with sputum cytology. Each case was reevaluated six times. Cases that were diagnosed as the same category by all six laboratories were selected as consensus cases to serve as standardized sputum cytology cases. Sixty-four cytotechnologists with various levels of experience in sputum cytology then reevaluated these consensus cases. Interrater agreement was calculated by kappa statistics including Fleiss' kappa. Results. All pairs of interlaboratory agreement for the 150 cases showed statistically significant kappa values, most pairs showing substantial agreement. Fleiss' kappa value across the six laboratories was 0.5. Twenty-six cases were identified as the consensus cases, and the agreement among observers with less experience of sputum cytology showed significantly lower than the agreement among those with considerable experience. Moreover, cytotechnologists with less experience under-diagnosed the slides significantly more often than those with considerable experience. Conclusion. When the observers have considerable experience with sputum cytology, interobserver agreement is good. Only cytotechnologists with considerable experience in this field make accurate diagnoses on sputum cytology.

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Three types of EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) such as gefitinib, erlotinib and afatinib are available for the treatment of EGFR mutation-positive lung cancer patients in Japan. Afatinib is an irreversible HER family (EGFR, HER2, HER4) blocker. Although treatment with this drug has a substantial clinical benefit, the frequency of adverse effects (AEs) such as rash, paronychia and diarrhea is high and management of these AEs is important. Two phase III studies (LUX-Lung 3, LUX-Lung 6) were performed to compare the efficacy of afatinib and platinum-based chemotherapy in previously untreated lung adenocarcinoma patients with EGFR mutations. Afatinib showed a significantly longer progression free survival (PFS) (primary endpoint) than chemotherapy in these two studies, and the results were similar to those of other clinical studies with first generation EGFR-TKIs (gefitinib, erlotinib). Afatinib also demonstrated a benefit in the overall survival (OS) for exon 19 deletion mutation-positive patients, which was not observed in other studies with first generation EGFR-TKIs. Although the mutation of threonine-790 to methionine (T790M) in EGFR has been reported to be a major cause of resistance to first generation EGFR-TKIs, the resistance mechanism to afatinib has not yet been elucidated. It is important to investigate the mechanisms of resistance to afatinib and to develop new strategies to overcome this problem. We herein summarize the utility of first line treatment with afatinib, while referring the results of both clinical studies and molecular biological studies.

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Now the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy is a standard first-line treatment for patients with non-small cell lung cancer (NSCLC) harboring an EGFR mutation. However, to further improve the clinical outcomes in this cohort, new treatment options need to be developed. The first-line combination of EGFR-TKI plus platinum-based doublet chemotherapy is a promising strategy. As a result, we conducted a randomized phase II NEJ005/TCOG0902 study and a phase III NEJ009 study to explore the efficacy and safety of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. The rationale of the combinatorial approaches and results of the NEJ005/TCOG0902 study are summarized in this report.

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To date, no drugs or strategies have been developed to prevent or overcome acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in EGFR-mutated non-small cell lung cancer (NSCLC). We hypothesized that the insertion of platinum-doublet chemotherapy after the initial response to EGFR-TKI might prevent the emergence of acquired resistance to EGFR-TKI and prolong the patient survival. To test this hypothesis, we carried out a phase II study of the following first-line treatment for patients with advanced NSCLC harboring EGFR mutations. Gefitinib was administered on days 1-56. Then, after a two-week drug-free period, three cycles of cisplatin and docetaxel were administered on days 71, 92, and 113. Thereafter, gefitinib was reinitiated on day 134 and continued until disease progression. This phase II study showed promising outcomes, including a median progression free survival of 19.5 months and median survival time of 48.0 months. To confirm this phase II result, a phase III clinical trial comparing gefitinib monotherapy and gefitinib combined with inserted platinum-based chemotherapy (cisplatin plus pemetrexed) started as an intergroup trial in Japan by the Japan Clinical Oncology Group (JCOG) and West Japan Oncology Group (WJOG) (JCOG1404/WJOG8214L, AGAIN study).

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The identification of driver mutations and the development of targeted therapies have significantly changed the treatment of non-small cell lung cancer (NSCLC). The rearranged during transfection (RET) fusion gene was first identified in 1985. Somatic RET mutations have been observed in 30-50% of sporadic medullary thyroid cancer, and somatic RET gene fusions have been observed in 30-50% of sporadic papillary thyroid cancer. In 2012, four studies identified fusions of the RET oncogene in NSCLC and RET fusion genes were present in 1-2% of lung adenocarcinomas. In addition, sorafenib, sunitinib, cabozantinib, vandetanib, ponatinib, lenvatinib, and regorafenib (BAY 73-4506) are known as multi-target agents which have significant activity against RET, and some of these agents have been approved for the treatment of advanced medullary thyroid cancer or other cancers. Therefore, these agents will be available as RET inhibitors for NSCLC with RET fusion genes in the clinical setting, and several clinical studies are currently ongoing. In this symposium, the current situation of the development of RET inhibitors will be reviewed.

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In Japan, the number of elderly patients with lung cancer is increasing along with the prolongation of life. In the 2012 Japan cancer registry, 73% of lung cancer deaths occurred in patients ≥70 years of age. The Japanese guidelines recommend monotherapy with third-generation agents as grade A treatment and carboplatin-based doublets as grade C1 treatment for elderly patients with an epidermal growth factor receptor (EGFR) wild-type status or unknown advanced non-squamous non-small cell lung cancer (NSCLC) and recommend the same regimen for elderly patients with advanced squamous cell lung cancer. However, three meta-analyses reported conflicting results regarding the use of monotherapy vs. doublet chemotherapy in elderly patients with advanced NSCLC. Therefore, no clear-cut consensus for optimal chemotherapy for this population exists. In Japan, a phase III trial evaluating the inferiority of carboplatin-pemetrexed doublet chemotherapy to docetaxel monotherapy is ongoing among elderly patients with advanced non-squamous NSCLC. Although no comparative trials in elderly patients with EGFR mutation-positive disease have been reported, the use of EGFR tyrosine kinase inhibitors (TKIs) in this population has been widely accepted based on several phase II trials in Japan. A Japan Clinical Oncology Group (JCOG) phase III trial demonstrated the superiority of daily carboplatin plus thoracic radiotherapy over radiotherapy alone for elderly patients with locally advanced stage III NSCLC. In elderly patients with extensive disease small cell lung cancer (ED-SCLC), carboplatin plus etoposide (CE) is considered to be a standard regimen, and a JCOG phase II/III study comparing carboplatin plus irinotecan with CE for elderly patients with ED-SCLC is ongoing. Although the use of a simple and effective comprehensive geriatric assessment (CGA) has been warranted for a long time, no standard CGA methods have been established to date. Additional clinical trials of elderly lung cancer patients are thus needed.

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Purpose. Idiopathic interstitial pneumonia (IIP) is associated with an increased risk of lung cancer. However, the contribution of anticancer therapies is unclear because these therapies, including surgery, may trigger acute exacerbation (AE), and are confounded by the progressive nature and poor prognosis of IIP. The purpose of the present study was to identify the predictors of both AE and long-term survival after surgical resection for lung cancer. Methods. We retrospectively analyzed the cases of 1,763 non-small cell lung cancer patients who underwent pulmonary resection between January 2000 and December 2009 after presenting with a clinical diagnosis of IIP at 61 institutions in Japan. Results. AE occurred in 9.3% of the patients; the mortality rate was 43.9%. A multivariate analysis identified the following seven risk factors for AE: anatomical surgical resection, male sex, a history of AE, preoperative steroid use, a high serum level of sialylated carbohydrate antigen KL-6, the usual appearance of interstitial pneumonia on CT, and a reduced percent predicted vital capacity (%VC). Unfortunately, no effective prophylactic medications could be identified. The overall 5-year survival rate was 40%, which was poorer than that in the historical control. The multivariate analysis revealed that wedge resection, %VC <80% and lower lobe cancer were predictors of poor survival. Of note, wedge resection reduced the incidence of death due to respiratory failure but resulted in a poorer long-term prognosis than lobectomy because of the higher incidence of cancer recurrence. We further developed a simple risk scoring system for predicting AE by giving weight to each of the seven risk factors. Conclusions. We identified seven risk factors for AE and three predictors of a poor prognosis after surgical resection for lung cancer associated with IIP. We further developed a simple risk scoring system for predicting AE. Using this risk scoring system, surgeons can preoperatively assess the risk of AE in each patient and may choose an appropriate surgical procedure in routine clinical practice.

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Objectives. To retrospectively investigate thoracoscopic lobectomy (TL) for clinical stage I (c-I) lung cancer. Methods. From April 2008 to December 2012, 325 consecutive patients with c-I lung cancer were treated with TL. We retrospectively studied 238 patients who underwent TL with lymph node dissection (LND) through four incisions (7, 7, 15, and 30 mm) and 255 patients who underwent open thoracotomy lobectomy (OTL) with LND. The postoperative data, including the prognosis, were thereafter evaluated. Results. There were significant differences in c-IA/IB and in pathological stage between the two study groups. Because this study was a retrospective study, there was some selection bias. The median follow-up was 43 months. The actuarial 5-year survival rates in both groups, including all-cause mortality, were 91.2% in the TL group and 86.8% in the OTL group (p=0.021). The relapse-free survival at 5 years was 89.5% in the TL group and 70.3% in the TL group (p<0.001). There was no significant difference in the recurrence site between the groups. In 325 TL patients, 11 patients were cN0-pN1 and seven were cN0-pN2. However, there were no recurrences at the dissected site and no patients with positive pleural lavage cytology after resection. However, there were five patients with carcinomatous pleuritis after resection. Conclusions. There was some selection bias between the two groups, but TL achieved a good prognosis. No postoperative recurrence due to technical aspects of TL were observed. Therefore, the operative indications for TL may include patients with clinical N1 or single station N2 lung cancer in whom angioplasty and bronchoplasty are unnecessary.

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Traditionally, radiation treatment planning for thoracic tumors has assumed such patients to be homogeneous. In the 2000s, the development of three-dimensional (3D) treatment planning systems has led to the widespread adoption of 3D planning in Japan. Calculations taking into account the presence of heterogeneity have now become available by 3D planning. This allows us to accurately evaluate the patient doses. We are also able to calculate the doses in organs at risks, but this new methodology is useful for determining the eligibility for definitive thoracic radiotherapy. In the era of 2D planning radiation therapy, there was no major difference in the tumor dose among sites or physicians if the treatment fields were adequately shaped. However, there is a fear of underdosing the primary tumor by more than 10% when correcting for heterogeneity and the increasing differences among sites and physicians. Standardization for treatment planning is therefore strongly needed. The recommended dose and fractionation for stage III non-small-cell lung cancer (NSCLC) ranges from 60 to 66 Gy daily 1.8 to 2.0 Gy fraction based on several prospective clinical trials. There is no evidence to support high dose radiotherapy of more than 70 Gy for stage III NSCLC. In the future, new strategies such as risk-adapted doses and fractionation approaches should be evaluated to improve the clinical results for stage III NSCLC.

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Stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) is regarded as one of the standard treatments currently available. Randomized trials which compare SBRT and surgery have been discontinued early due to the slow accrual of patients, although many physicians are interested in whether SBRT is indicated for operable patients. SBRT is available globally; however, there are differences in radiotherapy methods, such as fractionation, between Japan and other countries. The linear quadratic model (LQ model) is used to compare the effectiveness between different fractionation schedules. The predictive ability in the high-dose area by the LQ model is not adequate, thus many alternative models have been proposed. However, some investigators insist that the LQ model is adequate in the high-dose area. Although it is important to have a definite model, it is also important to establish the safety of SBRT in clinical research.

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Objective and Methods. Particle therapy (PT) using protons and carbon ions has advantageous physical properties for radiotherapy (RT). We herein demonstrate the effectiveness and feasibility of PT for both early and locally advanced non-small cell lung cancer (NSCLC) and discuss the future prospects of PT. Results. Stereotactic body radiation therapy (SBRT) and PT have dramatically improved the treatment outcomes for stage I lung cancer patients compared to conventional RT, and PT can further reduce the lung volumes irradiated at low to middle doses, a risk of developing radiation-induced lung injury (RILI) after thoracic RT, when the tumor diameter becomes particularly large. In fact, grade 3 lung morbidity rates after PT for stage I NSCLC were consistently very low irrespective of the T stage. To successfully treat locally advanced lung cancer, a larger irradiation field, a larger irradiation dose, and the concurrent use of chemotherapy are necessary, and it has a higher risk of developing severe lung morbidities. A recent randomized phase III study (RTOG0617) for stage III NSCLC did not show the effectiveness of concurrent chemoradiotherapy (CCRT) using a high irradiation dose (74 Gy/37 fr) compared with CCRT using standard dose irradiation, potentially due to a higher toxicity rate in the high-dose group. Conversely, the preliminary findings from phase II studies suggest the feasibility of CCRT at a total dose of 74 Gy using proton beams. Hence, a randomized phase III trial of high-dose CCRT for stage III NSCLC is now being performed to confirm the effectiveness of proton beam therapy. Conclusions. PT for both early and locally advanced NSCLC is an attractive RT method. Recent novel treatment techniques, such as a spot-scanning, will further allow us to spare the normal lung and reduce RILI after thoracic RT. The Japanese Radiation Oncology Study Group has elected to establish a particle therapy group, which will design and manage the future prospective study.

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The clinical development of third-generation EGFR-TKIs, MET, HSP90, mTOR inhibitors etc. has been sought to overcome acquired EGFR-TKI resistance. Phase I studies of third-generation EGFR-TKI, AZD9291 and CO-1686 drugs have demonstrated an approximately 60% response rate in patients positive for T790M, with a lower frequency of rashes and diarrhea than that associated with first- or second-generation EGFR-TKIs. A phase Ib study of cetuximab (EGFR antibody) and afatinib (second-generation EGFR-TKI) reported a response rate of 32% in T790M-positive patients and 25% in T790M-negative patients. This combination chemotherapy is promising, regardless of the T790M status, although it may produce severe rashes and/or diarrhea. A phase Ib/II study of INC280 (MET inhibitor) found a response rate of 21% (8 out of 38) in patients with a high expression of MET. In the future, further clinical development is needed to overcome acquired resistance to EGFR-TKIs, which is expected to progress based on the mechanism of resistance. Secondary biopsies and gene analyses have become important for detecting progression during EGFR-TKI treatment.

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EML4-ALK fusion gene-positive non-small cell lung cancer (NSCLC) was first reported in 2007. Crizotinib (Xalkori^®), an ALK tyrosine kinase inhibitor (TKI), was subsequently reported to be effective for ALK fusion gene-positive NSCLC in 2010. This led to its clinical adoption for this indication in Japan two years later. In 2014, alectinib (Alecensa^®) was clinically introduced in Japan. Meanwhile, it was reported as early as 2010 that secondary mutations in the ALK fusion gene occur as a mechanism of acquired resistance. Some conceivable mechanisms of acquired resistance to ALK-TKIs include secondary mutations (e.g., gatekeeper mutations), ALK fusion gene amplification, and the activation of the bypass track, though much has yet to be elucidated. It most likely will be necessary to develop treatment strategies in the future for each type of acquired resistance. Several clinical trials are ongoing or being planned as of 2015. In this article, we outline the development and current status of therapies for acquired resistance to ALK-TKIs.

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Apoptosis resistance has recently been reported to be a factor which induces resistance to EGFR-TKI at an early stage in EGFR mutant lung cancer. BIM is a BH3-only pro-apoptotic protein, and its upregulation is required for apoptotic induction by EGFR-TKI. Notably, a BIM deletion polymorphism occurs naturally in 13% of East Asian individuals, impairing the generation of the pro-apoptotic isoform required for EGFR-TKI, therefore conferring an inherent drug-resistant phenotype. We previously reported that an HDAC inhibitor, vorinostat, could increase the expression of functional BIM protein, which was sufficient to restore gefitinib sensitivity. An investigator-initiated Phase I trial using vorinostat and gefitinib combination therapy in a multi-institution study for EGFR mutant lung cancer patients who have a BIM polymorphism is currently under way.

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Objectives. In the present study, we elucidated the mechanism underlying EGFR inhibitor resistance and examined whether the anti-HER3 antibody patritumab can overcome this resistance. Furthermore, heregulin, a HER3 ligand, was assessed in regard to whether it could be used as a predictive biomarker of patritumab plus erlotinib therapy in patients with non-small cell lung cancer (NSCLC). Methods. The EGFR mutant NSCLC cell line PC9HRG with a high heregulin expression was used to evaluate the sensitivity of patritumab and erlotinib and the effects of these drugs on intracellular signaling. The heregulin expression was measured using tissue samples obtained from NSCLC patients treated with patritumab plus erlotinib or placebo plus erlotinib in a randomized phase II study (HERALD study). Results. PC9 cells were found to be sensitive to erlotinib, whereas PC9HRG cells were resistant to erlotinib, as HER3 was reactivated depending on the heregulin expression. The degree of susceptibility to patritumab also depended on the heregulin expression level, not the HER3 expression level, among 49 NSCLC cell lines. Resistance to erlotinib was overcome by the patritumab combination in PC9HRG cells. Therefore, patritumab plus erlotinib significantly prolonged the progression-free survival versus the placebo plus erlotinib in the NSCLC patients with a high heregulin expression in this randomized phase II clinical study. Conclusions. EGFR inhibitor resistance is induced by heregulin overexpression in NSCLC; however, this resistance is overcome by patritumab combination therapy.

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Crizotinib (March 2012) and alectinib (July 2014) represent the ALK inhibitors that have been approved for use in Japan. For advanced NSCLC, the Japan Lung Cancer Society guidelines recommend to devise a treatment strategy after determining the EGFR mutation status and whether a patient is ALK fusion gene-positive. Both of the above-mentioned agents are used upon a diagnosis of whether a patient is ALK fusion gene-positive. However, the two drugs differ because they both have their own companion diagnostic agent. This can create issues in the clinical setting. For instance, if a doctor wishes to administer alectinib to a patient for whom crizotinib has been effective after an ALK fusion gene-positive diagnosis, the doctor must re-test with the alectinib companion diagnostic. Several issues come to light when one considers how to diagnose whether a patient is ALK fusion gene-positive accurately with the shortest turn around time possible in order to provide patients with the most suitable drug therapy. It is important to manage the side effects of these drugs to maximize upon their effects. In order to properly manage the side effects, it is also important to engage in treatment while ascertaining the latest side effect data as well as information such as the "Treatment guide" supplied by the pharmaceutical companies. This paper touches upon case selection and side effect management when using ALK inhibitors based upon a similarly titled presentation at the 55th Annual Meeting of the Japan Lung Cancer Society (November 2014).

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Angiogenesis plays an important role in the development and differentiation of NSCLC. The VEGF pathway is critical to tumor angiogenesis and has become an important therapeutic target. VEGF and its receptor have been investigated as potential molecular targets for second-line NSCLC. In the case of bevacizumab, the efficacy of this approach has been established in the first-line setting. However, bevacizumab has not shown clinical efficacy as a second-line agent, and antiangiogenic, small-molecule TKIs, including vandetanib, sorafenib, and sunitinib, have also failed to demonstrate a significant overall survival (OS) benefit in NSCLC, despite some improvements in progression-free survival (PFS). The agents that are currently approved for second-line chemotherapy include docetaxel, pemetrexed and erlotinib. The survival benefit associated with second-line therapy is generally modest. The median OS improvement achieved with these agents is 7-8 months. Nintedanib (BIBF1120) is a potent, oral, small-molecule triple angiokinase inhibitor which targets VEGF receptors 1-3, platelet-derived growth factor receptors alpha and beta, and fibroblast growth factor receptors 1-3 along with RET and Flt3. The results of a recent Phase III trial (LUME-Lung 1) for nintedanib demonstrated a significant benefit in the primary endpoint of PFS and the key secondary endpoint of OS as a second-line therapy in combination with docetaxel in NSCLC. The median OS in adenocarcinoma was greater than 1 year. In the EU, nintedanib was approved for use in the treatment of lung cancer patients with advanced adenocarcinoma after first-line chemotherapy based on the positive results of the LUME-Lung 1 study. Phase I studies of second-line nintedanib combined with docetaxel or pemetrexed have been performed in Japanese patients with advanced NSCLC. In light of these promising clinical data, this review provides an overview of the clinical development of antiangiogenic agents, including nintedanib, which will be used as second-line treatments and summarizes the current clinical experience with nintedanib in the treatment of NSCLC, with a focus on the data that are relevant to routine clinical practice.

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The mainstay of medical treatment for advanced non-small cell lung cancer (NSCLC) had been chemotherapy with cytotoxic agents, as represented by a two-drug combination of a platinum compound plus a third-generation anti-cancer drug, for decades. However, the development of molecular targeted agents, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and anaplastic lymphoma kinase inhibitors, has substantially contributed to progress in the management of NSCLC in recent years. Moreover, maintenance therapy with pemetrexed has been shown to prolong the overall survival of patients. These advancements are, however, limited to non-squamous NSCLC, and cytotoxic agents continue to serve as the standard treatment for squamous cell carcinoma of the lung (squamous NSCLC). On the other hand, clinical trials are actively ongoing to evaluate the safety and effectiveness of promising cytotoxic agents such as S-1, nab-paclitaxel, and nedaplatin in patients with squamous NSCLC. Nedaplatin combined with docetaxel was demonstrated to be effective for the treatment of squamous NSCLC in 2015. In addition, newly developed drugs such as an anti-EGFR antibody and immune checkpoint inhibitors are emerging. Major advances in the medical treatment of squamous NSCLC are expected in the near future.

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The 2014 edition of the clinical guidelines for lung cancer in Japan included the following description, "Surgical resection may be considered after induction therapy for patients with clinical N2-IIIA non-small cell lung cancer (NSCLC)." However, the definition of resectable lung cancer may vary from institution to institution, and preoperative chemotherapy regimens and radiation doses have not been standardized. Moreover, large-scale clinical trials including INT0139, EORTC08941 could not prove the significance of surgery in combination with preoperative treatment for patients with stage III NSCLC. Recently, chemoradiotherapy has been associated with improved clinical outcomes in patients with unresectable stage III NSCLC. Some phase II trials have shown 2-year overall survival rates of 40-80%; thus, with appropriate patient selection, some patients with resectable stage III NSCLC may be completely cured with chemoradiotherapy. The West Japan Oncology Group, which has been developing a new treatment strategy for patients with unresectable stage III NSCLC, reported the first results of WJOG5008L at ASCO2015. We review the possible use of chemoradiotherapy in the treatment of patients with resectable stage III NSCLC with reference to the first results from WJOG5008L.

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It has been a part of daily practice to select patients for targeted therapies according to the results of genetic testing analyses. A basis of tumor molecular pathology is required to understand the advantages and disadvantages of the methods for the proper evaluation of the results. There are two types of cancer-associated genes: oncogenes and tumor suppressor genes. Currently, most molecular targeted therapies are developed for oncogenes, which can be categorized into four major genetic alterations. In this review, the four major genetic alterations, including gene mutation, gene amplification, gene rearrangement and protein overexpression, are reviewed and the detection methods and tissues types to be examined are discussed.

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Progress in drug development has led to the significant extension of overall survival in patients with advanced lung cancer. Although immunotherapy was previously expected to constitute a fourth type of treatment, there has been no evidence to indicate that it prolongs survival. Recently, new drugs which inhibit the immune checkpoints have been developed as a new type of immunotherapy. In particular, immune checkpoint inhibitors which target CTLA-4, PD-1 and PD-L1 have been rapidly developed and several large clinical trials have been conducted. However, since they have been reported to exhibit anti-tumor effects which differ from those of conventional anti-tumor agents, the efficacy of immunotherapy may not be adequately assessed by the conventional WHO and RECIST criteria. While new evaluation criteria, such as the irRC have been tried, they are not yet sufficient and some issues remain, in relation to the comparative tests that compare immunotherapy drugs to conventional cytotoxic anticancer drugs or molecular targeted drugs. Because immune checkpoint inhibitors tend to achieve greater improvements in survival in comparison to conventional treatment, and have the potential to dramatically improve the prognosis associated with advanced lung cancer, the creation of better evaluation criteria, the development of predictive biomarkers and the accumulation of data relating to the incidence of adverse events after the administration of immune checkpoint inhibitors is desired.

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Objective. We reviewed our institutional experience with cases of induction therapy followed by resection for advanced thymic tumors to determine patient outcomes and prognostic indicators. Method. The prognoses of 24 thymoma and 16 thymic cancer patients who underwent induction therapy followed by resection were retrospectively analyzed. The preoperative workup findings suggested great vessel invasion in 13 patients, mediastinal or intrathoracic lymph node metastasis in 3 patients and pleural dissemination in 11 patients. After the pathological diagnosis of the patient's biopsy specimens, they received induction therapy. There were 20, 13 and 7 patients with tumors that corresponded to Masaoka stages of III, IVa, and IVb, respectively. Results. The resection was extended to the surrounding organs in addition to thymectomy including the thymic tumor, such as the superior vena cava in 11 patients, the aorta in 1 patient, and the right brachiocephalic artery in 2 patients. Lobectomy was performed in 6 patients and pleuropneumonectomy was performed in 2 patients. There were no cases of operative mortality recorded among the patients who underwent induction therapy followed by surgery. Twenty-three patients had an R0 resection, 9 had an R1 resection and 8 had an R2 resection. The median follow-up period was 5.2 years. The 5-year survival rate for all patients was 82% (thymoma [93%], thymic cancer [63%], stage III [100%], stage IV [67%], R0 resection [100%], R1 resection [64%] and for R2 resection [60%]). There was no 5-year survivors among the thymic cancer patients who underwent an R1-R2 resection. Conclusion. A multimodal treatment strategy may result in a promising survival outcome for patients with advanced thymoma. Complete resection is the prognostic indicator in thymic cancer patients who undergo induction therapy followed by surgery.

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Objective. Patients with lung cancer have a higher risk for venous thromboembolism (VTE). Anticoagulation treatment for VTE is important in addition to the treatment for lung cancer. Warfarin is one of the anticoagulation treatments for VTE, however, recurrence of VTE is often problematic during warfarin treatment. In January 2012, the subcutaneous injection of heparin calcium at home was covered by health insurance in Japan, which may be added to potential anticoagulation treatment for VTE. Methods. We conducted a retrospective analysis of 29 patients who received initial anticoagulation treatment, including a heparin injection into the vein, and were subsequently treated with warfarin among 39 lung cancer patients with newly diagnosed VTE in the First Department of Medicine, Hokkaido University Hospital, between October 2006 and April 2014. Results. Eleven patients had recurrence of VTE. Of these, 9 patients received a subcutaneous injection of heparin calcium and 1 patient received fondaparinux sodium and responded. Although all 9 patients ultimately died of cancer, the subcutaneous injection of heparin calcium enabled 2 patients to continue to receive chemotherapy and ambulatory treatments for VTE without recurrence of VTE. Conclusions. This study demonstrates that patients with recurrence of VTE can continue to receive regular ambulatory chemotherapy for cancers in combination with the subcutaneous injection of heparin calcium at home.

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Background. Pulmonary spindle cell carcinoma which consists of only spindle cells is quite a rare disease and it is associated with a poor prognosis due to its rapid progression and resistance to chemotherapy. Case. A 78-year-old woman was referred to our hospital because of an abnormal lung shadow on a chest X-ray obtained during a health examination. Chest computed tomography (CT) at the initial visit showed a mass measuring 45 mm in diameter in the S² segment of the right lung, and lymph node enlargement of #2R, #7 and #11s was also observed. CT-guided lung biopsy revealed poorly-differentiated non-small-cell carcinoma of the lung, which was suspected to be pleomorphic carcinoma, and the patient was diagnosed to have cStage IIIA lung cancer. A follow-up CT at 1.5 months later showed the tumor growth to be 55 mm in diameter and polypoidal progression to the central side in the right upper lobe pulmonary vein was found. Since there is no chemotherapy that has been proven to be effective for the treatment of pleomorphic carcinoma, right upper lobectomy and node dissection ND2a-2 were performed. With the right superior pulmonary vein blocked in the pericardium, the right upper lobe pulmonary vein was transected. The extent of tumor progression was confirmed to be confined to within the vein, and its stump was closed by suturing. The tumor was pathologically diagnosed to be pulmonary spindle cell carcinoma, pStage IIIA. Postoperative adjuvant therapy was not performed because of the patient's condition. Distant metastatic lesions in the inguinal and pelvic lymph nodes and soft tissue of the buttocks were detected 3 months after surgery, and the patient died of the disease 9 months after surgery. Conclusion. Pulmonary spindle cell carcinoma has the possibility of demonstrating a rapid recurrence, even if complete resection is performed. Further studies are therefore needed to fully identify the characteristics of pulmonary spindle cell carcinoma and improve the patient prognosis.

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Background. Although there are reports to indicate that lung cancer screening is useful for the early detection of lung cancer, if examinees who require detailed examinations do not undergo secondary screenings, the significance of the examination itself will be lost, no matter how early the lung cancer is detected. Case. A 66-year-old woman underwent a computed tomography scan for lung cancer screening in May 2010, which revealed a ground glass nodule involving a solid component (size, 15 mm) in the right upper lobe. She was followed up, but later chose to discontinue the follow-up. In June 2014, the opacity had increased to 25 mm in size. She was suspected of having lung cancer. She underwent surgery and was diagnosed with lung adenocarcinoma. Postoperative adjuvant chemotherapy was administered. Conclusion. Lung cancer is a refractory cancer that is associated with an extremely poor prognosis; the 5-year survival rate is ≤15%. Our study suggests the necessity for proposing measures against non-compliance with detailed examinations or secondary screenings for patients who are suspected of having lung cancer. Additionally, images that are taken during follow-up examinations for ground glass nodules that are detected by screening should be interpreted, considering the expected progression of pathological findings and the possibility that an opportunity for curative resection might be missed.

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Background. Advances in research of the genes responsible for non-small cell lung cancer, especially adenocarcinoma, have now made it possible to select effective therapeutic agents, i.e., an anaplastic lymphoma kinase (ALK) inhibitor (crizotinib), in patients with the echinoderm microtubule associated protein like 4 (EML4)/ALK fusion gene. We herein report a case of bulky N2 lung cancer that was treated with crizotinib followed by surgery. Case. A 34-year-old man visited our hospital for an evaluation of abnormal shadows on a chest radiograph taken during a medical checkup. Chest computed tomography (CT) showed a nodule measuring 9 mm in diameter in the periphery of the right lower lobe and enlarged lymph nodes in the bifurcation of the trachea (#7) and between the lobar bronchi (#11i). Endobronchial ultrasound-guided transbronchial needle aspiration revealed adenocarcinoma in the lymph node (#7), and the patient was positive for the EML4/ALK fusion gene. He was diagnosed with cT1aN2M0, Stage IIIA lung cancer and thus was started on oral crizotinib. Two months after the start of this treatment, chest CT showed a reduction in the lung nodule and lymph nodes (#7, #11i) by 55%, thus leading to a decision to perform surgery. Right middle and lower lobectomy and lymph node dissection were performed. The pathological diagnosis was adenocarcinoma with mixed subtypes, ypT1aN1M0 Stage IIA, Ef.2. The patient has remained disease-free for 9 months, to date, since the surgery. Conclusion. We herein presented a patient with EML4/ALK fusion gene-positive lung cancer who was treated with ALK inhibitor followed by surgery. When treating cases of unresectable advanced lung cancer, it may still be possible to perform surgery after tumor shrinkage.

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Background. We herein report a case of a bronchial foreign body. This body was difficult to distinguish from lung cancer based on sputum cytology, which suggested a malignancy. Case. A man in his 70s underwent chest computed tomography due to persistent coughing. Stenosis of the right upper lobe bronchus was observed and he was admitted to our hospital. Sputum cytology was used to make a diagnosis, with the suspicion of a malignancy (adenocarcinoma). Bronchoscopy showed that there was a raised lesion with some necrosis in the right B³ inlet. Fluorodeoxyglucose positron-emission tomography at the same site and right hilar node showed an accumulation of fluorodeoxyglucose. According to these findings, we made the diagnosis of right upper lobe central type lung cancer (cT1aN1M0) and performed right upper lung wedge sleeve lobectomy. Postoperatively, a histopathological examination showed that the lesion of the B³ inlet portion was a foreign body (food residue). Regenerative atypia and squamous metaplasia were observed in the epithelium around this body. Atypical glandular epithelial cells that had been observed in sputum cytology appeared to be due to a reaction of the bronchial epithelium by erosion. Conclusion. We performed video-assisted thoracic surgery lobectomy for a bronchial foreign body. This foreign body was originally suspected as being adenocarcinoma according to sputum cytology and other examinations.

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Background. We herein report two cases of stage IV lung adenocarcinoma for which gefitinib administration resulted in a long-term survival of more than 10 years. Cases. Case 1 was a 76-year-old woman at the time of death. She was diagnosed with left S⁶ adenocarcinoma (cT2N1M1 stage IV) and treated with gefitinib starting in September 2002. The only adverse event was a mild grade 1 rash. After ten years and four months of gefitinib administration, her bone and liver metastases progressed. We discontinued gefitinib and then administered cytotoxic chemotherapy. However, the patient died eleven years and three months from the start of treatment. Case 2 was a 75-year-old man. He was diagnosed with right upper lobe lung adenocarcinoma (cT2N3M0 stage IIIB) and started chemoradiotherapy. Because a large number of skin metastases developed, the patient was treated with gefitinib starting in November 2002. The only adverse event was mild grade 1 diarrhea. The patient has continued to receive gefitinib for twelve years. A mutation in the epidermal growth factor receptor gene (exon 19) was identified in both cases after initiating gefitinib treatment. Conclusion. There have been few reports of long-term gefitinib administration. Further research is necessary to identify factors indicative of resistance to treatment after long-term gefitinib administration.

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Adenocarcinomas, squamous cell carcinomas, and small cell carcinomas, collectively referred to as primary lung carcinomas, account for over 90% of all primary lung tumors. Other lung tumors are uncommon and may have epithelial, tracheobronchial gland, neuroendocrine, lymphopoietic, hematopoietic, mesenchymal, or uncertain cell origin. With notable exceptions, the imaging appearances of these tumors are non-specific since most tumors demonstrate considerable overlap with their rare counterparts, as well as with more common primary lung cancers. Consequently, the diagnosis of unusual lung tumors is typically made retrospectively from a biopsy or pathological specimen. Nevertheless, the presence of certain clinical and radiological features may alert the radiologist to the possibility of an uncommon lung tumor. Low malignant potential tumors include carcinoids (typical and atypical), adenoid cystic carcinomas, and mucoepidermoid carcinomas, each of which originate near the central airway. Carcinoid tumors commonly show well-defined nodules with intense enhancement on contrast-enhanced CT, and adenoid cystic carcinomas have a striking tendency toward submucosal extension and manifest with circumferential and infiltrative growth. Benign pulmonary tumors include hamartomas and sclerosing pneumocytomas (formerly referred to as sclerosing hemangioma), each of which show well-defined and smooth marginated nodules. Intranodular fat and popcorn-like calcifications are reliable indicators of hamartomas. Sclerosing pneumocytomas have been described as well-defined nodules with intense enhancement without contact with the major bronchus and pulmonary vessels. MALT (mucosa-associated lymphoid tissue) lymphomas and diffuse large cell B-cell lymphomas are relatively common pulmonary lymphomas. MALT lymphomas are typically single or multifocal and comprise ill-defined nodules containing air bronchograms, which occasionally appear as focal consolidation. Mediastinal lymphadenopathy is uncommon in MALT lymphomas. On the other hand, diffuse large cell B-cell lymphomas, single or multiple solid pulmonary nodules or masses that mimic lung cancer, and mediastinal or hilar lymph node enlargement are usually present. Pulmonary sarcomas are very rare and typically present as solitary huge masses that mimic common primary lung cancers. Characteristic imaging findings of pulmonary sarcomas are pulmonary intimal sarcomas. The most characteristic finding is a vascular filling defect with varying enhancement or enhancement in a filling defect that virtually excludes thrombus.

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Objective. Adenosquamous lung carcinoma and lung pleomorphic carcinoma are rare forms of cancer. The frequency of occurrence is only a small percentage of all lung cancers. These are not considered to be sufficient. Methods. We retrospectively studied thin-section CT images and the clinical findings of the cases of adenosquamous lung carcinomas (16 cases) and lung pleomorphic carcinomas (19 cases) which were surgically resected at the Kanagawa Cancer Center. Result. Adenosquamous lung carcinoma was more prevalent among males than females. The diagnosis in these cases was made according to the symptoms of hemoptysis and abnormal findings on chest roentgenograms or CT. The tumors tended to be positioned in the peripheral part of the affected lobe. The components found in adenocarcinoma and squamous cell carcinoma tend to vary greatly, therefore the CT findings also show a large variation. The diameter of these tumors is relatively large. Vascular invasion, lymphatic permeation and pleural invasion are also observed in many cases. The accurate diagnosis rate before surgical resection is very low. The five-year survival rate ranges from 25-35% and thus is poor. No effective chemotherapeutic regimen has yet been established. Lung pleomorphic carcinoma is more prevalent among males than females. The diagnosis is usually made according to the symptom of hemoptysis and abnormal findings on chest roentgenograms. The tumors tend to develop in the peripheral part of the affected lobe. In many cases, the CT image findings demonstrate an oval shape and low density area or cavity in the tumor, which is consistent with pathological necrosis. Adenocarcinoma is the major cancerous component. Vascular invasion and pleural invasion are observed in many cases. The rate of making an accurate diagnosis before surgical resection is very low. The five-year survival rate ranges from 20-48% and is poor. No effective chemotherapeutic regimen has yet been established. Conclusion. Adenosquamous lung carcinomas and lung pleomorphic carcinomas present characteristic CT and clinical findings. Effective chemotherapeutic regimens must be established.

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