Response to chemotherapy could predict the prognosis of esophageal squamous cell carcinoma treated with neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) followed by surgery: long-term results in a single institute.

BACKGROUND: Preoperative chemotherapy with 5-fluorouracil and cisplatin (FP) followed by surgery has been considered a standard treatment for patients with stage II/III esophageal squamous cell carcinoma (ESCC) based on the results of a phase III trial (JCOG9907) in Japan. Subsequently, the phase III NExT trial (JCOG1109) revealed the survival benefit of the neoadjuvant DCF regimen, which adds docetaxel to FP, and it became a standard treatment. However, the long-term results and prognostic factors of neoadjuvant DCF therapy in the real world are unknown. METHODS: We retrospectively investigated 50 patients with ESCC treated with neoadjuvant DCF therapy from July 2012 to December 2017 at The University of Tokyo Hospital. RESULTS: Median overall survival (OS) and progression-free survival (PFS) were 32.3 [95% confidence interval (CI) 21.0-NA] and 10.0 months (95% CI 6.3-15.6), respectively. Median OS [not reached (95% CI 31.5-NA) vs. 21.4 months (95% CI 13.5-33.0); p = 0.028] and PFS [83.3 months (95% CI 6.4-NA) vs. 7.4 months (95% CI 6.0-12.8] were significantly longer in patients with an objective response than in non-responders. Of 44 surgical cases, median PFS tended to be longer in pathological lymph node metastasis-negative patients. Conversely, survival did not differ according to cStage (II/III vs. IV) or the average relative dose intensity (ARDI, ≥ 85% vs. < 85%). DISCUSSION: The response to neoadjuvant DCF therapy could predict patient prognosis. Additionally, pN+ tended to increase the recurrence risk, whereas cStage and ARDI did not influence survival.

Late-onset lethal complication of non-surgically managed massive gastric conduit necrosis after esophagectomy: a case report.

BACKGROUND: Gastric conduit necrosis (GCN) after esophagectomy is a serious complication that can prove fatal. Herein, we report a rare case of GCN with a severe course that improved with conservative treatment. CASE PRESENTATION: We present the case of a 78-year-old male patient who underwent an Ivor Lewis esophagectomy and developed a massive GCN. The patient was critically ill in the initial phase but recovered quickly; he also had a ruptured gallbladder and a bleeding jejunal ulcer. On the 22nd postoperative day, massive GCN was revealed on endoscopy. Considering the recovery course, careful observation with a decompressing nasal gastric tube was the treatment of choice. The GCN was managed successfully, having been completely replaced by fine mucosa within 9 months postoperatively. The patient completed his follow-up visit 5 years after surgery without any evident disease recurrence. Five and a half years after the surgery, the patient presented with progressive weakness and deterioration of renal function. Gastrointestinal endoscopy revealed a large ulcer at the anastomotic site. Three months later, computed tomography revealed a markedly thin esophageal wall, accompanied by adjacent lung consolidation. An esophagopulmonary fistula was diagnosed; surgery was not considered, owing to the patient's age and markedly deteriorating performance status. He died 2013 days after the diagnosis. CONCLUSIONS: Massive GCN after esophagectomy often requires emergency surgery to remove the necrotic conduit. However, this report suggests that a conservative approach can save lives and preserve the gastric conduit in these cases, thereby augmenting the quality of life.

Effective in vitro evaluation of the risk of histamine release related to valemetostat tosylate using MRGPRX2-expressing cells.

Mas-related G-protein-coupled receptor X2 (MRGPRX2), expressed on mast cells, is associated with drug-induced pseudo-allergic reactions. Although it is well known that there are differences of sensitivity between species in the pseudo-allergic reactions, no platform for evaluating a human risk of the pseudo-allergic reactions observed in nonclinical studies has been established. Valemetostat tosylate, developed as an anti-cancer drug, induced histamine release in a nonclinical study with dogs. The purpose of the current study was to identify the mechanism and assess the human risk of valemetostat-tosylate-induced histamine release using dog and human MRGPRX2-expressing cells. In an experiment with human or dog MRGPRX2-expressing cells, valemetostat tosylate caused activation of human and dog MRGPRX2. Importantly, the EC50 for dog MRGPRX2 was consistent with the Cmax value at which histamine release was observed in dogs. Furthermore, the EC50 for human MRGPRX2 was ca. 27-fold higher than that for dog MRGPRX2, indicating a species difference in histamine-releasing activity. In a clinical trial, histamine release was not observed in patients receiving valemetostat tosylate. In conclusion, an in vitro assay using human and animal MRGPRX2-expressing cells would be an effective platform to investigate the mechanism and predict the human risk of histamine release observed in nonclinical studies.

Identification of kynurenine and quinolinic acid as promising serum biomarkers for drug-induced interstitial lung diseases.

BACKGROUND: Drug-induced interstitial lung disease (DILD) is a lung injury caused by various types of drugs and is a serious problem in both clinical practice and drug development. Clinical management of the condition would be improved if there were DILD-specific biomarkers available; this study aimed to meet that need. METHODS: Biomarker candidates were identified by non-targeted metabolomics focusing on hydrophilic molecules, and further validated by targeted approaches using the serum of acute DILD patients, DILD recovery patients, DILD-tolerant patients, patients with other related lung diseases, and healthy controls. RESULTS: Serum levels of kynurenine and quinolinic acid (and kynurenine/tryptophan ratio) were elevated significantly and specifically in acute DILD patients. The diagnostic potentials of these biomarkers were superior to those of conventional lung injury biomarkers, Krebs von den Lungen-6 and surfactant protein-D, in discriminating between acute DILD patients and patients with other lung diseases, including idiopathic interstitial pneumonia and lung diseases associated with connective tissue diseases. In addition to identifying and evaluating the biomarkers, our data showed that kynurenine/tryptophan ratios (an indicator of kynurenine pathway activation) were positively correlated with serum C-reactive protein concentrations in patients with DILD, suggesting the potential association between the generation of these biomarkers and inflammation. Our in vitro experiments demonstrated that macrophage differentiation and inflammatory stimulations typified by interferon gamma could activate the kynurenine pathway, resulting in enhanced kynurenine levels in the extracellular space in macrophage-like cell lines or lung endothelial cells. Extracellular quinolinic acid levels were elevated only in macrophage-like cells but not endothelial cells owing to the lower expression levels of metabolic enzymes converting kynurenine to quinolinic acid. These findings provide clues about the molecular mechanisms behind their specific elevation in the serum of acute DILD patients. CONCLUSIONS: The serum concentrations of kynurenine and quinolinic acid as well as kynurenine/tryptophan ratios are promising and specific biomarkers for detecting and monitoring DILD and its recovery, which could facilitate accurate decisions for appropriate clinical management of patients with DILD.

Stratifin as a novel diagnostic biomarker in serum for diffuse alveolar damage.

Among the various histopathological patterns of drug-induced interstitial lung disease (DILD), diffuse alveolar damage (DAD) is associated with poor prognosis. However, there is no reliable biomarker for its accurate diagnosis. Here, we show stratifin/14-3-3σ (SFN) as a biomarker candidate found in a proteomic analysis. The study includes two independent cohorts (including totally 26 patients with DAD) and controls (total 432 samples). SFN is specifically elevated in DILD patients with DAD, and is superior to the known biomarkers, KL-6 and SP-D, in discrimination of DILD patients with DAD from patients with other DILD patterns or other lung diseases. SFN is also increased in serum from patients with idiopathic DAD, and in lung tissues and bronchoalveolar lavage fluid of patients with DAD. In vitro analysis using cultured lung epithelial cells suggests that extracellular release of SFN occurs via p53-dependent apoptosis. We conclude that serum SFN is a promising biomarker for DAD diagnosis.

Risk factors for intraocular pressure elevation during the early period post cataract surgery.

PURPOSE: To assess the risk factors for intraocular pressure (IOP) elevation during the early period post cataract surgery. STUDY DESIGN: Retrospective study. METHODS: This study involved 1587 eyes that underwent cataract surgery at the Baptist Eye Institute, Kyoto, Japan between April 2020 and May 2021. In all subjects, risk factors for early postoperative IOP elevation (i.e., an increase of IOP of 10 mmHg or more at 1-day postoperative compared with that at baseline, or a postoperative IOP of 28 mmHg or more) were analyzed by multivariate logistic regression analysis. RESULTS: Of the 1587 treated eyes in this study, 100 (6.3%) experienced early-postoperative IOP elevation. Of those 100 eyes, 78.0% were men, 27.0% had an axial length (AL) of ≥ 26.5 mm, 23.0% had a history of glaucoma treatment, 11.0% had poor mydriasis and 10.0% had intraoperative floppy iris syndrome (IFIS). Multivariate analysis findings revealed that male [odds ratio (OR) 4.36; 95% confidence interval (CI) 2.63-7.23; P < 0.001], AL of ≥ 26.5 mm (3.11; 1.83-5.30; P < 0.001), a history of glaucoma treatment (2.83; 1.63-4.91; P < 0.001), poorly mydriasis (2.63; 1.16-6.01; P = 0.02), IFIS (4.37; 1.78-10.74; P = 0.001) and baseline high IOP (1.09; 1.01-1.18; P = 0.03) were associated with increased IOP during the early period post cataract surgery. CONCLUSIONS: The findings in this study reveal that male sex, high myopia, a history of glaucoma treatment, poor mydriasis, IFIS and baseline high IOP are risk factors for IOP elevation during the early period post cataract surgery.

Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome.

PURPOSE: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation. DESIGN: Retrospective case study. PARTICIPANTS: A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort. METHODS: Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account. MAIN OUTCOME MEASURES: Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation. RESULTS: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001). CONCLUSIONS: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Trastuzumab-Induced Negative Chronotropic and Lusitropic Effects in Cynomolgus Monkeys.

ABSTRACT: Treatment with trastuzumab, an antihuman epidermal growth factor receptor type 2 humanized monoclonal antibody, has been associated with heart failure in certain patients with cancer; however, the mechanism underlying trastuzumab-induced cardiac dysfunction remains unclear. This study was conducted to clarify the cardiac effects of trastuzumab in cynomolgus monkeys, which are commonly used as cross-reactive species in preclinical safety evaluation. Monkeys were treated with trastuzumab weekly for 1 month (5 doses in total). At first and fifth doses for pressure-volume loop analysis, trastuzumab at 20 mg·kg-1·10 min-1, equivalent to the human therapeutic dose, was administered intravenously to isoflurane-anesthetized animals, followed by 60 mg·kg-1·10 min-1 at a 30-minute interval. The other doses were fixed at 80 mg·kg-1·10 min-1 under unanesthetized conditions. After the first dose, reduced heart rate, decreases in maximal rate of fall of left ventricular pressure, and prolonged time constant for isovolumic relaxation, which are predictors of drug-induced changes in lusitropy, were observed at 20 and 60 mg·kg-1. The changes after the fifth dose were comparable with those after the first dose, indicating trastuzumab did not show exacerbation of cardiac function during the 1-month trial. No significant changes in slope of preload recruitable stroke work, which is a load-independent inotropic parameter, were observed at either dose. In conclusion, trastuzumab-induced little inotropic effect but induced negative chronotropic or lusitropic effects in monkeys, which might be associated with impaired left ventricular diastolic function.

Comparison of short-term outcomes between transthoracic and robot-assisted transmediastinal radical surgery for esophageal cancer: a prospective study.

BACKGROUND: The present study aimed to assess the lower invasiveness of robot-assisted transmediastinal radical esophagectomy by prospectively comparing this procedure with transthoracic esophagectomy in terms of perioperative outcomes, serum cytokine levels, and respiratory function after surgery for esophageal cancer. METHODS: Patients who underwent a robot-assisted transmediastinal esophagectomy or transthoracic esophagectomy between April 2015 and March 2017 were included. The perioperative outcomes, preoperative and postoperative serum IL-6, IL-8, and IL-10 levels, and respiratory function measured preoperatively and at 6 months postoperatively were compared in patients with a robot-assisted transmediastinal esophagectomy and those with a transthoracic esophagectomy. RESULTS: Sixty patients with esophageal cancer were enrolled. The transmediastinal esophagectomy group had a significantly lower incidence of postoperative pneumonia (p = 0.002) and a significantly shorter postoperative hospital stay (p < 0.0002). The serum IL-6 levels on postoperative days 1, 3, 5, and 7 were significantly lower in the transmediastinal esophagectomy group (p = 0.005, 0.0007, 0.022, 0.020, respectively). In the latter group, the serum IL-8 level was significantly lower immediately after surgery and on postoperative day 1 (p = 0.003, 0.001, respectively) while the serum IL-10 level was significantly lower immediately after surgery (p = 0.041). The reduction in vital capacity, percent vital capacity, forced vital capacity, and forced expiratory volume at 1.0 s 6 months after surgery was significantly greater in the transthoracic esophagectomy group (p < 0.0001 for all four measurements). CONCLUSIONS: Although further, large-scale studies are needed to confirm our findings, robot-assisted transmediastinal esophagectomy may confer short-term benefits in radical surgery for esophageal cancer. TRIAL REGISTRATION: This trial was registered in the UMIN Clinical Trial Registry ( UMIN000017565 14/05/2015).

Adoptive γδT-cell transfer alone or combined with chemotherapy for the treatment of advanced esophageal cancer.

BACKGROUND AIMS: After therapy with platinum, 5-fluorouracil and taxane, no further recommended therapy is available for recurrent or metastatic esophageal cancer (r/mEC). Here the authors report two phase 1 trials of adoptive γδT-cell therapy, one for treatment-refractory r/mEC (γδT-monotherapy-P1, UMIN000001419) and the other for r/mEC with no prior systemic therapy (DCF-γδT-P1, UMIN000008097). METHODS: For γδT-monotherapy-P1, patients received four weekly and four biweekly injections of autologous γδT cells. For DCF-γδT-P1, patients received docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy consisting of docetaxel (60 mg/m2) and cisplatin (60 mg/m2) on day 1 and continuous injection of 5-fluorouracil (600 mg/m2/day) on days 1-5 of each 28-day cycle; additionally, they received autologous γδT-cell injections on day 15 and day 22 of each cycle. RESULTS: Twenty-six patients were enrolled for γδT-monotherapy-P1. No severe adverse events were associated with γδT-cell therapy. Median overall survival was 5.7 months (95% confidence interval [CI], 4.3-10.0), and median progression-free survival was 2.4 months (95% CI, 1.7-2.8). Eighteen patients received DCF-γδT-P1. All treatment-related adverse events were associated with DCF chemotherapy, not γδT injection. Median overall survival was 13.4 months (95% CI, 6.7-not reached), and median progression-free survival was 4.0 months (95% CI, 2.5-5.7). The response rate and disease control rate were 39% and 78%, respectively. CONCLUSIONS: The use of γδT-cell immunotherapy with or without chemotherapy was safe and feasible for r/mEC patients. Although the authors failed to demonstrate any clinical benefit of γδT-monotherapy-P1, survival benefits were observed in the DCF-γδT-P1 trial.

Esophageal cancer patients' survival after complete response to definitive chemoradiotherapy: a retrospective analysis.

BACKGROUND: Chemoradiotherapy is an alternative to surgery for esophageal cancer, with a putatively equivalent outcome. However, disease recurrence after a complete response is common and if follow-up surveillance detects recurrence, salvage treatments for potentially curable disease must follow. METHODS: We conducted a nation-wide questionnaire survey of institutions in Japan certified by the Japanese Esophageal Society to investigate outcomes of primary thoracic esophageal cancer patients initially treated by chemoradiotherapy with complete response diagnoses. The primary endpoint was overall survival, the secondary endpoint disease recurrence. Outcomes of patients who had undergone salvage treatments were also investigated. Cases were excluded from analysis if endoscopic study, endoscopic biopsy, or computed tomography data were lacking. RESULTS: At 41 institutes 544 case records were collected; valid data on 392 patients were obtained; 5-year survival was 74.8%, 5-year disease-free survival, 66.8%. Clinical staging before treatment significantly affected both overall and disease-free survival rates, but differences between adjoining stages were unexpectedly small. The primary relapse site was classified as primary site (n = 58), regional lymph nodes (n = 36), or distant disease (n = 34). Salvage treatments with curative intent (surgery, endoscopic treatments, and additional radiation) were performed on 38, 23, and 4 cases; 5-year survival after esophagectomy (n = 22), endoscopic treatment (n = 23), and lymphadenectomy (n = 9) was 47.4%, 70.9%, and 33.3%, respectively. CONCLUSIONS: A quarter of patients developed recurrent disease, mostly locoregional, after complete response. Complete response patients with originally advanced stage disease had fair clinical outcomes; salvage treatments after locoregional recurrence achieved modest long-term survival.

Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys.

Trastuzumab deruxtecan (T-DXd: DS-8201a) is an anti-human epidermal growth factor receptor 2 (HER2) Ab-drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T-DXd-induced lung toxicity in cynomolgus monkeys. Trastuzumab deruxtecan was injected i.v. into monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T-DXd-induced toxicity, DXd monohydrate was given i.v. to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T-DXd at 30 mg/kg or more. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to interstitial lung diseases (ILD)/pneumonitis related to anticancer drugs in patients, with an incidence that was dose-dependent and dose-frequency-dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T-DXd. The HER2 expression in monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T-DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T-DXd-related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T-DXd-induced ILD/pneumonitis in which target-independent uptake of T-DXd into alveolar macrophages could be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T-DXd therapy.

One-by-One Comparison of Lymph Nodes Between 18F-FDG Uptake and Pathological Diagnosis in Esophageal Cancer.

PURPOSE: Esophagectomy with extended lymph node (LN) dissection is a standard treatment for resectable esophageal cancer to prevent recurrence, but severe, potentially life-threatening postoperative complications are still important issues. Accurate diagnosis of LN metastases would enable the decision to dissect or leave the LNs in regions with high risk of complications. Advancements in intraoperative gamma probe and radioactivity detectors have made intraoperative navigation surgery possible using a radiotracer as a marker. F-FDG is one such candidate markers, and the diagnostic power of FDG through counting the radioactivity close to each LN should be elucidated. MATERIALS AND METHODS: In 20 patients, 1073 LNs including 38 metastatic LNs were prospectively investigated. Preoperative FDG PET was performed on the same day before esophagectomy and visually surveyed in each LN station to identify abnormal uptake. The FDG radioactivity of each individual dissected LN was measured by a well-type counter, and the pathological diagnosis was compared with LN radioactivity on a one-by-one basis and with the preoperative FDG PET findings for each LN station. RESULTS: Lymph node station-based analysis showed a sensitivity and specificity of 28.6% and 96.7%, respectively. One-by-one LN-based analysis using a cutoff value obtained from the receiver operating characteristic curve showed a sensitivity and specificity of 94.7% and 78.7%, respectively, demonstrating higher accuracy compared with the use of LN weight or the shortest diameter. CONCLUSIONS: The FDG uptake by each LN is a potentially useful marker for navigation surgery in esophageal cancer and has higher accuracy than LN weight or diameter.

Choroidal detachment-induced secondary angle-closure after trabeculectomy in patient with ocular venous congestion: A case report.

PURPOSE: To report a particular circumstance that led to the abnormal complication of choroidal detachment (CD)-induced secondary angle-closure after trabeculectomy with mitomycin C (MMC). OBSERVATIONS: An 82-year-old Japanese male patient with underlying chronic obstructive pulmonary disease and suspicion of ocular venous congestion in both eyes whom diagnosed as primary open-angle glaucoma with uncontrolled intraocular pressure (IOP) of his left eye then underwent an uneventful trabeculectomy with MMC. After the surgery, his left eye had high IOP with a shallow anterior chamber (A/C) but the bleb was hyperfiltration. The high CD was found by B-scan ultrasonography behind the iris and after conservative treatment, the CD was improved, A/C was deepened, and IOP was lower to 16 mmHg. CONCLUSION AND IMPORTANCE: CD-induced secondary angle-closure after trabeculectomy with MMC is a complication to be considered in patients with shallow A/C and high IOP. Fundus examination should be done to rule out this condition before any aggressive treatment as CD can resolve spontaneously with time. Clinicians should be aware of this condition especially in patients with any signs of ocular venous congestion as there have been few reports mentioned about the complication in the patients.

Two-stage Reconstruction Using a Free Jejunum/Ileum Flap After Total Esophagectomy.

BACKGROUND: Reconstruction after esophagectomy is conventionally performed with a gastric conduit. However, in cases where a gastric conduit is unavailable, reconstructive procedures vary in terms of flap type, operative timing, and conduit route. Single-stage surgery is associated with a long operation time and high surgical stress, resulting in perioperative mortality. Recent advances in reconstructive microsurgery have made free intestinal flap transfer safe and reliable. Therefore, to overcome the shortcomings with previous methods, we performed 2-stage surgery involving free jejunum/ileum transfer for reconstruction after esophagectomy. PATIENTS AND METHODS: From 2010 to 2018, 42 free jejunum/ileum flaps were transferred for reconstruction after esophagectomy in 41 patients. The diagnosis was esophageal cancer in 38 patients. All operations were performed in 2 stages. In most cases, total esophagectomy was performed in the first operation. The cervical stump of the esophagus was sutured to the cervical skin, creating an esophagostomy in the left neck. About 4 to 7 weeks after the first operation, the second operation was performed. The free jejunum/ileum flap was transferred through the subcutaneous route. Microvascular anastomosis was performed with the internal mammary artery and internal mammary vein, transverse cervical artery, internal and external jugular veins (internal jugular vein and EJV, respectively), and cephalic vein. The mean follow-up duration was 20 months. RESULTS: Free jejunum/ileum transfer was performed as the first operation in 4 cases and as the second operation in 38 cases. A free jejunal flap was used in 36 cases and free ileal flap was used in 6 cases. The recipient arteries were the internal mammary artery in 38 cases and transverse cervical artery in 4 cases. The recipient veins were the internal mammary vein in 15 cases, cephalic vein in 13 cases, EJV in 10 cases, and internal jugular vein in 10 cases. The flaps survived in all cases, except 1 case (41/42, 97.6%). The complications were anastomotic leakage of the flap in 9 cases, respiratory complications in 10 cases, and ileus in 2 cases. Perioperative mortality was not noted. CONCLUSIONS: Two-stage surgery using free jejunum/ileum flap transfer is a safe and reliable option for esophageal reconstruction in cases where gastric pull-up is unavailable.

The Impact of the Timing of Dosing on the Severity of UNC569-Induced Ultrastructural Changes in the Mouse Retina.

Mer proto-oncogene tyrosine kinase (MerTK), expressed in the retinal pigment epithelium (RPE), regulates the phagocytosis of shed photoreceptor outer segments. To investigate the influence of dosing time on MerTK inhibitor UNC569-induced retinal toxicity, UNC569 at 100 mg/kg was orally administered to male mice at 2 different Zeitgeber times (ZT5.5 or ZT22) for 28 days. Electron microscopy was conducted at ZT2 after the final dosing. Additionally, the visual cycle components (11-cis-retinal, all-trans-retinal, all-trans-retinol, and 11-cis-retinol), which play an important role in maintaining retinal homeostasis, were quantified by liquid chromatography/mass spectrometry/mass spectrometry. Under electron microscopic examination, the number of phagosomes and phagolysosomes in the RPE increased in both the ZT5.5 and ZT22 administered groups, while endoplasmic reticulum dilatation in the RPE and chromatin aggregation of photoreceptor nuclei were observed only in the ZT22 administered group. No change was observed in any of the visual cycle components. These results suggest that the timing of the dosing in relation to the physiological MerTK phosphorylation affected the severity of changes in the RPE, leading to the apoptosis of the photoreceptor cells.

A scoring system based on computed tomography for the correct diagnosis of xanthogranulomatous cholecystitis.

BACKGROUND: Xanthogranulomatous cholecystitis (XGC) is an uncommon variant of chronic cholecystitis. The differential diagnoses of XGC include gallbladder cancer (GBC), adenomyomatosis, and actinomycosis of the gallbladder. PURPOSE: To assess the usefulness of computed tomography (CT) findings in the diagnosis of XGC and differentiation from GBC. MATERIAL AND METHODS: We retrospectively assessed the pathological and radiological records of 13 patients with pathologically proven XGC and 33 patients with GBC. RESULTS: Significant differences were observed for the following five CT findings: diffuse wall thickening (XGC = 85%, GBC = 15%, P < 0.01); absence of polypoid lesions (XGC = 100%, GBC = 48%, P < 0.01); intramural nodules or bands (XGC = 54%, GBC = 9%, P < 0.01); pericholecystic infiltration (XGC = 69%, GBC = 9%, P < 0.01); and pericholecystic abscess (XGC = 23%, GBC = 0%, P = 0.018). We defined the scoring system based on how many of the five CT findings were observed. Our scoring system, which included these findings, revealed that patients with three or more findings had sensitivity of 77% (95% confidence interval [CI] = 57-87) and specificity of 94% (95% CI = 86-98). CONCLUSION: Our scoring system can assist in the differentiation of XGC from GBC.

Preoperative Low Vital Capacity Influences Survival After Esophagectomy for Patients with Esophageal Carcinoma.

BACKGROUND: Assessment of preoperative physiological status is crucial for optimizing clinical outcomes in patients undergoing surgery for esophageal carcinoma (EC). We aimed to evaluate the prognostic impact of pulmonary dysfunctions and their relationships with other physiological factors, especially sarcopenia, in EC patients receiving esophagectomy. METHODS: In total, 411 EC patients who underwent esophagectomy between 2006 and 2016 were retrospectively reviewed. Preoperative pulmonary functions were evaluated based on %vital capacity (%VC) and forced expiratory volume (FEV) 1.0%. The thresholds were set as the lowest quartile (99% for %VC and 68.6% for FEV1.0%) in this cohort. RESULTS: One hundred and two patients (24.8%) had low %VC (%VC < 99%), which was significantly associated with age, comorbidity, sarcopenia and postoperative complications, while not correlating with pathological variables. The overall survival (OS) of patients in the low %VC group was significantly poorer than that of those in the high %VC group (P < 0.001), especially in those with pStage 0-II diseases (P < 0.001). In contrast, survival was not stratified by FEV1.0% (P = 0.80). Notably, patients with both low %VC and sarcopenia showed very poor 5-year OS (30.3%). Multivariate analysis revealed low %VC to be independently associated with poor OS (P = 0.03). In the cause-specific survival analyses, low %VC was an independent predictor of deaths from non-EC-related causes (P = 0.03). CONCLUSIONS: Preoperative low %VC was independently associated with poor survival outcomes, especially when present in combination with sarcopenia, due to an increased risk of death from non-EC-related causes. Preoperative spirometry testing is useful for predicting long-term outcomes in EC patients undergoing esophagectomy.