Successful R0 resection after chemotherapy, including nivolumab, for gastric cancer with liver metastases: three case reports.

BACKGROUND: Advances in chemotherapy have increased clinical experience with conversion surgery for inoperable advanced gastric cancer. This report describes three patients with unresectable gastric cancer accompanied by multiple liver metastases. In all three patients, nivolumab resolved the liver metastases and subsequent conversion surgery achieved a pathological complete response. CASE PRESENTATION: In Case 1, a 68-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX plus nivolumab. The patient completed 13 cycles; however, only nivolumab was continued for 3 cycles because of adverse events. Distal gastrectomy and partial hepatic resection were performed because of a significant reduction in the size of the liver metastases as observed on magnetic resonance imaging (MRI). In Case 2, a 72-year-old man with clinical Stage IVB gastric cancer and multiple liver metastases initiated first-line therapy with SOX. Because of the subsequent emergence of new liver metastases, the patient transitioned to ramucirumab plus paclitaxel as second-line therapy. Third-line therapy with nivolumab was initiated because of side effects. MRI revealed necrosis within the liver metastasis, and the patient underwent proximal gastrectomy and partial hepatectomy. In Case 3, a 51-year-old woman with clinical Stage IVB gastric cancer accompanied by multiple metastases of the liver and para-aortic lymph nodes began first-line therapy with SOX plus nivolumab. The patient completed 10 cycles; however, only nivolumab was continued for 5 cycles because of adverse events. Computed tomography showed a significant decrease in the size of the para-aortic lymph nodes, while MRI indicated the presence of a singular liver metastasis. Distal gastrectomy and partial hepatic resection were subsequently performed. In all three cases, MRI revealed the presence of liver metastases; however, pathological examination showed no viable tumor cells. CONCLUSIONS: We herein present three cases in which chemotherapy, including nivolumab, elicited a response in patients with multiple unresectable liver metastases, ultimately culminating in R0 resection through conversion surgery. Although MRI showed liver metastases, pathological analysis revealed no cancer, underscoring the beneficial impact of chemotherapy.

Dysregulation of the TCF4 Isoform in Corneal Endothelial Cells of Patients With Fuchs Endothelial Corneal Dystrophy.

Purpose: This study evaluated the dysregulation of TCF4 isoforms and differential exon usage (DEU) in corneal endothelial cells (CECs) of Fuchs endothelial corneal dystrophy (FECD) with or without trinucleotide repeat (TNR) expansion in the intron region of the TCF4 gene. Methods: Three RNA-Seq datasets of CECs (our own and two other previously published datasets) derived from non-FECD control and FECD subjects were analyzed to identify TCF4 isoforms and DEU events dysregulated in FECD by comparing control subjects to those with FECD with TNR expansion and FECD without TNR expansion. Results: Our RNA-Seq data demonstrated upregulation of three TCF4 isoforms and downregulation of two isoforms in FECD without TNR expansion compared to the controls. In FECD with TNR expansion, one isoform was upregulated and one isoform was downregulated compared to the control. Additional analysis using two other datasets identified that the TCF4-277 isoform was upregulated in common in all three datasets in FECD with TNR expansion, whereas no isoform was dysregulated in FECD without TNR expansion. DEU analysis showed that one exon (E174) upstream of the TNR, which only encompassed TCF4-277, was upregulated in common in all three datasets, whereas eight exons downstream of the TNR were downregulated in common in all three datasets in FECD with TNR expansion. Conclusions: This study identified TCF4-277 as a dysregulated isoform in FECD with TNR expansion, suggesting a potential contribution of TCF4-277 to FECD pathophysiology.

Pretherapeutic factors predicting conversion surgery in unresectable pancreatic ductal adenocarcinoma: A retrospective study.

Recently, conversion surgery (CS) has been reported to improve the prognosis in patients with unresectable pancreatic ductal adenocarcinoma (UR-PDAC) with a favorable response to intense chemotherapy or chemoradiotherapy. However, few pretherapeutic parameters predict the attainability of CS in patients with UR-PDAC. The present study aimed to explore the pretherapeutic predictors for the attainability of CS in patients with UR-PDAC. The present study retrospectively evaluated 130 patients with UR-PDAC treated at Gifu University Hospital (Gifu, Japan) from January 2015 to December 2021. Survival analysis was performed using the Simon and Makuch-modified Kaplan-Meier method. The hazard ratio (HR) was estimated using a time-varying Cox regression model. The association between each predictor and CS was evaluated using the univariate analysis and age-adjusted Fine-Gray sub-distribution hazard model. The bootstrap bias-corrected area under the receiver operating characteristic curve analysis for predicting CS was used to assess the cut-off values for each predictor. The cumulative incidence rate was calculated with CS as the outcome when divided into two groups based on the cut-off value of each pretherapeutic predictor. Among the 130 patients included in the analysis, only 14 (11%) underwent CS. The median survival time was significantly longer in patients who underwent CS compared with patients without CS (56.3 vs. 14.1 months; P<0.001). The age-adjusted Fine-Gray sub-distribution hazard regression showed that the total protein (TP) [HR 2.81, 95% confidence interval (CI) 1.19-6.65; P=0.018], neutrophil-to-lymphocyte ratio (NLR) (HR 0.53, 95% CI 0.31-0.90; P=0.020), and lymphocyte-to-monocyte ratio (LMR) (HR 1.28, 95% CI 1.07-1.53; P=0.006) were significantly associated with CS. Moreover, TP ≥6.8, NLR <2.84 and LMR ≥3.87 were associated with a higher cumulative incidence of CS. In conclusion, pretherapeutic TP, NLR and LMR are clinically feasible biomarkers for predicting the attainability of CS in patients with UR-PDAC.

Association of Preoperative and Postoperative Plasma Syndecan-1 and Colorectal Cancer Outcome.

BACKGROUND/AIM: A three-dimensional network constructed using glycocalyx (GCX) extends throughout the cancer cell nest in human colorectal cancer (CRC). GCX was found to be closely related to cancer. We examined the prognostic correlation and potential of syndecan-1 (SDC1), a representative proteoglycan of GCX, as a biomarker. PATIENTS AND METHODS: We analyzed SDC1 in the transcriptomic profiles of a major publicly available CRC cohort from The Cancer Genome Atlas (TCGA) using a computational algorithm. We investigated serum SDC1 levels preoperatively and on postoperative day seven in 48 patients with stage I-III CRC who underwent surgery during July-December 2019 at Gifu University Hospital. RESULTS: For TCGA, no significant differences existed between the high and low SDC1 expression groups regarding disease-free, disease-specific, and overall survival for stage I-III, and only overall survival for stage IV was significantly different. In our study, among the 48 patients, 17 (no recurrence), 13 (1 recurrence), and 18 (10 recurrences) had stage I-III, respectively. Preoperative and postoperative day 7 SDC1 levels for patients with stage I-III were 10.7±2.3 and 9.9±3.1 ng/ml (p=0.40), 11.1±1.7 and 10.1±0.8 ng/ml (p=0.07), and 10.3±2.0 and 9.5±1.4 ng/ml (p=0.15), respectively. In stage II and III, patients were divided into two groups according to differences between preoperative and postoperative SDC1 levels (SDC1pre-pro). SDC1pre-pro ≤0 group significantly prolonged disease-free survival compared with SDC1pre-pro >0 group (p=0.048). CONCLUSION: Dynamic change in serum SDC1 levels serves as a prognostic biomarker for stage II and III colorectal cancer.

Oligometastasis of Gastric Cancer: A Review.

The concept of oligometastasis is not yet fully established in the field of gastric cancer. However, metastatic lesions that are localized, technically resectable at diagnosis, present a certain response to preoperative chemotherapy, and present favorable survival outcomes with local treatments, sometimes in combination with chemotherapy, are recognized as oligometastasis in the field of gastric cancer. Oligometastasis is noted in European Society for Medical Oncology guidelines and Japanese gastric cancer treatment guidelines, and local treatment is mentioned as one of the pivotal treatment options for oligometastasis. Solitary liver metastasis or a small number of liver metastases; retroperitoneal lymph node metastasis, especially localized para-aortic lymph node metastasis; localized peritoneal dissemination; and Krukenberg tumor are representative types of oligometastasis in gastric cancer. The AIO-FLOT3 trial prospectively evaluated the efficacy of multimodal treatments for gastric cancer with oligometastasis, including surgical resection of primary and metastatic lesions combined with chemotherapy, confirming favorable survival outcomes. Two phase 3 studies are ongoing to investigate the efficacy of surgical resection combined with perioperative chemotherapy compared with palliative chemotherapy. Thus far, the evidence suggests that multimodal treatment for oligometastasis of gastric cancer is promising.

Usefulness of an intraoperative flipped monitor in laparoscopic surgery with situs inversus totalis: a case report of laparoscopic-assisted ileocecal resection.

BACKGROUND: Situs inversus totalis (SIT) is a rare congenital condition that involves complete transposition (right to left reversal) of the visceral organs. Laparoscopic surgery can be challenging because of the mirror-image anatomy. We describe a surgical innovation in laparoscopic surgery for SIT. CASE PRESENTATION: A 41-year-old man with SIT was diagnosed with an appendiceal tumor and underwent laparoscopic-assisted ileocecal resection. Preoperatively, we evaluated anatomical variations using 3D-computed tomography and simulated mirror images by watching flipped videos of patients with normal anatomy undergoing similar operations. During the operation, port placement and the surgeons' standing positions were reversed. Additionally, two monitors were placed at the patient's head, with one monitor showing original images, and the other showing flipped images that looked the same as the normal anatomy. We checked the range of the mobilized region and important anatomical structures by watching the flipped monitor as needed. The patient's postoperative course was uneventful. CONCLUSIONS: Due to the complexities of laparoscopic surgery for SIT, preoperative preparation and surgical innovation are necessary for safe surgery. Several suggestions have been made to understand anatomical anomalies and improve operability; however, surgeons must focus on the mirror-image anatomy throughout the operation. Therefore, the use of intraoperative flipped monitor will be helpful for surgeons in reducing the risk of anatomical misidentification.

U-Net Convolutional Neural Network for Real-Time Prediction of the Number of Cultured Corneal Endothelial Cells for Cellular Therapy.

Corneal endothelial decompensation is treated by the corneal transplantation of donor corneas, but donor shortages and other problems associated with corneal transplantation have prompted investigations into tissue engineering therapies. For clinical use, cells used in tissue engineering must undergo strict quality control to ensure their safety and efficacy. In addition, efficient cell manufacturing processes are needed to make cell therapy a sustainable standard procedure with an acceptable economic burden. In this study, we obtained 3098 phase contrast images of cultured human corneal endothelial cells (HCECs). We labeled the images using semi-supervised learning and then trained a model that predicted the cell centers with a precision of 95.1%, a recall of 92.3%, and an F-value of 93.4%. The cell density calculated by the model showed a very strong correlation with the ground truth (Pearson's correlation coefficient = 0.97, p value = 8.10 × 10-52). The total cell numbers calculated by our model based on phase contrast images were close to the numbers calculated using a hemocytometer through passages 1 to 4. Our findings confirm the feasibility of using artificial intelligence-assisted quality control assessments in the field of regenerative medicine.

Technical outcomes of robotic-assisted surgery versus laparoscopic surgery for rectal tumors: a single-center safety and feasibility study.

PURPOSE: Robot-assisted surgery has a multi-joint function, which improves manipulation of the deep pelvic region and contributes significantly to perioperative safety. However, the superiority of robot-assisted surgery to laparoscopic surgery remains controversial. This study compared the short-term outcomes of laparoscopic and robot-assisted surgery for rectal tumors. METHODS: This single-center, retrospective study included 273 patients with rectal tumors who underwent surgery with anastomosis between 2017 and 2021. In total, 169 patients underwent laparoscopic surgery (Lap group), and 104 underwent robot-assisted surgery (Robot group). Postoperative complications were compared via propensity score matching based on inverse probability of treatment weighting (IPTW). RESULTS: The postoperative complication rates based on the Clavien-Dindo classification (Lap vs. Robot group) were as follows: grade ≥ II, 29.0% vs. 19.2%; grade ≥ III, 10.7% vs. 5.8%; anastomotic leakage (AL), 6.5% vs. 4.8%; and urinary dysfunction (UD), 12.1% vs. 3.8%. After adjusting for the IPTW method, although AL rates did not differ significantly between groups, postoperative complications of both grade ≥ II (odds ratio [OR] 0.66, 95% confidence interval [CI] 0.50-0.87, p < 0.01) and grade ≥ III (OR 0.29, 95% CI 0.16-0.53, p < 0.01) were significantly less frequent in the Robot group than in the Lap group. Furthermore, urinary dysfunction also tended to be less frequent in the Robot group than in the Lap group (OR 0.62, 95% CI 0.38-1.00; p = 0.05). CONCLUSION: Robot-assisted surgery for rectal tumors provides better short-term outcomes than laparoscopic surgery, supporting its use as a safer approach.

Association of Pre-operative Geriatric Nutritional Risk Index With Complete Adjuvant Chemotherapy and Prognosis Post-pancreatectomy.

BACKGROUND/AIM: The Geriatric Nutritional Risk Index (GNRI) predicts prognosis in various cancers. This study examined the correlation between GNRI, complete adjuvant chemotherapy (AC), and prognosis in patients with resected pancreatic cancer. PATIENTS AND METHODS: We retrospectively evaluated 123 patients with pancreatic cancer who underwent pancreatectomies at our institute between January 2010 and December 2020. Kaplan-Meier and Cox regression methods were used to assess survival. Factors associated with complete AC were identified using logistic regression analysis. RESULTS: Among the 123 patients with pancreatic cancer, 93 (75.6%) initiated AC, and 55 (44.7%) completed AC. In multivariate analysis, the pre-operative GNRI was an independent prognostic factor for overall survival (OS) [hazard ratio=1.63, 95% confidence interval (CI)=1.01-2.63; p=0.046]. Additionally, pre-operative GNRI was an independent predictor of complete AC (odds ratio=0.38, 95%CI=0.17-0.83; p=0.015). In the high (≥98) and low GNRI (<98) groups, patients who underwent complete AC had significantly longer OS than those who did not (p<0.001, respectively). However, the patients in the low GNRI group who underwent complete AC had no significant difference in OS compared to those in the high GNRI group who did not undergo complete AC (p=0.523). CONCLUSION: Pre-operative GNRI may predict complete AC and prognosis in resected pancreatic cancer.

Perioperative predictive factors of failure to rescue following highly advanced hepatobiliary-pancreatic surgery: a single-institution retrospective study.

BACKGROUND: Failure to rescue (FTR), defined as a postoperative complication leading to death, is a recently described outcome metric used to evaluate treatment quality. However, the predictive factors for FTR, particularly following highly advanced hepatobiliary-pancreatic surgery (HBPS), have not been adequately investigated. This study aimed to identify perioperative predictive factors for FTR following highly advanced HBPS. METHODS: This single-institution retrospective study involved 177 patients at Gifu University Hospital, Japan, who developed severe postoperative complications (Clavien-Dindo classification grades ≥ III) between 2010 and 2022 following highly advanced HBPS. Univariate analysis was used to identify pre-, intra-, and postoperative risks of FTR. RESULTS: Nine postoperative mortalities occurred during the study period (overall mortality rate, 1.3% [9/686]; FTR rate, 5.1% [9/177]). Univariate analysis indicated that comorbid liver disease, intraoperative blood loss, intraoperative blood transfusion, postoperative liver failure, postoperative respiratory failure, and postoperative bleeding significantly correlated with FTR. CONCLUSIONS: FTR was found to be associated with perioperative factors. Well-coordinated surgical procedures to avoid intra- and postoperative bleeding and unnecessary blood transfusions, as well as postoperative team management with attention to the occurrence of organ failure, may decrease FTR rates.

Short-term outcomes associated with the use of a new powered circular stapler for rectal reconstructions: a retrospective study comparing it to manual circular staplers using inverse probability of treatment weight analysis.

BACKGROUND: The most common postoperative complication in malignant rectal surgery is anastomotic leakage (AL). AL after anterior or low anterior resection in rectal tumors is a fatal postoperative complication. Recently, the first automated suture circular stapler, which is expected to reduce the incidence of AL, (J&J). MATERIALS AND METHODS: This study included a total of 248 rectal tumor patients who underwent double stapler technique (DST) anastomotic procedures in the department of gastroenterological surgery /pediatric surgery at Gifu University School of Medicine from January 2017 to December 2021. The experience of a single institution utilizing the The Echelon circular™ stapler (ECP stapler:Manual VS Automatic) in rectal surgery cases was evaluated retrospectively from maintained database. RESULT: One hundred thirty-nine patients (58.4%) were performed by manual circular stapling, 99 patients (41.6%) by powerd circular stapling. Diverting stoma was performed in 45 cases (32.4%) by manual circular stapling, 42 patients (42.4%) by powerd circular stapling Postoperative complications were occurred clavien-dindo grade II or higher in 57 cases (23.9%) and grade III or higher in 20 cases (8.4%). Anastomotic leakage occurred in 14 patients (5.9%) within all grades. After IPTW, the variables of patient characteristics was SMD ≤ 0.2 (Table.3), and there was a significant difference in anastomotic leakage (Odds Ratio (OR), 0.57; 95% Confidence Interval(CI), 0.34-0.98; p = 0.041). In addition, there was no significant difference in postoperative complications in grade II or higher (OR, 0.88; 95%CI, 0.65-1.19; p = 0.417) and grade III or higher (OR, 0.46; 95%CI, 0.29-0.74; p = 0.001) were significantly remarkable lower in powered circular stapling group. CONCLUSION: In this IPTW comparison of patients undergoing rectal reconstructions, the ECP trial cohort had lower risks of several surgical complications AL and statistically signifcant lower rates of ileus/bowel obstruction, infection, and bleeding as Clavien-Dindo ≥ grade II and III as compared with for whom manual circular staplers were used.

Development of Anterior Segment Focused Biologic Therapies to Regenerate Corneal Tissue for the Treatment of Disease: Drug Development Experience.

On February 24-27, 2021, the Association for Ocular Pharmacology and Therapeutics (AOPT) held its 15th biennial scientific meeting online. The meeting was organized by Dr. Sanjoy Bhattacharya of the University of Miami in conjunction with the board of trustees of the AOPT. The 3-day conference was attended by academic scientists, clinicians, and industry and regulatory professionals. The theme of the meeting was Restoring Vision through Regeneration and it was sponsored, in part, by the National Institutes of Health, Bright Focus, Regeneron, and Santen (USA). During the 3 days of the meeting, presentations from several sessions explored different aspects of regenerative medicine in ophthalmology, including optic nerve regeneration, drugs and devices in glaucoma, retinal neuroprotection and plasticity, visual perception, and degeneration of trabecular meshwork. This article summarizes the proceedings of the session on corneal regenerative medicine research and discusses emerging concepts in drug development for corneal epithelial and endothelial regeneration. Since the meeting in 2021, several of these concepts have advanced to clinical-stage therapies, but so far as of 2023, none has been approved by regional regulatory authorities in the United States. One form of corneal endothelial cell therapy has been approved in Japan and only for bullous keratopathy. Ongoing work is proceeding in the United States and other countries. Clinical Registration No: National Clinical Trials 04894110, 04812667; Japan Registry for Clinical Trials a031210199.

Systematic Review of the Diagnostic Criteria and Severity Classification for Fuchs Endothelial Corneal Dystrophy.

PURPOSE: There are no defined diagnostic criteria and severity classification for Fuchs endothelial corneal dystrophy (FECD), which are required for objective standardized assessments. Therefore, we performed a systematic literature review of the current diagnosis and severity classification of FECD. METHODS: We searched the Ovid MEDLINE and Web of Science databases for studies published until January 13, 2021. We excluded review articles, conference abstracts, editorials, case reports with <5 patients, and letters. RESULTS: Among 468 articles identified, we excluded 173 and 165 articles in the first and second screenings, respectively. Among the 130 included articles, 61 (47%) and 99 (76%) mentioned the diagnostic criteria for FECD and described its severity classification, respectively. Regarding diagnosis, slitlamp microscope alone was the most frequently used device in 31 (51%) of 61 articles. Regarding diagnostic findings, corneal guttae alone was the most common parameter [adopted in 23 articles (38%)]. Regarding severity classification, slitlamp microscopes were used in 88 articles (89%). The original or modified Krachmer grading scale was used in 77 articles (78%), followed by Adami's classification in six (6%). Specular microscopes or Scheimpflug tomography were used in four articles (4%) and anterior segment optical coherence tomography in one (1%). CONCLUSIONS: FECD is globally diagnosed by the corneal guttae using slitlamp examination, and its severity is predominantly determined by the original or modified Krachmer grading scale. Objective severity grading using Scheimpflug or anterior segment optical coherence tomography can be applied in the future innovative therapies such as cell injection therapy or novel small molecules.

P47-A153†Transplantation of cultured human corneal endothelial cells.

Multiple research groups now theorize that tissue engineering will provide novel therapies for treating corneal endothelial cell (CEC) decompensation. In 2013, we initiated first-in-man clinical research (not an Investigational New Drug [IND] clinical trial) of a CEC injection therapy at the Kyoto Prefectural University of Medicine in Japan. In a clinical trial, cultured CECs (CECs) supplemented with a rho-associated protein kinase (ROCK) inhibitor were injected into the anterior chamber. In all of our first 11 cases, the corneal transparency was restored with the regeneration of a monolayer sheet structure of corneal endothelium. As proof of concept of CEC injection therapy was obtained, we are currently developing a cellular product to deliver this therapy to all patients. To that end, we have established an efficient cell culture protocol and 'ready-to-use' frozen cells. In this presentation, I will introduce the current status of our developments to provide a platform for discussing future therapies for treating corneal endothelial decompensation.

Postoperative reflux esophagitis in laparoscopic distal gastrectomy with Billroth-I reconstruction for gastric cancer: Nutritional effect and preoperative risk factors.

INTRODUCTION: Postoperative reflux esophagitis represents a major complication of laparoscopic distal gastrectomy (LDG) with Billroth-I reconstruction (LDGBI). This study aimed to evaluate the nutritional effect and preoperative risk factors of postoperative reflux esophagitis in patients undergoing LDGBI for gastric cancer. METHODS: We retrospectively analyzed data of patients with (reflux [+]) and without (reflux [-]) postoperative reflux esophagitis who underwent LDGBI in our institution. Patient backgrounds, surgical outcomes, and perioperative nutritional status were compared. Preoperative risk factors for postoperative reflux esophagitis were also evaluated. RESULTS: Between January 2009 and December 2016, 242 patients underwent LDG for gastric cancer. Of these, 218 underwent Billroth-I reconstruction. Seventy-three patients were excluded because of nutritional or oncological reasons. Finally, 23 patients were enrolled as the reflux (+) group and 122 as the reflux (-) group. Although the preoperative/postoperative bodyweight ratio and albumin and hemoglobin values plateaued beyond 6 months postoperatively in the reflux (-) group, these parameters continued to decrease beyond this time in the reflux (+) group. The mean ± SD bodyweight ratios at 3 years postoperatively were 82.83% ± 9.73% and 89.45% ± 8.04% for the reflux (+) and reflux (-) group, respectively (P = .0006). Multivariate analysis revealed that postoperative reflux esophagitis was associated with postoperative body weight loss. Another multivariate analysis revealed preoperative hiatal hernia as an independent predictive factor for postoperative reflux esophagitis. CONCLUSION: The risk of reflux esophagitis after LDGBI in patients with hiatal hernia should be considered when deciding therapeutic approaches for such patients.

Shotgun proteomics identification of proteins expressed in the Descemet's membrane of patients with Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a slowly evolving, bilateral disease of the corneal endothelium, characterized by an abnormal accumulation of extracellular matrix (ECM) in the basement membrane (Descemet's membrane, DM). This results in the formation of small round excrescences, called guttae, and a progressive disappearance of endothelial cells. In the intermediate stage, the numerous guttae create significant optical aberrations, and in the late stage, the loss of endothelial function leads to permanent corneal edema. The molecular components of guttae have not been fully elucidated. In the current study, we conducted shotgun proteomics of the DMs, including guttae, obtained from patients with FECD and revealed that 32 proteins were expressed only in the FECD-DMs but not in the DMs of control subjects. Subsequent enrichment analyses identified associations with multiple ECM-related pathways. Immunostaining of flat-mounted DMs confirmed that 4 of the top 5 identified proteins (hemoglobin α, SRPX2, tenascin-C, and hemoglobin γδεß) were expressed in FECD-DMs but not in non-FECD-DMs. Fibrinogen α was strongly expressed in FECD-DMs, but weakly expressed in non-FECD-DMs. We also demonstrated that matrix-assisted laser desorption ionization imaging mass spectrometry (MALDI-IMS) can display the in situ spatial distribution of biomolecules expressed in the DM, including the guttae.

RNA-Seq-based transcriptome analysis of corneal endothelial cells derived from patients with Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is the most common inherited corneal disease. Fibrillar focal excrescences called guttae and corneal edema due to corneal endothelial cell death result in progressive vision loss. Multiple genetic variants have been reported, but the pathogenesis of FECD is not fully understood. In this study, we used RNA-Seq to analyze differential gene expression in the corneal endothelium obtained from patients with FECD. Differential expression analysis of transcriptomic profiles revealed that expression of 2366 genes (1092 upregulated and 1274 downregulated genes) was significantly altered in the corneal endothelium of patients with FECD compared to healthy subjects. Gene ontology analysis demonstrated an enrichment of genes involved in extracellular matrix (ECM) organization, response to oxidative stress, and apoptotic signaling. Several pathway analyses consistently indicated the dysregulation of ECM-associated pathways. Our differential gene expression findings support the previously proposed underlying mechanisms, including oxidative stress and apoptosis of endothelial cells, as well as the phenotypic clinical FECD hallmark of ECM deposits. Further investigation focusing on differentially expressed genes related to these pathways might be beneficial for elucidating mechanisms and developing novel therapies.

Late recurrent gastric carcinoma 12 years after surgery with attenuation of CD44 variant 9 expression.

BACKGROUND: Late recurrence of gastric cancer at 10 years post-gastrectomy is extremely rare, and the underlying mechanism remains unclear. We report a para-aortic lymph node metastasis case that recurred 12 years postoperatively. CASE PRESENTATION: A 44-year-old woman pathologically diagnosed with moderately to poorly differentiated adenocarcinoma with pT2(SS)pN2cM0pStageIIIA according to the Japanese Classification of Gastric Carcinoma (the 13th Edition) underwent laparoscopic distal gastrectomy with D1 + lymph node dissection. She received adjuvant chemotherapy with tegafur-uracil (400 mg/day) for 2 years. At postoperative year (POY) 5, a swollen lymph node was detected in the No.16b1lat lymph node station. However, positron emission tomography (PET) revealed normal uptake, and the levels of tumor markers were within normal limits; hence, the possibility of metastasis was considered low, and the patient was placed under observation. At POY 12, computed tomography revealed an enlargement of the No.16b1lat lymph node station, and PET showed abnormal uptake. Endoscopic ultrasound-guided fine-needle aspiration revealed a moderately differentiated adenocarcinoma. Hence, a diagnosis of recurrence of gastric cancer was made. The patient underwent para-aortic nodal dissection (PAND) of No.16b1lat & int stations. Immunochemical staining results also suggested the recurrence of gastric cancer. However, the expression of CD44 variant 9 (CD44v9), a cancer stem cell marker for gastric adenocarcinoma, was attenuated in the recurrent lesions compared with that in the primary lesions. Postoperatively, she received chemotherapy with tegafur-gimeracil-oteracil (80 mg/day) for 1 year. Bone metastasis was observed at POY 4 after PAND, and the IHC analysis showed a HER2 score of 3 + in a needle biopsy specimen of bone metastasis. The expression of CD44v9 was slightly positive. The patient is being treated with chemotherapy with FOLFOX + trastuzumab. CONCLUSIONS: A defense mechanism against reactive oxygen species has been reported as a mechanism causing recurrence of CD44v9-positive gastric cancer. Consequently, CD44v9-positive gastric cancer grows in metastatic organs, repeatedly self-renews, and proliferates to form recurrent lesions. In the present case, the degree of CD44v9 staining in recurrent lesions was suggested to be related to the recurrence time.