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Objectives: Wernicke encephalopathy (WE) is an acute neuropsychiatric disorder caused by thiamine deficiency. The classical triad of symptoms for WE include mental status changes, ataxia, and ophthalmoplegia. In contrast, more uncommon symptoms include hallucinations. Known risk factors include alcoholism, malignancies, and chronic kidney disease, particularly hemodialysis. However, WE in nonalcoholic adults is often overlooked., Methods: We report a WE patient with lung cancer undergoing hemodialysis who presented with the uncommon symptom of active hallucinations, which were improved by thiamine replacement therapy, despite a borderline whole blood thiamine concentration., Results: An 81-year-old woman with lung cancer and undergoing hemodialysis was referred to our psycho-oncology department for active hallucinations that appeared suddenly 24 days earlier. She had been diagnosed with lung cancer 6 months earlier and was undergoing chemotherapy and radiotherapy. She had no alcohol dependence or anorexia before or after admission. Physical examination revealed active visual hallucinations and delirium. On suspicion of WE, intravenous thiamine was administered. One day after administration, the hallucinations and delirium improved. Her whole blood thiamine concentration was borderline (24 ng/ml)., Significance of Results: WE might be a cause of active visual hallucinations as they disappeared on thiamine administration alone. We need to be aware of risk factors such as malignancies and hemodialysis, and it is important not to overlook WE.

Lazertinib, a novel third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), demonstrates marked efficacy in EGFR-mutant lung cancer. However, resistance commonly develops, prompting consideration of therapeutic strategies to overcome initial drug resistance mechanisms. This study aimed to elucidate the adaptive resistance to lazertinib and advocate novel combination treatments that demonstrate efficacy in preventing resistance as a first-line treatment for EGFR mutation-positive NSCLC. We found that AXL knockdown significantly inhibited lung cancer cell viability in the presence of lazertinib, indicating that AXL activation contributes to lazertinib resistance. However, long-term culture with a combination of lazertinib and AXL inhibitors led to residual cell proliferation and increased the MCL-1 expression level, which was mediated by the nuclear translocation of the transcription factor YAP. Triple therapy with an MCL-1 or YAP inhibitor in combination with lazertinib and an AXL inhibitor significantly reduced cell viability and increased the apoptosis rate. These results demonstrate that AXL and YAP/MCL-1 signals contribute to adaptive lazertinib resistance in EGFR-mutant lung cancer cells, suggesting that the initial dual inhibition of AXL and YAP/MCL-1 might be a highly effective strategy in eliminating lazertinib-resistant cells., (© 2024 The Author(s). Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

We previously reported that combined therapy with epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and AXL inhibitor ONO-7475 is effective in preventing the survival of drug-tolerant cells in high-AXL-expressing EGFR-mutated non-small cell lung cancer (NSCLC) cells. Nevertheless, certain residual cells are anticipated to eventually develop acquired resistance to this combination therapy. In this study, we attempted to establish a multidrug combination therapy from the first-line setting to overcome resistance to this combination therapy in high-AXL-expressing EGFR-mutated NSCLC. siRNA screening assay showed that fibroblast growth factor receptor 1 (FGFR1) knockdown induced pronounced inhibition of cell viability in the presence of the osimertinib-ONO-7475 combination, which activates FGFR1 by upregulating FGF2 via the c-Myc pathway. Cell-based assays showed that triple therapy with osimertinib, ONO-7475, and the FGFR inhibitor BGJ398 significantly increased apoptosis by increasing expression of proapoptotic factor Bim and reduced cell viability compared with that observed for the osimertinib-ONO-7475 therapy. Xenograft models showed that triple therapy considerably suppressed tumor regrowth. A novel therapeutic strategy of additional initial FGFR1 inhibition may be highly effective in suppressing the emergence of osimertinib- and ONO-7475-resistant cells., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T. Yamada received commercial research grants from Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, and Takeda Pharmaceutical Company Limited and speaking honoraria from Eli Lilly and Chugai-Roche. H. Kawachi received personal fees from Ono Pharmaceutical, Bristol-Myers Squibb, Chugai Pharmaceutical, AstraZeneca, Taiho Pharmaceutical, Eli Lilly Japan, and MSD outside the purview of the submitted work. A. Osoegawa received consultant honoraria from AstraZeneca and speaking honoraria from AstraZeneca, MSD Japan, Chugai Pharmaceutical, Bristol Myers Squibb, and Ono Pharmaceutical. T. Sakai received research grants from Otsuka Pharmaceutical, Taiho Pharmaceutical, and Oncolys BioPharma and a patent fee from JT Pharmaceutical. T. Yasuhiro and R. Kozaki are paid employees of Ono Pharmaceutical. S. Yano received research grants from Chugai-Roche and Boehringer-Ingelheim and speaking honoraria from Amgen, Chugai-Roche, Boehringer-Ingelheim, Novartis, and Pfizer. K. Takayama received research grants from Chugai-Roche and Ono Pharmaceutical and personal fees from AstraZeneca, Chugai-Roche, MSD-Merck, Eli Lilly, Boehringer-Ingelheim, and Daiichi-Sankyo. The other authors have no conflicts of interest to declare., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: With the evolution of technology in the field of thoracoscopy, three-dimensional (3D) endoscopic systems with 4 K resolution have recently come into use. This study aimed to determine perioperative outcomes of video-assisted thoracoscopic surgery (VATS) lobectomy performed a year after the 4 K three-dimensional (3D) endoscopic system installation and compare them with those of the high-definition (HD) 3D endoscopic system., Methods: We included patients who underwent complete VATS (cVATS) lobectomy for primary lung cancer using an HD3D endoscopic system (HD3D group, June 2015-September 2021, n = 251) or 4K3D endoscopic system (4K3D group, October 2021-September 2022, n = 47). The perioperative outcomes were compared between the two groups., Results: The operation time was significantly shorter in the 4K3D group (mean, 189.5 min) than in the HD3D group (208.5 min; p = 0.021), and the 4K3D group did not require conversion to thoracotomy or transfusion. The 4K3D group had less blood loss volume (4K3D group: mean, 24.0 mL vs. HD3D group: 43.3 mL; p = 0.105) and shorter chest drainage duration (4K3D group: mean, 2.3 days vs. HD3D group: 3.1 days; p = 0.115) and hospitalization period (4K3D group: mean, 7.9 days vs. HD3D group:10.0 days; p = 0.226) than the HD3D group, with no significant difference. No difference was observed in the incidence of ≥ Grade IIIa complications (p = 0.634)., Conclusion: The 4K3D endoscopic system significantly shortened the duration of cVATS lobectomy. It is useful for lung resection and may replace other endoscopy systems., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

Background: Emphysema is generally considered a poor prognostic factor for patients with nonsmall cell lung cancer; however, whether the poor prognosis is due to highly malignant tumors or emphysema itself remains unclear. This study was designed to determine the prognostic value of emphysema in patients with early-stage nonsmall cell lung cancer., Methods: A total of 721 patients with clinical stage IA nonsmall cell lung cancer who underwent complete resection between April 2007 and December 2018 were retrospectively analyzed regarding clinicopathological findings and prognosis related to emphysema., Results: The emphysematous and normal lung groups comprised 197 and 524 patients, respectively. Compared with the normal lung group, lymphatic invasion (23.9% vs. 14.1%, P = 0.003), vascular invasion (37.6% vs. 17.2%, P < 0.001), and pleural invasion (18.8% vs. 10.9%, P = 0.006) were observed more frequently in the emphysema group. Additionally, the 5-year overall survival rate was lower (77.1% vs. 91.4%, P < 0.001), and the cumulative incidence of other causes of death was higher in the emphysema group (14.0% vs. 3.50%, P < 0.001). Multivariable Cox regression analysis of overall survival revealed that emphysema (vs. normal lung, hazard ratio 2.02, P = 0.0052), age > 70 years (vs. < 70 years, hazard ratio 4.03, P < 0.001), and SUVmax > 1.8 (vs. ≤ 1.8, hazard ratio 2.20, P = 0.0043) were independent prognostic factors., Conclusions: Early-stage nonsmall cell lung cancer with emphysema has a tendency for the development of highly malignant tumors. Additionally, emphysema itself may have an impact on poor prognosis., (© 2024. The Author(s).)

Introduction: Several studies explored the association between thyroid transcription factor-1 (TTF-1) and the therapeutic efficacy of immunotherapy. However, the effect of TTF-1 on the therapeutic efficacy of programmed death-1 (PD-1) inhibitor/chemoimmunotherapy in patients with non-squamous non-small cell lung cancer (non-Sq NSCLC) with a programmed death-ligand 1 (PD-L1) tumor proportion score of 50% or more who are highly susceptible to immunotherapy remains unresolved. Therefore, we evaluated whether TTF-1 has a clinical impact on this population., Methods: Patients with non-Sq NSCLC and high PD-L1 expression who received PD-1 inhibitor monotherapy or chemoimmunotherapy between May 2017 and December 2020 were retrospectively enrolled. Treatment efficacy was compared after adjusting for baseline differences using propensity score matching., Results: Among the 446 patients with NSCLC with high PD-L1 expression, 266 patients with non-Sq NSCLC were analyzed. No significant differences in therapeutic efficacy were observed between the TTF-1-positive and -negative groups in the overall and propensity score-matched populations. Of chemoimmunotherapy, pemetrexed containing regimen significantly prolonged progression-free survival compared to chemoimmunotherapy without pemetrexed, regardless of TTF-1 expression (TTF1 positive; HR: 0.46 (95% Confidence interval: 0.26-0.81), p<0.01, TTF-1 negative; HR: 0.29 (95% Confidence interval: 0.09-0.93), p=0.02)., Discussion: TTF-1 expression did not affect the efficacy of PD-1 inhibitor monotherapy or chemoimmunotherapy in patients with non-Sq NSCLC with high PD-L1 expression. In this population, pemetrexed-containing chemoimmunotherapy demonstrated superior anti-tumor efficacy, irrespective of TTF-1 expression., Competing Interests: NN received personal fees from Chugai Pharmaceutical Co. Ltd., AstraZeneca KK., Eli Lilly Japan KK, and MSD KK outside the purview of the submitted work. HK received personal fees from Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan KK, and MSD KK outside the purview of the submitted work. TY received research grants from Ono Pharmaceutical, Janssen, AstraZeneca, and Takeda Pharmaceutical and has received speaking honoraria from Eli Lilly and Chugai Pharmaceutical outside the purview of the submitted work. MT received research grants from Boehringer Ingelheim, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Daiichi-Sankyo, Eisai, Chugai Pharmaceutical and Janssen, and personal fees from Chugai Pharmaceutical, Boehringer Ingelheim, AstraZeneca, Taiho Pharmaceutical, Eli Lilly, Novartis, Pfizer, Asahi Kasei Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, MSD, Bayer, Amgen, Kyowa-Kirin, and Nippon Kayaku, outside the purview of the submitted work. AO has received personal fees from Chugai-Roshe, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Japan, Nippon Kayaku, and Bristol Myers Squibb outside the purview of the submitted work. TK received personal fees from Chugai Pharmaceutical Co., Ltd. and MSD KK outside the purview of the submitted work. KCT received research grants from Chugai Pharmaceutical and Ono Pharmaceutical and personal fees from AstraZeneca, Chugai Pharmaceutical, MSD-Merck, Eli Lilly, Boehringer-Ingelheim, and Daiichi-Sankyo outside the purview of the submitted work. The remaining authors declare 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 © 2024 Nishioka, Kawachi, Yamada, Tamiya, Negi, Goto, Nakao, Shiotsu, Tanimura, Takeda, Okada, Harada, Date, Chihara, Hasegawa, Tamiya, Masui, Sai, Ishida, Katayama, Morimoto, Iwasaku, Tokuda, Kijima and Takayama.)

Background: Postoperative air leakage is a frequent complication after lung resection, and emphysema is a risk factor. However, no study has investigated the relationship between emphysema severity and postoperative complications related to air leak by the Goddard score (GS), a visual evaluation method of radiologic emphysema using computed tomography., Methods: This study included patients who underwent lobectomy for non-small cell lung cancer between April 2009 and March 2022. The utility of GS in predicting complications related to air leak (air leak prolonged for ≥5 days, pleurodesis, and reoperation for air leak) was investigated by receiver operating characteristic curve analysis and multivariable analysis with a logistic regression model., Results: This study included 477 patients. The GS was a significant predictor of complications related to air leak (area under the curve, 0.696; P < .001). Based on the receiver operating characteristic curve analysis, GS of 6 points was used as the cutoff point for multivariable analysis. In the multivariable analysis, GS of ≥6 points was a significant predictor of complications related to air leak (odds ratio, 2.719; P = .007). In the subgroup analysis of patients with emphysema, GS of ≥6 points was a significant predictor of complications related to air leak (P = .014)., Conclusions: The GS was useful in predicting complications related to air leak. Patients with radiologic findings of emphysema with GS of ≥6 points should be recognized as a high-risk group for complications related to air leak., (Copyright © 2024 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

As the adoption of segmentectomy for small-sized lung cancers expands, the need for more challenging completion lobectomy (CL) may arise to address surgical margin recurrence. Herein, we present a case of successful CL using a 4K three-dimensional (3D) (4K3D) endoscopy after segmentectomy. A 77-year-old male patient with lung cancer in the anterior segment (S3) of the left upper lobe underwent S3 segmentectomy. One year later, the patient experienced a recurrence at the surgical margin. CL was successfully performed under 4K3D endoscopy, same as the initial surgery. CL after segmentectomy requires meticulous preoperative planning and precise surgical maneuvering, and 4K3D endoscopy provides safe and reliable outcomes., (© 2024 Asia Endosurgery Task Force and Japan Society of Endoscopic Surgery and John Wiley & Sons Australia, Ltd.)

Driver oncogenes are investigated upfront at diagnosis using multi-CDx systems with next-generation sequencing techniques or multiplex reverse-transcriptase polymerase chain reaction assays. Additionally, from 2019, comprehensive genomic profiling (CGP) assays have been available in Japan for patients with advanced solid tumors who had completed or were expected to complete standard chemotherapy. These assays are expected to comprehensively detect the driver oncogenes, especially for patients with non-small cell lung cancer (NSCLC). However, there are no reports of nationwide research on the detection of driver oncogenes in patients with advanced NSCLC who undergo CGP assays, especially in those with undetected driver oncogenes at diagnosis. In this study, we investigated the proportion of driver oncogenes detected in patients with advanced NSCLC with undetectable driver oncogenes at initial diagnosis and in all patients with advanced NSCLC who underwent CGP assays. We retrospectively analyzed data from 986 patients with advanced NSCLC who underwent CGP assays between August 2019 and March 2022, using the Center for Cancer Genomics and Advanced Therapeutics database. The proportion of driver oncogenes newly detected in patients with NSCLC who tested negative for driver oncogenes at diagnosis and in all patients with NSCLC were investigated. Driver oncogenes were detected in 451 patients (45.7%). EGFR was the most common (16.5%), followed by KRAS (14.5%). Among the 330 patients with undetected EGFR, ALK, ROS1, and BRAF V600E mutations at diagnosis, 81 patients (24.5%) had newly identified driver oncogenes. CGP assays could be useful to identify driver oncogenes in patients with advanced NSCLC, including those initially undetected, facilitating personalized treatment., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor., Competing Interests: Declaration of competing interest T. Yamada received commercial research grants from Pfizer, Ono Pharmaceutical, Janssen Pharmaceutical K.K., AstraZeneca, and Takeda Pharmaceutical Company Limited and has received speaking honoraria from Eli Lilly. H. Kawachi received personal fees from Ono Pharmaceutical Co. Ltd., Chugai Pharmaceutical Co. Ltd., AstraZeneca KK, Taiho Pharmaceutical Co. Ltd., Eli Lilly Japan KK, and MSD KK, outside the purview of the submitted work. N. Furuya received personal fees from AstraZeneca, Chugai, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, MSD, Pfizer, Taiho, and Novartis. S. Watanabe received grants and personal fees from Boehringer Ingelheim and Nippon Kayaku. Personal fees from Lilly, Pfizer, Novartis Pharma, AstraZeneca, Chugai Pharma, Bristol-Myers, Ono Pharmaceutical, Daiichi Sankyo, and Taiho Pharmaceutical. S. Yano received research grants from Chugai Pharmaceutical and Boehringer-Ingelheim and has received speaking honoraria from Amgen, Chugai Pharmaceutical, Boehringer-Ingelheim, Novartis, and Pfizer. T. Sakai received research grants from Otsuka Pharmaceutical, Taiho Pharmaceutical and Oncolys BioPharma, and a patent fee from JT Pharmaceutical. K. Takayama reports receiving research grants from Chugai-Roche Co., and Ono Pharmaceutical Co., and personal fees from AstraZeneca Co., Chugai-Roche Co., MSD-Merck Co., Eli Lilly Co., Boehringer-Ingelheim Co., and Daiichi-Sankyo Co.No potential conflicts of interest were disclosed by the other authors., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: This study aimed to describe the course of patients with lung cancer from treatment initiation to end-of-life., Methods: This retrospective cohort study used Claims Data from the National Health Insurance and Advanced Elderly Medical Service System. We analyzed data from patients newly diagnosed with lung cancer between April 2013 and March 2021 who had been hospitalized at our University Hospital in urban area. We evaluated (1) treatment courses of these patients, and (2) end-of-life care and clinical factors related to end-of-life care., Results: A total of 818 patients who were diagnosed with lung cancer and received lung cancer treatment were included, of whom 200 were assessed for end-of-life. During the study period, 464 patients underwent surgery, while 308 received chemotherapy without undergoing surgery. The patients generally received lung cancer treatment within 2 years. The median time from initial treatment to death was 13 months for deceased patients. Patients in the palliative care unit (PCU) constituted 9% at 30 days before death, 25% at 7 days before death, and 40.5% on the day of death, whereas only 15% died at home. The prevalence of end-of-life care in the home/PCU was elevated among patients receiving molecular targeted drugs and in the female group., Conclusion: This study highlighted the patterns of end-of-life care following lung cancer treatment by using Claims Data. PCU utilization was concentrated in the period shortly before death, with fewer patients passing away at home. End-of-life care may be influenced by clinical factors, including the type of lung cancer treatment received, which may change the place of care., Competing Interests: Declaration of Conflicting InterestsThe authors declare no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Programmed cell death-ligand 1 (PD-L1) on tumor cells can be degraded to soluble form (sPD-L1) and enter circulation, however, the clinical significances of sPD-L1 in peripheral blood remains to be elucidated in non-small-cell lung cancer (NSCLC). We monitored plasma sPD-L1 levels during perioperative periods and evaluated PD-L1-positive cells in tumor tissues in patients with operable NSCLC. Then the correlation between preoperative plasma sPD-L1 levels and relapse-free survival (RFS) was analyzed retrospectively. In patients who underwent radical surgery (n = 61), plasma sPD-L1 levels (median; 63.5 pg/mL) significantly increased 1 month after surgery (72.2 pg/mL, P < 0.001). The combined score of PD-L1-positive cells including tumor cells and tumor-associated macrophages (TAMs) was significantly associated with preoperative plasma sPD-L1 levels. In patients with high levels of preoperative plasma sPD-L1, the probability of 5-year RFS was significantly poor for patients with low PD-L1 expression intensity of tumor cells (tcPD-L1) compared with those with high tcPD-L1 (33.3% vs. 87.5%, respectively, P = 0.016; 95% CI, 0.013-0.964). In former group, PD-L1-positive TAMs were markedly infiltrating compared with those from latter group (246.4 vs. 76.6 counts/mm 2 , respectively, P = 0.003). In NSCLC, plasma sPD-L1 can reflect the accumulation of PD-L1-posotive TAMs, not just PD-L1-positive tumor cells. In patients with high levels of preoperative plasma sPD-L1, the prognoses after surgery depends on which PD-L1-positive cells, tumor cells or TAMs, are the primary source of the sPD-L1. Thus, measuring both plasma sPD-L1 levels and PD-L1 expression status of tumor cells and TAMs is of benefit for assessment of postoperative prognosis in operable NSCLC., (© 2023. The Author(s).)

Background: Despite increasing reports of thiamine deficiency (TD) among cancer patients, there remain some patients with borderline thiamine concentrations (BTC). However, it is unclear whether such patients subsequently develop TD., Methods: Here, we report cases of cancer patients progressing to TD within a short time period after presentation with BTC (24-28 ng/ml)., Case 1: A 49-year-old female with lung cancer. During treatment for depression, the patient showed a decreased appetite, and a blood sample revealed BTC (25 ng/ml). Fourteen days later, she reported a continued loss of appetite, and despite the absence of the 3 classical signs of Wernicke encephalopathy (WE), additional testing showed a thiamine level of 23 ng/ml, leading to a diagnosis of TD., Case 2: A 65-year-old female developed depression during chemotherapy for angiosarcoma. Her blood sample revealed BTC (25 ng/ml). Seven days later, despite the absence of the classical signs of WE, a further testing revealed a thiamine level of 20 ng/ml., Case 3: A 41-year-old female developed depression during chemotherapy for ovarian cancer. No loss of appetite was observed, but a blood sample revealed BTC (25 ng/ml). Seven days later, despite the absence of the classical signs of WE or decreased appetite, further testing revealed a thiamine level of 19 ng/ml., Significance of Results: Depressed cancer patients with BTC may develop TD within a short time frame. To prevent TD, health-care professionals should maintain an awareness of its potential and the need for regular testing of thiamine level or prophylactic replacement therapy.

Importance: Immune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non-small cell lung cancer (NSCLC) for patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear., Objective: To clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection., Design, Setting, and Participants: This retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023., Exposure: ICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment., Main Outcomes and Measures: The primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics., Results: A total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups., Conclusions and Relevance: This cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.

Background: Programmed death-ligand 1 (PD-L1) inhibitor plus platinum-etoposide chemotherapy is used as a first-line treatment for extensive-stage small cell lung cancer (ES-SCLC), regardless of age., Objective: We examined the role of the Geriatric 8 (G8) screening tool for evaluating treatment outcomes in patients with ES-SCLC treated with PD-L1 inhibitor plus platinum-etoposide chemotherapy as first-line therapy., Patients and Methods: Between September 2019 and October 2021, we prospectively evaluated patients with ES-SCLC treated with immunochemotherapy at ten institutions in Japan. The G8 score was assessed before treatment initiation., Results: We evaluated 44 patients with ES-SCLC. Patients with G8 score > 11 had longer overall survival (OS) than those with G8 score ≤ 11 (not reached versus 8.3 months; log-rank test, p = 0.005). In univariate and multivariate analyses, G8 score > 11 [hazard ratio (HR) 0.34; 95% confidence interval (CI) 0.15-0.75; p = 0.008 and HR 0.34; 95% CI 0.14-0.82; p = 0.02, respectively) and performance status (PS) of 2 (HR 5.42; 95% CI 2.08-14.2; p < 0.001 and HR 6.94; 95% CI 2.25-21.4; p < 0.001, respectively) were independent prognostic factors for OS. Among patients with good PS (0 or 1), the OS in patients with G8 score > 11 was significantly longer than that in patients with G8 score ≤ 11 (not reached versus 12.3 months; log-rank test, p = 0.02)., Conclusions: G8 score evaluation before treatment initiation was useful as a prognostic factor for ES-SCLC patients who received PD-L1 inhibitors and platinum-etoposide chemotherapy, even with good PS., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Purpose: The effect of immuno-chemotherapy on patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic mutations remains poorly understood. This study aimed to characterize the efficacy of immuno-chemotherapy and determine the optimal treatment strategy for such patients., Methods: We conducted this retrospective cohort study on patients with NSCLC harboring oncogenic driver alterations and treated with an immune checkpoint inhibitor combined with chemotherapy at five institutions. The clinical characteristics and outcomes of immuno-chemotherapy for NSCLC with oncogenic mutations in a real-world setting were analyzed., Results: Among 846 patients diagnosed with advanced or recurrent NSCLC between April 2017 and April 2021, 43 patients with oncogenic mutations were treated with immuno-chemotherapy. The median age of patients was 68 (range 44-78) years; 42% of patients never smoked, and adenocarcinoma was the most common histology (95%). In patients with KRAS mutations (n = 10) or PD-L1 expression of 50% or greater (n = 10), the disease control rate was 100%. The median progression-free survival (PFS) was 5.4, 6.3, and 8.9 months in patients harboring mutations in EGFR, KRAS, and other genes, respectively (P = 0.22). Patients with PD-L1 expression of 50% or greater had significantly longer median PFS than patients with PD-L1 expression of less than 50% (16.4 vs. 5.1 months; P = 0.001). Two patients experienced grade 3 immuno-related adverse events., Conclusion: Immuno-chemotherapy has a clinical benefit and is safe for patients with oncogenic mutations. Notably, patients with PD-L1 expression of 50% or more experience greater benefit from immuno-chemotherapy than those with PD-L1 expression of less than 50%., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure., Methods: We retrospectively examined EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) therapy or platinum-based chemotherapy (Chemo) after EGFR-TKI therapy at five institutions in Japan., Results: A total of 57 patients with EGFR mutation were analyzed. The median progression-free survival (PFS) and overall survival (OS) in the ABCP (n = 20) and Chemo (n = 37) were 5.6 and 20.9 months, 5.4 and 22.1 months, respectively (PFS, p = 0.39; OS, p = 0.61). In programmed death-ligand 1 (PD-L1)-positive patients, median PFS in the ABCP group was longer than in the Chemo group (6.9 vs. 4.7 months, p = 0.89). In PD-L1-negative patients, median PFS in the ABCP group was significantly shorter than in the Chemo group (4.6 vs. 8.7 months, p = 0.04). There was no difference in median PFS between the ABCP and Chemo groups in the subgroups of brain metastases, EGFR mutation status, or chemotherapy regimens, respectively., Conclusion: The effect of ABCP therapy and chemotherapy was comparable in EGFR-mutant patients in a real-world setting. The indication for immunochemotherapy should be carefully considered, especially in PD-L1-negative patients., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: We previously reported that intraoperative findings of pleural plaques were worse prognostic factors of resected non-small cell lung cancer (NSCLC). However, differences in the presence of pleural plaques detected either intraoperatively or by CT findings have not been addressed., Method: We included 121 patients who underwent resection for NSCLC with intraoperatively detected pleural plaques. We investigated preoperative CT findings and compared the prognosis between patients with or without evidence of pleural plaque on CT., Results: Only 43% of patients with pleural plaques on intrathoracic findings had pleural plaques detected on preoperative CT. There were no differences in prognosis between patients with or without pleural plaque evidences on preoperative CT., Conclusion: The rate of detection of pleural plaques on preoperative CT is low even if they are present intraoperatively, and patients with intraoperative findings of pleural plaques have equally poor prognosis regardless of their evidences on preoperative CT., Competing Interests: Conflict of Interest The authors have no conflicts of interest., (Copyright © 2023 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.)

This study assessed the immunogenicity and safety of the BNT162b2 mRNA vaccine in lung cancer patients receiving anticancer treatment. We enrolled lung cancer patients receiving anticancer treatment and non-cancer patients; all participants were fully vaccinated with the BNT162b2 vaccine. Blood samples were collected before the first and second vaccinations and 4 ± 1 weeks after the second vaccination. Anti-severe respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein S1 subunit receptor-binding domain antibody titers were measured using the Architect SARS-CoV-2 IgG II Quant and Elecsys Anti-SARS-CoV-2 S assays. Fifty-five lung cancer patients and 38 non-cancer patients were included in the immunogenicity analysis. Lung cancer patients showed significant increase in the geometric mean antibody concentration, which was significantly lower than that in the non-cancer patients after the first (30 vs. 121 AU/mL, p  < .001 on Architect; 4.0 vs 1.2 U/mL, p  < .001 on Elecsys) and second vaccinations (1632 vs. 3472 AU/mL, p  = .005 on Architect; 213 vs 573 A/mL, p  = .002 on Elecsys). The adjusted odds ratio (aOR) for seroprotection was significantly lower ( p  < .05) in lung cancer patients than that in non-cancer patients. Analysis of the anticancer treatment types showed that the aOR for seroprotection was significantly lower ( p  < .05) in lung cancer patients receiving cytotoxic agents. They showed no increase in adverse reactions. BNT162b2 vaccination in lung cancer patients undergoing anticancer treatment significantly increased ( p  < .05) antibody titers and showed acceptable safety. Immunogenicity in these patients could be inadequate compared with that in non-cancer patients.

Background: Chemoimmunotherapy has become a standard treatment option for patients with untreated advanced non-small-cell lung cancer (NSCLC). However, numerous patients with advanced NSCLC develop disease progression. Therefore, the selection of second-line treatment after chemoimmunotherapy is crucial for improving clinical outcomes., Methods: Of 88 enrolled patients with advanced NSCLC who received chemoimmunotherapy, we retrospectively evaluated 33 who received second-line chemotherapy after progression of chemoimmunotherapy at six centers in Japan. Among them, 18 patients received docetaxel plus ramucirumab and 15 patients received single-agent chemotherapy., Results: The objective response rate in patients treated with docetaxel plus ramucirumab was significantly higher than that in patients treated with a single-agent chemotherapy regimen (55.6% vs. 0%, p < 0.001). The median progression-free survival (PFS) of patients who received docetaxel plus ramucirumab and single-agent chemotherapy was 5.8 months and 5.0 months, respectively (log-rank test p = 0.17). In the docetaxel plus ramucirumab regimen group, patients who responded to chemoimmunotherapy for ≥8.8 months had a significantly longer response to docetaxel plus ramucirumab than those who responded for <8.8 months (not reached vs. 4.1 months, log-rank test p = 0.003). In contrast, in the single-agent chemotherapy group, there was no significant difference in PFS between the ≥8.8- and <8.8-month PFS groups with chemoimmunotherapy (5.0 vs. 1.6 months, log-rank test p = 0.66)., Conclusion: Our retrospective observations suggest that the group with longer PFS with chemoimmunotherapy might be expected to benefit from docetaxel plus ramucirumab treatment in second-line settings for patients with advanced NSCLC., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Objective: Cancer patients often want to spend their final days at home, and it is essential that general practitioners have knowledge of and technical skills related to cancer medicine and symptom relief. Recent clinical studies have revealed that Wernicke encephalopathy (WE) is quite common in cancer patients. However, there have been no reports to date on WE in cancer patients undergoing home medical care., Methods: From a series of cancer patient undergoing home medical care, we reported a patient with lung cancer who developed WE., Results: An 84-year-old female with lung cancer undergoing home medical care developed an impaired mental state and an attention deficit. Her symptoms fulfilled the diagnostic criteria for delirium. WE was suspected as the patient's food intake had fallen from normal a month previously to somewhere between 50% or just a few mouthfuls. This diagnosis was supported by abnormal serum thiamine and the disappearance of delirium after thiamine administration., Significance of the Results: When delirium occurs in cancer patients undergoing home treatment, it is necessary to suspect thiamine deficiency as a potential cause, as appropriate diagnosis and treatment can prevent irreversible brain-related sequelae.

Objective: Cognitive dysfunction has a negative effect on cancer treatment; however, in a cancer setting, specific treatments can restore cognitive function. Such conditions are known as reversible dementia, with one of these being vitamin B12 (VB12) deficiency. However, there have been no reports of VB12 deficiency identified by preoperative evaluation in cancer patients., Method: We studied a patient who was referred to the Department of Psycho-oncology on suspicion of cognitive decline prior to lung cancer surgery. Preoperative evaluation revealed VB12 deficiency., Results: The patient was an 82-year-old woman diagnosed with lung cancer. She also presented with cognitive decline and, therefore, was referred to the Department of Psycho-oncology for preoperative evaluation. The patient scored 19 points on a Mini-Mental State Examination (MMSE), which is indicative of cognitive decline. As the onset of symptoms occurred several months previously and they were subacute, the possibility of reversible dementia was considered. Extensive examination revealed VB12 deficiency, and VB12 replacement therapy normalized the MMSE score to 25 points before surgery., Significance of the Results: When cognitive decline is observed in cancer patients, it is necessary to actively evaluate the serum levels of some B vitamins, including VB12.

Background: Clinically, locoregional recurrences following mucinous tumor resection are often experienced. However, it remains unclear whether mucinous tumors directly affect local recurrence or not, and if so, the mechanism is not known. Therefore, we investigated whether mucinous tumors are associated with locoregional recurrence after pulmonary resection and whether mucus extension is a risk factor for locoregional recurrence., Methods: The data of 152 patients who underwent pulmonary resection for metastases were reviewed. When mucus was partially or wholly present in the tumor based on macro- or microscopic identification, we assigned the tumor as mucinous. In mucinous tumors, when mucus was identified within the air spaces in the normal lung parenchyma, beyond the edge of the tumor, we assigned the tumor as positive for "mucus extension.", Results: The 5-year cumulative incidence of locoregional recurrence in patients with mucinous tumors was 48.1%, which was significantly higher than that observed in those with non-mucinous tumors (14.9%). Within the mucinous tumor, the presence of mucus extension beyond the tumor edge was an independent risk factor for locoregional recurrence after pulmonary resection (hazard ratio, 5.52; P = 0.019)., Conclusions: During the resection of mucinous cancer, surgeons should maintain sufficient distance from the tumor edge to prevent locoregional recurrences.

Abstract: Carcinomatous meningitis (CM) is a critical issue for physicians. However, no study has reported a simple and useful diagnostic or predictive marker for CM.This study aimed to elucidate the potential markers for diagnosing CM derived from cerebrospinal fluid (CSF).We retrospectively enrolled 78 lung cancer patients with suspected CM during the clinical course, including 42 CM and 36 non-CM patients. We compared the clinical and CSF findings, including carcinoembryonic antigen (CEA), between CM and non-CM patients, and explored the diagnostic markers for early identification of CM as well as the contributing factors for mortality.On CSF analysis, with cutoff values of CEA ≥5 ng/ml, total protein (TP) in CSF ≥45 g/dl, and total cell count (TCC) ≥7 cells/μL, the sensitivity, specificity, and area under the curve (AUC) for CM were 85.7%, 84.6%, and 0.887 (95% CI: 0.758-1.0, P < .001); 80.5%, 69.4%, and 0.755 (95% CI: 0.646-0.865, P < .001); and 56.1%, 100%, and 0.817 (95% CI: 0.722-0.912, P < .001), respectively. TP levels in CSF ≥the patients' age had a sensitivity, specificity, and an AUC of 48.8%, 77.8%, and 0.633 (95% CI: 0.722-0.912, P = .045) for CM, respectively. Among CM patients, patients with 'TP in CSF (>patients' age)" (n = 19, P = .008) showed significantly shorter 90-day survival probability than the residual patients (n = 20). None of the CSF parameters could predict the risk of mortality on Cox regression analysis.The cutoff value of CEA ≥5 ng/ml in CSF is a simple and useful method with a high diagnostic value for CM diagnosis, but not a suitable predicting factor for mortality. 'TP in CSF >patients' age" might be a novel factor for assessing short-term mortality., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Programmed cell death-ligand 1 (PD-L1) expression on tumor cells is induced by interferon-gamma, suggesting the induction of an anti-tumor immune response. In turn, binding of PD-L1 to programmed cell death 1 (PD-1) triggers an immune checkpoint pathway that contributes to tumor growth. Though it remains to be elucidated, the clinical significance of PD-L1 expression might vary with tumor progression in non-small-cell lung cancer (NSCLC). Immunohistochemical analysis of PD-L1 was done in tumor specimens from patients who underwent radical surgery for stage I-IIIA NSCLC (n = 228). Tumor PD-L1 expression intensity was semi-quantitatively scored and its correlation with various clinicopathological features and postoperative relapse-free survival (RFS) was assessed relative to pathological stage. In stage I, postoperative RFS was significantly prolonged in patients with a high PD-L1 score compared with a low PD-L1 score, exhibiting 5-year relapse-free probabilities of 94.1% and 75.1%, respectively (P = 0.031). A multivariate analysis revealed that a high PD-L1 score was a prognostic factor of longer postoperative RFS (hazard ratio: 0.111, P = 0.033). Conversely, in stages II and IIIA, patients with a high PD-L1 score tended to suffer from postoperative tumor recurrence. In early-stage NSCLC, high tumor PD-L1 expression status represents a biomarker to predict good prognosis after radical surgery and may reflect the induction of an antitumor immune response. However, in locally advanced stage NSCLC, tumor PD-L1 expression status may reflect the execution of an immune checkpoint pathway and predicts the incidence of postoperative tumor recurrence.

Although non-small cell lung cancer can metastasize to any part of the body, metastasis to the gallbladder is extremely rare. We present a case of acute cholecystitis caused by gallbladder metastasis from non-small cell lung cancer. A 66-year-old man diagnosed with primary stage IV T4N3M1b non-small cell lung cancer was admitted to our hospital to receive chemotherapy, during which he presented with right upper abdominal pain. Abdominal contrast-enhanced computed tomography showed an enhanced mass at the neck of the gallbladder and gallbladder distension with obvious wall thickening. Acute cholecystitis caused by obstruction of the gallbladder neck by malignancy was suspected. Open cholecystectomy, extrahepatic bile duct resection, and Roux-en-Y choledochojejunostomy were performed. Pathological and immunohistochemical examinations revealed gallbladder metastasis originating from non-small cell lung cancer. In conclusion, when a patient with lung cancer presents with acute cholecystitis, the rare possibility of gallbladder metastasis should be considered.

Pulmonary benign metastasizing leiomyoma (PBML) is a rare entity. We herein report a case of PBML found as multiple bilateral lung nodules 11 years after total hysterectomy. The patient was a 53-year-old woman with past surgical history of abdominal total hysterectomy for a uterine leiomyoma at the age of 42. She was referred to our department for further evaluation of multiple pulmonary nodules detected by a chest radiography. A chest computed tomography revealed multiple bilateral small lung nodules less than 10 mm in diameter. 18-fluorodeoxyglucose (FDG) positron emission tomography showed no significant FDG accumulation to these nodules. The patient finally underwent video assisted thoracoscopic wedge resection of the lower lobe of the right lung for surgical biopsy. The final pathological diagnosis was PBML, based on the comparative evaluation of the surgical specimens from the lung and the uterus. No evidence of enlargement in the remaining pulmonary nodules was noted for 9 months after surgical lung biopsy.

Objectives: The pathological T descriptor of lung invasive mucinous adenocarcinoma (IMA) is currently defined according to mucin spread, whereas that of lung non-mucinous adenocarcinoma is defined according to invasive lesion. This study aimed to evaluate and compare the prognostic impact of mucin spread, tumor cell spread, and invasive lesion in patients with lung IMA., Materials and Methods: Twenty-seven patients with completely resected pT1-4N0M0 IMA were evaluated. The radiological size (RS), mucin spread size (MS), tumor cell spread size (TS), and invasive size (IS) of the primary tumors were determined. Cox proportional hazards models were used to estimate recurrence-free survival (RFS). Because the MS, TS, and IS may be mutually confounding factors, they were evaluated using separate multivariate models including potential prognostic factors identified as significant on univariate analyses., Results: The median postoperative follow-up time was 4.9 years. TS and IS were significantly smaller than RS by a median of 0.3 cm (p = 0.027) and 1.4 cm (p < 0.0001), whereas MS and RS were not significantly different (p > 0.999). Univariate analyses identified T descriptors defined by MS, TS, and IS as potentially negative prognostic factors, in addition to age >75 years and carcinoembryonic antigen >5 ng/mL. Multivariate analyses revealed that T factors defined by MS, TS, and IS were significant predictors of RFS (p < 0.0001, p = 0.0002, and p = 0.0067, respectively)., Conclusion: MS is a reasonable determinant of the pathological T descriptor of lung IMA. TS and IS are potential candidates, although they remain discordant with RS. If the TS or IS is to be considered a candidate for the pathological T descriptor of lung IMA, the discordance with RS should first be resolved. If IS is used to define pathological T factor, clear criteria for mucinous AIS/MIA with IMA features should be developed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: To develop a dictionary learning (DL)-based processing technique for improving the image quality of sub-millisievert chest computed tomography (CT)., Materials and Methods: Standard-dose and sub-millisievert chest CT were acquired in 12 patients. Dictionaries including standard- and low-dose image patches were generated from the CT datasets. For each patient, DL-based processing was performed for low-dose CT using the dictionaries generated from the remaining 11 patients. This procedure was repeated for all 12 patients. Image quality of normal thoracic structures on the processed sub-millisievert CT images was assessed with a 5-point scale (5 = excellent, 1 = very poor). Lung lesion conspicuity was also assessed on a 5-point scale., Results: Image noise on sub-millisievert CT was significantly decreased with DL-based image processing (48.5 ± 13.7 HU vs 20.4 ± 7.9 HU, p = 0.0005). Image quality of lung structures was significantly improved with DL-based method (middle level of lung, 2.25 ± 0.75 vs 2.92 ± 0.79, p = 0.0078). Lung lesion conspicuity was also significantly improved with DL-based technique (solid nodules, 3.4 ± 0.6 vs 2.7 ± 0.6, p = 0.0273)., Conclusion: Image quality and lesion conspicuity on sub-millisievert chest CT images may be improved by DL-based post-processing.

Objectives: Cancer-associated fibroblasts (CAFs) are a dominant cell type in tumor stroma and support the generation of pro-tumorigenic microenvironment. CAFs have frequent opportunities to interact with immune cells infiltrating the tumor stroma, but the process remains to be determined. In this study, we focused on immune checkpoint mechanism. We also examined the induction of programmed cell death-ligand 1 (PD-L1) on CAFs by immune cell, and the clinical significance of PD-L1-expressed CAFs in non-small cell lung cancer (NSCLC)., Materials and Methods: CAFs were isolated from human NSCLC tissues, and PD-L1 expression levels in CAFs were analyzed by real-time polymerase chain reaction and flow-cytometry. Following immunohistochemical analysis of PD-L1 in surgically resected pN0M0 NSCLC (n = 125, including 88 invasive adenocarcinomas and 37 squamous cell carcinomas), the correlation of PD-L1-positive CAFs with clinicopathological features was investigated., Results: PD-L1 mRNA and protein expression on CAFs was upregulated by exogenously supplemented interferon-gamma (IFN-γ) and downregulated through the depletion of IFN-γ. PD-L1 expression on CAFs was upregulated by co-culture with activated lymphocytes releasing IFN-γ. Immunohistochemistry revealed that PD-L1-positive CAFs were observed in 31 cases (24.8%). Postoperative relapse-free survival was significantly prolonged in patients with PD-L1-positive CAFs as compared with those with PD-L1-negative CAFs, with 5-year relapse-free probabilities of 84.5% and 66.3%, respectively (P = 0.031). Multivariate analysis revealed that PD-L1 expression on CAFs was an independent prognostic factor of longer relapse-free survival after surgery (hazard ratio: 3.225, P = 0.027)., Conclusion: PD-L1 expression on CAFs is reversibly regulated by environmental stimuli including IFN-γ from activated lymphocytes. In the non-metastatic NSCLC, PD-L1 expression on CAFs suggests the induction of anti-tumor immune responses, contributing to better prognosis after surgery., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: Wernicke encephalopathy (WE) is a neuropsychiatric disorder caused by thiamine deficiency, and is sometimes overlooked because of the diversity of clinical symptoms., Method: From a series of WE patients with cancer, we report a lung cancer patient who developed WE, the main symptom of which was agitation.ResultA 50-year-old woman with lung cancer was referred to our psycho-oncology clinic because of agitation lasting for three days. No laboratory findings or drugs explaining her agitation were identified. Although the patient did not develop delirium, ophthalmoplegia, or ataxia, WE was suspected because she experienced a loss of appetite loss lasting 5 weeks. This diagnosis was supported by abnormal serum thiamine and disappearance of agitation one hour after intravenous thiamine administration.Significance of resultsThis report emphasizes the clinical diversity of WE and indicates the limits of the ability to diagnose WE from typical clinical symptoms. The presence of a loss of appetite for more than two weeks may be the key to the accurate diagnosis of WE.

Objectives: Multiple programmed cell death ligand-1 (PD-L1) immunohistochemistry assays are currently used as companion or complementary diagnostic tools for anti-programmed cell death-1 immunotherapies. We aimed to characterize two PD-L1 immunohistochemistry assays (Dako 22C3 and 28-8) for non-small cell lung cancer (NSCLC) in clinical laboratories., Materials and Methods: Surgical specimens from 420 patients with pathological stages IA to IIIA NSCLC were investigated. The archived samples were freshly cut into 5-μm-thick sections stained with antibodies 22C3 and 28-8, and tumoral PD-L1 expression was evaluated in two clinical laboratories, respectively. Overall, positive, and negative percent agreement (OPA, PPA, and NPA, respectively) at specified PD-L1 cutoffs were calculated to assess the concordance between 22C3 and 28-8 assays., Results: Tumoral PD-L1 expression of ≥ 1% was detected by either 22C3 or 28-8 assays in 176 cases (41.9%), whereas 22C3 revealed a significantly higher tumoral PD-L1 expression compared to 28-8 (median 30% vs. 10%, p < 0.0001). OPA was 89.0, 90.2, and 91.9% at 1, 25, and 50% cutoff levels. When 22C3 was compared to a standard assay 28-8, the PPA was 85.5, 98.3, and 94.9%, whereas NPA was 91.0, 89.0, and 91.6% at 1, 25, and 50%. On the other hand, when 28-8 was compared to 22C3, PPA was 84.4% at 1%, but it decreased to 58.3 and 53.6% at 25 and 50%; whereas NPA remained high (91.7, 99.7, and 99.4% at 1, 25 and 50%, respectively)., Conclusion: Our analysis revealed that, despite the high OPA, there was discordance in the PPA between 22C3 as a standard assay and 28-8 as a comparator assay at 25% and 50% PD-L1 cutoff levels, indicating that the results of 28-8 could be translated to those of 22C3 but not vice versa., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Immune checkpoint mechanisms such as the programmed cell death-ligand 1-programmed cell death 1 (PD‑L1-PD‑1) axis are utilized by tumor cells to evade the cytotoxicity of effector immune cells. However, environmental factors responsible for the expression of PD‑L1 on tumor cells remain to be fully elucidated. We hypothesized that an immunological interaction with tumor-infiltrating CD8+ lymphocytes (CD8+ TILs) would contribute to PD‑L1 expression in tumor cells. To verify this hypothesis, we examined the effect of interferon-γ (IFN-γ), a cytokine secreted by CD8+ TILs, on PD‑L1 expression in pulmonary squamous cell carcinomas in vitro. We also evaluated the expression of PD‑L1 and major histocompatibility complex (MHC) class I molecules on tumor cells and CD8+ TILs in squamous cell carcinomas of the lung (n=77) by immunohistochemistry. IFN-γ upregulated PD‑L1 expression on pulmonary squamous carcinoma cells, and the reaction was reversible. In cases where which MHC class I molecule-positive tumor cells were dominant (n=72, 93.5%), cases in which PD‑L1-positive tumor cells were dominant (PD‑L1+ tumor cell‑dominant cases; n=45) were more frequently observed than PD‑L1-negative tumor cell‑dominant cases (n=27) (P=0.006). The number of CD8+ TILs was significantly higher in PD‑L1+ tumor cell‑dominant cases compared with PD‑L1- tumor cell‑dominant cases (P=0.005). These data suggest that the de novo expression of PD‑L1 on tumor cells is upregulated by IFN-γ secreted from CD8+ TILs upon recognition of the tumor cells with an MHC class I molecule.

Purpose: To demonstrate the feasibility of respiratory gating during whole-body scan for lung lesions in routine 18 F-FDG PET/CT examinations using a time-of-flight (TOF)-capable scanner to determine the effect of respiratory gating on reduction of both misregistration (between CT and PET) and image blurring, and on improvement of the maximum standardized uptake value (SUVmax)., Materials and Methods: Patients with lung lesions who received FDG PET/CT were prospectively studied. Misregistration, volume of PET (Vp), and SUVmax were compared between ungated and gated images. The difference in respiratory gating effects was compared between lesions located in the upper or middle lobes (UML) and the lower lobe (LL). The correlation between three parameters (% change in misregistration, % change in Vp, and lesion size) and % change in SUVmax was analyzed., Results: The study population consisted of 60 patients (37 males, 23 females; age 68 ± 12 years) with lung lesions (2.5 ± 1.7 cm). Fifty-eight out of sixty respiratory gating studies were successfully completed with a total scan time of 20.9 ± 1.9 min. Eight patients' data were not suitable for analysis, while the remaining 50 patients' data were analyzed. Respiratory gating reduced both misregistration by 21.4 % (p < 0.001) and Vp by 14.2 % (p < 0.001). The SUVmax of gated images improved by 14.8 % (p < 0.001). The % change in misregistration, Vp, and SUVmax by respiratory gating tended to be larger in LL lesions than in UML lesions. The correlation with % change in SUVmax was stronger in % change in Vp (r = 0.57) than % change in misregistration (r = 0.35). There was no statistically significant correlation between lesion size and % change in SUVmax (r = -0.20)., Conclusions: Respiratory gating during whole-body scan in routine TOF PET/CT examinations is feasible and can reduce both misregistration and PET image blurring, and improve the SUVmax of lung lesions located primarily in the LL.

Febrile neutropenia frequently develops after chemotherapy. There is little evidence to indicate the type of antimicrobial agents that should be used in the treatment of febrile neutropenia in patients with solid tumors. The objective is to determine the efficacy and safety of cefepime (CFPM) and meropenem (MEPM) in the treatment of febrile neutropenia in lung cancer patients in a prospective randomized study. FN patients with lung cancer were randomly divided into CFPM or MEPM groups. The primary end-point was the response rate. The secondary end-points were the defervescence rates at 72 h, 7 days, 14 days and the incidence of adverse events. Twenty-one patients were treated with CFPM and 24 patients were treated with MEPM. One patient died of FN. The CFPM treatment completion rate was 17.65% (95% CI; 0.00-35.77%), while the MEPM treatment completion rate was 38.10% (95% CI; 17.33-58.87%). The defervescence rates at 72 h, 7 days, and 14 days were 70.59%, 86.67%, and 100.00%, respectively in the CFPM group; and 65.00%, 84.21%, and 92.31% in the MEPM group. Adverse events were observed in 33.33% of the CFPM group and 45.83% of the MEPM group. The response rate of the CFPM group was 94.12% (95% CI; 73.02-98.95%), while that of the MEPM group was 85.71% (95% CI; 65.36-95.02%). No differences were found in the efficacy or safety of CFPM and MEPM in the treatment of febrile neutropenia in patients with lung cancer., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Micropapillary pattern is a distinct histopathological pattern, and usually shows a high frequency of lymphatic invasion and lymph node metastases. This pattern is also reported in lung adenocarcinoma, however, only one cytological report of lung adenocarcinoma with micropapillary pattern has been reported. In this study, we analyzed the cytological features of this type of carcinoma in the pleural or pericardial effusion. This study was comprised of 5 consecutive cases of lung adenocarcinoma with micropapillary pattern, in which the tumor cells were present in the pleural or pericardial effusion and whose diagnoses were histopathologically confirmed. The characteristic cytological findings in the pleural or pericardial effusion were as follows: i) tightly cohesive small nests of tumor cells showing papillary structure without fibrovascular core, ii) these nests were comprised of approximately 5-20 tumor cells, iii) cauliflower-like and acinar-like structures were also observed, iv) intracytoplasmic vacuoles were observed in 40% of the cases, and v) the neoplastic cells had large round to oval nuclei containing coarse chromatin and occasional conspicuous nucleoli. It has been reported that the presence of micropapillary structure and intracytoplasmic vacuolation are also characteristic cytological features of micropapillary carcinoma of the urinary bladder, therefore, they are thought to be common cytological features of carcinomas with micropapillary pattern. Consequently, detection of these features can lead to a cytodiagnosis of lung adenocarcinoma with micropapillary pattern in the pleural or pericardial effusion. Recognition of these features is important because this type of tumor shows an aggressive clinical course.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a rare hamartomatous cystic lesion, characterized by the presence of large cysts, which are histopathologically lined by pseudostratified ciliated cells. It has been recognized that rare cases of type 1 CCAM show malignant transformation, usually bronchioloalveolar carcinoma (BAC) or adenocarcinoma. Herein, we describe a case of BAC arising in type 1 CCAM with K-ras mutation. A 9-year-old Japanese girl presented with fever. Computed tomography demonstrated large cystic lesions in her right lower lung. Histopathological study of the resected specimen revealed multiple cysts, which were lined by pseudostratified ciliated cells, and occasionally interspersed with mucous cells without atypia. A small focus of proliferation of columnar cells showing lepidic growth pattern was present. These columnar cells had abundant mucin in the cytoplasm and mildly to moderately enlarged nuclei. Accordingly, a diagnosis of BAC arising in type 1 CCAM was made. Polymerase chain reaction analysis revealed K-ras mutation at codon 12 in the BAC component. The presence of mucous cell/goblet cell hyperplasia and atypical adenomatous hyperplasia is a well known phenomenon in type 1 CCAM. A recent study clearly demonstrated K-ras mutation in these lesions, which are thought to be precursors of BAC. Therefore, the concept of malignant transformation in the sequence from type 1 CCAM to mucous cell hyperplasia to atypical adenomatous hyperplasia to BAC and invasive adenocarcinoma due to K-ras mutation has been proposed. Careful histopathological analysis is important for evaluation of malignant lesions in type 1 CCAM.

Although there are three kinds of stupor in psychiatry, dissociative stupor is the most commonly recognized. In psychiatric clinics or emergency rooms, dissociative stupor is common, but in an oncology setting it is hardly known. Therefore, distinguishing dissociative stupor from consciousness disorder is occasionally difficult, especially in the advanced or terminal phase. We report an advanced lung cancer patient who presented dissociative stupor mimicking consciousness disorder. It is necessary to distinguish between consciousness disorder and dissociative stupor. In addition, consultation with a psychiatrist should be taken into consideration.

Objective: The advantage of transbronchial biopsy (TBB) using endobronchial ultrasonography (EBUS) with a guide sheath (GS) over TBB without EBUS guidance was investigated in this study., Materials and Methods: A retrospective chart review was conducted at Nagasaki University Hospital, Japan. Data were collected from all cases of peripheral pulmonary lesions (PPLs) undergoing either EBUS-GS-guided TBB or TBB without EBUS guidance in our department from December 2003 through November 2009. The diagnostic yield in each group was compared, after adjustment for other factors., Results: In total 110 PPLs were investigated in 102 patients: 65 (59.1%) were examined with EBUS-GS-guided TBB (EBUS-GS group) and 45 (40.9%) were TBB without EBUS guidance (non-EBUS group). Both procedures were performed under x-ray fluoroscopy. Basic characteristics were similar between the two groups. Of all EBUS examined lesions, 53 (81.5%) were visualized by EBUS. The diagnostic yields in EBUS-GS group and non-EBUS group were 64.6% and 46.7%, respectively (p=0.08). Adjusting for size and location of lesions, the yield of EBUS-GS guidance was 1.46 (95% confidence interval 1.03 to 2.05) times higher than without EBUS guidance. When the lesion was visualized by EBUS, the diagnostic yield ratio was further increased to 1.63 (95% CI 1.16 to 2.27)., Conclusion: EBUS-GS-guided TBB demonstrates a higher diagnostic yield than TBB without EBUS guidance.

A 79-year-old man was diagnosed with relapsing polychondritis, from symptoms of bilateral auricular deformity and pigmentation, polyarthralgia, and audiovestibular damage, and from histological examination of the left auricular cartilage. The left auricular cartilage biopsy specimen revealed cartilage destruction with infiltration of plasmacytes expressing IgG4. This case suggests that IgG4 may be involved in the pathogenesis and etiology of relapsing polychondritis.

We report a case of a 72-year-old woman who died of primary lung clear cell adenocarcinoma. She was an active smoker, but with no other significant previous medical abnormalities. She visited our hospital with complaining of hemoptysis lasting for a month. Her sputum production and coughing had also increased. Chest X-ray films showed obstructive pneumonia in the left lower lobe. Chest computed tomography (CT) showed a tumor shadow and collapsed portion in the left hilar area. Sputum cytology and further diagnostic tests revealed stage IV lung adenocarcinoma. Chemotherapy with carboplatin and paclitaxel was initiated, but no improvement was obtained. She died from progressive cancer invasion into the airway. An autopsy revealed that more than 90% of the cancer cells were clear cells. These cancer calls were positive for PAS and occasionally showed Alcian blue-positive intracytoplasmic mucin and glandular structures. They were immunocytochemically stained with cytokeratin 7 but not with cytokeratin 20. According to previous reports in the literature, cases of primary lung clear cell adenocarcinoma are very rare.

Background/aims: Patients with intraductal papillary-mucinous neoplasm (IPMN) of the pancreas are likely to have a better prognosis than those with conventional pancreatic ductal adenocarcinoma. Recently there have been some reports on extrapancreatic malignant neoplasms (EPM) occurring in patients with IPMN. The purpose of this study was to discover the characteristic features of IPMN with EPM compared with IPMN without EPM., Methods: 61 patients with IPMN who underwent surgery at Tohoku University Hospital between 1988 and 2006 were retrospectively analyzed., Results: The 61 patients with IPMN in this study comprised 25 with intraductal papillary-mucinous adenomas (IPMA) and 36 with intraductal papillary-mucinous carcinomas (IPMC) including 6 with invasive carcinomas. Synchronous and metachronous EPM were observed in 15 out of the 61 patients (24.6%). Three of these patients, including 2 with IPMA and 1 with invasive carcinoma associated with IPMC, died of the EPM. None of the features, including sex, age, smoking, family history, macroscopic types (main duct type or branch duct type), histological types (gastric, intestinal, pancreatobiliary or oncocytic), and aberrant expression of molecules including CDKN2A, TP53, SMAD4 and DUSP6, except for the histological diagnoses were associated with the occurrence of EPM, i.e., the EPM occurred more often in patients with IPMA (10 out of 25) than in those with IPMC (5 out of 36) in our series (p = 0.0199 by the chi(2) test, p = 0.0330 by Fisher's exact probability test, p = 0.0422 by Yates' correction)., Conclusion: Patients with IPMA were more likely to have EPM than those with IPMC. Patients with IPMA are usually expected to have a fair prognosis but EPM could be fatal in some of them, so it must be noted during follow-up., (Copyright 2008 S. Karger AG, Basel and IAP.)

It is well known that antecedent term delivery and metastasis to sites other than the lungs and vagina are high risk factors for patients with gestational trophoblastic neoplasia. Here we report on a patient with choriocarcinoma who presented with brain and lung metastases after term delivery and was treated by EMA-CO chemotherapy. A 31-year-old woman delivered a healthy infant at term. Frequent episodes of hemoptysis occurred beginning 3 weeks after the delivery. On admission to our hospital, she had lesions in the uterus, lungs and brain as well as motor aphasia and hemiplagia. The pretreatment beta-hCG level was 21,000 ng/ml and the WHO score was 16 (high-risk group). The EMA-CO regimen was administrated as first-line chemotherapy and the patient achieved complete remission after 7 courses. Treatment was terminated after 11 courses and maintained with etoposide (25 mg/day) for 6 months. The patient has remained in complete remission for more than 16 years without other adjuvant therapies. We believe that EMA-CO can currently be considered the regimen of first choice for most high-risk patients with gestational trophoblastic neoplasia in view of its effectiveness and excellent tolerability.

We have analyzed extracellular matrix(ECM) of a case of pulmonary epithelioid hemangioendothelioma (PEH). Type IV collagen and laminin were existed in the ECM and were condensed around the tumor cell nests in meshwork pattern. Elastica-van Gieson stain revealed elastic fibers in this meshwork. These findings suggested that enhanced basement membrane protein synthesis in PEH seems to be responsible for the accumulation of abundant ECM. Analysis of the ECM seems to be quite useful for the differential diagnosis of this tumor.

We present a very rare case of metachronous triple cancers, including small cell carcinoma of the lung, as well as prostate and male breast cancer. To our knowledge, this is the first documented case of its kind. A 64-year-old man was referred to our hospital with left nipple retraction. He had previously undergone lobectomy of the right lung as treatment for small cell lung cancer at 57 years of age, and at 61 years of age, he had undergone prostatectomy and bilateral orchiectomy for prostate cancer, histologically determined to be moderately or poorly differentiated adenocarcinoma. Physical examination identified a painless irregular hard tumor in the left breast. Ultrasonography and magnetic resonance imaging (MRI) showed a nodular mass, and fine needle aspiration cytology of the mass revealed adenocarcinoma. Modified radical mastectomy was performed. Histological examination revealed that the breast tumor was scirrhous carcinoma, t1, n0, m0, stage T. Immunohistochemistry demonstrated that the prostate tumor was positive for prostatic specific antigen (PSA) and negative for estrogen receptor (ER), while the breast tumor was positive for ER and negative for PSA. Primary breast cancer was diagnosed. At present, 1 year and 8 months after surgical removal of the breast cancer, the patient has had no recurrence of breast cancer, small cell lung cancer, or prostate cancer. We discuss the possible causes of the triple cancers in this case with reference to the literature.