Lymphangioleiomyomatosis as a potent lung cancer risk factor: Insights from a Japanese large cohort study.

BACKGROUND AND OBJECTIVE: Lymphangioleiomyomatosis (LAM) is a rare neoplastic disease associated with the functional tumour suppressor genes TSC1 and TSC2 and causes structural destruction in the lungs, which could potentially increase the risk of lung cancer. However, this relationship remains unclear because of the rarity of the disease. METHODS: We investigated the relative risk of developing lung cancer among patients diagnosed with LAM between 2001 and 2022 at a single high-volume centre in Japan, using data from the Japanese Cancer Registry as the reference population. Next-generation sequencing (NGS) was performed in cases where tumour samples were available. RESULTS: Among 642 patients diagnosed with LAM (sporadic LAM, n = 557; tuberous sclerosis complex-LAM, n = 80; unclassified, n = 5), 13 (2.2%) were diagnosed with lung cancer during a median follow-up period of 5.13 years. All patients were female, 61.5% were never smokers, and the median age at lung cancer diagnosis was 53 years. Eight patients developed lung cancer after LAM diagnosis. The estimated incidence of lung cancer was 301.4 cases per 100,000 person-years, and the standardized incidence ratio was 13.6 (95% confidence interval, 6.2-21.0; p = 0.0008). Actionable genetic alterations were identified in 38.5% of the patients (EGFR: 3, ALK: 1 and ERBB2: 1). No findings suggested loss of TSC gene function in the two patients analysed by NGS. CONCLUSION: Our study revealed that patients diagnosed with LAM had a significantly increased risk of lung cancer. Further research is warranted to clarify the carcinogenesis of lung cancer in patients with LAM.

Association between the efficacy and immune-related adverse events of pembrolizumab and chemotherapy in non-small cell lung cancer patients: a retrospective study.

BACKGROUND: The combination of immune-checkpoint inhibitors with chemotherapy has become the standard of treatment for non-small cell lung cancer (NSCLC) patients. However, the association between therapeutic efficacy and the development of immune-related adverse events (irAEs) remains unclear in patients treated with combination therapy. We aimed to investigate the frequency of irAEs, and the association between therapeutic efficacy and the development of irAEs in patients with NSCLC. MATERIALS AND METHODS: We retrospectively surveyed patients with chemo-naïve advanced NSCLC who received pembrolizumab plus platinum-based chemotherapy or pembrolizumab monotherapy at Juntendo University Hospital, Japan, between February 2017 and May 2021. RESULTS: Among 148 patients (median [range] age, 68 (33-85) years; 107 men [72.3%] and 41 women [27.7%]), 74 each received pembrolizumab plus chemotherapy and pembrolizumab monotherapy. IrAEs were observed in 46 (62.2%) and 41 patients (55.4%) in the combination therapy and monotherapy group, respectively. Patients with irAEs showed significantly longer progression-free survival (PFS) than those without irAEs in the combination therapy group (8.9 vs. 5.7 months; Hazard Ratio [HR], 0.53; 95% CI, 0.29-0.98; P = 0.041) and monotherapy group (11.7 vs. 5.0 months; HR, 0.40; 95% CI, 0.22-0.70; P = 0.001). In the multivariable analysis, development of irAEs was positively associated with PFS in both the groups (HR, 0.48; 95% CI, 0.26-0.89; P = 0.019 and HR, 0.38; 95% CI, 0.21-0.68; P < 0.01). In the inverse probability of treatment weighting adjusted analysis, development of irAEs was significantly associated with combination therapy (OR, 0.56; 95% CI, 0.34-0.91; P = 0.019). CONCLUSION: Our study demonstrated that the incidence of irAEs was associated with favorable efficacy in patients treated with pembrolizumab plus chemotherapy, as well as pembrolizumab monotherapy. Also, the addition of chemotherapy to pembrolizumab significantly increased the incidence of irAEs.

Survival past five years with advanced, EGFR-mutated or ALK-rearranged non-small cell lung cancer-is there a "tail plateau" in the survival curve of these patients?

BACKGROUND: The prognosis of patients with NSCLC harboring oncogenic driver gene alterations, such as EGFR gene mutations or ALK fusion, has improved dramatically with the advent of corresponding molecularly targeted drugs. As patients were followed up for about five years in most clinical trials, the long-term outcomes beyond 5 years are unclear. The objectives of this study are to explore the clinical course beyond five years of chemotherapy initiation and to investigate factors that lead to long-term survival. METHODS: One hundred and seventy-seven patients with advanced, EGFR-mutated or ALK-rearranged NSCLC who received their first chemotherapy between December 2008 and September 2015 were included. Kaplan Meier curves were drawn for the total cohort and according to subgroups of patients' characteristics. RESULTS: Median OS in the total cohort was 40.6 months, the one-year survival rate was 89%, the three-year survival rate was 54%, and the five-year survival rate was 28%. Median OS was 36.9 months in EGFR-mutated patients and 55.4 months in ALK-rearranged patients. The OS curve seemed to plateau after 72 months, and most of the patients who were still alive after more than five years are on treatment. Female sex, age under 75 years, an ECOG PS of 0 to 1, ALK rearrangement, postoperative recurrence, and presence of brain metastasis were significantly associated with longer OS. CONCLUSIONS: A tail plateau was found in the survival curves of patients with advanced, EGFR-mutated and ALK-rearranged NSCLC, but most were on treatment, especially with EGFR-mutated NSCLC.

High lymphocyte population-related predictive factors for a long-term response in non-small cell lung cancer patients treated with pemetrexed: a retrospective observational study.

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.

Preservation of the nipple-areola complex in skin-sparing mastectomy for early breast cancer.

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: The outcomes of SSM in this series were excellent and NSM might have been an option for about one-third of the patients.

Surfactant protein-D predicts prognosis of interstitial lung disease induced by anticancer agents in advanced lung cancer: a case control study.

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.

Oct4 plays a crucial role in the maintenance of gefitinib-resistant lung cancer stem cells.

Several recent studies have suggested that cancer stem cells (CSCs) are involved in resistance to gefitinib in non-small cell lung cancer (NSCLC). Oct4, a member of the POU-domain transcription factor family, has been shown to be involved in CSC properties of various cancers. We previously reported that Oct4 and the putative lung CSC marker CD133 were highly expressed in gefitinib-resistant persisters (GRPs) in NSCLC cells, and GRPs exhibited characteristic features of the CSCs phenotype. The aim of this study was to elucidate the role of Oct4 in the resistance to gefitinib in NSCLC cells with an activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9, which express the EGFR exon 19 deletion mutation, were transplanted into NOG mice, and were treated with gefitinib in vivo. After 14-17 days of gefitinib treatment, the tumors still remained; these tumors were referred to as gefitinib-resistant tumors (GRTs). PC9-GRTs showed higher expression of Oct4 and CD133. To investigate the role of Oct4 in the maintenance of gefitinib-resistant lung CSCs, we introduced the Oct4 gene into PC9 and HCC827 cells carrying an activating EGFR mutation by lentiviral infection. Transfection of Oct4 significantly increased CD133-positive GRPs and the number of sphere formation, reflecting the self-renewal activity, of PC9 and HCC827 cells under the high concentration of gefitinib in vitro. Furthermore, Oct4-overexpressing PC9 cells (PC9-Oct4) significantly formed tumors at 1 × 10 cells/injection in NOG mice as compared to control cells. In addition, PC9-Oct4 tumors were more resistant to gefitinib treatment as compared to control cells in vivo. Finally, immunohistochemical analysis revealed that Oct4 was highly expressed in tumor specimens of EGFR-mutant NSCLC patients with acquired resistance to gefitinib. Collectively, these findings suggest that Oct4 plays a pivotal role in the maintenance of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC.

Cerebral infarction in advanced non-small cell lung cancer: a case control study.

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.

Treatment with insulin-like growth factor 1 receptor inhibitor reverses hypoxia-induced epithelial-mesenchymal transition in non-small cell lung cancer.

Insulin-like growth factor 1 receptor (IGF1R) is expressed in many types of solid tumors including non-small cell lung cancer (NSCLC), and enhanced activation of IGF1R is thought to reflect cancer progression. Epithelial-mesenchymal transition (EMT) has been established as one of the mechanisms responsible for cancer progression and metastasis, and microenvironment conditions, such as hypoxia, have been shown to induce EMT. The purposes of this study were to address the role of IGF1R activation in hypoxia-induced EMT in NSCLC and to determine whether inhibition of IGF1R might reverse hypoxia-induced EMT. Human NSCLC cell lines A549 and HCC2935 were exposed to hypoxia to investigate the expression of EMT-related genes and phenotypes. Gene expression analysis was performed by quantitative real-time PCR and cell phenotypes were studied by morphology assessment, scratch wound assay, and immunofluorescence. Hypoxia-exposed cells exhibited a spindle-shaped morphology with increased cell motility reminiscent of EMT, and demonstrated the loss of E-cadherin and increased expression of fibronectin and vimentin. Hypoxia also led to increased expression of IGF1, IGF binding protein-3 (IGFBP3), and IGF1R, but not transforming growth factor ß1 (TGFß1). Inhibition of hypoxia-inducible factor 1α (HIF1α) with YC-1 abrogated activation of IGF1R, and reduced IGF1 and IGFBP3 expression in hypoxic cells. Furthermore, inhibition of IGF1R using AEW541 in hypoxic condition restored E-cadherin expression, and reduced expression of fibronectin and vimentin. Finally, IGF1 stimulation of normoxic cells induced EMT. Our findings indicated that hypoxia induced EMT in NSCLC cells through activation of IGF1R, and that IGF1R inhibition reversed these phenomena. These results suggest a potential role for targeting IGF1R in the prevention of hypoxia-induced cancer progression and metastasis mediated by EMT.

Pemetrexed for advanced non-small cell lung cancer patients with interstitial lung disease.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients with interstitial lung disease (ILD) need to be approached carefully given the high incidence of pulmonary toxicity. Pemetrexed (PEM) is the key drug for the treatment of NSCLC. However, its safety, especially with respect to the exacerbation of ILD, and efficacy in NSCLC patients with ILD have yet to be established. METHOD: We investigated the safety and efficacy of PEM monotherapy in NSCLC patients with or without idiopathic interstitial pneumonia (IIPs). The medical charts of these patients were retrospectively reviewed. RESULTS: Twenty-five patients diagnosed as having IIPs (IIPs group) and 88 patients without ILD (non-ILD group) were treated with PEM monotherapy at Juntendo University Hospital between 2009 and 2013. In the IIPs group, 12 patients were found to have usual interstitial pneumonitis (UIP) on chest computed tomography (CT) (UIP group) and the other 13 patients showed a non-UIP pattern on chest CT (non-UIP IIPs group). Three patients in the IIPs group (2 in the UIP group and 1 in the non-UIP IIPs group) and 1 in the non-ILD group developed pulmonary toxicity during treatment (3.5% overall, 12.0% in the IIPs group versus 1.1% in the non-ILD group). Moreover, all 3 patients in the IIPs group died of pulmonary toxicity. Overall survival tended to be longer in the non-ILD group than in the IIPs group (p = 0.08). Multivariate analyses demonstrated that IIPs was the only significant independent risk factor for PEM-related pulmonary toxicity. CONCLUSION: We found that the incidence of PEM-related pulmonary toxicity was significantly higher amongst NSCLC patients with IIPs than among those without IIPs. Particular care must be taken when administering PEM to treat NSCLC patients with IIPs.

Trophoblast Cell Surface Antigen 2 Expression in Thymic Carcinoma: Brief Report.

Introduction: Trophoblast cell surface antigen 2 (TROP2) is a transmembrane glycoprotein overexpressed in various cancer types. Although TROP2-targeting therapy is currently attracting attention, little is known about TROP2 expression in thymic carcinoma. Methods: TROP2 gene expression in thymic epithelial tumors was analyzed using RNA-sequencing (RNA-seq) data for 122 cases obtained from The Cancer Genome Atlas. Immunohistochemistry (IHC) staining with anti-TROP2 antibody (SP295) was performed in 26 cases of thymic carcinoma tissues surgically resected at Juntendo University. Results: RNA-seq data analysis from The Cancer Genome Atlas revealed that TACSTD2 (gene encoding TROP2) expression was significantly higher in thymic carcinoma than in thymoma (adjusted p = 6.64e-05). There was also a trend of increasing expression in the order of thymoma type B1, B2, B3, and thymic carcinoma. As for IHC in thymic carcinoma, TROP2 expression was localized to the membrane of cancer cells. Intensity 0, 1, and 2 was observed in six (23.1%), 11 (42.3%), and nine (34.6%) cases, respectively, leading to TROP2 positivity in 20 cases (76.9%). The median proportion of TROP2-positive tumor cells and the median H-score were 25.0% (range: 0%-100%) and 25.0 (range: 0-200), respectively. No relevant factors were identified in the analysis of TROP2 expression and patient background. Although not significant, high TROP2 expression (H-score ≥ 50) tended to be associated with shorter survival. Conclusions: TROP2 expression in thymic carcinoma was confirmed by both RNA-seq and IHC, with high expression observed in IHC for intensity (76.9%) and proportion. TROP2 could be a potential target in thymic carcinoma.

Hyperprogressive disease under anti-PD-1 rechallenge after initial response to anti-PD-1 treatment for non-small cell lung cancer: a case report.

Background: Hyperprogressive disease is an unexpected response pattern observed in immune checkpoint therapy and associated with poor prognosis. The rechallenge of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitors can be a treatment option in non-small cell lung cancer (NSCLC) patients who once responded to them. Here, we reported the hyperprogressive phenomenon after PD-1/PD-L1 rechallenge in a patient with NSCLC. Case Description: This case report described a patient with recurrent large cell lung cancer undergoing hyperprogressive disease with pleural and pericardial dissemination shortly after the pembrolizumab rechallenge, although he had a favorable response to the initial pembrolizumab treatment. A lower ratio of CD8+ T cells to Foxp3+ regulatory T cells was distributed in the cell blocks of pleural and pericardial effusion which were taken after hyperprogressive disease, compared to the resected tumor microenvironment. Neutrophil-to-lymphocyte ratio (NLR) was lower in peripheral blood when the disease was controlled and it rose when the disease progressed. Notably, NLR increased dramatically when hyperprogression occurred. Conclusions: For the first time, we reported that a patient who showed a favorable response to initial anti-PD-1 treatment underwent hyperprogressive disease when rechallenging the same immunotherapy. The increased Foxp3+ regulatory T cells in the tumor microenvironment and the longitudinal change of NLRs in peripheral blood were suggested to be associated with hyperprogressive disease.

Clinical potential of SKP2 as diagnostic marker and therapeutic target in small cell lung cancer.

BACKGROUND: Small cell lung cancer (SCLC) is the most aggressive type of lung cancer. The overall survival has not improved significantly over the last decades because no major therapeutic breakthroughs have been achieved for over 15 years. METHODS: We analyzed a genome-wide loss-of-function screening database to identify vulnerabilities in SCLC for the development of urgently needed novel therapies. RESULTS: We identified SKP2 (encoding S-phase kinase-associated protein 2) and CKS1B (encoding CDC28 protein kinase regulatory subunit 1B) as the two most essential genes in that order in SCLC. Notably, SKP2 and CKS1B comprise the p27 binding pocket of the E3 ubiquitin ligase SCFSKP2 complex. Immunohistochemistry on tissue microarrays revealed that SKP2 was expressed in >95% of samples at substantially higher levels than that observed for commonly used neuroendocrine markers. As expected, SCLC cell lines were sensitive to SKP2 inhibition. Furthermore, SKP2 or CKS1B knockdown induced apoptosis in RB1 mutant cells, whereas it induced senescence in RB1 wild-type cells. CONCLUSION: Although the mechanism underlying SKP2 knockdown-induced growth inhibition differs between RB1-wild-type and -mutant SCLC, SKP2 can be considered a novel therapeutic target for patients with SCLC regardless of the RB1 mutation status. Our findings indicate that SKP2 is a potential novel clinical diagnostic marker and therapeutic target in SCLC.

MNK1 expression increases during cellular senescence and modulates the subcellular localization of hnRNP A1.

Heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) is an RNA-binding protein that modulates splice site usage, polyadenylation, and cleavage efficiency. This protein has also been implicated in mRNA stability and transport from the nucleus. We have previously demonstrated that hnRNP A1 had diminished protein levels and showed cytoplasmic accumulation in senescent human diploid fibroblasts. Furthermore, we have shown that inhibition of p38 MAPK, a key regulator of cellular senescence, elevated hnRNP A1 protein levels and inhibited hnRNP A1 cytoplasmic localization. In this study, we have explored the possible involvement of MNK1, one of the downstream effector of p38 MAPK, in the regulation of hnRNP A1. We have demonstrated that pharmacological inhibition of MNK1 by CGP 57380 decreased the phosphorylation levels of hnRNP A1 in young and senescent fibroblast cells and blocked the cytoplasmic accumulation of hnRNP A1 in senescent cells. In addition, MNK1 formed a complex with hnRNP A1 in vivo. The expression levels of MNK1, phospho-MNK1, and phospho-eIF4E proteins were found to be elevated in senescent cells. These data suggest that MNK1 regulates the phosphorylation and the subcellular distribution of hnRNP A1 and that MNK1 may play a role in the induction of senescence.

Association between tooth loss and orodigestive cancer mortality in an 80-year-old community-dwelling Japanese population: a 12-year prospective study.

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.

Clinical characteristics of adrenal insufficiency induced by pembrolizumab in non-small-cell lung cancer.

BACKGROUND AND AIM: Immune checkpoint inhibitors have significantly improved the clinical outcomes of many cancer types, but they induce a range of immune-related adverse events (irAEs). Although adrenal insufficiency (AI) is a rare irAE, it can lead to serious consequences. This study aimed to determine the clinical features of patients with advanced non-small-cell lung cancer (NSCLC) who developed AI following pembrolizumab treatment. METHODS: We retrospectively reviewed and analyzed the clinical data of all patients with NSCLC treated with pembrolizumab at Juntendo University Hospital from February 2017 to December 2020. The diagnosis of AI was established based on the Endocrine Emergency Guidance for the acute management of endocrine complications of checkpoint inhibitor therapy in the UK and the clinical practice guidelines of the Japan Endocrine Society. RESULT: AI was clinically suspected in 59 out of 186 patients treated with pembrolizumab, and 10 (5.4%) cases were confirmed. The symptoms included hyponatremia (n = 9), fatigue (n = 8), and loss of appetite (n = 6). All patients had low adrenocorticotropic hormone (ACTH) levels, and five patients were diagnosed with isolated ACTH deficiency. All patients completely recovered with corticosteroid replacement. The median time to onset of AI was 8.0 (range 3.8-15.2) months. The median progression-free survival in these patients was 22.4 (95% confidence interval 11.2-not reached) months. CONCLUSION: The incidence of AI among patients treated with pembrolizumab is more frequent than previously reported. In addition, secondary AI, especially isolated ACTH deficiency, is a major form of AI induced by pembrolizumab.

A Retrospective, Multicenter, Observational Study to Evaluate Clinical Outcomes of Lorlatinib After Alectinib in Patients With ALK-Positive NSCLC in Japan.

Introduction: Lorlatinib is an ALK tyrosine kinase inhibitor approved in Japan for the treatment of advanced ALK+ NSCLC. There has been little evidence about lorlatinib efficacy after first-line (1L) alectinib in clinical practice in Japan. Methods: We retrospectively analyzed patients with advanced ALK+ NSCLC previously treated with 1L alectinib at multiple sites in Japan. Primary objectives were to collect patient demographics at baseline and estimate time to treatment failure (TTF) with second-line (2L) or third-line (3L) or later line (≥3L) lorlatinib treatment. Secondary objectives included objective response rate (ORR) with lorlatinib, reason for discontinuation and time to last treatment failure with lorlatinib, TTF and ORR of alectinib, and combined TTF. Results: Among the 51 patients included in the study, 29 (56.9%) received 2L and 22 (43.1%) received ≥3L lorlatinib treatment. At lorlatinib initiation, brain metastases were reported in 25 patients (49.0%), and 32 (62.7%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Median TTF with lorlatinib was 11.1 months (95% confidence interval [CI]: 4.6-13.8) in any line, 10.8 months (95% CI: 3.9-13.8) in 2L, and 11.5 months (95% CI: 2.9-not reached) in ≥3L. Median TTF was 11.5 months (95% CI: 3.9-not reached) in patients with brain metastases at lorlatinib initiation and 9.9 months (95% CI: 4.3-13.8) in patients without brain metastases. ORR was 35.7% with any-line lorlatinib treatment. Conclusions: Patient characteristics and efficacy were comparable with previous reports when lorlatinib was given after 1L alectinib in patients with ALK+ NSCLC.

Prognostic value of metabolic tumor burden on 18F-FDG PET in nonsurgical patients with non-small cell lung cancer.

PURPOSE: The objective of this study was to assess the prognostic value of metabolic tumor burden on 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) positron emission tomography (PET)/CT measured with metabolic tumor volume (MTV) and total lesion glycolysis (TLG), independent of Union Internationale Contra la Cancrum (UICC)/American Joint Committee on Cancer (AJCC) tumor, node, and metastasis (TNM) stage, in comparison with that of standardized uptake value (SUV) in nonsurgical patients with non-small cell lung cancer (NSCLC). METHODS: This study retrospectively reviewed 169 consecutive nonsurgical patients (78 men, 91 women, median age of 68 years) with newly diagnosed NSCLC who had pretreatment (18)F-FDG PET/CT scans. The (18)F-FDG PET/CT scans were performed in accordance with National Cancer Institute guidelines. The MTV of whole-body tumor (MTV(WB)), of primary tumor (MTV(T)), of nodal metastases (MTV(N)), and of distant metastases (MTV(M)); the TLG of whole-body tumor (TLG(WB)), of primary tumor (TLG(T)), of nodal metastases (TLG(N)), and of distant metastases (TLG(M)); the SUV(max) of whole-body tumor (SUV(maxWB)), of primary tumor (SUV(maxT)), of nodal metastases (SUV(maxN)), and of distant metastases (SUV(maxM)) as well as the SUV(mean) of whole-body tumor (SUV(meanWB)), of primary tumor (SUV(meanT)), of nodal metastases (SUV(meanN)), and of distant metastases (SUV(meanM)) were measured with the PETedge tool on a MIMvista workstation with manual adjustment. The median follow-up among survivors was 35 months from the PET/CT (range 2-82 months). Statistical methods included Kaplan-Meier curves, Cox regression, and C-statistics. RESULTS: There were a total of 139 deaths during follow-up. Median overall survival (OS) was 10.9 months [95% confidence interval (CI) 9.0-13.2 months]. The MTV was statistically associated with OS. The hazard ratios (HR) for 1 unit increase of ln(MTV(WB)), √(MTV(T)), √(MTV(N)), and √(MTV(M)) before/after adjusting for stage were: 1.47/1.43 (p < 0.001/<0.001), 1.06/1.05 (p < 0.001/<0.001), 1.11/1.10 (p < 0.001/<0.001), and 1.04/1.03 (p = 0.007/0.043), respectively. TLG had statistically significant associations with OS with the HRs for 1 unit increase in ln(TLG(WB)), √(TLG(T)), √(TLG(N)), and √(TLG(M)) before/after adjusting for stage being 1.36/1.33 (p < 0.001/<0.001), 1.02/1.02 (p = 0.001/0.002), 1.05/1.04 (p < 0.001/<0.001), and 1.02/1.02 (p = 0.003/0.024), respectively. The ln(SUV(maxWB)) and √(SUV(maxN)) were statistically associated with OS with the corresponding HRs for a 1 unit increase before/after adjusting for stage being 1.46/1.43 (p = 0.013/0.024) and 1.22/1.16 (p = 0.002/0.040). The √(SUV(meanN)) was statistically associated with OS before and after adjusting for stage with HRs for a 1 unit increase of 1.32 (p < 0.001) and 1.24 (p = 0.015), respectively. The √(SUV(meanM)) and √(SUV(maxM)) were statistically associated with OS before adjusting for stage with HRs for a 1 unit increase of 1.26 (p = 0.017) and 1.18 (p = 0.007), respectively, but not after adjusting for stage (p = 0.127 and 0.056). There was no statistically significant association between OS and √(SUV(maxT)), ln(SUV(meanWB)), or √(SUV(meanT)). There was low interobserver variability among three radiologists with intraclass correlation coefficients (ICC) greater than 0.94 for SUV(maxWB), ln(MTV(WB)), and ln(TLG(WB)). Interobserver variability was higher for SUV(meanWB) with an ICC of 0.806. CONCLUSION: Baseline metabolic tumor burdens at the level of whole-body tumor, primary tumor, nodal metastasis, and distant metastasis as measured with MTV and TLG on FDG PET are prognostic measures independent of clinical stage with low inter-observer variability and may be used to further stratify nonsurgical patients with NSCLC. This study also suggests MTV and TLG are better prognostic measures than SUV(max) and SUV(mean). These results will need to be validated in larger cohorts in a prospective study.

[An analysis of mental disorders of international students visiting the Mental Health Service at Tsukuba University Health Center].

With the expected increase in the number of international students coming to Japan as part of the Ministry of Education, Culture, Sports, Science & Technology's "300,000 Foreign Student (Global 30) Plan", the demands on university mental health facilities will also increase. However, the rate of mental disorders of recent international students has not been fully evaluated. As part of an initiative to establish effective treatment measures for the mental health of international students, we investigated the present status and recent trends of these students who visited the Mental Health Service (MHS) in the Tsukuba University Health Center. The demographic characteristics, pathway, stress, and diagnosis of international students who visited the MHS from 2005 to 2010 were investigated retrospectively based on medical records. The subjects were 59 international students (15 male, 44 female; mean age: 28.4). The consultation rate of international students was significantly lower than that of Japanese students each year. Although the rate is almost stable in Japanese students (2.1-2.5%), it has increased significantly in international students, from 0.5% in 2005 to 1.4% in 2010. A larger percentage of the subjects were from Asia (66%), compared to the former Soviet Union (10%) and Europe (7%). A greater proportion of the subjects were graduate students (67%). The diagnoses were as follows: depression (34%), adjustment disorder (32%), insomnia (15%), and schizophrenia (9%). The percentage requiring emergency consultation was 24%, including the most severe cases that had to return to their home country. Sixty-nine percent of the subjects stayed in Japan for more than 1 year. Half of the subjects decided to visit the MHS themselves. The results of the present study show that the consultation rate of international students was lower than that of Japanese students in spite of the "culture shock" experienced by international students. This result is in agreement with previous reports. Among international students, however, there is a trend indicating an increase of visits to the MHS in recent years, approaching the rate for Japanese students. Preparations for emergency consultation are still important.

A Novel Therapeutic Strategy Targeting the Mesenchymal Phenotype of Malignant Pleural Mesothelioma by Suppressing LSD1.

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-GSK3ß 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.