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Background Zinc‐finger E‐box‐binding homeobox 1 (ZEB1) is an important regulator of epithelial‐mesenchymal transition (EMT) and is involved in the maintenance of cancer stem cells (CSCs) via miR‐200c and BMI1 pathway. Recent studies revealed that ZEB1 contributes to the EMT‐mediated acquired resistance to gefitinib in EGFR‐mutant non‐small cell lung cancer (NSCLC). However, the precise role of ZEB1 in the maintenance of lung CSCs that lead to acquired resistance to gefitinib remains unclear. Methods PC9 and HCC827 NSCLC cell lines were treated with high concentrations of gefitinib, and surviving cells were referred to as “gefitinib‐resistant persisters” (GRPs). ZEB1 knockdown or overexpression was performed to determine the biological significance of ZEB1 in the CSC features of GRPs, and animal models were studied for in vivo validation. Expression of ZEB1, BMI1, and ALDH1A1 was analyzed by immunohistochemistry in tumor specimens from NSCLC patients with acquired resistance to gefitinib. Results GRPs had characteristic features of mesenchymal and CSC phenotypes with high expression of ZEB1 and BMI1, and decreased miR‐200c, in vitro and in vivo. ZEB1 silencing attenuated the suppression of miR‐200c, resulting in the reduction in BMI1 and reversed the mesenchymal and CSC features of GRPs. Furthermore, ZEB1 overexpression induced EMT and increased the levels of CD133‐ and BMI1‐positive GRPs in vitro and gefitinib resistance in vivo. Finally, ZEB1, BMI1, and ALDH1A1 were highly expressed in tumor specimens from EGFR‐mutant NSCLC patients with gefitinib resistance. Conclusions ZEB1 plays an important role in gefitinib‐resistant lung CSCs with EMT features via regulation of miR‐200c and BMI1., Gefitinib‐resistant persisters (GRPs) of EGFR‐mutant NSCLC cells have characteristic features of mesenchymal and CSC phenotypes. ZEB1 is highly expressed in GRPs and involved in the maintenance of lung CSCs resistant to gefitinib via miR‐200c‐BMI1 pathway.

Background Regimens combining pemetrexed (PEM) and immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) or programmed death-ligand 1 (PD-L1) are widely used for the treatment of advanced non-squamous non-small-cell lung cancer (NSq-NSCLC). Recently, PEM was shown to induce immunogenic cell death (ICD) and to enhance immune-regulatory genes. Some patients demonstrate an extremely long-term response to PEM. It is possible that the continued response in these patients is dependent on not only the pharmacological induction of cytotoxic cell death but also antitumor immunity. However, factors that can predict outcomes associated with long-term PEM administration using blood test results have not yet been elucidated. We investigated the clinical characteristics and predictive factors in patients with advanced NSq-NSCLC who underwent long-term PEM maintenance therapy. Methods In total, 504 patients with advanced NSq-NSCLC who received PEM combination therapy/monotherapy (n = 414) or paclitaxel (PTX) combination therapy (n = 90) between January 2010 and November 2019 were recruited; 381 patients were retained for the final analysis. Patients treated with PEM (n = 301) were divided into subgroups according to the total cycles of PEM (≥ 17 [n = 25] for the long-term administration group and ≤ 16 [n = 276] for the intermediate/short-term group) and compared with another population (n = 80) treated with PTX combination regimen. We investigated clinical features and predictive biomarkers, focusing on immune-regulatory factors, absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), and PD-1 and PD-L1 expression, to predict long-term response to PEM. Results The long-term PEM administration group exhibited a higher ALC and a lower NLR than the shorter-term group did. Both these markers displayed greater association with progression-free survival and overall survival in the PEM combination therapy group than in the PTX combination therapy group. Increased PD-1 lymphocytes were associated with the long-term PEM response group, as PD-L1 expression in tumors was associated with a high incidence of immune-related adverse effects following ICI administration. Conclusions ALC, NLR, and PD-1 expression are PEM-mediated predictive biomarkers that are indirectly related to tumor immunity and can provide useful predictive information on the long-term response to PEM in patients with NSq-NSCLC.

Background Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Combination therapies with first-generation EGFR-TKIs and bevacizumab have been reported to prolong progression-free survival (PFS). However, there are few data on the combination of afatinib and bevacizumab. Methods In this phase I trial, we evaluated the safety of afatinib plus bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring EGFR mutations. This study consisted of two cohorts. In the dose-finding cohort, enrolled patients were treated with afatinib at a dose of 20, 30, or 40 mg/day (days 1-21) plus bevacizumab at a dose of 15 mg/kg (day 1) in 21-day cycles. This cohort was performed according to a 3 + 3 manner. In the expansion cohort, enrolled patients received the recommended dose (RD) based on the results of the dose-finding cohort. The serum trough concentration of afatinib was determined at the steady state. Results Seventeen patients were enrolled in this study (6 patients in the dose-finding cohort and 11 patients in the expansion cohort). There were no dose-limiting toxicities (DLTs) with afatinib at a dose of 30 mg/day. With afatinib at a dose of 40 mg/day, two of two patients experienced DLTs (grade 3 diarrhea) in cycle 1. With these results, afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg was determined as the RD. Eleven patients in the expansion cohort were treated with the RD. Common treatment-related adverse events (AEs) with the RD were diarrhea (79%), rash (71%), perionychia (64%), and stomatitis (50%). Grade 3 AEs with the RD were diarrhea (7%), perionychia (7%), and hypertension (7%). There were no grade 4/5 AEs or cases of interstitial lung disease. Dose-proportional increases in serum afatinib trough concentrations at steady state were not observed. The response rates (RRs) and disease control rates were 55% and 100% in EGFR-TKI-naive patients. Re-biopsy was performed in eight patients after progressive disease following the study treatment, and three patients acquired a T790M mutation. Conclusions Afatinib at a dose of 30 mg/day plus bevacizumab at a dose of 15 mg/kg q3w is well tolerated.

Background and Purpose In breast cancer patients receiving neoadjuvant chemotherapy (NAC), immediate breast reconstruction (IBR) is controversial. We retrospectively investigated whether IBR after mastectomy influenced the short and long-term outcome of patients receiving NAC. Patients and Methods Between April 2007 and December 2017, 525 breast cancer patients received NAC at our hospital of which 186 patients underwent total mastectomy alone, 55 underwent total mastectomy followed by IBR, and 284 underwent breast conserving surgery (BCS). Patients receiving IBR were compared to patients who did not receive IBR. The NAC regimen was 4 cycles of epirubicin, 5-fluorouracil and cyclophosphamide followed by 4 cycles of docetaxel. Decision making for post mastectomy radiotherapy (PMRT) followed national comprehensive cancer network guidelines. PMRT is not contraindication for patients receiving IBR, however risk such as capsular contracture was informed to patients. Tissue expander was replaced to silicon breast implant within two to three months, and radiotherapy started within 4 to 6 weeks after surgery. In other surgical-procedure, such as direct-to-implant breast reconstruction, BCS or mastectomy alone, radiotherapy started 6-8 weeks later. Post-mastectomy radiation was applied equally with the same selection criteria to both groups. Results Patients in the IBR and BCS groups were on average younger than patients in the mastectomy alone group (p After a median of 76.4 month, 2 patients (4.2%) in the IBR group, 13 patients (4.5%) in the BCS group and 17 patients (9.1%) showed locoregional recurrences. Five-year locoregional recurrence-free survival was 96.1% in the IBR group, 96.8% in the BCS group and 90.1% in the mastectomy alone group (p= 0.032). Five-year distant disease-free survival was 92.9 % in the IBR group, 93.9% in the BCS group and 85.3 % in the mastectomy alone group (p= 0.0008). Five-year overall survival was 98.0 % in the IBR group, 98.4% in the BCS group and 92.3 % in the mastectomy alone group (p= 0.0004). Multivariate analysis showed that IBR was not associated with worse prognosis. Transverse rectus abdominis muscle flap necrosis was seen in one patient. Any breast implant or tissue expander related complications including infection and capsular contracture were not encountered. Conclusions IBR after total mastectomy can be performed safely and was not associated with worse prognosis in patients receiving NAC and therefore IBR may be the preferred strategy in select cases. Citation Format: Hiroko Nogi, Makiko Kamio, Takashi Kazama, Naoko Shimada, Takayuki Ishigaki, Hisashi Shioya, Yasuo Toriumi, Eijiro Nagasaki, Hiroshi Takeyama. Impact of immediate breast reconstruction after mastectomy on the short and long-term outcome of patients receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-14-08.

Malignant pleural mesothelioma (MPM) is a highly aggressive tumor that has a low overall survival; however, no significant treatment advances have been made in the past 15 years. Large-scale molecular studies have identified a poor prognostic subset of MPM linked to the epithelial–mesenchymal transition (EMT) that may contribute toward resistance to chemotherapy, suggesting that EMT could be targeted to treat patients with MPM. Previously, we reported that histone modifiers regulating EMT could be therapeutic targets; therefore, in this study, we investigated whether targeting lysine-specific demethylase 1 (LSD1/KDM1), a histone-modifying enzyme responsible for demethylating histone H3 lysine 4 and lysine 9, could represent a novel therapeutic strategy for MPM. We suppressed LSD1 and investigated the EMT phenotype using EMT marker expression and wound-healing assay; and chemosensitivity using apoptosis assay. We found that suppressing LSD1 induces an epithelial phenotype in sarcomatoid MPM cells, while attenuating the mesenchymal phenotype sensitized MPM cells to cisplatin-induced apoptosis. Subsequent genome-wide identification, comprehensive microarray analysis, and Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq) to assess genome-wide changes in chromatin accessibility suggested that LSD1 directly regulates milk fat globulin protein E8 (MFGE8), an integrin ligand that is involved in the FAK pathway. Furthermore, we found that LSD1 regulates the mesenchymal phenotype and apoptosis by activating the FAK–AKT–GSK3β pathway via a positive feedback loop involving MFGE8 and Snail expression, thereby leading to cisplatin resistance. Implications: This study suggests that LSD1 regulates the mesenchymal phenotype and apoptosis, and that LSD1 inhibitors could be combined with the cisplatin as a novel therapy for patients with MPM.

Background There are few studies that directly compare the effects of osimertinib on patients with non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation between the generation of prior EGFR tyrosine kinase inhibitors (TKIs). Methods We retrospectively reviewed clinical data from the medical records of consecutive patients with advanced NSCLC who had developed resistance to first‐ or second‐generation EGFR‐TKIs due to EGFR T790M mutation and were subsequently treated with osimertinib at Juntendo University Hospital. In patients with available tumor samples, target amplicon sequencing analyses were performed to explore the genetic biomarkers. Results A total of 38 patients with NSCLC harboring EGFR T790M mutation were treated with osimertinib. Eight patients were classified into group A (afatinib followed by osimertinib) and 30 patients were classified into group B (first‐generation EGFR‐TKI followed by osimertinib). Progression‐free survival (PFS) was significantly longer in group A than in group B (median PFS; not reached vs. 11.0 months, P = 0.018). Fourteen patients had available tissue samples collected before osimertinib treatment for target sequencing. In group A we found no additional mutations, other than EGFR T790M mutation. On the other hand, there were three samples in which other mutations emerged, in addition to EGFR T790M mutation, in group B. Conclusions PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs. Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment. Key points Significant findings of the study: PFS of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs. What this study adds: Additional mutations other than EGFR T790M may affect the efficacy of osimertinib treatment., There are few studies that directly compare the difference between the generation of prior EGFR tyrosine kinase inhibitors (TKIs) before osimertinib treatment in patients with non‐small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) T790M mutation. In our retrospective study, progression‐free survival of osimertinib was significantly longer in patients with NSCLC harboring EGFR T790M mutation after treatment with afatinib than in patients after treatment with first generation EGFR‐TKIs.

Skin-sparing mastectomy (SSM) enables a radical cure of breast cancer while overcoming the cosmetic issues related to surgery. We review our experience of performing SSMs and assess whether preservation of the nipple–areola complex (NAC) could have been an option for some patients who underwent SSM. The subjects of this retrospective study were women who underwent SSM that utilized four incision types; namely, the so-called tennis racket incision, a periareolar and midaxillary incision, an areola-sparing and midaxillary incision, and a small transverse elliptical incision. We assessed whether preservation of the NAC would have been an option in SSM, based on histologic examination of three serial cut surfaces of the specimen around the nipple, ruling out the option when evidence of the malignant lesion/s was found in at least one of the following locations: in the nipple, within a 1-cm radius from the base of the nipple, or within 1 cm from the surface of the NAC. We performed 193 SSMs. The cumulative 10-year local disease-free survival rate was 98%, with 89% of patients reporting levels of satisfaction with the reconstructed breast, of excellent, very good, or good. We evaluated that 70 of the 193 procedures could have been performed as nipple-sparing mastectomy (NSM). The outcomes of SSM in this series were excellent and NSM might have been an option for about one-third of the patients.

Background Cryoablation (CA) is a nonsurgical focal therapy for small tumours. To detect residual or relapsed tumour after CA of renal cancer, contrast - enhanced imaging is generally used to identify tumour blood flow, but no definitive criteria are established for such follow-up after CA of breast cancer. Aims The aim of this study was to compare the usefulness of contrast-enhanced ultrasonography (CEUS) and magnetic resonance (MR) imaging for assessing residual tumours and local relapse following CA of small breast cancers. Methods We enrolled 4 patients treated by CA at our institution between January 2015 and December 2016 for luminal A breast cancer with maximum tumour size of 1.5cm and neither distant metastasis nor metastatic findings in sentinel lymph node biopsy, who underwent CEUS and MR imaging before CA. In addition to our standard postoperative follow-up for breast cancer, these patients underwent CEUS every 3 months and MR imaging every 6 months after CA. Results Six months after CA, no patient showed enhancement at the lesion site on MR imaging, but there were two with continued enhancement on CEUS. They underwent vacuum -assisted breast biopsy under US guidance followed by histopathological examination of tissue that identified no malignancy. Conclusion Our findings of focal enhancement within ablated breast tissue in CEUS after CA is likely attributable to the much higher sensitivity of CEUS to that of other modalities to even slight vascularization. Further investigation in more patients is needed to clarify the utility of CEUS to detect residual or relapsed tumour after CA of small breast cancer.

Highlights • We report an extremely rare case of breast metastasis from RCC. • Including the present case, only 23 cases of breast metastasis from RCC have been described in the literature. • It is important that the differential diagnosis of primary breast cancer and metastatic breast cancer be de determined by histological examination. • Minimally invasive surgery or nonsurgical ablation should be performed in accordance with the prognosis., Introduction The breast is a rare site for metastatic disease. We report a rare case of breast metastasis 9 years after nephrectomy for renal cell carcinoma (RCC) and include a review of the relevant literature. Presentation of case An 82-year-old woman who developed an RCC underwent left nephrectomy in 2005. In October 2014, computed tomography (CT) revealed a mass of approximately 1 cm in the lateral portion of the right breast. Breast ultrasonography (US) revealed a well-circumscribed, hypoechoic mass at the same site. Fine needle aspiration (FNA) was performed, but the sample was inadequate because it did not capture breast duct epithelial cells. In June 2015, follow-up US revealed enlargement of the mass, and core needle biopsy (CNB) was performed to confirm the diagnosis. Histological examination resulted in the diagnosis of breast metastasis from an RCC. The patient underwent surgery for partial mastectomy in November 2015. The patient was asymptomatic and free of detectable disease at 18-month follow-up. Discussion The diagnosis of breast metastasis by imaging examination is difficult, and the results of FNA examination are often inconclusive because of the absence of breast duct epithelial cells. Only 22 cases of breast metastasis from RCC have been described in the literature. In almost all the reported cases, lumpectomy or partial mastectomy was performed. Conclusion It is important that histological diagnosis be determined by CNB and by other methods if the patient has a history of malignancy, and minimally invasive therapy should be performed in accordance with the prognosis.

Emphysema is a significant feature of chronic obstructive pulmonary disease (COPD). Studies involving an emphysematous mouse model require optimal lung fixation to produce reliable histological specimens of the lung. Due to the nature of the lung's structural composition, which consists largely of air and tissue, there is a risk that it collapses or deflates during the fixation process. Various lung fixation methods exist, each of which has its own advantages and disadvantages. The lung fixation method presented here utilizes constant pressure to enable optimal tissue evaluation for studies using an emphysematous mouse lung model. The main advantage is that it can fix many lungs with the same condition at one time. Lung specimens are obtained from chronic cigarette smoke-exposed mice. Lung fixation is performed using specialized equipment that enables the production of constant pressure. This constant pressure maintains the lung in a reasonably inflated state. Thus, this method generates a histological specimen of the lung that is suitable to evaluate cigarette smoke-induced mild emphysema.

Background: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the current major modality for the diagnosis of sarcoidosis with hilar and mediastinal lymphadenopathy because of its higher diagnostic yield and safety; however, predictors for the pathological diagnosis of sarcoidosis by EBUS-TBNA remain uncertain. The objective of this study was to determine a novel predictor for the pathological diagnosis of sarcoidosis by EBUS-TBNA. Methods: Patients with pathological and/or clinical diagnosis of sarcoidosis were identified from patients who underwent EBUS-TBNA between February 2010 and December 2017, retrospectively. We extracted data on age, sex, stage of disease, number of punctured lymph nodes, number of punctures per procedure and target lymph node, and size of punctured lymph node. Next, we divided patients into groups of pathological positive and negative by EBUS-TBNA, and multivariate logistic regression analysis was performed following univariate analyses to evaluate the efficacy of these parameters as a predictive factor of the pathological diagnosis of sarcoidosis by EBUS-TBNA. Results: We selected 89 patients involving 115 mediastinal and hilar lymph nodes. The diagnostic yield of sarcoidosis by EBUS-TBNA was 74/89 (83.1%). There were no significant differences in the size of lymph node and number of punctures between the groups, there was a significant difference in age by univariate analyses. In addition, multivariate logistic regression revealed that age was significantly associated with pathological diagnosis of sarcoidosis by EBUS-TBNA [5 years = 1 unit, odds ratio (OR), 0.79; 95% CI, 0.64–0.97; P=0.03]. Conclusions: The diagnostic yield of sarcoidosis by EBUS-TBNA was higher in younger than older patients. Therefore, age may be a novel independent predictor for the pathological diagnosis of sarcoidosis by EBUS-TBNA.

Background Chemotherapy is a standard treatment for patients with advanced non-small cell lung cancer (NSCLC); however, it occasionally causes adverse events. Serious adverse events (SAEs) are defined as any untoward medical occurrence that is related to drug use and results in life-threatening experiences, prolonged or initial hospitalization, or significant or persistent disability. However, as few studies have reported on the risk factors for SAEs, we aimed to identify the factors that could predict SAEs in NSCLC. Patients and methods We retrospectively reviewed the medical records of patients treated with pemetrexed plus cisplatin (PC), paclitaxel plus carboplatin plus bevacizumab (BVCP), docetaxel monotherapy (DTX), or pemetrexed monotherapy (PEM) at Juntendo University Hospital between January 2010 and March 2012. Two investigators reviewed the clinical records and judged SAEs. Multivariate analyses were performed to identify independent risk factors for SAEs among the following factors: gender, age, performance status, line of chemotherapy, preexisting interstitial lung disease (ILD), smoking status, and chemotherapeutic regimen. Results A total of 252 patients received chemotherapy (male/female, 162/90; median age [range], 66 years [36–92 years]; stage III/stage IV/postoperative recurrence, 53/145/54; adenocarcinoma/squamous cell carcinoma/not otherwise specified, 211/24/17; PC/BVCP/PEM/DTX, 50/ 51/ 67/ 84). Of these, 30 (11.9%) patients experienced SAEs. The SAEs were anorexia/nausea in 10 patients, febrile neutropenia (FN) in eight, drug-induced ILD in six, infection (sepsis, pleural infection, soft tissue infection) in three, elevated creatinine level in one, pneumothorax in one, and gastric hemorrhage in one. Treatment-related death was noted in four patients, two with drug-induced ILD, one with FN, and one with infection. Multivariate analysis revealed that preexisting ILD (odds ratio=5.06; p=0.0012) and the chemotherapeutic regimen (p=0.00-0.03) were significantly associated with SAEs. Conclusions Preexisting ILD and the chemotherapeutic regimen were risk factors for the prediction of SAEs in the treatment of NSCLC in clinical practice.

A 64-year-old man with the bone marrow metastasis due to malignant pleural mesothelioma (MPM) was diagnosed with anemia, leukoerythroblastosis, thrombocytopenia, and lower back pain. A bone marrow biopsy demonstrated infiltrative malignant mesothelioma lesions in the bone marrow. The patient died within 15 days of the detection of the bone marrow involvement. Physicians should consider performing a bone marrow biopsy to diagnose bone marrow metastasis and treat patients with palliative chemotherapy at an earlier phase of the disease. To our knowledge, this is the first report of an MPM patient having bone marrow metastasis with anemia, leukoerythroblastosis, and thrombocytopenia.

Background Interstitial lung diseases induced by anticancer agents (ILD-AA) are rare adverse effects of anticancer therapy. However, prognostic biomarkers for ILD-AA have not been identified in patients with advanced lung cancer. Our aim was to analyze the association between serum biomarkers sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), and clinical characteristics in patients diagnosed with ILD-AA. Methods Between April 2011 and March 2016, 1224 advanced lung cancer patients received cytotoxic agents and epidermal growth factor receptor tyrosine kinase inhibitors at Juntendo University Hospital and Juntendo University Urayasu Hospital. Of these patients, those diagnosed with ILD-AA were enrolled in this case control study. ΔKL-6 and ΔSP-D were defined as the difference between the levels at the onset of ILD-AA and their respective levels prior to development of ILD-AA. We evaluated KL-6 and SP-D at the onset of ILD-AA, ΔKL-6 and ΔSP-D, the risk factors for death related to ILD-AA, the chest high resolution computed tomography (HRCT) findings, and survival time in patients diagnosed with ILD-AA. Results Thirty-six patients diagnosed with ILD-AA were enrolled in this study. Among them, 14 patients died of ILD-AA. ΔSP-D in the patients who died was significantly higher than that in the patients who survived. However, ΔKL-6 did not differ significantly between the two groups. Moreover, ΔSP-D in patients who exhibited diffuse alveolar damage was significantly higher than that in the other patterns on HRCT. Receiver operating characteristic curve analysis was used to set the optimal cut off value for ΔSP-D at 398 ng/mL. Survival time for patients with high ΔSP-D (≥ 398 ng/mL) was significantly shorter than that for patients with low ΔSP-D. Multivariate analysis revealed that ΔSP-D was a significant prognostic factor of ILD-AA. Conclusions This is the first research to evaluate high ΔSP-D (≥ 398 ng/mL) in patients with ILD-AA and to determine the risk factors for ILD-AA in advanced lung cancer patients. ΔSP-D might be a serum prognostic biomarker of ILD-AA. Clinicians should evaluate serum SP-D during chemotherapy and should carefully monitor the clinical course in patients with high ΔSP-D.

Background Advanced non-small cell lung cancer (NSCLC) patients often develop thromboembolic events, including cerebral infarction (CI). However, the relationship between advanced NSCLC and CI has not been thoroughly investigated. We examined the association between advanced NSCLC and CI and risk factors for CI in advanced or post-operative recurrent NSCLC patients. Methods We retrospectively investigated 515 patients diagnosed with advanced or post-operative recurrent NSCLC at Juntendo University Hospital between April 2009 and March 2014. Results Among the 515 patients evaluated, 15 patients (2.9 %) developed CI after diagnosis of advanced or post-operative recurrent NSCLC. Univariate and multivariate analyses were conducted, and brain metastasis was the only significant independent risk factor for CI (odds ratio 5.24, 95 % confidence interval 1.72–16.10, p = 0.004). The incidence was 6.3 % in these patients. The median survival time was 36 days, and 1-year survival rate was 6.7 % after development of CI. Overall survival from diagnosis of advanced NSCLC or post-operative recurrence was significantly shorter in patients with CI than in patients without CI (223 days versus 895 days; HR, 3.46; 95 % confidence interval, 2.04–6.02; p = 0.001). Conclusions The incidence of CI is high in advanced or post-operative recurrent NSCLC, and is especially higher in patients with brain metastasis than in those without brain metastasis. Moreover, CI may affect patient’s prognosis. Careful monitoring for the development of CI in patients with advanced or post-operative recurrent NSCLC is needed, especially for patients with brain metastasis.

Objective: Poor oral health has been reported to be a risk indicator of mortality, however, few data are available regarding the relationship between chewing ability and mortality. We examined the relationship between self-assessed chewing ability and mortality in elderly subjects. Design: Prospective study. Subjects and methods: Participating in the study were 697 people (277 males, 420 females) from 1282 individuals (80 years old) residing in Fukuoka Prefecture, Japan. Data on oral and systemic health status through questionnaires, accompanied by physical and laboratory blood examinations were obtained. Chewing ability was assessed based on the number of types of food each subject reported as able to chew by questionnaire. Results: A total of 108 subjects died between 1998 and 2002. Those with the lowest number of chewable foods were associated with higher risk of mortality than those with the ability to chew all of the 15 types of food surveyed [hazard ratio (HR) = 2.38, 95% confidence interval (95% CI) = 1.07–5.29], though other parameters including current smoking, low serum albumin, and poor physical health status were more significant. Further, reduced chewing ability of soft foods increased the risk (HR = 2.65, 95% CI = 1.20–5.87). Conclusion: Chewing ability was associated with mortality in a population of 80-year-old community residents, and may be a predictor for survival rate.

Docetaxel or pemetrexed monotherapy is recommended either as a second-line treatment for non-small cell lung cancer (NSCLC) patients without EGFR mutation or ALK fusion genes or as a third-line treatment for patients with EGFR mutation or ALK fusion. However, efficacy and survival for these two settings have not been compared, leaving it unclear whether these two populations can be included in the same clinical trials. Moreover, prognostic factors for patients who are recommended to receive docetaxel/pemetrexed monotherapy are largely unknown. Docetaxel or pemetrexed was administered to 67 EGFR wild-type patients as a second-line treatment following one platinum-based combination chemotherapy and to 17 EGFR mutant patients as a third-line treatment following EGFR tyrosine kinase inhibitors and one platinum-based combination chemotherapy. Docetaxel and pemetrexed were administered at 60 and 500 mg/m2, respectively, every 3 weeks until disease progression, intolerable toxicity, or patient refusal. Overall survivals (OSs) between the two groups were compared using the log-rank test, and prognostic factors were evaluated via Cox’s proportional hazards models. The median OS was 345.5 days in the EGFR wild-type second-line group and 616 days in the EGFR mutant third-line group. Multivariate analyses revealed that the stage before first-line treatment, performance status, and EGFR status were significant prognostic factors. When planning clinical studies of NSCLC patients recommended to receive docetaxel or pemetrexed as single-agent chemotherapy, the EGFR status and stage before first-line treatment should be considered as stratification factors of randomized clinical studies.

This paper demonstrates that foraging summer-form females of the Japanese yellow swallowtail butterfly Papilio xuthus have colour vision. The butterflies were trained to feed on sucrose solution placed on a disk of a particular colour in a cage set in the laboratory. After a few such training runs, a butterfly was presented with the training colour randomly positioned within an array of disks of other colours, but with no sucrose solution. The results indicate that the butterflies learn rapidly to select the training colour reliably among different colours. The training colour was also correctly selected when it was covered with neutral density filters to reduce its brightness, or even when the colour was presented together with disks of a variety of shades of grey. These results demonstrate convincingly, for the first time, that a butterfly has true colour vision.

Activation of epidermal growth factor receptor (EGFR) triggers anti-apoptotic signaling, proliferation, angiogenesis, invasion, metastasis, and drug resistance, which leads to development and progression of human epithelial cancers, including non-small cell lung cancer (NSCLC). Inhibition of EGFR by tyrosine kinase inhibitors such as gefitinib and erlotinib has provided a new hope for the cure of NSCLC patients. However, acquired resistance to gefitinib and erlotinib via EGFR-mutant NSCLC has occurred through various molecular mechanisms such as T790M secondary mutation, MET amplification, hepatocyte growth factor (HGF) overexpression, PTEN downregulation, epithelial-mesenchymal transition (EMT), and other mechanisms. This review will discuss the biology of receptor tyrosine kinase inhibition and focus on the molecular mechanisms of acquired resistance to tyrosine kinase inhibitors of EGFR-mutant NSCLC.

Cerebral ischemia causes delayed neuronal cell death in the hippocampus resulting in sequential cognitive impairments. Hyper-activated inflammation following ischemia is one of the etiologies for delayed neuronal cell death. In the present study, using a transient global ischemia mouse model, we showed that auraptene (AUR), a citrus coumarin, effectively inhibited microglia activation, cyclooxygenase-2 expression by astrocytes, and neuronal cell death in the hippocampus following ischemic insults. These results suggest that AUR acts as a neuroprotective agent in the ischemic brain, which may be mediated by suppression of the inflammatory response.

The periodontal conditions of 2424 pregnant and 1565 non-pregnant women were assessed according to the community periodontal index of treatment needs (CPITN). The aim of this survey was to obtain information which is necessary for the planning of preventive programs of periodontal disease for pregnant women. 95% of the pregnant women and 96% of the non-pregnant women had some signs of periodontal disease. The % of pregnant women having 4 or 5 mm pockets was significantly higher than that of non-pregnant women, increased with the month of pregnancy, reached a maximum of 31%) in the 8-month group, but decreased to the control level in the 9-month group. These changes were interpreted to suggest that the increase of pocket depth during pregnancy was caused by gingival enlargement rather than by periodontal destruction. The results show that pregnant women had a healthier periodontal condition when compared with non-pregnant women, i.e., the number of sextants with healthy periodontal tissues was higher, the % of people having deep pockets (6 mm or deeper) was lower, and the need for prophylaxis was lower in pregnant than in non-pregnant women. These findings suggest that a special program of periodontal disease prevention for pregnant women is not necessary.

Few have studied the association between chewing ability and longevity.In this prospective study, we analyzed 697 80-year-old participants residing in Fukuoka Prefecture, Japan. Chewing ability was assessed on the basis of the types of food that each participant reported being able to chew.During follow-up, 108 participants died. Patients reporting the lowest numbers of chewable foods were associated with higher risks of cardiovascular mortality than those who were able to chew all the types of food surveyed (multivariate hazard ratio: 4.60; 95% confidence interval: 1.01-21.1).Impaired dentition status with poor masticatory ability was an independent risk factor for cardiovascular mortality in active elderly individuals.

e18527 Background: As the efficacy of chemotherapy for advanced lung cancer patients has been increased, some advanced lung cancer patients may benefit from combined modality therapy including surg...

e19129 Background: Serious adverse events, which cause immediate hospitalization, prolonged hospitalization, permanent damage, or death, are clinically defined as severe adverse events (SAEs). Few ...

e19043 Background: The aim of this study was to examine the effect of hydration with magnesium and mannitol without furosemide on the nephrotoxocity accompanying combination chemotherapy using cisplatin and pemetrexed in patients with advanced non-small cell lung cancer (NSCLC). Methods: Fifty patients with NSCLC who received cisplatin plus pemetrexed, using either old hydration protocol including normal saline with mannitol and furosemide, or a new one including normal saline with magnesium and mannitol without furosemide were retrospectively analyzed. Nephrotoxicity was compared between patients treated using the old protocol and those treated with the new protocol. Univariate and multivariate analyses were performed to identify the independent factors associated with protection against nephrotoxicity in patients with NSCLC who received cisplatin plus pemetrexed. Results: Thirty patients received the old hydration protocol, while 20 patients were treated using the new hydration protocol. The patients treated using the new hydration protocol showed a significantly greater increase in creatinine clearance (p=0.0004) and a decrease in the serum creatinine level (p=0.0148) after one course of chemotherapy compared with those treated using the old hydration protocol. There were no differences in the chemotherapeutic response or overall survival between the groups (p=0.572). The new hydration protocol with supplemented magnesium with mannitol without furosemide was an independent factor for the protection against nephrotoxicity induced by cisplatin and pemetrexed in patients with advanced NSCLC (HR 0.232 (95% CI: 0.055-0.986), p=0.039). Conclusions: These results demonstrate that the new hydration protocol comprising supplementation with magnesium without furosemide could prevent the nephrotoxicity induced by cisplatin and pemetrexed without affecting the treatment outcome.

Oral health conditions, including dental conditions, temporomandibular joint (TMJ) conditions, denture status, and oral hygiene status, were assessed on 1908 institutionalized elderly people 65 yr of age and older at 29 of the 30 existing institutions in the city of Kitakyushu, Japan. The percentage of edentulous people was 27% in the 65-74-yr-old group, and increased with age to 56% in the 85 yr and older group. In dentate persons, the mean number of remaining teeth and DF teeth were 13.4 and 8.6, 9.5 and 6.8, and 8.4 and 6.5 in the groups aged 65-74 yr old, 75-84 yr old, and 85 yr and older, respectively. 81% of all the persons examined had no unusual symptoms in their TMJ. A clicking sound was the most frequent symptom (17%). Hygiene of both their teeth and dentures was very poor. Of all the subjects, 36% needed new full and/or partial denture(s), and 41% needed only repair. When the institutionalized elderly people were compared according to their general health condition, no clear differences were observed in percentage of edentulousness, mean number of remaining teeth and DF teeth, and TMJ conditions. However, a higher level of both untreated teeth and denture treatment needs, and poorer oral hygiene, was found in elderly people having poor general health than was observed in those with better health.(ABSTRACT TRUNCATED AT 250 WORDS)

Background A growing body of evidence has indicated a possible association between oral and gastrointestinal (orodigestive) cancers and periodontal disease or tooth loss. However, the evidence remains contradictory. This study investigated whether tooth loss, which is indicative of poor oral health and a potential source of oral infections, is associated with death from orodigestive cancer. Methods The study included 656 subjects in Fukuoka prefecture, Japan, who were 80 years old at baseline in 1998. All subjects underwent oral clinical examination and answered a questionnaire to determine their background characteristics. Cause of death over the 12-year follow-up was recorded from the registers at the Public Health Centers and classified according to the WHO International Classification of Diseases. Statistical analysis of associations was performed using Kaplan-Meier and Cox multivariate regression analyses. Results A significant association was observed between tooth loss (continuous variable) and cancer death (hazard ratio (HR): 1.03, 95% confidence interval (CI): 1.00–1.07), after adjustment for potential confounders, including sex and smoking status. However, that association became insignificant in the fully adjusted model. On the other hand, tooth loss was significantly associated with orodigestive cancer (HR: 1.06, 95% CI: 1.01–1.13), even in the fully adjusted model including place of residence as a part of socioeconomic status. Conclusions This study provides the first evidence in a prospective study in a Japanese population that tooth loss is associated with increased orodigestive cancer mortality, although the causality remains unclear.