Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

AIM: Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. METHODS: From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12 weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. RESULTS: In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p = 0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p = 0.015) in the univariate analysis and 0.315 (p = 0.023) in the multivariate analysis. CONCLUSIONS: In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. CLINICAL TRIAL REGISTRATION: UMIN Clinical Trials Registry with the number UMIN000043798.

M2-like tumor-associated macrophages promote epithelial-mesenchymal transition through the transforming growth factor ß/Smad/zinc finger e-box binding homeobox pathway with increased metastatic potential and tumor cell proliferation in lung squamous cell carcinoma.

Epithelial-mesenchymal transition (EMT) promotes primary tumor progression toward a metastatic state. The role of tumor-associated macrophages (TAMs) in inducing EMT in lung squamous cell carcinoma (LUSC) remains unclear. We aimed to clarify the significance of TAMs in relation to EMT in LUSC. We collected 221 LUSC specimens from patients who had undergone surgery. Immunohistochemistry was performed to evaluate M1-like and M2-like TAM distribution and EMT by E-cadherin and vimentin staining. Human LUSC cell lines (H226 and EBC-1) and a human monocyte cell line (THP-1) were used for in vitro experiments. M2-like polarization of TAMs and EMT marker expression in LUSC cells were evaluated by western blotting. The biological behavior of LUSC cells was evaluated by migration, invasion, and cell proliferation assays. Immunohistochemical analysis showed that 166 (75.1%) tumors were E-cadherin-positive and 44 (19.9%) were vimentin-positive. M2-like TAM density in the tumor stroma was significantly associated with vimentin positivity and worse overall survival. Western blotting demonstrated higher levels of CD163, CD206, vascular endothelial growth factor, and transforming growth factor beta 1 (TGF-ß1) in TAMs versus unstimulated macrophages. Furthermore, increased TGF-ß1 secretion from TAMs was confirmed by ELISA. TAM-co-cultured H226 and EBC-1 cells exhibited EMT (decreased E-cadherin, increased vimentin). Regarding EMT-activating transcriptional factors, phosphorylated Smad3 and ZEB-family proteins were higher in TAM-co-cultured LUSC cells than in parental cells. TAM-co-cultured H226 and EBC-1 cells demonstrated enhanced migration and invasion capabilities and improved proliferation. Overall, the present study suggests that TAMs can induce EMT with increased metastatic potential and tumor cell proliferation in LUSC.

Distinct approaches (antecolic and retrocolic) according to tumor location in laparoscopic and endoscopic cooperative surgery for non-ampullary duodenum tumors.

AIM: Laparoscopic and endoscopic cooperative surgery for early non-ampullary duodenum tumors (D-LECS) is now noted because of its safety and lower invasiveness. Here, we introduce two distinct approaches (antecolic and retrocolic) according to the tumor location during D-LECS. METHODS: From October 2018 to March 2022, 24 patients (25 lesions) underwent D-LECS. Two (8%), two (8%), 16 (64%), and five (20%) lesions were located in the first portion, in the second portion to Vater's papilla, around the inferior duodenum flexure, and in the third portion of the duodenum, respectively. The median preoperative tumor diameter was 22.5 mm. RESULTS: Antecolic and retrocolic approaches were employed in 16 (67%) and 8 (33%) cases, respectively. LECS procedures, such as two-layer suturing after full-thickness dissection and laparoscopic reinforcement by seromuscular suturing after endoscopic submucosal dissection (ESD), were performed in five and 19 cases, respectively. Median operative time and blood loss were 303 min and 5 g, respectively. Intraoperative duodenal perforations occurred in three of 19 cases during ESD; however, they were successfully laparoscopically repaired. Median times until start diet and postoperative hospital stay were 4.5 and 8 days, respectively. Histological examination of the tumors revealed nine adenomas, 12 adenocarcinomas, and four GISTs. Curative resection (R0) was achieved in 21 cases (87.5%). In a comparison of the surgical short outcomes between antecolic and retrocolic approaches, there was no significant difference. CONCLUSION: D-LECS can be a safe and minimally invasive treatment option for non-ampullary early duodenal tumors, and two distinct approaches according to the tumor location are feasible.

Efficacy of a new traction method using ring-shaped thread for endoscopic submucosal dissection in the pharynx.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a minimally invasive treatment for pharyngeal cancers. However, pharyngeal ESD is sometimes technically challenging because of the narrow and complex space in which to work. Traction is important to complete the procedure efficiently. Here, we report the technical details and efficacy of a new traction method for pharyngeal ESD using ring-shaped thread and grasping forceps. METHODS: We analyzed pharyngeal ESD performed between January 2016 and March 2021 at our Institute. We designated cases resected using ring-shaped threads "Group R" and those resected without ring-shaped threads as conventional "Group C", and compared the technical outcomes between them. Multivariate analysis and the inverse probability treatment weighting (IPTW) method using propensity scores were adjusted by confounding variables. RESULTS: We analyzed 89 lesions from 68 patients, of which 46 were in Group R and 43 in Group C. Median procedure time and median dissection speed were significantly shorter in Group R than C (37 min vs. 55 min, and 16.0 mm2/min vs. 7.0 mm2/min, respectively, both P < 0.05). These results were confirmed by both multivariate analysis and after IPTW adjustment. All lesions were resected en bloc, and the complete resection rate was not significantly different between Group R and C (91.3% vs. 79.1%, P = 0.14). There were no treatment-related adverse events in either group. CONCLUSIONS: The traction method using ring-shaped thread increases the efficiency of pharyngeal ESD. This simple new traction method should be a useful option for pharyngeal ESD.

Usefulness of an artificial intelligence system for the detection of esophageal squamous cell carcinoma evaluated with videos simulating overlooking situation.

OBJECTIVES: Artificial intelligence (AI) systems have shown favorable performance in the detection of esophageal squamous cell carcinoma (ESCC). However, previous studies were limited by the quality of their validation methods. In this study, we evaluated the performance of an AI system with videos simulating situations in which ESCC has been overlooked. METHODS: We used 17,336 images from 1376 superficial ESCCs and 1461 images from 196 noncancerous and normal esophagi to construct the AI system. To record validation videos, the endoscope was passed through the esophagus at a constant speed without focusing on the lesion to simulate situations in which ESCC has been missed. Validation videos were evaluated by the AI system and 21 endoscopists. RESULTS: We prepared 100 video datasets, including 50 superficial ESCCs, 22 noncancerous lesions, and 28 normal esophagi. The AI system had sensitivity of 85.7% (54 of 63 ESCCs) and specificity of 40%. Initial evaluation by endoscopists conducted with plain video (without AI support) had average sensitivity of 75.0% (47.3 of 63 ESCC) and specificity of 91.4%. Subsequent evaluation by endoscopists was conducted with AI assistance, which improved their sensitivity to 77.7% (P = 0.00696) without changing their specificity (91.6%, P = 0.756). CONCLUSIONS: Our AI system had high sensitivity for the detection of ESCC. As a support tool, the system has the potential to enhance detection of ESCC without reducing specificity. (UMIN000039645).

Risk stratification of advanced colorectal neoplasia after baseline colonoscopy: Cohort study of 17 Japanese community practices.

BACKGROUND AND AIM: In Japan, risk stratification after baseline colonoscopy is not widely accepted. We investigated the findings of baseline colonoscopies at 17 community practices and evaluated the risk of the incidence of advanced neoplasia over a 5-year period. METHODS: This retrospective cohort study enrolled 3115 subjects over 40 years of age who underwent baseline colonoscopies and had at least one repeated colonoscopy within 5 years. Each group was classified based on the endoscopic findings of the baseline colonoscopy: no neoplasia/diminutive polyp <5 mm (N/D); small adenoma <10 mm; advanced adenoma; invasive cancer, respectively. We examined the incidence of advanced neoplasia during these 5 years and investigated the relationship between the surveillance colonoscopy and newly detected advanced neoplasia. RESULTS: The small adenoma group did not show any significant increased risk as compared to the N/D group (hazard ratio [HR]: 0.799. 95% CI 0.442-1.443). There was a significantly increased risk in the advanced adenoma and invasive cancer groups (HR: 4.996, 95% CI 2.940-8.491, HR: 3.737, 95% CI 1.309-10.666). Cancer incidences during the study period were 0.18% in the N/D group, and 1.9% in the invasive cancer group, respectively. Undergoing surveillance colonoscopies twice within 5 years decreased the risk of advanced neoplasia. CONCLUSIONS: There was a close relationship between the endoscopic findings of baseline colonoscopies and subsequent advanced neoplasia development. Risk stratification for advanced neoplasia based on the baseline findings can serve as a useful index for determining the optimal interval and frequency of colonoscopies over a 5-year period.

Clinicopathological, endoscopic, and molecular characteristics of the "skirt" - a new entity of lesions at the margin of laterally spreading tumors.

BACKGROUND AND STUDY AIM: A slightly elevated flat lesion with wide pits has occasionally been observed at the margin of laterally spreading tumors (LSTs) and is known as a "skirt." The aim of this study was to evaluate the clinicopathological, endoscopic, and genetic characteristics of a skirt. PATIENTS AND METHODS: Consecutive LSTs were examined to evaluate the pathological, endoscopic, and genetic characteristics. Pathological characteristics, including the dimension of the cryptic opening (DCO), width of the individual gland (WIG), DCO to WIG ratio, and microvessel diameter were elucidated and compared with those of hyperplastic polyps, low grade dysplasia (LGD), and normal mucosa. The endoscopic findings of pit and microvascular patterns were assessed. Gene mutation analyses were performed for the KRAS, BRAF, NRAS, and PIK3CA genes. RESULTS: A skirt was identified in 35 of 1023 LSTs, and 80 % of lesions with a skirt had a component of either intramucosal or submucosal adenocarcinoma. The DCO, WIG, and DCO to WIG ratio of the skirt were significantly larger than those of other lesions. The microvessel diameters in skirts were significantly smaller than those in LGDs. Regarding the endoscopic findings, 30 skirts showed pits with a coral reef-like appearance, and all skirt regions were found to have a type I capillary pattern. KRAS mutation at codon 146 was found in the nodular part in one of five LSTs with a skirt. CONCLUSION: The skirt is a newly identified lesion distinct from hyperplastic polyps and LGDs, suggesting the presence of a novel pathway for rectal carcinogenesis from LSTs with a skirt.

Incidence and risk factors of synchronous colorectal cancer in patients with esophageal cancer: an analysis of 480 consecutive colonoscopies before surgery.

BACKGROUND: The precise incidence rates of multiple primary colorectal cancers in esophageal cancer patients are unknown. METHODS: In total, 480 consecutive patients with esophageal cancers surgically resected in the Kumamoto University Hospital received preoperative total colonoscopy for the assessment of colorectal disease between April 2005 and February 2016. We retrospectively investigated the occurrence of synchronous colorectal cancer with esophageal cancer. In addition, we examined the risk factors for the incidence of multiple primary colorectal cancers. RESULTS: Of the 480 patients, 14 (2.9 %) had synchronous colorectal cancers, 13 had well-differentiated tubular adenocarcinomas, and 1 had papillary adenocarcinoma. Other 14 patients had metachronous colorectal cancer. The current incidence rates of synchronous and total (both synchronous and metachronous) colorectal cancers outnumbered those in normal healthy population and those in esophageal cancer patients which previously reported by The Japan Esophageal Society. The age ≥70 years (hazard ratio 4.82, 95 % confidence interval 1.473-15.78; p = 0.009) and Brinkman index ≥800 (hazard ratio 3.47, 95 % confidence interval 1.056-11.37; p = 0.040) were the independent risk factors for the incidence of synchronous colorectal cancer. They were also the independent risk factors for the incidence of total colorectal cancer. CONCLUSIONS: The results of the present study suggested that pretreatment screening with total colonoscopy is meaningful for patients with esophageal cancer, because the frequency of synchronous colorectal cancer was not negligible. Particularly, in patients >70 years and with history of heavy smoking, pretreatment colonoscopy might be necessary.

The global distribution of pure anorthosite on the Moon.

It has been thought that the lunar highland crust was formed by the crystallization and floatation of plagioclase from a global magma ocean, although the actual generation mechanisms are still debated. The composition of the lunar highland crust is therefore important for understanding the formation of such a magma ocean and the subsequent evolution of the Moon. The Multiband Imager on the Selenological and Engineering Explorer (SELENE) has a high spatial resolution of optimized spectral coverage, which should allow a clear view of the composition of the lunar crust. Here we report the global distribution of rocks of high plagioclase abundance (approaching 100 vol.%), using an unambiguous plagioclase absorption band recorded by the SELENE Multiband Imager. If the upper crust indeed consists of nearly 100 vol.% plagioclase, this is significantly higher than previous estimates of 82-92 vol.% (refs 2, 6, 7), providing a valuable constraint on models of lunar magma ocean evolution.

Fifth carpometacarpal fracture dislocations fixed with Meta-HUS®: a series of 31 cases.

Fracture dislocations of the fifth carpometacarpal are usually treated by percutaneous K-wires despite occasional complications: displacement, stiffness, malunions, and arthritis. Our aims were to evaluate the use of locked K-wire fixation for these fracture dislocations. Our series includes 31 fracture dislocations, five extra-articular and 26 articular, 21 of which were at the base of the metacarpal, four at the hamate, and one involving both the hamate and the metacarpal. Mean tourniquet time was 22 min and irradiation 2 mGy. After reduction, an M4 M5 K-wire and a carpometacarpal wire were connected using an MetaHUS® connector. Immediate immobilization was allowed. Return to normal activity was resumed at 6.5 weeks. At around 15 months follow-up, mean pain score was 8.5, Quick DASH was 6.36, and overall grip strength was 92%, TAM of the fifth ray was 96% of the contralateral side. There were two displacements that were re-operated with good result, three superficial infections, and one case of stiffness. All fractures healed without arthritis. Overall, percutaneous K-wire and splinting of fracture dislocations of the fifth carpometacarpal joint is unstable, and internal fixation can cause adhesions and stiffness. Our results show that the percutaneous locked K-wire technique is a good alternative as it associates closed reduction with K-wire fixation and a solid fixation using an external connector. This technique allows immediate mobilization of the hand and removal of hardware in clinic.

Intracarpal tunnel contents: evaluation of the effects of corticosteroid injection with sonoelastography.

PURPOSE: To define the stiffness of the intracarpal tunnel contents and to evaluate the effect of corticosteroid injection on the intracarpal tunnel contents by using sonoelastography. MATERIALS AND METHODS: This study was conducted with the approval of the institutional review boards, and all participants provided written, informed consent. Both hands were studied in 20 healthy volunteers, including eight men (mean age, 59.6 years; range, 50-76 years) and 12 women (mean age, 61.0 years; range, 39-79 years) and 22 hands were studied in 20 patients with carpal tunnel syndrome (CTS) (five men [mean age, 49.0 years] and 15 women [mean age, 61.1 years]; range, 39-89 years) between April 2012 and August 2012. The stiffness of the intracarpal tunnel contents was estimated as the standardized acoustic coupler (AC)-to-intracarpal tunnel contents surrounding the nerve (AC/C) strain ratio, analyzed with the Mann-Whitney U test. The patients were treated with corticosteroid injections, and the strain ratio was reexamined 6 weeks later, analyzed with the Wilcoxon t test. RESULTS: The mean AC/C strain ratio in the CTS patients was 12.6 ± 4.7 (standard deviation), which was higher (stiffer) than that in the healthy volunteers with a mean strain ratio of 8.2 ± 3.5 (P = .0013). Six weeks after the injection, the mean AC/C strain ratio had decreased to 8.5 ± 4.1 (P = .00069, compared with the preinjection value) in the CTS patients. CONCLUSION: The stiffness of the intracarpal tunnel contents in untreated CTS patients is higher than that of healthy volunteers but decreases 6 weeks after corticosteroid injection.

Sonoelastography: musculoskeletal applications.

All participants for image samplings provided written informed consent. Conventional B-mode ultrasonography (US) has been widely utilized for musculoskeletal problems as a first-line approach because of the advantages of real-time access and the relatively low cost. The biomechanical properties of soft tissues reflect to some degree the pathophysiology of the musculoskeletal disorder. Sonoelastography is an in situ method that can be used to assess the mechanical properties of soft tissue qualitatively and quantitatively through US imaging techniques. Sonoelastography has demonstrated feasibility in the diagnosis of cancers of the breast and liver, and in some preliminary work, in several musculoskeletal disorders. The main types of sonoelastography are compression elastography, shear-wave elastography, and transient elastography. In this article, the current knowledge of sonoelastographic techniques and their use in musculoskeletal imaging will be reviewed.

Carpal tunnel syndrome: diagnosis by means of median nerve elasticity--improved diagnostic accuracy of US with sonoelastography.

PURPOSE: To compare the elasticity of the median nerve (MN) between healthy volunteers and patients with carpal tunnel syndrome (CTS) and to evaluate the diagnostic utility of sonoelastographic measurements of the elasticity of the MN. MATERIALS AND METHODS: This study was performed with institutional review board approval and written informed consent from all participants. Hands in 22 healthy volunteers and in 31 patients with symptomatic CTS were studied. The cross-sectional area (CSA) and the elasticity of the MN, which was measured as the acoustic coupler (AC)/MN strain ratio, were evaluated. RESULTS: Both hands in 22 healthy volunteers (three men [mean age, 52.7 years; age range, 41-65 years]; 19 women [mean age, 62.2 years; age range, 40-88 years]) and 43 hands in 31 patients with symptomatic CTS (three men [mean age, 69.0 years; age range, 46-88 years]; 28 women [mean age, 61.2 years; age range, 39-92 years]) were studied. Both the AC/MN strain ratio and the CSA in the patients with CTS were significantly higher than those in the healthy volunteers (P < .001). The presence of CTS was predicted by means of AC/MN strain ratio and CSA cutoff values, respectively, of 4.3 and 11 mm(2), with areas under the receiver operating characteristic curves (AUCs) of 0.78 (95% confidence interval [CI]: 0.69, 0.88) and 0.85 (95% CI: 0.78, 0.93). A logistic model that combined the AC/MN strain ratio and the CSA improved diagnostic accuracy for CTS, with an AUC of 0.91 (95% CI: 0.85, 0.97; P < .001). CONCLUSION: Sonoelastography provides significant improvement in the diagnostic accuracy of the ultrasonographic assessment of CTS.

Clinicopathological differences of laterally spreading tumors arising in the colon and rectum.

PURPOSE: Laterally spreading tumors (LST) have been recognized worldwide. The aim of our retrospective study was to evaluate the clinicopathological differences of LST arising in the colon and rectum. METHODS: We investigated the clinical records of consecutive patients with LST that were endoscopically or surgically resected at our hospital between February 2006 and March 2011. LST were classified into three types: granular-homogenous (LST-GH), granular-nodular mixed (LST-GM), and nongranular (LST-NG) types. We also defined the hardly elevated flat lesion with a dilated pit pattern that occurs at the margins of LST as the "skirt." The clinicopathological characteristics of the LST arising in the colon and rectum, including the presence of the skirt, were compared. RESULTS: A total of 496 colorectal LST in 435 patients were examined. LST-GM was predominant in the rectum, whereas LST-NG was predominant in the colon (p < 0.001). The mean tumor size was larger in the rectum (39.3 ± 17.9 mm) than the colon (25.8 ± 13.6 mm) (p < 0.001). Low-grade dysplasia frequency was lower in the rectum than the colon (4 vs. 37%, p < 0.001). The skirt was identified in 15 lesions (3.0%), with a higher incidence in the rectum than the colon (17 vs. 0.5%, p < 0.001). The skirt was found only in LST-GM. CONCLUSIONS: A greater proportion of LST-GM, greater mean size, and lower incidence of low-grade dysplasia were found in rectal LST. The skirt was a novel and unique finding, primarily observed in rectal LST-GM cases.

Nerve transfer to the deltoid muscle using the nerve to the long head of the triceps with the da Vinci robot: six cases.

BACKGROUND: Nerve transfer to the deltoid muscle using the nerve to the long head of the triceps is a reliable method for restoration of deltoid function. The aim of this retrospective study was to report the results of nerve transfer to the deltoid muscle using the nerve to the long head of the triceps procedure using a robot. METHODS: Our series included six patients (mean age 36.3 years) with total deltoid muscle paralysis. A da Vinci-S robot was placed in position. After dissection of the quadrilateral and triangular spaces, the anterior branch of the axillary nerve and the branch to the long head of the triceps were transected, and then robotically sutured with two 10-0 nylon stiches. In two cases, an endoscopic procedure was tried under carbon dioxide (CO2) insufflation. RESULTS: In all patients except one, deltoid function against resistance (M4) was obtained at the last follow-up evaluation. The average shoulder abduction was 112 degrees. No weakness of elbow extension was observed. In two cases with the endoscopic technique, vision was blurred and conversion to open technique was performed. CONCLUSION: The advantages of robotic microsurgery are motion scaling and disappearance of physiological tremor. Reasons for failure of the endoscopic technique could be explained by insufficient pressure. We had no difficulty using the robot without the sensory feedback. The robot-assisted nerve transfer to deltoid muscle using the nerve to the long head of the triceps was a feasible application for restoration of shoulder abduction after brachial plexus or axillary nerve injury. Therapeutic Study. Level of Evidence IV.

Comprehensive Cancer Genomic Profiling of Liver Metastasis Led to the Unexpected Identification of Colorectal Cancer.

Comprehensive genomic profiling (CGP) of a metastatic liver tumor biopsy specimen suggested that the patient, who was initially diagnosed with cholangiocarcinoma, had colorectal cancer. The identification of both FBXW7 and APC mutations is deemed characteristic of colorectal cancer. Indeed, subsequent colonoscopy revealed sigmoid colon carcinoma that led to tumor resection followed by systemic chemotherapy. CGP is principally used to identify agents that might potentially benefit the patient. However, results must be interpreted carefully to ensure consistency with the initial diagnosis.

BRAF-mutant mismatch repair deficient invasive colon cancer regressing to sessile serrated lesion.

A 69-year-old female was presented with a history of sigmoid colon cancer, uterine cancer, and intrahepatic carcinomas. After computed tomography revealed a disseminated nodule located in the peritoneum, colonoscopy demonstrated a rather flat-to-slightly elevated lesion with a depressed area located in the ascending colon. The flat component showed color similar to its surrounding area, and the depressed area showed redness and an expanded appearance. We obtained a biopsy specimen from the depressed area, and microscopic examination revealed well-differentiated adenocarcinoma, which was immunohistochemically positive for BRAF V600E-mutated and PMS2 proteins, and showed loss of MSH2 and MSH6 protein expressions. These findings suggested the lesion to have transformed from a sessile serrated lesion (SSL) to mismatch repair (MMR) deficient colon cancer. The patient underwent surgical removal of the nodule, which interpreted as metastasis of intrahepatic cholangiocarcinoma histopathologically. After postoperative chemotherapy, the follow-up colonoscopy revealed only the flat portion of the lesion without depressed area. Consequently, we performed an endoscopic resection, and microscopic examination confirmed the existence of BRAF V600E-mutated protein-positive and MMR protein-retained SSL without residual carcinoma. This is the first report of BRAF-mutant and MMR-deficient colon cancer, in association with SSL, showing regression.