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Objectives: Tumors caused by failure of the DNA-mismatch repair system generally show microsatellite instability (MSI). High-frequency MSI cancers have been shown to be susceptible to immuno-oncology therapies. The aim of this study was to evaluate the clinical reliability of a rapid immunohistochemistry (IHC) technique for intraoperatively assessing molecular status through detection of tumoral deficiencies in the expression of mismatch repair proteins (dMMR; MLH1, MSH2, MSH6, and PMS2)., Methods: The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within a minimum of 13 min during surgery. Sixteen formalin-fixed paraffin-embedded (FFPE) tumor samples from 3 dMMR patients with Lynch syndrome and 6 FFPE samples from 6 dMMR-cancer patients were collected to establish an IHC protocol for MMR proteins. Next, 26 surgical patients treated and whose MSI status was determined using PCR-based tests were retrospectively analyzed. The concordance of dMMR diagnoses for thoracic tumors between the conventional (frozen section (FS)- and FFPE-IHCs) and rapid AC-mixing IHC with FSs were compared., Results: A rapid IHC protocol using primary antibodies against four MMR proteins (mixed 5-10 min) was established (entire process within 40 min). The concordance rate for MMR-IHC between the conventional and rapid IHC was 100%. dMMR diagnoses including an MSI-high pulmonary sarcoma patient entirely matched between FS- and FFPE-IHC., Conclusion: Rapid MMR-IHC could potentially serve as a clinical tool for intraoperative determination of tumor MSI/dMMR status. AC-mixing technology will contribute to improving pathological diagnostic capability through the development of an original and innovative rapid IHC., (© 2024. The Author(s), under exclusive licence to The Japanese Association for Thoracic Surgery.)

The nature of microRNA (miRNA) dysfunction in carcinogenesis remains controversial because of the complex connection between miRNA structural diversity and biological processes. Here, we found that oncofetal IGF2BP3 regulates the selective production of a subset of 3'-isoforms (3'-isomiRs), including miR-21-5p and Let-7 family, which induces significant changes in their cellular seed occupancy and structural components, establishing a cancer-specific gene expression profile. The D-score, reflecting dominant production of a representative miR-21-5p+C (a 3'-isomiR), discriminated between clinical early-stage lung adenocarcinoma (LUAD) cases with low and high recurrence risks, and was associated with molecular features of cell cycle progression, epithelial-mesenchymal transition pressure, and immune evasion. We found that IGF2BP3 controls the production of miR-21-5p+C by directing the nuclear Drosha complex to select the cleavage site. IGF2BP3 was also involved in the production of 3'-isomiRs of miR-425-5p and miR-454-3p. IGF2BP3-regulated these three miRNAs are suggested to be associated with the regulation of p53, TGF-β, and TNF pathways in LUAD. Knockdown of IGF2BP3 also induced a selective upregulation of Let-7 3'-isomiRs, leading to increased cellular Let-7 seed occupancy and broad repression of its target genes encoding cell cycle regulators. The D-score is an index that reflects this cellular situation. Our results suggest that the aberrant regulation of miRNA structural diversity is a critical component for controlling cellular networks, thus supporting the establishment of a malignant gene expression profile in early stage LUAD., Competing Interests: Competing interests statement:The authors declare no competing interest.

Purpose: To assess the risk factors for thrombosis in the pulmonary vein stump (PVT) and the efficacy of proximal ligation in preventing PVT after lobectomy., Methods: In total, 649 surgical patients with lung cancer were retrospectively reviewed. To compare the clinical effectiveness of PV proximal ligation, the simple stapler group (290 patients) and the proximal ligation group (359 patients who underwent thread ligation at the pericardial reflection with/without a stapler) were analyzed., Results: In the simple stapler group, 12 of 290 patients (4.1%) developed PVT. Among these, 9 of 58 underwent left upper lobectomy (LUL). In contrast, 5 of the 359 patients (1.4%) in the proximal ligation group developed PVT. All five patients received LUL. The incidence of PVT in the proximal ligation group was significantly lower than that in the simple stapler group (p = 0.0295) as well as in the analysis by LUL alone (p = 0.0263). A logistic regression analysis indicated that higher BMI and LUL were associated with the development of PVT (p = 0.0031, p < 0.0001), and PV proximal ligation reduced PVT (p = 0.0055)., Conclusion: Proximal ligation of the PV has the potential to prevent PVT, especially after LUL., (© 2024. The Author(s) under exclusive licence to Springer Nature Singapore Pte Ltd.)

Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal squamous cell carcinoma (ESCC). Our previous findings suggest that high expression of toll-like receptor (TLR) 4, which recognizes lipopolysaccharide (LPS) released from periodontal pathogens, correlates with a poor prognosis after esophagectomy for ESCC. We therefore hypothesized that LPS influences cancer cell proliferation and disease progression in ESCC. We used 8 ESCC cell lines to investigate how LPS affects ESCC cell proliferation and migration activity. We also assessed mRNA and protein expression to determine how LPS affects cytokine production and whether blocking TLR4 signaling attenuates that effect. We also used a mouse xenograft model to investigate whether LPS upregulates ESCC tumor progression in vivo. We then determined whether C-C motif chemokine ligand 2 (CCL2) expression in clinical samples correlates with 5-year overall survival (OS) and disease-specific survival (DSS) in ESCC patients after esophagectomy. LPS significantly upregulated cell proliferation and migration in all ESCC lines. It also upregulated CCL2 production. In vivo, subcutaneous LPS administration significantly increased ESCC tumor volume in mice. In clinical samples, high CCL2 expression significantly correlated with 5-year OS and DSS. There was also a significant correlation between CCL2 and TLR4 expression status, suggesting the involvement of an LPS-TLR4-CCL2 cascade in clinical settings. LPS significantly upregulates cell proliferation and tumor progression through an LPS-TLR4-CCL2 cascade and influences prognosis after esophagectomy for ESCC. This suggests improving the oral environment has the potential to improve the prognosis of ESCC patients after esophagectomy., Competing Interests: None., (AJCR Copyright © 2024.)

When a mass occurs at the staple line following lung resection, it can be difficult to distinguish between local cancer recurrence and granuloma. We present a case of a staple-line granuloma with 18F-fluorodeoxyglucose-positron emission tomography uptake and elevated serum carbohydrate antigen 19-9 (CA19-9) in a patient with ovarian cancer lung metastasis. After granuloma resection, serum CA19-9 levels normalized, and CA19-9 positive cells were identified in the resected tumor. Therefore, serum CA19-9 elevation does not rule out a staple-line granuloma. Whereas granulomas on computed tomography (CT) scans tend to show smooth shadows along the staple line unilaterally, detailed CT evaluation may help diagnostic differentiation. Differentiation based on imaging and tumor markers has limitations. However, core needle biopsy has the risk of misdiagnosis and tumor cell dissemination, therefore surgical resection should be considered when comprehensive findings indicate a potential recurrence., (© 2024 The Author(s). Thoracic Cancer published by John Wiley & Sons Australia, Ltd.)

Introduction: Determining a surgical strategy for early-stage lung cancer requires an accurate histologic diagnosis. Immunohistochemistry (IHC) enables reliable diagnosis of histological types but requires more time and more tumor tissue slides than hematoxylin and eosin staining. We aimed to assess the clinical validity of a new rapid multiplex IHC technique utilizing alternating current (AC) mixing for intraoperative lung cancer diagnosis., Methods: Forty-three patients who underwent radical resection of lung cancers were enrolled in a retrospective observational study. Frozen sections were prepared from lung tumor samples, and rapid IHC employing AC mixing was implemented alongside a multiplex IHC protocol targeting thyroid transcription factor-1 + cytokeratin 5, desmoglein 3 + Napsin A, and p63 + tripartite motif containing 29. We then evaluated the concordance between intraoperative diagnoses derived from rapid multiplex IHC and final pathology., Results: The concordance rate between the pathological diagnosis made with added rapid multiplex IHC and the final pathology was 93.0% (Cohen's 𝜅 coefficient = 0.860 and 95% CI: 0.727-0.993). When considering only adenocarcinoma and squamous cell carcinoma, the diagnoses were in agreement for all cases., Conclusions: We suggest rapid multiplex IHC as a promising tool for determining surgical strategies for lung tumors., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: Accurate clinical staging is crucial for selection of optimal oncological treatment strategies in non-small cell lung cancer (NSCLC). Although brain MRI, bone scintigraphy and whole-body PET/CT play important roles in detecting distant metastases, there is a lack of evidence regarding the indication for metastatic staging in early NSCLCs, especially ground-grass nodules (GGNs). Our aim was to determine whether checking for distant metastasis is required in cases of clinical T1N0 GGN., Methods: This was a retrospective study of initial staging using imaging tests in patients who had undergone complete surgical R0 resection for clinical T1N0 Stage IA NSCLC., Results: A total of 273 patients with cT1N0 GGNs (n = 183) or cT1N0 solid tumors (STs, n = 90) were deemed eligible. No cases of distant metastasis were detected on initial routine imaging evaluations. Among all cT1N0M0 cases, there were 191 incidental findings on various modalities (128 in the GGN). Most frequently detected on brain MRI was cerebral leukoaraiosis, which was found in 98/273 (35.9%) patients, while cerebral infarction was detected in 12/273 (4.4%) patients. Treatable neoplasms, including brain meningioma and thyroid, gastric, renal and colon cancers were also detected on PET/CT (and/or MRI). Among those, 19 patients were diagnosed with a treatable disease, including other-site cancers curable with surgery., Conclusions: Extensive staging (MRI, scintigraphy, PET/CT etc.) for distant metastasis is not required for patients diagnosed with clinical T1N0 GGNs, though various imaging modalities revealed the presence of adventitious diseases with the potential to increase surgical risks, lead to separate management, and worsen patient outcomes, especially in elderly patients. If clinically feasible, it could be considered to complement staging with whole-body procedures including PET/CT., (© 2024. The Author(s).)

Background: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy., Methods: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS., Results: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS., Conclusion: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy., (© 2024. The Author(s).)

Objective: To test the hypothesis that neoadjuvant chemoradiotherapy (NACRT) is more effective against hot esophageal squamous cell carcinoma (ESCC) and that it may upregulate tumor immunogenicity., Background: There have been several recent reports showing the efficacy of immune check-point inhibitors (ICIs) against esophageal cancer, especially immunologically hot tumors. In addition, several studies have suggested that chemotherapy and radiotherapy may convert cold tumors to hot tumors., Methods: Of 105 ESCC patients who underwent surgery after NACRT between 2010 and 2018 at our hospital, 99 whose biopsy tissue samples were obtained were enrolled. Based on immunohistochemical analysis, tumors that were FOXA1 (+) and/or EYA2 (+) were defined as hot tumors, others were cold tumors. We then investigated the association between tumor immunogenicity and clinicopathological features., Results: The 29 patients with hot tumors before NACRT had a significantly better 5-year disease-specific survival (DSS) rate than the remaining 70 patients with cold tumors (85% vs 64%; P = 0.036). In a multivariate analysis, tumor immunogenicity was a significant independent predictor of DSS. Of 68 patients without a pathological complete response (non-pCR) in their primary tumor, 51 (75%) had hot tumors after NACRT. Moreover, 75% (36/48) of tumors that were cold before NACRT were converted to hot tumors after NACRT., Conclusions: Patients with hot ESCC tumors treated with NACRT plus esophagectomy had a better prognosis than those with cold tumors. NACRT upregulated cold tumor immunogenicity to hot tumors, suggesting NACRT may increase the sensitivity of ESCC to adjuvant ICIs., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: We examined whether preoperative inspiratory muscle weakness (IMW) is a risk factor for postoperative pulmonary complications (PPCs) in patients with esophageal cancer who underwent subtotal esophagectomy., Methods: This single-center retrospective cohort study enrolled patients with esophageal cancer who underwent a scheduled subtotal esophagectomy between June 2020 and May 2022. Maximal inspiratory pressure (MIP) was measured as inspiratory muscle strength using a respiratory dynamometer, and we defined IMW as MIP < 80% of the predicted value. Our primary outcome comprised overall PPCs. We investigated the relationship between IMW and PPCs using the Bayesian logistic regression model., Results: After exclusion, 72 patients were included in this study. IMW was identified in 26 patients (36%), and PPCs developed in 28 patients (39%). Among patients with IMW, 15 (58%) developed PPCs. Preoperative IMW was associated with PPCs (mean odds ratio [OR]: 3.58; 95% credible interval [95% CrI]: 1.29, 9.73) in the unweighted model. A similar association was observed in the weighted model adjusted for preoperative and intraoperative contributing factors (mean OR: 4.15; 95% CrI: 2.04, 8.45)., Conclusions: Preoperative IMW was associated with PPCs in patients with esophageal cancer who underwent subtotal esophagectomy. This association remained after adjusting for preoperative and intraoperative contributing factors., (© 2023 Wiley Periodicals LLC.)

Osimertinib is a standard treatment for patients with EGFR-mutated non-small cell lung carcinoma (NSCLC). We evaluated the relationship between plasma osimertinib concentrations and treatment outcome in patients with NSCLC for this cohort study. The plasma levels of osimertinib and its metabolite AZ5104 were measured a week after the start of treatment (P1). The primary endpoint was to evaluate the correlation between plasma concentration and adverse events (AEs). The correlation with treatment efficacy was one of the secondary endpoints. In patients with CNS metastases, the concentration in the cerebrospinal fluid was also measured. Forty-one patients were enrolled. The frequency of AEs was highest for rash, followed by anorexia and thrombocytopenia. Thirty-eight cases provided measurements for P1. The median plasma concentration of osimertinib was 227 ng/mL, and that of AZ5104 was 16.5 ng/mL. The mean CNS penetration rate of two cases was 3.8%. The P1 in the group with anorexia was significantly higher than that in the group without anorexia (385.0 ng/mL vs. 231.5 ng/mL, p = 0.009). Divided into quartiles by P1 trough level, Q2 + Q3 (164-338 ng/mL) had longer PFS, while Q1 and Q4 had shorter PFS. An appropriate plasma level of osimertinib may avoid some adverse events and induce long PFS. Further large-scale trials are warranted.

Aim: Akita Prefecture has the largest proportion of older inhabitants and the highest cancer mortality rate in Japan. Lung cancer is one of the biggest killers, and early detection is critical. Chest X-ray examinations are the main screening method for lung cancer; however, the COVID-19 pandemic has affected the screening system. Here, we evaluate how COVID-19 has affected lung cancer screening in Akita Prefecture., Methods: Using the Akita General Health Corporation database, the average annual number of chest X-ray screening tests, close examinations and lung cancer diagnoses (stratified by sex and age) was evaluated during 2016-2019, and compared with the 2020 values. Furthermore, data on lung cancer registrations from 2018 to 2020 were obtained from the Collaborative Akita Prefecture Hospital-Based Cancer Registration System and analyzed., Results: The average annual number of screening tests, close examinations and lung cancer diagnoses declined (by >50%) between 2016 to 2019 and 2020, especially among older people (aged ≥65 years). Furthermore, by stage, the number of patients with early-stage lung cancer (stage 0-I) decreased, and the number with advanced-stage cancer (stage IV) increased., Conclusions: The COVID-19 pandemic reduced lung cancer screening participation, especially among the older adult population in Akita Prefecture, resulting in a decrease in lung cancer diagnoses through screening. This might have reduced the number of early-stage cancer registrations. It is necessary to improve health education among the public regarding the importance of chest X-ray screening. Geriatr Gerontol Int 2023; 23: 622-627., (© 2023 Japan Geriatrics Society.)

Tumor-derived G-CSF is a well-known factor to aggravate disease progression in various types of cancers. In this study, we investigated a role of G-CSF in squamous cell carcinoma (SCC). High expression of G-CSF in the tumor tissues of esophageal SCC (ESCC) patients correlated with poor prognosis. Murine SCC NR-S1M cells produce considerable amount of G-CSF, which expression is correlated with its metastatic potentials. Deletion of G-CSF in NR-S1M cells mitigated tumor growth and metastasis to lymph node and lung of subcutaneous NR-S1M tumors in the mice. Mechanistically, G-CSF enhanced cell proliferation in autocrine manner in vitro, whereas in NR-S1M tumor-bearing mice, accumulation of plasma G-CSF was associated with expansion of peripheral neutrophils, which led to a decreased proportion of CD8 + T cells. Antibody depletion of neutrophils restored the number of CD8+ T cells and modestly suppressed tumor outgrowth, albeit no changes in distant metastasis. We propose that G-CSF produced by NR-S1M cells facilitates tumor progression in mice through bi-functional effects to promote neutrophil recruitment and tumor cell proliferation, which may render poor prognosis to the ESCC patients with high G-CSF expression., (© 2023 Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

Background: Tracheobronchial injury (TBI) is a rare but potentially life-threatening trauma that requires prompt diagnosis and treatment. We present a case in which a patient with COVID-19 infection was successfully treated for a TBI through surgical repair and intensive care with extracorporeal membrane oxygenation (ECMO) support., Case Presentation: This is the case of a 31-year-old man transported to a peripheral hospital following a car crash. Tracheal intubation was performed for severe hypoxia and subcutaneous emphysema. Chest computed tomography showed bilateral lung contusion, hemopneumothorax, and penetration of the endotracheal tube beyond the tracheal bifurcation. A TBI was suspected; moreover, his COVID-19 polymerase chain reaction screening test was positive. Requiring emergency surgery, the patient was transferred to a private negative pressure room in our intensive care unit. Due to persistent hypoxia and in preparation for repair, the patient was started on veno-venous ECMO. With ECMO support, tracheobronchial injury repair was performed without intraoperative ventilation. In accordance with the surgery manual for COVID-19 patients in our hospital, all medical staff who treated this patient used personal protective equipment. Partial transection of the tracheal bifurcation membranous wall was detected and repaired using 4-0 monofilament absorbable sutures. The patient was discharged on the 29th postoperative day without postoperative complications., Conclusions: ECMO support for traumatic TBI in this patient with COVID-19 reduced mortality risk while preventing aerosol exposure to the virus., (© 2023. The Author(s).)

Aim: Because the optimal treatment strategy for borderline resectable (cT3br) thoracic esophageal cancer patients remains unclear, it is of great interest whether preoperative neoadjuvant therapy for cT3br could achieve results comparable to those seen with resectable T3 cancer (cT3r). We speculated that preoperative neoadjuvant chemoradiotherapy (NACRT) would be particularly effective in cT3br thoracic esophageal cancer patients and compared to cT3br and cT3r., Methods: Of 186 cT3 thoracic esophageal cancer patients treated with intended NACRT, 162 received radical esophagectomy. More than 97% were squamous cell carcinomas. Patients were partitioned into two groups according to whether invasion of adjacent organs was suspected (cT3br and cT3r). Treatment outcomes and survival were analyzed., Results: Sixty-eight patients (36.6%) were classified as cT3br and 118 (63.4%) as cT3r. The cT3br group had significantly more tumors in the upper and middle mediastinum ( p  < 0.0001) and more cases with cM1 (lymph node) ( p  = 0.0104) than the cT3r group. In addition, the cT3br patients receiving esophagectomy exhibited a significantly lower pathological complete response rate than the cT3r patients ( p  = 0.0374). However, the R0 resection rate did not differ between the cT3br and cT3r patients ( p  = 0.0978), and the two groups treated with intended NACRT had similar 5-year overall (OS) and disease-specific survival (DSS) ( p  = 0.3831 and p  = 0.9020). In addition, the incidence and patterns of recurrence did not differ between the cT3br and cT3r patients receiving esophagectomy ( p  = 0.8109 and p  = 0.3128)., Conclusions: Preoperative neoadjuvant chemoradiotherapy appears to be a promising treatment for patients with borderline resectable thoracic esophageal squamous cell carcinoma., Competing Interests: All authors declare no actual or potential financial conflicts of interest., (© 2023 The Authors. Annals of Gastroenterological Surgery published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Gastroenterological Surgery.)

Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (P interaction  = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications., (© 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Most so-called "beneficial bacteria" in gut microbiota are Gram-positive, and TLR6 recognizes the peptidoglycan (PGN) present in their cell walls. We hypothesized that a high TLR6 expression status predicts a more favorable prognosis after esophagectomy. We used an ESCC tissue microarray (TMA) to examine TLR6 expression status in ESCC patients and to determine whether TLR6 expression status correlates with prognosis after curative esophagectomy. We also examined whether PGN influences the cell proliferation activity of ESCC lines. Clinical ESCC samples from 177 patients tested for the expression of TLR6 were categorized as 3+ (n = 17), 2+ (n = 48), 1+ (n = 68), or 0 (n = 44). High TLR6 expression (3+ and 2+) correlated with significantly more favorable 5-year overall survival (OS) and disease-specific survival (DSS) after esophagectomy than a lower TLR6 expression (1+ and 0). Univariate and multivariate analyses showed that TLR6 expression status is an independent prognostic factor that affects 5-year OS. PGN significantly inhibited the cell proliferation activity of ESCC lines. This is the first study to show that high TLR6 expression status predicts a more favorable prognosis in locally advanced thoracic ESCC patients after curative esophagectomy. PGN released from "beneficial bacteria" seems to have potential to inhibit the cell proliferation activity of ESCC.

Objectives: The division of inferior pulmonary ligament (IPL) during upper lobectomy (UL) was believed to be mandatory to dilate the remaining lung sufficiently. However, the benefits, especially postoperative pulmonary function, remain controversial. This study aimed to evaluate whether IPL division leads to pulmonary dysfunction., Methods: This retrospective study included 213 patients who underwent UL between 2005 and 2018. They were categorized into an IPL division group (D group, n = 106) and a preservation group (P group, n = 107). Postoperative dead space at the lung apex, pulmonary function and complications were assessed using chest X-rays and spirometry. Changes in bronchial angle, cross-sectional area and circumference of the narrowed bronchus on the excised side were measured on three-dimensional computed tomography., Results: There was no significant difference in the postoperative complication rate, the dead space area, forced vital capacity (FVC), or forced expiratory volume in 1 s (FEV1) between the 2 groups after right UL (FVC; P = 0.838, FEV1; P = 0.693). By contrast, after left UL pulmonary function was significantly better in the P than in the D group (FVC; P = 0.038, FEV1; P = 0.027). Changes in bronchial angle did not significantly differ between the 2 groups. The narrowed bronchus's cross-sectional area (P = 0.021) and circumference (P = 0.009) were significantly smaller in the D group than in the P group after left UL., Conclusions: IPL division during left UL caused postoperative pulmonary dysfunction and airflow limitation due to bronchial kinking. IPL preservation may have a beneficial impact on postoperative pulmonary function., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery.)

The advantages of salvage esophagectomy through robotic-assisted surgery for patients with clinically diagnosed tumor invasion of adjacent vital organs (cT4b) or patients with scar tissue from definitive chemoradiotherapy (dCRT) are still only rarely reported. A man in his 60s with middle thoracic esophageal cancer (cT4b [left main bronchus] N1 M0 cStage IIIC) received dCRT (60 Gy). After the chemoradiotherapy, upper gastrointestinal endoscopy revealed a residual primary tumor, and we performed robotic-assisted thoracoscopic subtotal esophagectomy and gastric tube reconstruction via a retrosternal route with three-field lymphadenectomy. Although it was difficult to dissect the tumor from adjacent organs, especially the left main bronchus and left inferior pulmonary vein, due to loss of the dissecting layer and scarring, R0 surgery was achieved. With robot-assisted thoracoscopic surgery, the high-magnification, high-resolution, and three-dimensional images; the stable surgical field with full countertraction made with the robotic arm forceps, which were readily adjusted; and the stable motion of the robotic arm without physiological tremor are considerable advantages for salvage esophagectomy for cT4b tumors. It goes without saying that sufficient experience with robot-assisted surgery and sufficient understanding and surgical skill in esophageal cancer surgery under suitable surgical indications and timing are required to make use of these advantages.

Background: Sleeve lobectomy is recommended to avoid pneumonectomy and preserve pulmonary function in patients with central lung cancer. However, the relationship between postoperative pulmonary functional loss and resected lung parenchyma volume has not been fully characterized. The aim of this study was to evaluate the relationship between pulmonary function and lung volume in patients undergoing sleeve lobectomy or pneumonectomy., Methods: A total of 61 lung cancer patients who had undergone pneumonectomy or sleeve lobectomy were analyzed retrospectively. Among them, 20 patients performed pulmonary function tests, including vital capacity (VC) and forced expiratory volume in 1 s (FEV1) tests, preoperatively and then about 6 months after surgery. VC and FEV1 ratios were calculated (measured postoperative respiratory function/predicted postoperative respiratory function) as the standardized pulmonary functional loss ratio., Results: Thirty-day operation-related mortality was significantly lower after sleeve lobectomy (3.2%) than pneumonectomy (9.6%). The 5-year relapse-free survival rate was 46.67% versus 29.03%, and the 5-year overall survival rate was 63.33% versus 38.71% in patients receiving sleeve lobectomy versus pneumonectomy. The VC ratio in the pneumonectomy group was better than in the sleeve lobectomy group (1.003 ± 0.117 vs. 0.779 ± 0.12; p = 0.0008), as was the FEV1 ratio (1.132 ± 0.226 vs. 0.851 ± 0.063; p = 0.0038)., Conclusions: Both short-term and long-term outcomes were better with sleeve lobectomy than pneumonectomy. However, actual postoperative pulmonary function after pneumonectomy may be better than clinicians expect, and pneumonectomy should still be considered a treatment option for patients with sufficient pulmonary reserve and in whom sleeve lobectomy is less likely to be curative., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Knowledge of the histologic type and primary origin of pulmonary tumors is essential when preparing a surgical strategy. Intraoperative diagnosis of hematoxylin and eosin (H&E)-stained frozen sections is the gold standard, but reliable pathology requires time-consuming immunohistochemistry (IHC) to distinguish among histological types/organ origins and to analyze molecular status. The aim of this study was to evaluate the clinical reliability of a new rapid-IHC technique for intraoperative diagnosis of pulmonary tumors. In total, 169 patients with undiagnosed pulmonary tumors were enrolled in a multicenter prospective observational study. At three institutes, pulmonary tumor samples were collected through core needle biopsy and/or surgery to determine surgical strategies. Using a new device for rapid IHC, we applied a high-voltage, low-frequency alternating current (AC) field, which mixes the available antibody as the voltage is switched on/off. Rapid IHC can provide tumor histologic type/origin diagnoses within 20 min, as opposed to the 3-6 h required for conventional IHC. No false diagnoses of malignancy were rendered in any of the cases when using simple H&E staining. With H&E staining alone, the overall definitive diagnosis rate, the rate of defined tumor origin, and the rate of determined histological type were 76.92%, 85.80%, and 90.53%, respectively. When rapid IHC was added, those rates were significantly improved to 88.76%, 94.67%, and 91.72%, respectively. By providing prompt and accurate intraoperative histological/molecular analysis, rapid IHC driven by AC mixing could serve as an effective clinical tool guiding the surgical strategy for undiagnosed pulmonary tumors., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Metastasis predicts poor prognosis in cancer patients. It has been recognized that specific tumor microenvironment defines cancer cell metastasis, whereas the underlying mechanisms remain elusive. Here we show that Galectin-7 is a crucial mediator of metastasis associated with immunosuppression. In a syngeneic mouse squamous cell carcinoma (SCC) model of NR-S1M cells, we isolated metastasized NR-S1M cells from lymph nodes in tumor-bearing mice and established metastatic NR-S1M cells in in vitro culture. RNA-seq analysis revealed that interferon gene signature was markedly downregulated in metastatic NR-S1M cells compared with parental cells, and in vivo NR-S1M tumors heterogeneously developed focal immunosuppressive areas featured by deficiency of anti-tumor immune cells. Spatial transcriptome analysis (Visium) for the NR-S1M tumors revealed that various pro-metastatic genes were significantly upregulated in immunosuppressive areas when compared to immunocompetent areas. Notably, Galectin-7 was identified as a novel metastasis-driving factor. Galectin-7 expression was induced during tumorigenesis particularly in the microenvironment of immunosuppression, and extracellularly released at later stage of tumor progression. Deletion of Galectin-7 in NR-S1M cells significantly suppressed lymph node and lung metastasis without affecting primary tumor growth. Therefore, Galectin-7 is a crucial mediator of tumor metastasis of SCC, which is educated in the immune-suppressed tumor areas, and may be a potential target of cancer immunotherapy., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Objectives: Locoregional recurrence of non-small cell lung cancer (NSCLC) occurs even among patients with stage I disease, as a result of tumor proliferative activity. The aim of this study was to evaluate the clinical reliability of a new rapid immunohistochemistry (IHC) technique for assessing malignant potential through detection of tumoral Ki-67 expression., Materials and Methods: The rapid IHC method uses non-contact alternating current (AC) mixing to achieve more rapid/stable staining within 20 min during surgery. First, to investigate the association between clinical outcomes and tumoral Ki-67 labeling with rapid IHC, 21 pairs of surgical patients treated between 2012 and 2020 for pStage IA1-3 NSCLC with/without recurrence were retrospectively reviewed. Second, 40 frozen section (FS) samples in patients with NSCLC for whom radical surgery was planned between April 2021 and February 2022 were deemed eligible for comparison of the clinical performance of conventional IHC and intraoperative rapid Ki-67 IHC with FS., Results: Detection of tumoral Ki-67 expression using rapid IHC with formalin-fixed, paraffin-embedded (FFPE) blocks was significantly associated with clinical outcomes in R0 pStage IA NSCLC surgical patients, including overall and recurrence-free survival (P = 0.0043 and P &lt; 0.0001, respectively). Levels of Ki-67 expression among resectable NSCLC patients detected using rapid IHC with FS significantly correlated with those detected using conventional FFPE-IHC (p &lt; 0.001). An intraoperative cut-off of &gt; 7.5 % tumor cell Ki-67 positivity accurately predicted pathological stage more advanced than IA3 [P = 0.0185, Odds ratio = 20.477, 95 % confidence interval (CI): 1.660-252.55]., Conclusion: Rapid Ki-67 IHC with AC mixing could potentially serve as a clinical tool for intraoperative determination of tumor malignancy status. The present study suggests that segmentectomy for early small NSCLCs is oncologically safe and a reasonable alternative to lobectomy, but only when there is adequate intraoperative selection for primary tumors with low-grade malignancy, which could be verified using intraoperative rapid Ki-67 IHC with FS., 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 © 2022 Elsevier B.V. All rights reserved.)

Background/aim: Minerals and trace elements (TEs) play vital roles in normal biological functions and in all cancers. Breast carcinoma is the most commonly occurring cancer in women. The aim of this study was to evaluate changes in TE levels before and after breast cancer surgery and the clinical utility and reliability of TE levels assayed using inductively coupled plasma mass spectrometry (ICP-MS)., Patients and Methods: Thirteen patients with ductal carcinoma in situ (DCIS) and 34 with invasive ductal carcinoma (IDC) treated with planned surgery were enrolled between August 2017 and February 2019. Blood samples were collected before and the day after resection of the primary tumor. All enrolled patients received mastectomy or quadrantectomy and axillary lymph node dissection/biopsy. Serum TE concentrations were determined using ICP-MS., Results: Changes in boron, titanium, vanadium, chromium, copper, zinc, and selenium levels from before to after surgery differed between IDC and DCIS patients. Boron and copper levels before surgery and changes in titanium, vanadium, and chromium before and after surgery are potential predictors distinguishing DCIS from IDC. Subset analysis showed that chromium is a potential biomarker for luminal subtype, while titanium and chromium are potential biomarkers for pathological staging., Conclusion: Changes in serum TEs before and after surgery may help with diagnosis and staging of breast cancer and in establishing TE supplementation protocols., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To determine whether esophagectomy provides a survival advantage in octogenarians with resectable thoracic esophageal cancer., Summary Background Data: Elderly patients with thoracic esophageal cancer do not always receive the full standard treatment; however, advanced age alone should not preclude the use of effective treatment that could meaningfully improve survival., Methods: We retrieved the 2008 to 2011 data from the National Database of Hospital-based Cancer Registries from the National Cancer Centerin Japan, divided the patients into a ≥75 group (75-79 years; n = 2935) and a ≥80 group (80 years or older; n = 2131), and then compared the patient backgrounds and survival curves. A multivariable Cox proportional hazards regression model was developed to compare the effects of esophagectomy and chemoradiotherapy in the 2 groups., Results: A significantly greater percentage of patients were treated with esoph-agectomy in the ≥75 group (34.6%) than the ≥80 group (18.4%). Among patients who received esophagectomy, the 3-year survival rate was 51.1% in the ≥ 75 group and 39.0% in the ≥80 group (P < 0.001). However, among patients who received chemoradiotherapy, there was no difference in survival curve between the 2 groups (P = 0.17). Multivariable Cox proportional hazard analysis revealed that esoph-agectomy for clinical Stage ii-iii patients was significantly associated to better survival (adjusted HR: 0.731) (95%CI: 0.645-0.829, P < 0.001) in the ≥75 group but not the ≥ 80 group when compared with chemoradiotherapy., Conclusions: Many octogenarians do not necessarily get a survival benefit from esophagectomy. However, patients should be evaluated based on their overall health before ruling out surgery based on age alone., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: The mechanism underlying cancer cell metastasis from the tumor to regional lymph nodes is not yet fully understood. We hypothesized that peritumoral neutrophil accumulation promotes regional lymph node metastasis in thoracic esophageal squamous cell cancer., Methods: Between 2010 and 2019, 126 thoracic esophageal squamous cell cancer patients received curative (R0) esophagectomy without preoperative treatment in our hospital. Using paraffin-embedded resected tumors, we performed immunohistochemical analysis of CD16b-positive neutrophil accumulation in the peritumoral area, which was defined as a 1-mm region centered on the border separating the malignant cell nests from the host tissue. The relationship between the density of peritumoral CD16b staining and pathological lymph node metastasis or 5-year overall survival was evaluated., Results: Although the clinicopathological characteristics of CD16b-high and CD16b-low patients did not differ, greater pathological lymph node metastasis (P < .001) and lymphatic invasion by the tumor (P = .024) and a poorer 5-year survival (P = .010) were seen in CD16b-high patients. Moreover, CD16b-positive neutrophil density was generally higher in the peritumoral area than within the tumor itself. Univariate and multivariate analyses showed that CD16b-positive neutrophil accumulation was an independent factor for lymph node metastasis with an odds ratio >25 (P < .001). On the other hand, blood neutrophil counts did not correlate with lymph node metastasis., Conclusion: Peritumoral accumulation of CD16b-positive neutrophils is an independent factor strongly correlated with lymph node metastasis in thoracic esophageal squamous cell cancer., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Sublobar resection is considered the gold standard for selected patients with pulmonary metastasis or who are compromised in some way. However, an unfavorable outcome after sublobar resection is local/margin recurrence. The aim of this study was to evaluate the clinical reliability of a new rapid-stapler lavage immunocytochemistry (ICC) technique for assessing margin malignancy. The method uses non-contact alternating current (AC) mixing to achieve more stable staining., Methods: Twenty-one patients who underwent sublobar resection, including 16 wedge resections, for pulmonary metastasis or lung cancer in a compromised host between September 2016 and December 2017 were retrospectively reviewed. All margin specimens were intraoperatively evaluated with HE staining of frozen sections and stapler lavage cytology using Papanicolaou staining and rapid-ICC., Results: Rapid-stapler lavage ICC can be used to diagnose surgically safe margins within 20 min during sublobar resections. Although in all cases margins were diagnosed as cancer free based on HE staining of frozen sections, two of four patients diagnosed with malignant-positive margins based on rapid ICC experienced local/margin recurrence., Conclusions: Rapid-stapler lavage ICC with AC mixing could potentially serve as a clinical tool for prompt determination of margin malignant status after pulmonary sublobar resection., (© 2021. The Japanese Association for Thoracic Surgery.)

Objectives: For thymic epithelial tumors, simple contact with adjacent structures does not necessarily mean invasion. The purpose of our study was to develop a simple noninvasive technique for evaluating organ invasion using routine pretreatment computed tomography (CT)., Methods: This retrospective study analyzed the pathological reports on 95 mediastinal resections performed between January 2003 and June 2020. Using CT images, the length of the interface between the primary tumor and neighboring structures (arch distance; Adist) and maximum tumor diameter (Dmax) was measured, after which Adist/Dmax (A/D) ratios were calculated. Receiver operating characteristic (ROC) curves were used to analyze the Adist and A/D ratios., Results: An Adist cut-off of 37.5 mm best distinguished between invaded and non-invaded mediastinal great veins based on ROC curves. When Adist > 37.5 mm was used for diagnosis of invasion of the brachiocephalic vein (BCV) or superior vena cava (SVC), the sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and area under the ROC curve for diagnosis of invasion were 61.9%, 92.5%, 81.25%, 82.2%, 81.97%, and 0.76429, respectively. Moreover, there were significant differences between BCV/SVC Adist > 37.5 mm and ≤ 37.5 mm for 10-year relapse-free survival and 10-year overall survival (p < 0.01)., Conclusions: When diagnosing invasion of the mediastinal great veins based on Adist > 37.5 mm, we achieved a higher performance level than the conventional criteria such as irregular interface with an absence of the fat layer. Measurement of Adist is a simple noninvasive technique for evaluating invasion using CT. Key Points • Simple contact between the primary tumor and adjacent structures on CT does not indicate direct invasion. • Using CT images, the length of the interface between the primary tumor and neighboring structures (arch distance; Adist) is a simple noninvasive technique for evaluating invasion. • Adist > 37.5 mm can be a supportive tool to identify invaded mediastinal great veins and surgical indications for T3 and T4 invasion by thymic epithelial tumors., (© 2021. European Society of Radiology.)

Background: The aim of the present study was to use surgical and histological results to develop a simple noninvasive technique to improve nodal staging using preoperative PET/CT in patients with resectable lung cancer., Methods: Preoperative PET/CT findings (pStage IB-III 182 patients) and pathological diagnoses after surgical resection were evaluated. Using PET/CT images to determine the standardized uptake value (SUV) ratio, the SUV max of a contralateral hilar lymph node (on the side of the chest opposite to the primary tumor) was measured simultaneously. The I/C-SUV ratio was calculated as ipsilateral hilar node SUV/contralateral hilar node SUV. Receiver operating characteristic (ROC) curves were then used to analyze those data., Results: Based on ROC analyses, the cutoff I/C-SUV ratio for diagnosis of lymph node metastasis was 1.34. With a tumor ipsilateral lymph node SUV max ≥2.5, an IC-SUV ratio ≥1.34 had the highest accuracy for predicting N1/N2 metastasis; the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of nodal staging were 60.66, 85.11, 84.09, 62.5 and 71.29%, respectively., Conclusions: When diagnosing nodal stage, a lymph node I/C-SUV ratio ≥1.34 can be an effective criterion for determining surgical indications in advanced lung cancer., (© 2022 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Background: Patients with 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET)-positive lymph nodes before treatment have a poor prognosis after esophagectomy. This study investigated whether FDG uptake into lymph nodes on FDG-PET (PET-N) during the pre- or posttreatment stage is more predictive of survival for thoracic esophageal squamous cell carcinoma (TESCC) patients who received neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy., Methods: Of 129 TESCC patients with clinical lymphatic metastasis who underwent curative-intent esophagectomy after NACRT between 2010 and 2018, 97 who received PET before and after NACRT were enrolled in the study. The study defined lymph nodes with a maximum standardized uptake value (SUV max ) greater than 2.5 on FDG-PET before NACRT as cPET-N(+) and after NACRT as CRT-cPET-N(+). Both the cPET-N(+) and CRT-cPET-N(-) patients were defined as PET-N responders. Survival was analyzed using the Kaplan-Meier method and Cox proportional hazard models., Results: No significant difference in survival was detected between the cPET-N(+) and cPET-N(-) patients. However, the CRT-cPET-N(-) patients had significantly better 5-year overall survival (OS) and disease-specific survival (DSS) than the CRT-cPET-N (+) patients. The PET-N responders had significantly better 5-year OS and DSS than the PET-N non-responders, and PET-N response was an independent prognostic factor for 5-year DSS., Conclusion: The PET-N response is a highly predictive prognostic marker for TESCC patients who undergo NACRT followed by esophagectomy. The PET-N response may help clinicians to establish a strategy for perioperative treatments that improves survival for patients with lymph node metastasis in TESCC., (© 2021. Society of Surgical Oncology.)

Background: Platinum agents are taken up into cells by copper transporter (CTR) 1 (gene code: SLC31A1) and are excreted from cells by copper-transporting P-type adenosine triphosphatase (ATP7B) and multidrug resistance-associated protein (MRP) 2 (gene code: ABCC2). In addition, glutathione S transferase (GST) P1 is involved in the metabolism of platinum agents. The present study aimed to determine whether the rate of grade 3-4 hematological toxicity associated with platinum plus 5-fluorouracil (5-FU) therapy in 239 patients with esophageal cancer was affected by the SLC31A1 rs10981694A>C and rs12686377G>T, ATP7B rs9535828A>G, GSTP1 rs1695A>G, and ABCC2 -24C>T polymorphisms., Methods: Chemotherapy consisted of protracted infusion of 5-FU (800 mg/m 2 /day) on days 1-5 and cisplatin or nedaplatin (80 mg/m 2 /day) on day 1., Results: A total of 82 of 239 patients developed grade 3-4 hematological toxicity after chemotherapy. Univariate analysis showed that ABCC2 -24C/T + T/T genotypes (P = 0.038), radiation therapy (P = 0.013), baseline white blood cell count < 6000/μL (P = 0.003), and baseline neutrophil count < 3900/μL (P = 0.021) were statistically significant predictors of grade 3-4 hematological toxicity. Multivariate analysis revealed that ABCC2 -24C/T + T/T genotypes (P = 0.036), radiation therapy (P = 0.005), and baseline white blood cell count < 6000/μL (P < 0.001) were significant risk factors., Conclusions: We determined that ABCC2 -24C>T is significantly associated with grade 3-4 hematological toxicity after platinum plus 5-FU therapy. These findings might contribute to improved treatment strategies for patients with esophageal cancer., (© 2021. The Japan Esophageal Society.)

Background: Tumor regression grade (TRG) after neoadjuvant therapy is reportedly predictive of prognosis in esophageal cancer patients, as lack of a response to neoadjuvant therapy is associated with a poor prognosis. However, there is little information available on the timing and pattern of recurrence after esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC) that takes into consideration TRG after neoadjuvant chemoradiotherapy (NACRT). Here, in an effort to gain insight into a treatment strategy that improves the prognosis of NACRT non-responders, we evaluated the patterns and timing of recurrence in TESCC patients, taking into consideration TRG after NACRT., Methods: A total of 127 TESCC patients treated with NACRT and esophagectomy between 2009 and 2017 were enrolled in this observational cohort study. TRGs were assigned based on the proportion of residual tumor cells in the area (TRG1, ≥1/3 viable cancer cells; 2, < 1/3 viable cancer cells; 3, no viable cancer cells). We retrospectively investigated the timing and patterns of recurrence and the prognoses in TESCC patients, taking into consideration TRG after NACRT., Results: The 127 participating TESCC patients were categorized as TRG1 (42 patients, 33%), TRG2 (56 patients, 44%) or TRG3 (29 patients, 23%). The locoregional recurrence rate was higher in TRG1 (36.4%) patients than combined TRG2-3 (7.4%) patients. Patients with TRG3 had better prognoses, though a few TRG3 patients experienced distant recurrence. There were no significant differences in median time to first recurrence or OS among patients with locoregional or distant recurrence. There was a trend toward better OS in TRG2-3 patients with recurrence than TRG1 patients with recurrence, but the difference was not significant., Conclusions: NACRT non-responders (TRG1 patients) experienced higher locoregional recurrence rates and earlier recurrence with distant or locoregional metastasis. TRG appears to be useful for establishing a strategy for perioperative treatments to improve TESCC patient survival, especially among TRG1 patients. (303 words)., (© 2021. The Author(s).)

To address the major issue of regional disparity in the treatment for elderly cancer patients in an aging society, we compared the treatment strategies used for elderly patients with thoracic esophageal cancer and their survival outcomes in metropolitan areas and other regions. Using the national database of hospital-based cancer registries in 2008-2011, patients aged 75 years or older who had been diagnosed with thoracic esophageal cancer were enrolled. We divided the patients into two groups: those treated in metropolitan areas (Tokyo, Kanagawa, Osaka, Aichi, Saitama, and Chiba prefectures) with populations of 6 million or more and those treated in other areas (the other 41 prefectures). Compared were patient backgrounds, treatment strategies, and survival curves at each cancer stage. In total, 1236 (24%) patients from metropolitan areas and 3830 (76%) patients from nonmetropolitan areas were enrolled. Patients in metropolitan areas were treated at more advanced stages. There was also a difference in treatment strategy. The 3-year survival rate among cStage I patients was better in metropolitan areas (71.6% vs. 63.7%), and this finding mainly reflected the survival difference between patients treated with radiotherapy alone. For cStage II-IV patients, there were no differences. Multivariable Cox proportional hazard analysis including interaction terms between treatment areas, cStage, and the first-line treatments revealed that treatments in the metropolitan areas were significantly associated with better survival among patients treated with radiotherapy alone for cStage I cancer. Treatment strategies for elderly patients with thoracic esophageal cancer and its survival outcomes differed between metropolitan areas and other regions., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Esophageal cancer recurrence in solitary mediastinal lymph node that may possibly been left behind in the first surgery differs from other recurrence patterns because it is still local disease and offers the possibility of complete cure through resection, but it is technically difficult. We resected recurrent mediastinal lymph nodes in six cases. A left transthoracic approach was used in three patients. Other approaches were left thoracoabdominal, right open transthoracic and transcervical. R0 resections were achieved in five patients without severe surgical stress or postoperative complications. Overall survival after resection of recurrent lymph nodes was 43 (16-82) months. Approaches to resection of recurrent solitary mediastinal lymph nodes after esophagectomy should be consider to perform curative treatment safely and less invasively.

Background: Video-assisted thoracoscopic surgery (VATS) is being used to treat esophageal submucosal tumors (SMTs) all over the world. However, this technique is difficult when the tumor is large and located on the left side wall of the esophagus, within the upper mediastinum. This is because, with VATS, the surgical forceps have a limited range of motion. Robot-assisted thoracoscopic surgery (RATS) using the da Vinci surgical system may be extremely useful for enucleation of esophageal SMTs within the narrow upper mediastinum., Case Presentation: A female in her thirties experiencing epigastric pain visited our hospital and was diagnosed with a large esophageal leiomyoma within the upper mediastinum. From its size (10 cm), it was judged to have malignant potential. We performed SMT enucleation using RATS with a da Vinci surgical system Xi. This was our second case using this system. The patient was placed in the left lateral position. Four da Vinci trocars (8 mm) were inserted into the 10th, 7th, 5th and 3rd intercostal spaces (ICS), and an assist port was added in the 5th ICS. We opened the superior mediastinal pleura cranially and caudally from the arch of the azygos vein and expanded the superior mediastinum after dividing the azygos vein. We made an incision in the muscular layer of the esophagus and, using a monopolar hook and monopolar scissors, enucleated the esophageal tumor in a protective manner so as not to damage its capsule or mucosa while applying appropriate robot-specific counter traction. We then sewed up the muscularis using 4-0 Vicryl, inserting the endoscope into the thoracic esophagus to substitute for a bougie. In addition, the pleura was sutured using barbed suture. The surgical procedure was straightforward and smooth. The patient was discharged on postoperative day 4 with no surgical complications. The tumor was definitively diagnosed pathologically from paraffin sections as a benign esophageal leiomyoma., Conclusions: RATS enables more delicate and precise esophageal SMT enucleation without surgical complications, though various challenges remain to be overcome.

Background: A pathological complete response (pCR) after neoadjuvant chemoradiotherapy (NACRT) ensures long-term survival in esophageal squamous cell carcinoma (ESCC) patients following esophagectomy, but pCR patients are a minority. The aim here was to identify prognostic factors in patients with non-pCR ESCC after NACRT., Methods: This is a retrospective study. Investigated were 5-year overall survival (OS), disease-specific survival (DSS), and relapse-free survival (RFS) among non-pCR ESCC patients divided into pT0N0, primary site pCR (pT0N+), lymph node pCR (pT+N0), and non-pCR in both the tumor and lymph node (pT+N+) subgroups after NACRT and esophagectomy. Focusing on the SUV max reduction rate in the primary tumor in 88 patients who underwent FDG-PET before and after NACRT, we used univariate and multivariate Cox proportional hazard models to identify prognostic factors., Results: Although there were no significant survival differences among non-pCR ESCC patients with pT0N+, pT+N0, or pT+N+, survival rate among pT+N+patients was the poorest. After setting a 60% cutoff for the SUV max reduction rate in the tumor, RFS curves for non-pCR patients significantly differed between patients above the cutoff and those below it. For pT+N+ patients, the SUV max reduction rate (<60% vs ≥ 60%) was an independent prognostic factor of OS, DSS, and RFS., Conclusion: Because ESCC patients with SUV max reduction rates of <60% in the tumor after NACRT and categorized as pT+N+ after NACRT had significantly poorer prognoses, even after esophagectomy, a change in treatment strategy may be an option to improve survival.

Background: The interval between preoperative chemoradiotherapy and surgery reportedly affects perioperative outcomes and survival; however, the optimal interval in esophageal cancer patients remains uncertain., Objective: Our aim was to determine whether a prolonged interval between preoperative neoadjuvant chemoradiotherapy (NACRT) and esophagectomy affects the outcomes of esophageal cancer patients., Methods: A total of 131 patients with esophageal cancer received curative surgery following NACRT at Akita University Hospital between 2009 and 2017. We divided these patients into two groups based on the median interval from NACRT to esophagectomy, and compared the rates of pathological complete response (pCR), surgical outcomes, and survival., Results: The median interval from NACRT to esophagectomy was 39 days (range 21-95). Of the 131 patients, 70 (53%) received esophagectomy after 39 days or more from completion of NACRT. There were no significant differences in the clinicopathological features, including pCR rates, between the two groups. Prolongation of the interval from NACRT to esophagectomy was significantly associated with an increased rate of anastomotic leakage and recurrent laryngeal nerve palsy (p = 0.0225 and p = 0.0022, respectively); however, no association with overall survival was detected., Conclusions: A prolonged interval between NACRT and esophagectomy had no impact on pCR rates or survival. However, delaying esophagectomy may increase the likelihood of surgical complications such as anastomotic leakage and recurrent laryngeal nerve palsy.

Background: Immune checkpoint inhibitors (ICIs) are a promising advance in the treatment of patients with lung cancer. However, each ICI has been tested with an independently designed companion diagnostic assay that is based on a unique antibody. Consequently, the different trial-validated programmed death ligand 1 (PD-L1) immunohistochemistry (IHC) assays should not be considered interchangeable. Our aim was to compare the performance of each available PD-L1 antibody for its ability to accurately measure PD-L1 expression and to investigate the possibility of harmonization across antibodies through the use of a new rapid IHC system, which uses noncontact alternating current (AC) mixing to achieve more stable staining., Methods: First, 58 resected non-small cell lung cancer (NSCLC) specimens were stained using three PD-L1 IHC assays (28-8, SP142, and SP263) to assess the harmonization achieved with AC mixing IHC. Second, specimens from 27 patients receiving ICIs for postoperative recurrent NSCLC were stained using the same IHC method to compare the clinical performance of ICIs to PD-L1 scores. All patients received a tumor proportion score (TPS) with the 22C3 companion diagnostic test., Results: Better staining was achieved with the new AC mixing IHC method than the conventional IHC in PD-L1-positive cases, and the interchangeability of some combinations of assays was increased in PD-L1-positive. In addition, AC mixing IHC provided more appropriate overall response rates for ICIs in all assays., Conclusions: Stable PD-L1 IHC driven by AC mixing helped to improve TPS scoring and patient selection for ICIs through interchangeable assays., (© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The oncological advantages of robot-assisted thoracoscopic esophagectomy (RATE) over conventional thoracoscopic esophagectomy (TE) for thoracic esophageal cancer have yet to be verified. In this study, we retrospectively analyzed clinical data to compare the incidences of recurrence within the surgical field after RATE and TE as an indicator of local oncological control. Among 121 consecutive patients with thoracic esophageal or esophagogastric junction cancers for which thoracoscopic surgery was indicated, 51 were treated with RATE while 70 received TE. The number of lymph nodes dissected from the mediastinum, duration of the thoracic portion of the surgery, and morbidity due to postoperative complications did not differ between the two groups. However, the rate of overall local recurrence within the surgical field was significantly (P = 0.039) higher in the TE (9%) than the RATE (0%) group. Lymph node recurrence within the surgical field occurred in left recurrent nerve, left tracheobronchial, left main bronchus and thoracic paraaortic lymph nodes, which were all difficult to approach to dissect. The other two local failures occurred around the anastomotic site. This study indicates that using RATE enabled the incidence of recurrence within the surgical field to be reduced, though there were some limitations.

Background: Insulin-like growth factor-II mRNA binding protein 3 (IGF2BP3) is an oncofetal RNA-binding protein normally involved in cell growth and migration during the early stages of embryogenesis. However, it is also expressed in various cancers, and the relationship between IGF2BP3 and the clinicopathological features and prognosis of esophageal squamous cell carcinoma patients is not fully understood. Our aim in this study was to determine whether IGF2BP3 expression status correlates with prognosis in patients with advanced thoracic esophageal squamous cell carcinoma., Methods: The IGF2BP3 expression statuses of 177 patients treated with esophagectomy without preoperative therapy were evaluated immunohistochemically using tissue microarray analysis. The relationships between IGF2BP3 expression status and clinicopathological features and survival were then assessed using appropriate statistics., Results: Among 177 esophageal tumors, 122 (68.9%) expressed high levels of IGF2BP3. In patients undergoing surgery alone, IGF2BP3-high expression was significantly associated with a poorer prognosis. By contrast, there were no significant associations between IGF2BP3 expression and clinicopathological features or outcomes in patients treated with surgery plus postoperative adjuvant chemotherapy., Conclusions: IGF2BP3 positivity in advanced thoracic esophageal squamous cell carcinoma is associated with adverse clinical outcomes in patients treated with surgery alone., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Neoadjuvant chemoradiotherapy (NACRT) followed by esophagectomy is now the standard treatment for patients with resectable advanced thoracic esophageal squamous cell carcinoma (ESCC) worldwide. However, the efficacy of NACRT followed by esophagectomy with three-field lymph node dissection for clinical Stage III patients and for clinical Stage IVB patients with supraclavicular LN metastasis has not yet been determined., Methods: Between 2008 and 2018, 94 ESCC patients diagnosed as clinical Stage III and 18 patients diagnosed as clinical Stage IVB with supraclavicular LN metastasis as the only distant metastatic factor were treated with NACRT followed by esophagectomy with extended lymph node dissection at Akita University Hospital. Long-term survival and the patterns of recurrence in these 112 patients were analyzed., Results: The median follow-up period of censored cases was 60 months. The five-year OS and DSS rates among the clinical Stage III patients were 57.6% and 66.6%, respectively. The five-year OS and DSS rates among the clinical Stage IVB patients were 41.3% and 51.6%, respectively. The most frequent recurrence pattern was distant metastasis (69.2%) in the Stage III patients and LN metastasis (75.0%) in the Stage IVB patients., Conclusion: NACRT followed by esophagectomy with three-field LN dissection is feasible and offers the potential for long-term survival of clinical Stage III ESCC patients and even clinical Stage IVB patients with supraclavicular LN metastasis as the only distant metastatic factor. At least in patients with upper and middle thoracic ESCC, treating supraclavicular LNs as regional LNs seems to be appropriate.

The relationship between the SLC31A1 (protein: copper transporter 1) rs10981694 A > C and ATP7B (protein: P-type adenosine triphosphatase 7B) rs9535828 A > G polymorphisms on the overall survival and disease-free survival of 104 Japanese patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemoradiotherapy (CRT) was investigated. Chemotherapy consisted of protracted infusion of 5-fluoracil (800 mg/m 2 /day) on days 1-5 and cisplatin or nedaplatin (80 mg/m 2 /day) on day 1. The median (range) follow-up was 47 (6-127) months. The 5-year overall and disease-free survival rates were 71.2% and 60.6%, respectively. The 5-year overall survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (91.7% vs. 65.0%, P = 0.018). The 5-year disease-free survival rate was significantly higher in patients with the SLC31A1 rs10981694 C allele compared with the rs10981694 A/A genotype (79.2% vs. 55.0%, P = 0.043). In addition, univariate and multivariate analyses showed the SLC31A1 rs10981694 A > C polymorphism to be a significant prognostic factor affecting 5-year overall survival after neoadjuvant CRT. However, the overall and disease-free survival rates after surgery did not differ significantly among the ATP7B rs9535828 genotypes. In conclusion, only the SLC31A1 rs10981694 A/A genotype was an independent predictor of a poorer 5-year overall survival. Therefore, in neoadjuvant CRT for ESCC patients, the effect of platinum was affected by the SLC31A1 rs10981694 A > C polymorphism. The presence of this polymorphism should be considered when devising neoadjuvant CRT regimens or treatment strategies for ESCC.

Background: Human epidermal growth factor receptor 2-in situ hybridization (HER2-ISH) is widely approved for diagnostic, prognostic biomarker testing of formalin-fixed paraffin-embedded tissue blocks. However, cytologic ISH analysis has a potential advantage in tumor samples such as pleural effusion and ascites that are difficult to obtain the histological specimens. Our aim was to evaluate the clinical reliability of a novel rapid cytologic HER2 fluorescence ISH protocol (rapid-CytoFISH)., Materials and Methods: Using a new device, we applied a high-voltage/frequency, noncontact alternating current electric field to tissue imprints and needle rinses, which mixed the probe within microdroplets as the voltage was switched on and off (AC mixing). Cytologic samples (n = 143) were collected from patients with immunohistochemically identified HER2 breast cancers. The specimens were then tested using standard dual-color ISH using formalin-fixed paraffin-embedded tissue (FFPE-tissue DISH) for HER2-targeted therapies, CytoFISH, and rapid-CytoFISH (completed within 4 h)., Results: All 143 collected cytologic specimens (50 imprinted cytology specimens from resected tumors and 93 liquid-based cytology specimens from needle rinses) were suitable for FISH analysis. The HER2/chromosome enumeration probe (CEP) 17 ratios did not significantly differ between FFPE-tissue DISH and either CytoFISH protocol. Based on HER2 scoring criteria, we found 95.1% agreement between FFPE-tissue DISH and CytoFISH (Cohen's kappa coefficient = 0.771 and 95% confidence interval (CI): 0.614-0.927)., Conclusion: CytoFISH could potentially serve as a clinical tool for prompt determination of HER2 status in breast cancer cytology. Rapid-CytoFISH with AC mixing will enable cancer diagnoses and HER2 status to be determined on the same day a patient comes to a clinic or hospital., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Although lobectomy is considered the standard surgery for any non-small cell lung cancer (NSCLC), recent evidence indicates that for early NSCLCs segmentectomy may be equally effective. For segmentectomy to be oncologically safe, however, adequate intraoperative lymph node staging is essential. The aim of this study was to compare the results of a new rapid-IHC system to the HE analysis for intraoperative nodal diagnosis in lung cancer patients considered for segmentectomy., Methods: This retrospective study analyzed the pathological reports from NSCLC resections over a six-year period between 2014 and 2020. Using a new device for rapid-IHC, we applied a high-voltage, low-frequency alternating current (AC) field, which mixes the antipancytokeratin antibody as the voltage is switched on/off. Rapid-IHC can provide a nodal diagnosis within 20 minutes., Results: Frozen sections from 106 resected lymph nodes from 70 patients were intraoperatively evaluated for metastasis. Of those, five nodes were deemed positive based on both HE staining and rapid-IHC. In addition, rapid-IHC alone detected isolated tumor cells in one hilar lymph node. Three cStage IA patients with nodal metastasis detected with HE staining and rapid-IHC received complete lobectomies. Five-year relapse-free survival and overall survival among patients receiving segmentectomy with rapid-IHC were 88.77% and 88.79%, respectively., Conclusions: Rapid-IHC driven by AC mixing is simple, highly accurate, and preserves nodal tissue for subsequent tests. This system can be used effectively for intraoperative nodal diagnosis. Rapid immunohistochemistry based on alternating-current field mixing (completed within 20 minutes) is simple and highly accurate. This system will assist clinicians when making intraoperative diagnoses of lymph node metastasis and deciding upon the appropriate surgical procedure in segmentectomy for lung cancer., Key Points: SIGNIFICANT FINDINGS OF THE STUDY: Rapid immunohistochemistry driven by alternating-current field mixing (completed within 20 minutes intraoperatively) is simple, highly accurate, and preserves lymph node tissue for subsequent pathological examination, including molecular assessments., What This Study Adds: Segmentectomy for lung cancer is oncologically safe, but only when there is adequate intraoperative node staging. Rapid immunohistochemistry will assist clinicians when making intraoperative nodal diagnoses., (© 2020 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: In cases of non-small cell lung cancer (NSCLC), surgery remains the best option for cure, but surgery is of benefit only when the disease is localized. Although adjuvant chemotherapy reportedly has a significant beneficial effect on survival, the benefit of a carboplatin (CBDCA) regimen is unclear. We therefore investigated the efficacy and tolerability of CBDCA (area under the curve 5) plus gemcitabine (GEM, 1000 mg/m 2 ) as adjuvant chemotherapy., Methods: A total of 82 pStage IB-IIIA NSCLC patients who had undergone complete resection and received adjuvant chemotherapy were analyzed retrospectively. Among them, 65 patients received CBDCA + GEM and 17 received CDDP + VNR. Propensity score analysis generated 17 matched pairs of both groups., Results: Sixty-five patients received CBDCA + GEM. Their 5-year relapse-free survival (RFS) and overall survival were 47.8% (median, 52.5 months) and 76.9% (median, 90.1 months), respectively. Toxicities, which included neutropenia, nausea/anorexia, fatigue, and vasculitis, were significantly milder than with CDDP + VNR. There were no significant differences in RFS between CBDCA + GEM and CDDP + VNR (p = 0.079) after matching for age, performance status, and pStage., Conclusion: CBDCA + GEM was effective and well tolerated as adjuvant chemotherapy, with a manageable toxicity profile.

Background/aim: The platelet distribution width (PDW) and serum C-reactive protein (CRP) levels are known to be predictive of prognosis in various malignancies. Our aim was to determine whether combining PDW and serum CRP levels produces a prognostic indicator for esophageal cancer (EC) patients., Patients and Methods: A total of 168 EC patients who underwent neoadjuvant therapy prior to esophagectomy were included in this study., Results: We defined a combined PDW and CRP (CPC) score as follows: patients with both low pretherapeutic PDW (≤12.4 fl) and high postoperative serum CRP levels (≥0.5 mg/dl) were assigned a score of 2, while patients with one or neither of those were assigned a score of 1 or 0. A multivariable analysis showed that the CPC score was a significant risk factor for overall (p=0.006) and recurrence-free (p=0.004) survival., Conclusion: The CPC score is a strong prognostic indicator in EC patients., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)