Search

Background and Objective: Until recently, the standard first-line treatment for advanced urothelial carcinoma (UC) was platinum-based combination chemotherapy followed by avelumab maintenance therapy for patients without progressive disease (PD). For patients with advanced UC who experience PD or recurrence, standard-of-care treatment is pembrolizumab monotherapy based on the phase 3 KEYNOTE-045 study. This post hoc analysis of the KEYNOTE-045 study evaluated the efficacy of pembrolizumab compared with chemotherapy by the best response to prior platinum-based chemotherapy., Methods: Patients with advanced UC that progressed or recurred after first-line platinum-based chemotherapy were randomly assigned 1:1 to receive either pembrolizumab 200 mg every 3 wk (Q3W) for ≤2 yr or investigator's choice of chemotherapy (paclitaxel [175 mg/m 2 ], docetaxel [75 mg/m 2 ], or vinflunine [320 mg/m 2 ], each Q3W). Endpoints included overall survival (OS) from the initiation of the last treatment prior to death, objective response rate (ORR), and duration of response (DOR) as per Response Evaluation Criteria in Solid Tumors version 1.1 from the date of the first response., Key Findings and Limitations: An objective response to pembrolizumab was observed in all groups in terms of a prior response to first-line platinum-based chemotherapy. Median OS, ORR, and median DOR were numerically greater with pembrolizumab than with chemotherapy across subgroups. Patients with PD as the best response to prior platinum-based chemotherapy had the poorest OS outcomes. Limitations include a lack of formal hypothesis testing., Conclusions and Clinical Implications: When compared with chemotherapy, prolonged OS and durable responses to second-line pembrolizumab were observed independently of the response to or type of prior platinum-based chemotherapy. These findings further support pembrolizumab as second-line treatment for advanced UC., (Copyright © 2024 Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA., The Author(s). Published by Elsevier B.V. All rights reserved.)

Objectives: To examine real-world characteristics, journey, and outcomes among patients with locoregional, nonmetastatic renal cell carcinoma (RCC)., Methods: A retrospective analysis of medical records from the ConcertAI Oncology Dataset was performed on adults in the United States with newly diagnosed nonmetastatic RCC between January 2012-December 2017 who received surgical treatment, and were followed until August 2021. Patients were stratified based on the risk of recurrence after nephrectomy. Recurrence rate and survival outcomes were assessed., Results: The cohort (n = 439) had a median age of 64 years, 66.1% were male, and 76.5% had clear-cell histology. The median follow-up time from nephrectomy was 39.3 months overall, 41.0 months for intermediate-high-risk patients (n = 377; 85.9%) and 24.1 months for high-risk patients (n = 62; 14.1%). For intermediate-high- and high-risk patients, respectively, 68.4% and 56.5% had ≥1 medical oncologist visit after nephrectomy. Of 260 patients with documentation of postoperative imaging assessments, 72% were ordered by medical oncologists, and the median time from initial nephrectomy to the first scan was 110 days (intermediate-high-risk) and 51 days (high-risk). Provider-documented recurrence occurred in 223 (50.8%) patients, of whom 41.7% had ≥1 medical oncologist visit before the recurrence. Three-year disease-free survival (DFS), and overall survival rates were 49.4% and 80.8% (all patients): 27.7% and 64.7% (high-risk); and 52.9% and 83.3% (intermediate-high-risk)., Conclusions: Our study reports low DFS after nephrectomy for patients with intermediate-high- and high-risk RCC. Subsequent approval and use of new and newly approved adjuvant therapeutic options could potentially delay or prevent recurrence., (© 2024 Merck Sharp & Dohme LLC and The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The effect of lymph node dissection (LND) on the efficacy of immune checkpoint inhibitor (ICI) remains unclear. The purpose of this study was to examine the difference in the effect of ICI between patients with non-small cell lung cancer (NSCLC) according to the extent of LND performed in surgery prior to postoperative recurrence., Methods: A total of 134 patients with postoperative recurrence (surgery group, n=26) or unresectable advanced lung cancer (non-surgery group, n=108) who were treated with ICIs between January 2016 and December 2022 were included for analysis. In the surgery group, 16 patients underwent systematic LND, whereas the remaining 10 patients underwent selective LND. Progression-free survival with ICI treatment (ICI-PFS) and overall survival (OS) were compared between the surgery and non-surgery groups and between the systematic and selective LND groups using the inverse probability of treatment weighting (IPTW) method to adjust for patient background characteristics., Results: In the IPTW-adjusted analysis, the 2-year PFS rate with ICI treatment was 31.2% in the surgery group and 27.3% in the non-surgery group (P=0.19); the corresponding 2-year OS rates were 69.6% and 62.2%, respectively (P=0.10). In the surgery group, the 2-year PFS rates under ICI were 20.0% in the systematic LND group and 45.7% in the selective LND group (P=0.03)., Conclusions: IPTW-adjusted analysis indicated no difference in prognosis between patients with postoperative recurrence and those with advanced unresectable lung cancer. However, in patients with postoperative recurrence, the extent of LND was a significant predictor of ICI-PFS. These findings suggest that systematic LND may reduce the efficacy of ICI, indicating that preoperative ICI administration may be warranted., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-23-1806/coif). N.I. received grants and contracts from Chugai Pharma and Ono Pharma; payments or honoraria for lectures, presentations, speakers, manuscript writing, or educational events from Chugai Pharma, Ono Pharma, Bristol Meyers, and MSD; and has leadership or fiduciary roles in the Japan Surgical Society and the Japan Lung Cancer Society. The other authors have no conflicts of interest to declare., (2024 Journal of Thoracic Disease. All rights reserved.)

Introduction: Metastatic urothelial carcinoma (mUC) has poor prognosis. A high unmet need exists for novel treatment for those who are unfit for platinum-based chemotherapy., Methods: We aimed to describe real-world temporal changes in patient characteristics and 1L treatment selection for mUC patients in the United States following the approval of anti-PD-1/L1 treatments. This study was a retrospective, observational study using anonymized and structured oncology electronic medical record (EMR) data from IQVIA and the US Oncology Network iKnowMed (USON)., Results: After approval of 1L anti-PD-1/L1 treatment for mUC, there is a marked increase in the use of 1L anti-PD-1/L1 monotherapies, accompanied by a proportional decrease in 1L platinum-based treatments and non-guideline-based therapy; particularly among the elderly (> 75 years) and those with poor ECOG performance status (ECOG PS 2+)., Discussion: Anti-PD-1/L1 monotherapies fulfill the prior unmet need of frail mUC patients who are ineligible for platinum-based therapies., Competing Interests: GD serves on the executive council of National Community Oncology Dispensing Association, Inc. NCODA and received a payment from AJMC Institute for value-based medicine in June 2022. HL, MB, PS, BM, and KI are Merck employees and own Merck stock. SA is an employee of Ontada. RM reports research funding from Merck, unrelated to this project and serves as a consultant for Bristol Myers Squibb Bristol Myers Squibb (BMS), Seagen, Astellas, and Flatiron. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Doshi, Li, Burcu, Annavarapu, Wells, Imai, Moreno, Singhal and Mamtani.)

Introduction: Pembrolizumab was recently approved as an adjuvant treatment of renal cell carcinoma (RCC), based on prolonged disease-free survival compared to placebo in the phase III KEYNOTE-564 trial. The objective of this study was to evaluate the cost-effectiveness of pembrolizumab as monotherapy in the adjuvant treatment of RCC post-nephrectomy, from a US health sector perspective., Patients and Methods: A Markov model with 4 health states (disease-free, locoregional recurrence, distant metastases, and death) was developed to compare the cost and effectiveness of pembrolizumab versus routine surveillance or sunitinib. Transition probabilities were estimated using patient-level KEYNOTE-564 data (cutoff: June 14, 2021), a retrospective study, and published literature. Costs of adjuvant and subsequent treatments, adverse events, disease management, and terminal care were estimated in 2022 US$. Utilities were based on EQ-5D-5L data collected in KEYNOTE-564. Outcomes included costs, life-years (LYs), and quality-adjusted LYs (QALYs). Robustness was assessed through one-way and probabilistic sensitivity analyses., Results: Total cost per patient was $549,353 for pembrolizumab, $505,094 for routine surveillance, and $602,065 for sunitinib. Over a lifetime, pembrolizumab provided gains of 0.96 QALYs (1.00 LYs) compared to routine surveillance, yielding an incremental cost-effectiveness ratio of $46,327/QALY. Pembrolizumab dominated sunitinib with 0.89 QALYs (0.91 LYs) gained while saving costs. At a $150,000/QALY threshold, pembrolizumab was cost-effective versus both routine surveillance and sunitinib in 84.2% of probabilistic simulations., Conclusion: Pembrolizumab is projected to be cost-effective as an adjuvant RCC treatment versus routine surveillance or sunitinib based on a typical willingness-to-pay threshold., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Treatment of non-muscle-invasive bladder cancer (NMIBC) is guided by risk stratification using clinical and pathologic criteria. This study aimed to develop a natural language processing (NLP) model for identifying patients with high-risk NMIBC retrospectively from unstructured electronic medical records (EMRs) and to apply the model to describe patient and tumor characteristics., Methods: We used three independent EMR-derived data sets including adult patients with a bladder cancer diagnosis in 2011-2020 for NLP model development and training (n = 140), validation (n = 697), and application for the retrospective cohort analysis (n = 4,402). Deep learning methods were used to train NLP recognition of medical chart terminology to identify seven high-risk NMIBC criteria; model performance was assessed using the F1 score, weighted across features. An algorithm was then used to classify each patient as high-risk NMIBC (yes/no). Manually reviewed records served as the gold standard., Results: The F1 scores after model training were >0.7 for all but one uncommon feature (prostatic urethral involvement). The highest area under the receiver operating curves (AUC) was observed for Ta (0.897) and T1 (0.897); the lowest AUC was for carcinoma in situ (CIS; 0.617). For high-risk NMIBC classification, positive predictive value was 79.4%, negative predictive value was 93.2%, and false-positive rate was 8.9%. Sensitivity and specificity were 83.7% and 91.1%, respectively. Of 748 patients manually confirmed as having high-risk NMIBC, 196 (26%) had CIS (of whom 19% also had T1 and 23% also had Ta disease); 552 tumors (74%) had no associated CIS., Conclusion: The NLP model, combined with a rule-based algorithm, identified high-risk NMIBC with good performance and will enable future work to study real-world treatment patterns and clinical outcomes for high-risk NMIBC.

In cases of right upper and lower bilobectomy, careful manipulation is required to avoid lung torsion, as only the right middle lobe remains in the right thoracic cavity. We report a case of successful right upper and lower bilobectomy with no torsion of the middle lobe. Our technique prevents postoperative lung torsion by fixing the lung to the chest wall and pericardial fat with silk threads. In situations where lung torsion is a concern after lung resection, fixing the remaining lungs with silk thread is effective in preventing lung torsion., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

Renal interstitial fibrosis (RIF) is a common pathological manifestation of chronic kidney diseases. Epithelial-mesenchymal transition (EMT) of tubular epithelial cells is considered a major cause of RIF. Although long non-coding RNAs (lncRNAs) are reportedly involved in various pathophysiological processes, the roles and underlying molecular mechanisms of lncRNAs in the progression of RIF are poorly understood. In this study, we investigated the function of lncRNAs in RIF. Microarray assays showed that expression of the lncRNA lnc-CHAF1B-3 (also called claudin 14 antisense RNA 1) was significantly upregulated in human renal proximal tubular cells by both transforming growth factor-β1 (TGF-β1) and hypoxic stimulation, accompanied with increased expression of EMT-related genes. Knockdown of lnc-CHAF1B-3 significantly suppressed TGF-β1-induced upregulated expression of collagen type I alpha 1, cadherin-2, plasminogen activator inhibitor-1, snail family transcriptional repressor I (SNAI1) and SNAI2. Quantitative reverse transcriptase PCR analyses of paraffin-embedded kidney biopsy samples from IgA nephropathy patients revealed lnc-CHAF1B-3 expression was correlated positively with urinary protein levels and correlated negatively with estimated glomerular filtration rate. In situ hybridization demonstrated that lnc-CHAF1B-3 is expressed only in proximal tubules. These findings suggest lnc-CHAF1B-3 affects the progression of RIF by regulating EMT-related signaling. Thus, lnc-CHAF1B-3 is a potential target in the treatment of RIF., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors.)

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints., Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334., Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab., Interpretation: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy., Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA., Competing Interests: Declaration of interests TP reports having served as a consultant or adviser for Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Incyte, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; research funding paid to institution from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Eisai, Exelixis, Ipsen, Johnson & Johnson, Merck, Merck Serono, MSD, Novartis, Pfizer, Roche, and Seattle Genetics; and travel, accommodations, and expenses from AstraZeneca, Ipsen, MSD, Pfizer, and Roche. PT reports research funding from MSD. SHP reports having served as a consultant or adviser for Janssen Oncology and Lilly; and research funding from Ono Pharmaceutical. Bxports having served as a consultant or adviser for Bristol Myers Squibb, MSD Oncology, and Pfizer/EMD Serono; honoraria from Bristol Myers Squibb, Eisai, EUSA Pharma, Ipsen, Merck, MSD Oncology, and Pfizer; research funding paid to institution from Calithera Biosciences, Ipsen, MSD Oncology, and Pfizer/EMD Serono; serving as a speaker for Eisai, MSD Oncology, and Pfizer; and travel, accommodations, and expenses from EUSA Pharma and Ipsen. TF reports research funding paid to institution from AstraZeneca, Janssen, and MSD; and travel, accommodations, and expenses from Bristol Myers Squibb, MSD, and Roche. SNS reports having served as a consultant or adviser for Bicycle Therapeutics, Bristol Myers Squibb, Boxer Capital, Duke Street Bio, Eisai, Ellipses Pharma, EMD Serono, EUSA Pharma, MedAnnex, MSD, Pfizer, and Vaccitech; having served as a speaker for Bristol Myers Squibb, EUSA Pharma, and Ipsen; research funding paid to institution from BiolineRx, BioNTech, Boston Pharmaceuticals, Incyte, MSD, Nouscom, Nucana, Roche, Sapience Therapeutics, Scancell, Sierra Oncology, and Verastem; and travel, accommodations, and expenses from Bristol Myers Squibb, EUSA Pharma, and Ipsen. HG reports personal speaker fees from MSD; and personal advisory fees from MSD, Roche, Merck, Bristol Myers Squibb, Pfizer, and Ipsen. JLL reports honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, MSD, and Pfizer; having served as an advisr or consultant for Alteogen, AstraZeneca, BMS Korea, GI Innovation, Merck, MSD, Pfizer, and Sanofi/Aventis; research funding paid to institution from AstraZeneca/MedImmune, Bayer Schering Pharma, Bristol Myers Squibb, Janssen, MSD, Novartis, Pfizer, Roche/Genentech, and Seattle Genetics; and owns stock in Amgen, BeiGene, Black Diamond Therapeutics, Innovent Biologics, Johnson & Johnson/Janssen, Karyopharm Therapeutics, Merck, Myovant Sciences, and Zymeworks. NS reports having served as a consultant or adviser for Bristol Myers Squibb, Eisai, EUSA Pharma, MSD, and Roche; having served as a speaker for Pfizer; and research funding from MSD. AT-V reports honoraria from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche/Genentech, and Sanofi; having served as a consultant for Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Novartis, Pfizer, Roche, and Sanofi; research funding paid to institution from Pfizer; and travel, accommodations, and expenses from Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Ipsen, Janssen, MSD, Pfizer, and Roche. MG-G reports having served as a consultant or adviser for Amgen, Astellas Medivation, AstraZeneca, Bayer/Onyx, Bristol Myers Squibb, Ipsen, Janssen-Cilag, MSD Oncology, Pfizer, Roche, and Sanofi; research funding paid to institution from AstraZeneca, Ipsen, Janssen-Cilag, Merck, MSD Oncology, Pfizer, and Roche; and travel, accommodations, and expenses from Astellas Pharma, AstraZeneca, AstraZeneca, Ipsen, Janssen-Cilag, Pfizer, and Roche. MM reports research funding from MSD. NBH reports having served as a consultant or adviser for AVEO, Calithera Biosciences, Eisai, Exelixis, MSD, Pfizer, and Roche/Genentech; and has provided expert testimony for Lilly. PS reports honoraria from Bristol Myers Squibb and Novartis; research funding paid to institution from Boehringer Ingelheim, Chiltern, G1 Therapeutics, Gilead Sciences, Merrimack, MSD, Parexel, PAREXEL/Puma Biotechnology, PPD Global, Regeneron, and Tesaro; and travel, accommodations, and expenses from Pierre Fabre and Roche. JEB and LX are employees of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. KI is an employee of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, and owns stock in Merck & Co, Inc, Rahway, NJ, USA. DIQ reports having served as a consultant or adviser for Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Exelixis, Genentech/Roche, Janssen Oncology, MSD, Myovant Sciences, Novartis, Pfizer, Seattle Genetics, and US Biotest; honoraria from Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Exelixis, Genentech/Roche, MSD, Myovant Sciences, Novartis, Pfizer, and Seattle Genetics; research funding paid to institution from Genentech/Roche, Merck, and Pfizer; and travel, accommodations, and expenses from Astellas Pharma, Bayer, Bristol Myers Squibb Japan, Exelexis, Merck, and Roche. TKC reports institutional and personal support, paid and unpaid support for research, participating in advisory boards, consultancy, and honoraria from AstraZeneca, Aravive, Aveo, Bayer, Bristol Myers Squibb, Calithera, Circle Pharma, Eisai, EMD Serono, Exelixis, GlaxoSmithKline, IQVA, Infinity, Ipsen, Jansen, Kanaph, Lilly, Merck, Nikang, Nuscan, Novartis, Pfizer, Roche, Sanofi/Aventis, Surface Oncology, Takeda, Tempest, UpToDate, and CME events (Peerview, OncLive, and MJH), outside the submitted work; institutional patents filed on molecular mutations, immunotherapy response and toxicity, and ctDNA; equity in Tempest, Pionyr, Osel, Precede Bio; being part of committees in the National Comprehensive Cancer Network, GU Steering Committee, American Society of Clinical Oncology, European Society for Medical Oncology, Academic and Community Cancer Research United, and KidneyCAN; having mentored several non-US citizens on research projects partly funded by non-US sources; and additional independent funding from drug companies or royalties for research around the subject matter paid to institution. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In 2018, the US Food and Drug Administration (FDA) limited the indication for immune checkpoint inhibitors (ICI) in metastatic bladder cancer to patients with programmed cell death protein ligand-1 (PD-L1)-positive tumors. The impact of the label change on survival outcomes remains unknown. We conducted a controlled interrupted time series analysis using a nationwide electronic health record-derived oncology dataset. We used Cox regression to compare mortality in the post- vs prelabel change periods among affected (initiators of ICI or carboplatin-based chemotherapy) vs unaffected (initiators of cisplatin-based chemotherapy) patients. The use of ICI, carboplatin, and cisplatin was similar pre- and postlabel change, but PD-L1 testing increased postlabel change. In adjusted models, survival did not differ after the FDA label change policy compared with prior to the label change in any of the groups. The FDA label restriction on immunotherapy was associated with increased PD-L1 testing but not with changes in treatment patterns or mortality among patients with metastatic bladder cancer., (© The Author(s) 2022. Published by Oxford University Press.)

Background: This study aimed to investigate the efficacy of adjuvant chemotherapy for pathologic stage I non-small cell lung cancer (NSCLC) with high risk for recurrence., Methods: Prospectively collected data from 1278 patients with pathologic stage I NSCLC according to eighth edition staging guidelines who were undergoing lobectomy were retrospectively analyzed. Factors associated with high risk for recurrence were determined using the multivariable Cox proportional hazards model for recurrence-free survival (RFS). Survival was compared between patients who received adjuvant chemotherapy and those who did not., Results: In multivariable analysis, age (≥70 years), invasive component size (>2 cm), visceral pleural invasion, lymphatic invasion, and vascular invasion were identified as independent factors for RFS. In patients with high-risk factors for recurrence such as pathologic T1c or T2a or lymphovascular invasion (high-risk group; n = 641), adjuvant chemotherapy resulted in significantly longer RFS and overall survival (n = 222; 5-year RFS, 81.4%; 5-year overall survival, 92.7%) than in patients who did not receive adjuvant chemotherapy (n = 418; 5-year RFS, 73.8%; P = .023; 5-year overall survival, 81.7%; P < .0001). In patients without any high-risk factors for recurrence (low-risk group; n = 637), RFS was not significantly different between those who received adjuvant chemotherapy (n = 83; 5-yeat RFS, 98.1%) and those who did not (n = 554; 5-year RFS, 95.7%; P = .30)., Conclusions: Adjuvant chemotherapy may improve survival in patients with pathologic stage I NSCLC who have factors associated with high risk for recurrence, such as pathologic T1c or T2a or lymphovascular invasion., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Even if lung cancer is detected at an early stage, surgery may be difficult in patients with severe comorbidities, like interstitial pneumonia (IP). Radiation therapy cannot be performed due to the high risk of acute IP exacerbation. Therefore, an effective alternative, such as photodynamic therapy (PDT), is required. To prove that acute exacerbation is not induced after PDT in peripheral lung cancer, we investigated the effects of PDT on IP rat models., Methods: Bleomycin (BLM) was administered intratracheally. Seven days after administration, left thoracotomy was performed. Talaporfin sodium was injected, and diode laser irradiation (664 nm, 150mW, 100J/cm 2 ) was performed. Seven days after PDT, the whole blood and left lungs were collected. A total of 23 rats, comprising BLM + PDT (n = 4), BLM + non-PDT (n = 10), non-BLM + PDT (n = 2), non-BLM + non-PDT (n = 5), and two rats that died immediately after PDT were observed. Serum levels of Krebs von den Lungen-6, surfactant protein-D, lactate dehydrogenase, and serum C-reactive protein were measured. Fibrosis and macrophage scorings, and the ​​collagen fibers percentage were examined by staining with hematoxylin and eosin, Elastica van Gieson, anti-α smooth muscle antibody, and anti-CD68 antibodies., Results: There was no remarkable difference in the values of each marker in fibrosis and macrophage scores with or without PDT. In case of death, fibrosis was mild, and PDT was not affected., Conclusions: In IP rat models, PDT did not induce lung fibrosis or acute exacerbation., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Although tsunamis are dispersive water waves, hazard maps for earthquake-generated tsunamis neglect dispersive effects because the spatial dimensions of tsunamis are much greater than the water depth, and dispersive effects are generally small. Furthermore, calculations that include non-dispersive effects tend to predict higher tsunamis than ones that include dispersive effects. Although non-dispersive models may overestimate the tsunami height, this conservative approach is acceptable in disaster management, where the goal is to save lives and protect property. However, we demonstrate that offshore frequency dispersion amplifies tsunamis caused by outer-rise earthquakes, which displace the ocean bottom downward in a narrow area, generating a dispersive short-wavelength and pulling-dominant (water withdrawn) tsunami. We compared observational evidence and calculations of tsunami for a 1933 M w 8.3 outer-rise earthquake along the Japan Trench. Dispersive (Boussinesq) calculations predicted significant frequency dispersion in the 1933 tsunami. The dispersive tsunami deformation offshore produced tsunami inundation heights that were about 10% larger than those predicted by non-dispersive (long-wave) calculations. The dispersive tsunami calculations simulated the observed tsunami inundation heights better than did the non-dispersive tsunami calculations. Contrary to conventional practice, we conclude that dispersive calculations are essential when preparing deterministic hazard maps for outer-rise tsunamis., (© 2021. The Author(s).)

Objective: We aimed to determine the influences of surgical procedures on the postoperative death of octogenarians with clinical Stage IA non-small cell lung cancer excluding cT1mi., Methods: We compared overall survival and the cumulative incidence of death due to all and other causes among 1 130 279, and 191 consecutive patients aged ≤79 and ≥80 years after lobectomy, segmentectomy and wedge resection at three institutions. Death due to other causes was defined as death due to any cause except non-small cell lung cancer., Results: The median followup was 53 months. The 5-year overall survival rates for patients aged ≥ 80 and ≤ 79 years after lobectomy, segmentectomy and wedge resection were respectively, 78.0% (95% confidence interval, 63.8%-87.2%) versus 91.2% (95% confidence interval, 89.0%-92.9%), 68.1% (95% confidence interval, 45.2%-83.1%) versus 90.0% (95% confidence interval, 84.6%-93.5%), and 62.7% (95% confidence interval, 44.0-76.7%) versus 84.4% (95% confidence interval, 76.3%-89.9%) (P < 0.01 for all). The cumulative incidence of death due to other causes after wedge resection was similar between patients aged ≥ 80 and ≤ 79 years (P = 0.45), but significantly higher in those aged ≥ 80, than ≤ 79 years after lobectomy or segmentectomy (P = 0.00015 and 0.00091, respectively)., Conclusions: The influence of wedge resection on death due to other causes was lower than that of lobectomy or segmentectomy in patients with non-small cell lung cancer aged ≥ 80 years. Wedge resection might be a useful option for octogenarians even if they can tolerate lobectomy/segmentectomy to avoid postoperative death due to causes other than non-small cell lung cancer., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Patients with renal-cell carcinoma who undergo nephrectomy have no options for adjuvant therapy to reduce the risk of recurrence that have high levels of supporting evidence., Methods: In a double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, patients with clear-cell renal-cell carcinoma who were at high risk for recurrence after nephrectomy, with or without metastasectomy, to receive either adjuvant pembrolizumab (at a dose of 200 mg) or placebo intravenously once every 3 weeks for up to 17 cycles (approximately 1 year). The primary end point was disease-free survival according to the investigator's assessment. Overall survival was a key secondary end point. Safety was a secondary end point., Results: A total of 496 patients were randomly assigned to receive pembrolizumab, and 498 to receive placebo. At the prespecified interim analysis, the median time from randomization to the data-cutoff date was 24.1 months. Pembrolizumab therapy was associated with significantly longer disease-free survival than placebo (disease-free survival at 24 months, 77.3% vs. 68.1%; hazard ratio for recurrence or death, 0.68; 95% confidence interval [CI], 0.53 to 0.87; P = 0.002 [two-sided]). The estimated percentage of patients who remained alive at 24 months was 96.6% in the pembrolizumab group and 93.5% in the placebo group (hazard ratio for death, 0.54; 95% CI, 0.30 to 0.96). Grade 3 or higher adverse events of any cause occurred in 32.4% of the patients who received pembrolizumab and in 17.7% of those who received placebo. No deaths related to pembrolizumab therapy occurred., Conclusions: Pembrolizumab treatment led to a significant improvement in disease-free survival as compared with placebo after surgery among patients with kidney cancer who were at high risk for recurrence. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-564 ClinicalTrials.gov number, NCT03142334.)., (Copyright © 2021 Massachusetts Medical Society.)

Background: PD-1 and PD-L1 inhibitors are active in metastatic urothelial carcinoma, but positive randomised data supporting their use as a first-line treatment are lacking. In this study we assessed outcomes with first-line pembrolizumab alone or combined with chemotherapy versus chemotherapy for patients with previously untreated advanced urothelial carcinoma., Methods: KEYNOTE-361 is a randomised, open-label, phase 3 trial of patients aged at least 18 years, with untreated, locally advanced, unresectable, or metastatic urothelial carcinoma, with an Eastern Cooperative Oncology Group performance status of up to 2. Eligible patients were enrolled from 201 medical centres in 21 countries and randomly allocated (1:1:1) via an interactive voice-web response system to intravenous pembrolizumab 200 mg every 3 weeks for a maximum of 35 cycles plus intravenous chemotherapy (gemcitabine [1000 mg/m 2 ] on days 1 and 8 and investigator's choice of cisplatin [70 mg/m 2 ] or carboplatin [area under the curve 5] on day 1 of every 3-week cycle) for a maximum of six cycles, pembrolizumab alone, or chemotherapy alone, stratified by choice of platinum therapy and PD-L1 combined positive score (CPS). Neither patients nor investigators were masked to the treatment assignment or CPS. At protocol-specified final analysis, sequential hypothesis testing began with superiority of pembrolizumab plus chemotherapy versus chemotherapy alone in the total population (all patients randomly allocated to a treatment) for the dual primary endpoints of progression-free survival (p value boundary 0·0019), assessed by masked, independent central review, and overall survival (p value boundary 0·0142), followed by non-inferiority and superiority of overall survival for pembrolizumab versus chemotherapy in the patient population with CPS of at least 10 and in the total population (also a primary endpoint). Safety was assessed in the as-treated population (all patients who received at least one dose of study treatment). This study is completed and is no longer enrolling patients, and is registered at ClinicalTrials.gov, number NCT02853305., Findings: Between Oct 19, 2016 and June 29, 2018, 1010 patients were enrolled and allocated to receive pembrolizumab plus chemotherapy (n=351), pembrolizumab monotherapy (n=307), or chemotherapy alone (n=352). Median follow-up was 31·7 months (IQR 27·7-36·0). Pembrolizumab plus chemotherapy versus chemotherapy did not significantly improve progression-free survival, with a median progression-free survival of 8·3 months (95% CI 7·5-8·5) in the pembrolizumab plus chemotherapy group versus 7·1 months (6·4-7·9) in the chemotherapy group (hazard ratio [HR] 0·78, 95% CI 0·65-0·93; p=0·0033), or overall survival, with a median overall survival of 17·0 months (14·5-19·5) in the pembrolizumab plus chemotherapy group versus 14·3 months (12·3-16·7) in the chemotherapy group (0·86, 0·72-1·02; p=0·0407). No further formal statistical hypothesis testing was done. In analyses of overall survival with pembrolizumab versus chemotherapy (now exploratory based on hierarchical statistical testing), overall survival was similar between these treatment groups, both in the total population (15·6 months [95% CI 12·1-17·9] with pembrolizumab vs 14·3 months [12·3-16·7] with chemotherapy; HR 0·92, 95% CI 0·77-1·11) and the population with CPS of at least 10 (16·1 months [13·6-19·9] with pembrolizumab vs 15·2 months [11·6-23·3] with chemotherapy; 1·01, 0·77-1·32). The most common grade 3 or 4 adverse event attributed to study treatment was anaemia with pembrolizumab plus chemotherapy (104 [30%] of 349 patients) or chemotherapy alone (112 [33%] of 342 patients), and diarrhoea, fatigue, and hyponatraemia (each affecting four [1%] of 302 patients) with pembrolizumab alone. Six (1%) of 1010 patients died due to an adverse event attributed to study treatment; two patients in each treatment group. One each occurred due to cardiac arrest and device-related sepsis in the pembrolizumab plus chemotherapy group, one each due to cardiac failure and malignant neoplasm progression in the pembrolizumab group, and one each due to myocardial infarction and ischaemic colitis in the chemotherapy group., Interpretation: The addition of pembrolizumab to first-line platinum-based chemotherapy did not significantly improve efficacy and should not be widely adopted for treatment of advanced urothelial carcinoma., Funding: Merck Sharp and Dohme, a subsidiary of Merck, Kenilworth, NJ, USA., Competing Interests: Declaration of interests TP reports honoraria and research funding from Merck Sharp and Dohme (a subsidiary of Merck, Kenilworth, NJ, USA), AstraZeneca, and Roche; honoraria from BMS, Seattle Genetics, Ipsen, Merck Sharp and Dohme, Novartis, and Pfizer; fees for a consultant or advisory role for AstraZeneca, BMS, Exelexis, Incyte, Ipsen, Merck Sharp and Dohme, Novartis, Pfizer, and Seattle Genetics; and travel expenses and accommodations from AstraZeneca and Roche. TC reports research funding from Merck Sharp and Dohme. MO reports research funding from Merck Sharp and Dohme; personal honoraria from Roche, Sanofi Aventis, and Astellas; institutional honoraria from Janssen; fees for a consultant or advisory role for Janssen, Sanofi Aventis, and Astellas; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from BMS, Janssen, and AstraZeneca. NM reports research funding from Merck Sharp and Dohme, Astellas, Chugai, Eli Lilly, Janssen, Pfizer, and Taiho; and fees for a consultant or advisory role for Chugai, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. LG reports research funding from Merck Sharp and Dohme; fees for a consultant or advisory role for Janssen, Merck Sharp and Dohme, and Pfizer; and travel expenses and accommodations from Janssen, and Pfizer. SY-SC reports research funding from Merck Sharp and Dohme; and fees for a consultant or advisory role for AstraZeneca, BMS, and Merck Sharp and Dohme. YF reports research funding from Merck Sharp and Dohme, Tersera, Janssen, Astellas, and IMV; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, Sanofi Aventis, and Tersera; and fees for travel for Sanofi Aventis, and Tersera. SO reports research funding from Merck Sharp and Dohme, BMS, Sanofi Aventis, Pfizer, Novartis, Bayer, and Ipsen; personal honoraria from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen; institutional honoraria from Bayer and Pfizer; and travel expenses and accommodations from BMS, Merck, Sanofi Aventis, Pfizer, Novartis, Janssen, Astellas, Bayer, and Ipsen. CV reports research funding from Merck Sharp and Dohme, and Leo Pharma; fees for a consultant or advisory role for AstraZeneca, Merck Sharp and Dohme, GSK, Astellas, Ipsen, Roche, and BMS; and travel expenses and accommodations from Roche. RMB reports research funding from Merck Sharp and Dohme; honoraria from Sanofi Aventis, Roche, and Merck Sharp and Dohme; fees for a consultant or advisory role for Sanofi Aventis, Bayer, Janssen, AstraZeneca, Merck Sharp and Dohme, Roche, and Asofarma; and travel expenses and accommodations from Roche, Sanofi Aventis, Astellas, Janssen, Merck Sharp and Dohme, Bayer, Pharmacyclics, Clovis, and Eli Lilly. AF reports research funding from Merck Sharp and Dohme; honoraria from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics; and travel expenses and accommodations from Merck Sharp and Dohme, AstraZeneca, Pfizer, and Seattle Genetics. SG reports research funding from Merck Sharp and Dohme, and travel expenses and accommodations from Roche. YL reports research funding from Merck Sharp and Dohme, Sanofi Aventis, and Janssen; personal honoraria from Roche, Astellas, Janssen, Seattle Genetics, AstraZeneca, BMS, Merck Sharp and Dohme, Pfizer, Sanofi Aventis, and Ipsen; institutional honoraria from Janssen and Pfizer; and travel expenses and accommodations from Roche, Janssen, AstraZeneca, Merck Sharp and Dohme, and Sanofi Aventis. AR-V reports research funding from Merck Sharp and Dohme, Pfizer, and Takeda; honoraria from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis; fees for a consultant or advisory role for Astellas, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Ipsen, Clovis, and Roche; and travel expenses and accommodations from Astellas, AstraZeneca, Bayer, BMS, Janssen, Merck Sharp and Dohme, Pfizer, Roche, Ipsen, and Sanofi Aventis. RM reports research funding from Merck Sharp and Dohme; honoraria from MedLearning and Flatiron; and fees for a consultant or advisory role for Roche, Seattle Genetics, and Astellas. EYY reports research funding from Merck Sharp and Dohme, Bayer, Blue Earth, Daiichi-Sankyo, Dendreon, Pharmacyclics, Seattle Genetics, and Taiho; and fees for a consultant or advisory role for Abbvie, Advanced Accelerator Applications, Bayer, Clovis, Janssen, Merck Sharp and Dohme, and Sanofi Aventis. KN, KI, and BHM are employees of Merck Sharp and Dohme and report stock ownership. AA reports research funding from Merck Sharp and Dohme, Clovis, BMS, AstraZeneca, Bayer, Progenics, Janssen, Genentech, Esanik, Ionis, Arcus Biosciences, and Prometheus; honoraria from Merck Sharp and Dohme, BMS, and AstraZeneca; fees for a consultant or advisory role for Merck Sharp and Dohme, BMS, AstraZeneca, Pfizer, and Merck Serono; speaker bureau or expert testimony role for AstraZeneca; and travel expenses and accommodations from Merck Sharp and Dohme, BMS, and AstraZeneca., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The 2011 Tohoku-oki earthquake occurred in the Japan Trench 10 years ago, where devastating earthquakes and tsunamis have repeatedly resulted from subduction of the Pacific plate. Densely instrumented seismic, geodetic, and tsunami observation networks precisely recorded the event, including seafloor observations. A large coseismic fault slip that unexpectedly extended to a shallow part of megathrust fault was documented. Strong lateral variations of the coseismic slip near the trench were recorded from marine geophysical studies, along with a possible cause of these variations. The seismic activities in east Japan are still higher than those before the earthquake, and crustal deformation is still occurring. Although the recurrence probability of a great earthquake (magnitude = ~9) in the Japan Trench in the near future is very low, a large normal fault earthquake seaward of the Japan Trench is a concerning possibility., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Complex segmentectomy creates several intricate intersegmental planes; however, it has not been fully established in lung cancer treatment. We compared the oncologic outcomes of complex segmentectomy and lobectomy through a large cohort, multicenter database using propensity score-matched analysis., Methods: We retrospectively analyzed data from 1517 patients with clinical stage I lung cancer with a solid component size 2.0 cm or less, who underwent surgical resection at 3 institutions between 2010 and 2018. Complex segmentectomy (n = 240) and location-adjusted lobectomy (n = 851) as well as surgical results were analyzed for all patients and their propensity score-matched pairs., Results: The prognosis of patients undergoing complex segmentectomy was not significantly different from that of patients undergoing lobectomy (5-year cancer-specific survival [CSS] rate, 96.4% versus 97.2%, P = .69; and 5-year recurrence-free interval [RFI] rate, 95.8% versus 93.4%, P = .19). This trend was also identified in subanalyses for pure solid tumors. However, there were major differences in clinicopathologic features between the 2 groups. After propensity score-matched analysis, proper matching of patients was ascertained. In 219 propensity score-matched pairs, long-term outcomes were similar between patients undergoing complex segmentectomy (5-year CSS, 96.0%; 5-year RFI, 95.5%) and lobectomy (5-year CSS, 97.8%; 5-year RFI, 95.9%). Propensity score-adjusted multivariable analysis for RFI revealed that prognosis associated with complex segmentectomy was comparable to the prognosis obtained with lobectomy (hazard ratio = 0.98; 95% confidence interval, 0.33-2.40; P = .98)., Conclusions: Complex segmentectomy provides acceptable oncologic outcomes in clinical stage I lung cancer treatment., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: Anatomical resection with lymph node dissection is the standard treatment for early non-small cell lung cancer, whereas wedge resection is considered as a compromise. We aimed to determine whether wedge resection without lymph node dissection could be a treatment option for patients aged ≥80 years., Methods: We assessed 669 patients with clinical stage IA non-small cell lung cancer, whole tumour sizes ≤2 cm and a consolidation to tumour ratio of >0.5 who underwent R0 resection at three institutions between 2010 and 2016. We selected 58 of them who were aged ≥80 years and analysed their clinicopathological findings and prognosis after surgical procedures over a median follow-up of 38 months. Propensity scores for surgical procedures were calculated using age, gender, smoking status and solid tumour size on computed tomography., Results: Three-year overall and recurrence-free survival rates after wedge resection and after segmentectomy + lobectomy for patients aged ≥80 years did not significantly differ (overall survival: 88.9% [95% confidence interval, 69.4-96.3%] vs. 75.5% [95% confidence interval, 51.5-88.8%], P = 0.95; recurrence-free survival: 85.2% [95% confidence interval: 65.2-94.2%] vs. 68.0% [95% confidence interval, 44.4-83.2], P = 0.57). Multivariable Cox regression analysis of overall survival with propensity scores revealed that surgical procedure was not an independent predictor of a poor prognosis (hazard ratio: 0.86 (0.28-2.6), P = 0.78) in patients aged ≥80 years., Conclusions: Wedge resection might be an alternative to lobectomy or segmentectomy with lymph node dissection for patients aged ≥80 years with early non-small cell lung cancer., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

The aim of this study was to evaluate the feasibility of a combination therapy of photodynamic therapy (PDT) and airway stent placement using a transparent silicone stent (gold studded stent [GSS]). Laser irradiation (664 nm, continuous wave) was performed through the GSS using a straight and cylindrical fiber 1.0 cm away from a power meter. There are two types of GSS: the TD type for the trachea and the BD type for the bronchus. Laser outputs were set to 150 mW, 180 mW, 210 mW, 240 mW, 270 mW, and 300 mW. The laser powers passing through the both types of GSS were measured three times for each outputs and the averages were calculated. Based on the results, animal experiment was performed using two female pigs. Under general anesthesia, a GSS (BD type) was inserted into trachea of pigs, and PDT using NPe6 as a photosensitizer was performed by 100 J/cm 2 laser irradiation on parts of the trachea with and without a GSS. Immediately after and 1 week after PDT, pig tracheas were harvested and histological analysis was performed. Histological analysis of areas with or without the stent showed edematous changes between the cartilage and submucosal layer immediately after PDT, and necrotic changes 1 week later. The effectiveness of NPe6-PDT for pigs' trachea covered by the stent was same as trachea without the stent. The use of a GSS may enable PDT to be effective even in the area covered by the stent.

Background: The prognosis of patients with cT1N0 lung adenocarcinoma is better when tumors include mixed ground glass opacity (GGO), compared with pure solid tumors. However, whether the prognosis of patients with mixed GGO tumors is favorable regardless of the solid component size remains unknown. Therefore, we aimed to determine the prognostic role of the solid component size in mixed GGO., Methods: We retrospectively analyzed the clinicopathological findings and prognoses of 856 patients with mixed GGO tumors based on solid component size during a median follow-up of 45 months, among 1215 patients with cT1N0 lung adenocarcinoma according to the TNM Classification of Malignant Tumors, Eighth Edition, who underwent R0 resection at 3 institutions between 2010 and 2015., Results: Four-year recurrence-free survival rates were significantly worse for patients with mixed GGO cT1c tumors (solid component size: 2-3 cm; 81.5%; 95% confidence interval [CI], 72.8%-87.7%) than for those with cT1mi+1a tumors (0-1 cm; 96.8%; 95% CI, 94.2%-98.2%) and cT1b (1-2 cm; 95.3%; 95% CI, 92.1%-97.2%) (both P < .001), although that for cT1b tumors was comparably favorable to those of T1mi+1a tumors. Multivariable Cox regression analysis of recurrence-free survival revealed that a solid component size of 2 cm to 3 cm (cT1c) vs less than or equal to 2 cm (cT1mi+1a+1b) was an independent prognostic factor (hazard ratio, 4.16; 95% CI, 2.24-7.72; P < .001)., Conclusions: The prognostic impact of a solid component size less than or equal to 2 cm and greater than 2 cm significantly differs after complete resection of GGO-mixed T1N0 lung adenocarcinoma. The prognosis of patients with solid components less than or equal to 2 cm is favorable, whereas the behavior of those solid components greater than 2 cm is more aggressive., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: Recurrence risk of resected lung adenocarcinoma is represented by pathological stage (pStage), histological subtype, and potentially by EGFR mutation. However, the relationship among these factors and their combined impact on prognosis are unclear., Materials and Methods: Using a multicenter database, we retrospectively investigated the prognostic impact of EGFR mutation status in relation to pStage and histological subtype in resected pN0-1M0 lung adenocarcinoma., Results: Among 1155 pN0-1M0 adenocarcinoma cases, pStage 0 and IA1-IB were confirmed predominantly in EGFR-positive cases. AIS, MIA, and lepidic predominant adenocarcinoma were also more frequently found in EGFR-positive cases and showed no/little recurrence regardless of EGFR mutation status. The 5-year recurrence-free survival (RFS) of papillary, acinar, solid, and micropapillary predominant adenocarcinoma was stratified by pStage (IA1-IB, IIA-IIIA) or histological malignant subtype (intermediate or high malignant subtype), and more finely subdivided by EGFR mutation status. Positive EGFR mutation cases showed worse RFS in both classifications. Low malignant subtype and pStage IA1-IB intermediate malignant subtype showed low frequency of recurrence. Whereas, in pStage IA1-IB high malignant subtype and pStage IIA-IIIA cases, EGFR-positive cases showed poorer 5-year RFS than EGFR-negative (49.6% and 75.6%, respectively, hazard ratio [HR] = 1.84, 95% CI = 1.38-7.42, p <  0.01) and multivariate analysis indicated positive EGFR mutation status was significantly related to poorer PRF (HR = 2.005, 95% CI = 1.029-3.906, p =  0.041)., Conclusion: EGFR mutation harbored primarily in early-stage or low-malignant histological subtypes with no/little recurrence. In pN0-1M0 adenocarcinoma with higher risk of recurrence, positive EGFR mutation cases showed worse RFS. EGFR mutation status enables better stratification of recurrence risk when considering pStage and histological malignant subtype., Competing Interests: Declaration of Competing Interest None. Financial/nonfinancial disclosures: None Other contributions: The authors would like to thank Editage (www.editage.jp) for English language editing., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: The open-label, randomized, active-controlled KEYNOTE-045 study (NCT02256436) showed that second-line pembrolizumab significantly improved overall survival (OS) of patients with advanced/metastatic urothelial cancer (UC) that progressed after first-line platinum-containing chemotherapy, compared with standard chemotherapy (paclitaxel, docetaxel, or vinflunine). Pembrolizumab is approved for patients with bladder cancer in Japan., Patients and Methods: Analysis was performed in the subgroup of Japanese patients enrolled in the KEYNOTE-045 study. Coprimary end points were OS and progression-free survival (PFS). Objective response rate (ORR) and safety were secondary end points., Results: Fifty-two Japanese patients (pembrolizumab, n = 30; chemotherapy, n = 22) were followed up for a median of 26.1 months. Patients who received pembrolizumab compared with chemotherapy had a 19% lower risk for death (hazard ratio [HR] 0.81, 95% CI 0.44-1.50); after adjusting for baseline covariates, the HR for OS was 0.61 (95% CI 0.32-1.15). The 24-month OS rate was higher with pembrolizumab (26.9% vs 14.3%). PFS was 2.0 and 4.9 months for pembrolizumab and chemotherapy, respectively (HR 1.71, 95% CI 0.95-3.08). ORR was similar for pembrolizumab and chemotherapy (20.0% vs 18.2%); durability of response was higher with pembrolizumab: 67% and 33% of patients, respectively, maintained a response for > 12 months. Treatment-related adverse events, including grade 3-5 events, occurred less frequently with pembrolizumab., Conclusions: Pembrolizumab provided durable antitumor activity in patients with locally advanced/metastatic UC that progressed after platinum-containing chemotherapy in the overall population and in the Japanese subgroup; safety profile was consistent with that previously observed for pembrolizumab.

The aim of the present study was to investigate epidermal growth factor receptor ( EGFR ) mutations as a prognostic factor for postoperative patients with positive EGFR mutations treated with postoperative platinum-based adjuvant chemotherapy (PBAC), and whether two common EGFR mutations exhibit different responses to PBAC. A total of 110 patients who underwent complete surgical resection were enrolled, and overall survival (OS) and disease-free survival (DFS) were investigated based on EGFR mutation status and PBAC. The 3 year OS rate in patient groups were as follows: Patients with EGFR mutations (MT) undergoing PBAC, 89.3%; MT patients without PBAC, 83.3%; wild-type (WT) patients with PBAC, 82.3%; and WT patients without PBAC, 62.2%. Statistically significant differences were observed between WT patients based on PBAC (P=0.026). No statistically significant differences were observed between MT patients with PBAC and MT patients without PBAC. On the basis of mutation subtypes, the 3 year OS rate of patient groups were as follows: Patients with in-frame deletions in exon19 (19 del) with PBAC, 92.3%; patients with 19 del without PBAC, 85.7%; patients with the point mutation L858R inexon21 (21L858R) with PBAC, 86.7%; and patients with 21L858R without PBAC, 81.5%; the respective 3-year DFS rates were 53.8, 14.3, 40.2 and 26.9%. Statistically significant differences were observed in the DFS rates in 19 del patients, which was dependent on PBAC (P=0.040). EGFR mutation-positive patients exhibited a decreased benefit from PBAC for increasing in survival rate compared with WT patients. It may be necessary to consider postoperative strategies based on EGFR mutations and their subtype in the future., (Copyright: © Kawaguchi et al.)

Background: Quantitative computed tomography (CT) histogram analysis of tumors is reported to help distinguish between invasive and less invasive lung cancers. This study aimed to clarify whether CT histogram analysis of tumors can be used to classify patients with clinical stage 0 to IA non-small cell lung cancer according to pathologic lymph node (pN) status., Methods: Predictive factors associated with pN metastasis were identified from the derivation dataset including 629 patients with clinical stage 0 to IA non-small cell lung cancer who underwent complete resection with lymph node dissection (surgeries between 2008 and 2013). The validation dataset including 238 patients (surgeries between 2014 and 2015) were subsequently reevaluated. Clinicosurgical factors, including CT histogram analysis of tumors (CT value percentiles 2.5, 25, 50, 75, and 97.5, skewness, and kurtosis) were assessed., Results: Seventy-three patients (12%) in the derivation cohort and 35 patients (15%) in the validation cohort had positive nodes. The pN status significantly affected survival in the entire population: 5-year overall survival of 93.1% vs 71.1% and 5-year disease-free survival of 85.9% vs 43.1% for negative vs positive (both P < .001). On multivariate analysis in the derivation cohort, the 75th percentile CT value (P < .001), age (P = .003), and comorbidities (P = .006) were significantly associated with pN metastasis. The area under the curve and the cutoff level of the 75th percentile CT value relevant to pN metastasis were 0.729 and 1.5 HU, respectively, and the threshold value provided accuracy of 71% for the validation cohort., Conclusions: Histogram analysis of CT imaging metrics of tumors contributes to noninvasive prediction of pN metastasis in patients with clinical stage 0 to IA non-small cell lung cancer., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Objective: This study examined the prevalence of chronic comorbidities and the use of co-medications among people living with HIV (PLWH) on antiretrovirals in Japan, compared with age-matched controls without HIV., Methods: This was an observational, retrospective, cross-sectional study using a hospital claims database of Japanese hospitals with advanced medical capabilities (i.e., advanced treatment hospitals, general hospitals, acute care hospitals). We extracted data for PLWH aged ≥18 years with a prescription record of antiretrovirals between January 2010 and December 2015, and for age-, sex-, and hospital-matched people without HIV. For each group, chronic comorbidities (diabetes, hypertension, lipid disorders, vascular diseases, chronic kidney failure, cancers, psychiatric disorders, osteoporosis, and hepatitis B/C co-infection), and co-medications were examined by age group., Results: We analyzed data for 1445 PLWH and 14,450 people without HIV. The proportion of patients with multiple comorbidities was much greater among PLWH than controls of the same age group. Lipid disorders and diabetes were more prevalent in PLWH than controls (31.6% vs. 10.3% and 26.8% vs. 13.2%, respectively), both of which were more common in PLWH at earlier ages. Cancer was present in 8.1% of PLWH and 8.9% of controls. A greater proportion of PLWH used multiple co-medications other than antiretrovirals at earlier ages than controls., Conclusion: PLWH taking antiretrovirals in Japan had a greater burden of comorbidities and co-medications with increasing age than people without HIV. In addition to appropriate management of comorbidities, medication reconciliation according to patients' co-medication profiles is important for successful management of this patient population., (Copyright © 2018 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: This study aimed to predict the malignant potential of clinical stage I non-small cell lung cancer (c-I NSCLC) by semiautomatic three-dimensional (3D) volumetric measurement of a tumor (3D-data) and the axial computed tomography (CT) data derived from a 3D volumetric dataset (2D-data). The predictive performance was evaluated in terms of overall survival (OS), disease-free survival (DFS), and pathological invasive factors (positive lymphatic invasion, blood vessel invasion, pleural invasion, or lymph node metastasis)., Methods: We identified 252 patients (122 male; mean age, 68 years; range, 23-84 years) with c-I NSCLC who underwent high resolution CT and reconstruction of 3D imaging, followed by complete resection between January 2012 and December 2015. In this study, 2D-data including whole tumor size (WTS) and solid-part size (SPS) and 3D-data including whole tumor volume (WTV) and solid-part volume (SPV) acquired by a 3D volume rendering software were analyzed., Results: The area under the receiver operating characteristic (ROC) curve for WTS, SPS, WTV, SPV relevant to recurrence was 0.667, 0.727, 0.654, and 0.751 while analyses of ROC curves revealed optimal WTS, SPS, WTV, and SPV cut-off values to predict recurrence of 2.48 cm, 2.03 cm, 3,258 mm 3 and 1,889 mm 3 , respectively. The association between SPS and SPV was the coefficient of determination ( R 2 ) =0.59. Multivariate analysis showed that SPV >1,889 mm 3 (P=0.016) and male (P=0.041) were significant predictors of OS whereas SPV >1,889 mm 3 (P=0.001), male (P=0.003), and the serum carcinoembryonic antigen value (P=0.041) were significantly correlated with DFS. SPS, SPV as well as the combination of SPS and SPV were all significantly correlated with the prediction of OS and DFS, and the incidence of pathological invasive factors., Conclusions: SPV and the integrated use of SPS and SPV was highly beneficial for the prediction of postoperative prognosis in c-I NSCLC., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Objectives: The aim of this study was to analyze the accuracy of computed tomography (CT) and F-18 fluorodeoxyglucose-positron emission tomography/CT (FDG-PET/CT) to distinguish lepidic growth adenocarcinoma (LGA), including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic-predominant adenocarcinoma, all of which have favorable survival outcomes, from the more aggressive and invasive non-LGA subtypes., Materials and Methods: We identified 225 patients with c-0/I adenocarcinoma of the lung who underwent PET/CT and 3DCT followed by complete resection. Maximum standardized uptake values (SUVmax) of FDG and several histogram parameters were analyzed. Histological grades were classified according to the predominant subtype (G1: lepidic; G3: micropapillary or solid; and G2: subtypes other than G1/G3)., Results: The proportion of pathological invasive factors (lymphatic vessel involvement/blood vessel invasion/pleural invasion/lymph node metastasis) of patients with preinvasive adenocarcinoma, G1, G2, and G3 tumors were 0%, 3.6%, 48.0%, and 100%, respectively; p <  0.001). Multivariate analysis with CT-related parameters demonstrated that 75 th percentile CT attenuation value (75 th %, p <  0.001) and maximum CT attenuation value (maxCT, p =  0.009) were associated with incidence of non-LGA, whereas the value of SUVmax demonstrated a significant correlation (p <  0.001). When all patients were dichotomized according to ground-glass opacities (GGO)/solid-dominancy for CT maximum diameter, a significant correlation with non-LGA was shown in patients with solid-dominant tumor on SUVmax (p <  0.001) and with GGO-dominant tumor on 75 th % (p =  0.006) and maxCT (p =  0.007). The combination of one of the two significant histogram parameters and SUVmax revealed higher predictive performance for pathological high malignant features (positive pathological invasive factors, non-LGA, and the highly malignant subtype covering G2 with moderately or poorly-differentiated carcinoma and G3) than the individual use of either factor., Conclusion: The 75 th %, maxCT, and SUVmax were highly useful in distinguishing LGA from non-LGA in c-0/I adenocarcinoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Introduction: Diabetes mellitus is a progressive disease with cardiovascular complications. This study evaluated the effects of liraglutide, a glucagon-like peptide-1 analogue and the dipeptidyl peptidase 4 inhibitors sitagliptin and linagliptin on cardiac function in type 2 diabetes patients with renal impairment., Materials and Methods: A total of 139 patients who were referred because of suboptimal glycaemic control were randomly assigned to liraglutide 0.9 mg/d (n = 45), sitagliptin 50 mg/d, (n = 49) or linagliptin 5 mg/d (n = 45) at enrolment and were evaluated. Blood glucose, glycosylated haemoglobin and serum creatinine were assayed every 3 months for 48 months. Echocardiography was performed every 12 months for 48 months., Results: Compared with baseline, fasting glucose, postprandial glucose, and systolic and diastolic pressure, but not estimated glomerular filtration rate, significantly decreased in all three groups. Albuminuria decreased from 24 to 48 months with liraglutide, but only from 24 to 30 months with sitagliptin and linagliptin. Diastolic function, assessed by E/e' or left atrial dimension improved only with liraglutide., Conclusions: Liraglutide was effective for glucose and blood pressure control, reduced albuminuria and improved diastolic function. Diastolic function was not improved by sitagliptin and linagliptin., (© 2018 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Objectives: The aim of this study was to conduct comparative analyses of the biological malignant potential of clinical stage IA adenocarcinoma using positron emission tomography/computed tomography (PET/CT), high-resolution CT (HRCT), and three-dimensional CT (3DCT). The predictive performance of these parameters was evaluated in terms of clinical outcomes and pathological invasiveness (positive lymphatic permeation, blood-vessel invasion, pleural invasion, and lymph-node metastasis)., Materials and Methods: We enrolled 170 patients with c-IA adenocarcinoma who underwent PET/CT, HRCT, and 3D reconstruction of lung structures using the Synapse Vincent system (Fujifilm Corporation, Tokyo, Japan) followed by complete resection. Maximum standardized uptake values (SUV max ) of F 18 -fluorodeoxyglucose and the size and volume of the solid part of the tumor were quantified and analyzed in relation to surgical outcomes., Results: Univariate analysis demonstrated that all the three parameters and whole-tumor volume were associated with unfavorable disease-free survival (DFS), while the volume of the solid part was the independent predictor on multivariate analysis (p < .001). The receiver operating characteristic curves for pathological invasiveness, determined using the variables dichotomized at each cut-off level (SUV max 2.4; solid-part size 1.23 cm; solid-part volume 779 mm 3 ), showed that all were significantly correlated with pathological invasiveness and prognosis, whereas the combination of SUV max and the solid-part volume was the most powerful predictor of survival and pathological invasiveness compared to any other parameters: the 4-year DFS and proportion of pathological invasiveness in patients with SUV max  > 2.4 and solid-part volume > 779 mm 3 versus those with SUV max  ≤ 2.4 or solid-part volume ≤779 mm 3 were 81.2% versus 98.3% (p < .001) and 84.3% versus 15.1% (p < .001), respectively., Conclusion: In c-IA adenocarcinoma, the volume of the solid part of the tumor was the independent predictor for unfavorable DFS, and the integration of the volume of the solid part and SUV max was highly beneficial for the prediction of survival and pathological invasiveness., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: To investigate the prevalence of chronic comorbidities and the use of comedications in people living with HIV (PLWH) and on antiretrovirals in Japan, by using a hospital claims database., Design: Observational, retrospective, cross-sectional study., Setting: A hospital claims database of Japanese hospitals that have advanced medical treatment capabilities (ie, advanced treatment hospitals, general hospitals, acute care hospitals), which include those providing acute and chronic care (excluding nursing homes or hospices)., Participants: A total of 1445 PLWH aged ≥18 years and with a prescription record of antiretrovirals between January 2010 and December 2015 were identified from the database., Outcome Measures: The number and types of chronic comorbidities, as well as the number and types of comedications, in different age groups of the PLWH., Results: The median (range) age of patients was 45 (18-90) years, and 90.4% were men. Of the 1445 patients, 972 (67.3%) had at least one chronic comorbidity. Common chronic comorbidities included lipid disorders (31.6%), diabetes (26.8%), hypertension (18.2%) and hepatitis B/C coinfection (18.2%). Patients in the older age groups had greater numbers of chronic comorbidities. The most common chronic comorbidities in the older age groups were hypertension, diabetes and lipid disorders. The majority of patients used at least one comedication, and those in the older age groups used greater numbers of comedications. The most common therapeutic category of comedication included antacids, antiflatulents and antiulcerants (31.7%). Of 151 malignancies reported in 117 patients, 84 were AIDS-defining cancers and 67 were non-AIDS-defining cancers., Conclusions: Chronic comorbidities and comedications were common among PLWH in Japan taking antiretrovirals; particularly among older patients, who more frequently used comedications. This suggests the need for giving special attention to the appropriate management of this patient population., Competing Interests: Competing interests: DJR, KI and KT are employees of MSD K.K., Tokyo, Japan. TN has received no funding for this study but received lecture fees from MSD K.K., Tokyo, Japan., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To quantify the risk of pneumococcal pneumonia (PP) and invasive pneumococcal disease (IPD) in adults aged ≥19 years with underlying medical conditions compared with healthy adults of the same age in Japan., Design: An observational, retrospective, cohort study using two healthcare claims databases in Japan: Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases., Participants: A total of 10.4 million individuals, representing 9.3 million person-years of follow-up, were included in the analysis. Eleven medical conditions as well as PP and IPD were identified by the International Statistical Classification of Diseases and Related Health Problems version 10 diagnostic codes and/or local disease codes used in Japan., Primary Outcome Measures: Adjusted rate ratios (RRs) for PP and IPD in adults with a medical condition versus adults without any medical condition were calculated using multivariate Poisson regression models with age and/or sex as covariates., Results: In the JMDC and MDV databases, respectively, adults ≥19 years with a medical condition (RRs for PP: 3.3 to 13.4, 1.7 to 5.2; RRs for IPD: 12.6 to 43.3, 4.4 to 7.1), adults with two or more medical conditions (PP: 11.6, 2.8; IPD: 18.7, 5.8) and high-risk adults (PP: 12.9, 1.8; IPD: 29.7, 4.0) were at greater risk of PP and IPD compared with their healthy counterparts. Adults aged 50-64 years with an underlying medical condition (PP rate: 38.6 to 212.1 per 100 000 person-years) had a higher rate of PP than those aged ≥65 years without any condition (PP rate: 13.2 to 93.0 per 100 000 person-years)., Conclusions: Adults of all ages with an underlying medical condition are at greater risk of PP and IPD compared with adults without any medical condition. This risk increases with the number of underlying medical conditions. Our results support extending pneumococcal vaccination to younger adults with an underlying medical condition, especially those aged 50-64 years., Competing Interests: Competing interests: KI, AS and SK are employees of MSD K.K., a group of Merck Sharp & Dohme Corp., which is a subsidiary of Merck & Co., Inc. (Kenilworth, New Jersey, USA). KN and MA received research grants and lecture fees from MSD K.K. TP and MAK are employees of Merck & Co., Inc. Employees may hold stock and/or stock options in the company. The study sponsor, Merck & Co., Inc., and MSD K.K. reviewed the study design; participated in the collection, analysis and interpretation of the data; critically reviewed the report and decided to submit the paper for publication., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: The second-generation photosensitizer NPe6 has strong anti-tumor effects with a much shorter photosensitive period than the first-generation photosensitizer Photofrin. Although photosensitive period has been reduced, skin photosensitivity is still a major side effect of photodynamic therapy (PDT). Therefore, we conducted a prospective study to investigate whether the NPe6 fluorescence intensity in skin after PDT could be measured effectively in human patients to improve the management of a patient's photosensitive period., Methods: The NPe6 fluorescence measurements using a constructed fluorescence sensing system at the inside of the arm were acquired prior to and 5 and 10min after NPe6 administration as well as at the time of PDT (4-5h after administration), at discharge (2 or 3days after PDT), and at 1 or 2 weeks after PDT. Participants were interviewed as to whether they had any complications at 2 weeks after PDT., Results: Nine male patients and one female patient entered this study. Nine patients were inpatients and one patient was an outpatient. All of the measurements of NPe6 fluorescence in the skin could be obtained without any complications. The spectral peak was detected at the time of discharge (2-3days after administration) in most cases and it decreased at 1 or 2 weeks after PDT., Conclusions: The fluorescence of NPe6 in the skin could be detected feasibly using the fluorescence sensing system in human patients. Measuring the relative concentration of NPe6 in the skin indirectly by measuring fluorescence intensity might be useful to predict the period of skin photosensitivity after PDT., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Extramedullary hematopoiesis (EMH) is hematopoiesis in organs outside the bone marrow and most frequently occurs in the liver, spleen, and lymph nodes. We report a case of perirenal EMH revealed by kidney biopsy in a patient with primary myelofibrosis. We observed only bilateral kidney enlargement with plain computed tomography (CT) and ultrasonography before obtaining a renal biopsy. We obtained a percutaneous biopsy from the lower pole of the left kidney using ultrasonographic guidance. Ultrasonography just after the renal biopsy revealed no bleeding around the kidney. However, early the next morning, the patient developed severe hemorrhagic shock. Contrast-enhanced CT at that time revealed a massive hematoma in the left posterior perirenal space and bilateral abnormalities of the perirenal soft tissues. In patients with primary myelofibrosis, if plain CT shows an abnormal renal enlargement, EMH should be considered. In addition, a contrast-enhanced CT should be obtained before performing a percutaneous renal biopsy to assess for the possibility of perirenal EMH in these patients.

We report a successful endoscopic ultrasonography-guided drainage of a huge infected multilocular walled-off necrosis (WON) that was treated by a modified single transluminal gateway transcystic multiple drainage (SGTMD) technique. After placing a wide-caliber fully covered metal stent, follow-up computed tomography revealed an undrained subcavity of WON. A large fistula that was created by the wide-caliber metal stent enabled the insertion of a forward-viewing upper endoscope directly into the main cavity, and the narrow connection route within the main cavity to the subcavity was identified with a direct view, leading to the successful drainage of the subcavity. This modified SGTMD technique appears to be useful for seeking connection routes between subcavities of WON in some cases.

Acute obstructive suppurative cholangitis (AOSC) due to biliary lithiasis is a life-threatening condition that requires urgent biliary decompression. Although endoscopic retrograde cholangiopancreatography (ERCP) with stent placement is the current gold standard for biliary decompression, it can sometimes be difficult because of failed biliary cannulation. In this retrospective case series, we describe three cases of successful biliary drainage with recovery from septic shock after urgent endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) was performed for AOSC due to biliary lithiasis. In all three cases, technical success in inserting the stents was achieved and the patients completely recovered from AOSC with sepsis in a few days after EUS-CDS. There were no procedure-related complications. When initial ERCP fails, EUS-CDS can be an effective life-saving endoscopic biliary decompression procedure that shortens the procedure time and prevents post-ERCP pancreatitis, particularly in patients with AOSC-induced sepsis.

We report a case of metachronous multiple lung adenocarcinoma at the cut-end, diagnosed 4 years after sublobar resection for adenocarcinoma in situ (AIS), on the basis of discordance of epidermal growth factor receptor (EGFR) mutation status between the first and second tumor. The patient was an 81-year-old Japanese man, whose chest computer tomography (CT) scan showed mixed ground-glass opacity in the right upper lobe of the lung. Wedge resection was performed and a diagnosis of AIS, non-mucinous (18 × 14 mm), with a margin of 6 mm, was made. A tumor at the cut-end was seen on a CT scan 4 years later, and abnormal uptake was identified by fluorine-18 fluorodeoxyglucose-positron emission tomography. Right upper lobectomy and lymph node dissection were performed and the tumor was diagnosed as invasive adenocarcinoma, acinar predominant. Discordance of EGFR mutation status between the first tumor, harboring exon 19 deletion, and the second tumor, having an L858R point mutation in exon 21, revealed that the second tumor was metachronous multiple lung cancer. This case demonstrates the necessity of comparing EGFR mutation status between the first tumor and the second tumor at the cut-end.

To identify a possible new treatment modality for malignant pleural mesothelioma (MPM), we examined whether combination treatment consisting of pemetrexed chemotherapy and photodynamic therapy (PDT) using the photosensitizer NPe6, enhanced the antitumor effect in both in vitro and in vivo models. We also investigated preclinical treatment schedules. Four human malignant mesothelioma cell lines (MSTO‑211H, H2052, H2452 and H28) were assayed using the WST assay after treatment with pemetrexed and NPe6‑PDT. The treatment schedule for the combination treatment was examined using nude mice. Pemetrexed pre‑treatment enhanced the lethal effect of NPe6‑PDT in the four malignant mesothelioma cell lines, but NPe6‑PDT followed by pemetrexed treatment did not enhance cell lethality in the in vitro assay. Pemetrexed pre‑treatment did not enhance the intracellular accumulation of NPe6, which is one of the determinants of the antitumor effect of PDT. In nude mice injected with MSTO‑211H cells and then treated using a combination of pemetrexed and NPe6‑PDT (10 mg/kg NPe6, 10 J/cm(2) laser irradiation), the tumor volume decreased by 50% but subsequently increased, reaching the pre‑treatment value after 14 days. Pemetrexed treatment followed by NPe6‑PDT resulted in an 80% reduction in the tumor size and inhibited re‑growth. NPe6‑PDT followed by pemetrexed treatment resulted in a 60% reduction in tumor size but did not inhibit re‑growth. NPe6‑PDT induced the expression of thymidylate synthase (TS), which confers resistance to pemetrexed, and NPe6‑PDT followed by pemetrexed treatment did not enhance the treatment outcome in vivo. In conclusion, combination treatment, consisting of pemetrexed followed by NPe6‑PDT, should be further investigated as a new treatment modality for MPM. In the future, this combination treatment may contribute to a reduction in local recurrence and a prolonged survival period in patients with MPM.

Background: The rapid aging of the population in Japan has been accompanied by an increased rate of surgery for lung cancer among elderly patients. It is thus an urgent priority to map out a treatment strategy for elderly patients with primary lung cancer. Although surgical resection remains standard treatment for early stage non-small-cell lung cancer (NSCLC), it is now essential to confirm the status of epidermal growth factor receptor (EGFR) gene mutations when planning treatment strategies. Furthermore, several studies have reported that EGFR mutations are an independent prognostic marker in NSCLC. However, the relations between age group and the molecular and pathological characteristics of NSCLC remain unclear. We studied the status of EGFR mutations in elderly patients with NSCLC and examined the relations of EGFR mutations to clinicopathological factors and outcomes according to age group., Methods: A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene exons 19, 20, and 21 and KRAS gene exons 12 and 13 were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method., Results: EGFR mutations were detected in 185 (47.7%) and KRAS mutations were detected in 33 (8.5%) of the 388 patients. EGFR mutations were found in a significantly higher proportion of patients younger than 80 years (younger group; 178/359, 49.6%) than in patients 80 years or older (older group; 7/29, 24.1%) (P = 0.008). In contrast, KRAS mutations were more common in the older group (6/29, 20.7%) than in the younger group (27/359, 7.5%) (P = 0.014). The older group showed a trend toward a higher rate of 5-year overall survival among elderly patients with EGFR mutations (100%) than among those with wild-type EGFR (66.2%), but the difference was not significant., Conclusions: Our results suggest that the EGFR status of patients with NSCLC differs between patients 80 years or older and those younger than 80 years. EGFR mutation status might be a prognostic marker in elderly patients with completely resected NSCLC.

Objective: We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE., Materials and Methods: We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests., Results: FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors., Conclusion: FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Exostosis occurs in the ribs either sporadically or as a manifestation of a genetic disorder known as hereditary multiple exostoses. Costal exostosis may cause chest pain and, on rare occasions, result in hemothorax, pneumothorax, hemopneumothorax, and diaphragmatic or pericardial laceration. We report a case of pneumothorax in a 16-year-old boy with exostosis in the right seventh and eighth ribs. He previously received a diagnosis of multiple exostoses and underwent costal resection. The lung and pleura were injured because of long-term friction between the exostoses and the visceral pleura.To the best of our knowledge, this is only the fourth report of pneumothorax caused by costal exostosis. Moreover, all previously reported cases of pneumothorax or hemopneumothorax caused by costal exostosis, including the present case, involved lower lobe injury.

Solitary pulmonary capillary hemangioma (SPCH) is a rare benign lung tumor that must be distinguished from small and early lung cancers. Here, we report a case of SPCH for which we performed frozen section diagnosis. The patient was a 55-year-old Japanese woman. Five years before the operation, mixed ground-glass opacity was detected by computed tomography in the left posterior basal segment of the lower lobe (S10). Because the interior tumor density of the ground-glass opacity increased slightly, video-assisted thoracic surgery wedge resection was performed. Frozen section diagnosis revealed a benign tumor without proliferation of atypical epithelial cells. The tumor had narrow alveolar lumens, thickened alveolar septa and a clear boundary separating it from normal lung tissue. The proliferated lumens varied in size and were lined with single layers of flat cells. After the operation, immunohistochemical staining of a paraffin section revealed that the thickened alveolar septa resulted from the proliferation of capillary vessels, the flat cells of which were positive for CD31 and CD34 and negative for podoplanin; the tumor was diagnosed as SPCH. Here, we discuss the pathological features of SPCH on frozen sections with reference to this case and review previous related reports., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

We report a rare case of lung adenocarcinoma in which micropapillary components were considered to cause stump recurrence. A woman in her fifties was diagnosed with lung cancer in the right middle lobe with invasion to the upper lobe, which was treated by a right middle lobectomy together with upper lobe partial resection. The cancer was pathologically diagnosed as adenocarcinoma and had a free surgical margin. There was no recurrence during the following 5 years and 8 months, and thus periodical surveillance, including computed tomography, was stopped. However, 2 years and 7 months after this, she was discovered to have an abnormal shadow on chest radiography, and a thorough examination revealed a 3-cm-sized tumor involving the previous surgical margin. Therefore, she underwent right upper lobectomy. We pathologically re-evaluated the first tumor and found that it was an adenocarcinoma with a micropapillary component in the periphery, 6mm away from the surgical margin. In addition, a few tiny clusters of tumor cells were found to be floating within the alveolar spaces near the margin. The first and second tumors showed almost the same histological mixture of components of adenocarcinoma and the same EGFR mutation. From these results, we concluded the second tumor was a stump recurrence originating from the first tumor resection. This case illustrates the importance of careful pathological investigation when an autosuture instrument is used for a partial resection in a case of lung adenocarcinoma with micropapillary components. In such cases, it is particularly important to clarify if micropapillary components are floating near a stump., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Hemophagocytic syndrome (HPS) is an unrecognized complication occurring in the acute stage of human immunodeficiency virus (HIV) infection that is seldom reported in the literature. We herein present a case of HPS that occurred during the seroconversion stage of HIV infection. In this case, pancytopenia and liver dysfunction related to HPS recovered after the initiation of antiretroviral therapy (ART). This report indicates the importance of early recognition of HPS and suggests that prompt initiation of ART has the potential to control HPS in the acute stage of HIV infection.

More than half of persons living with HIV infection in the United States (U.S.) will be ≥50 years of age by 2020, including postmenopausal women. We conducted a systematic literature review about the effects of (1) HIV infection on age at menopause and (2) menopause on antiretroviral therapy (ART) response, in order to inform optimal treatment strategies for menopausal women living with HIV infection. We used the Ovid Medline database from 1980 to 2012. We included studies that focused on HIV-infected persons, included postmenopausal women, and reported outcome data for either age at menopause or response to ART across menopause. We identified six original research articles for age at menopause and five for response to ART across menopause. Our review revealed that current data were conflicting and inconclusive; more rigorous studies are needed. Disentangling the effects of menopause requires well-designed studies with adequate numbers of HIV-infected and HIV-uninfected women, especially disproportionately affected women of color. Future studies should follow women from premenopause through menopause, use both surveys and laboratory measurements for menopause diagnoses, and control for confounders related to normal aging processes, in order to inform optimal clinical management for menopausal women living with HIV.

We report the first known case of syphilis with simultaneous manifestations of proctitis, gastritis, and hepatitis. The diagnosis of syphilitic proctitis and gastritis was established by the demonstration of spirochetes with anti-Treponema pallidum antibody staining in biopsy specimens. Unusual manifestations of secondary syphilis completely resolved after 4 weeks of antibiotic therapy.