Transabdominal Preperitoneal Repair for an External Supravesical Hernia With an Incarcerated Ovary: A Case Report.

External supravesical hernias with ovarian incarceration have not been reported previously. Here, we describe transabdominal preperitoneal (TAPP) repair of an external supravesical hernia with ovarian incarceration. A 68-year-old woman presented to our outpatient clinic with the chief complaint of right inguinal swelling and pain. A 3-cm-diameter mass in the right inguinal region that was difficult to reduce was palpable, and computed tomography (CT) revealed a suspicious lesion of the right hydrocele of the canal of Nuck. Hydrocelectomy was performed through an inguinal incision, and the external inguinal ring was repaired using the Marcy method. The histopathological examination confirmed the diagnosis of the canal of Nuck. Three months postoperatively, the patient again presented with right inguinal pain, and CT revealed a right femoral hernia requiring surgical repair. Intraoperative findings revealed a right external supravesical hernia with an incarcerated ovary, which was laparoscopically reduced and repaired with a mesh. At the three-month follow-up, there were no postoperative complications or recurrences. Incarcerated ovaries with inguinal hernias have been reported in girls; however, incarcerated ovaries with external supravesical hernias have not been reported in women. Although the preoperative diagnosis was difficult to make in this case, the laparoscopic approach led to the diagnosis and successful mesh repair. Although optimal mesh repair of external supravesical hernias using TAPP has not been established, we believe that 2-5 cm around the hernial orifice, the Hesselbach triangle, and the lateral triangle should be covered with mesh.

Short- and long-term outcomes of transanal decompression tube and self-expandable metallic stent for obstructive colorectal cancer based on a multicenter database (KYCC2110).

AIM: There are well-known methods for decompressing the colorectal tract before surgery, including transanal decompression tubes (TDT) and self-expanding metallic stents (SEMS). This study aimed to compare the short and long-term results in patients with malignant large bowel obstruction in whom TDT or SEMS were placed before surgery. METHODS: This retrospective observational study enrolled 225 patients with malignant large bowel obstruction in whom TDT or SEMS were placed preoperatively and underwent R0 resection between 2008 and 2020. One-to-two propensity score matching was performed according to patient characteristics. Short- and long-term outcomes were compared. The primary endpoint was relapse-free survival (RFS). The secondary endpoints were the overall survival (OS) and postoperative complication rate. RESULTS: Fifty-seven patients in the TDT group and 114 in the SEMS group were matched. The 3-year RFS rates were 66.7% in the TDT group and 69.9% in the SEMS group (p = 0.54), and the 3-year OS rates were 90.5% in the TDT group and 87.1% in the SEMS group (p = 0.52). No significant differences in the long-term results were observed between the two groups. Regarding short-term results, the SEMS group had significantly fewer stoma construction (p = 0.007) and shorter postoperative hospitalization (p < 0.001). The incidence of postoperative complications (grade ≥ 2) was significantly lower in the SEMS group (p = 0.04). CONCLUSION: No significant differences in the long-term results were observed between the TDT and SEMS group. The SEMS showed significant usefulness in terms of improving short-term outcomes.

[A Case of HER2-Positive Advanced Gastric Cancer with Liver Metastasis Treated by Laparoscopic Surgery after Chemotherapy and Achieved Pathological Complete Response].

A 77-year-old man presented to our hospital with diarrhea and weight loss. Upper gastrointestinal endoscopy revealed advanced Type 3 gastric cancer measuring 40 mm in the lower greater curvature of the stomach. Biopsy from a gastric tumor revealed moderately differentiated tubular adenocarcinoma overexpressing HER2. Abdominal contrast-enhanced computed tomography(CT)showed multiple liver metastases in S3 and S5. We diagnosed HER2-positive gastric cancer with liver metastasis. Systemic chemotherapy was administrated, with a total of 13 courses of combination therapy with S-1, oxaliplatin and trastuzumab. After chemotherapy, the primary tumor was significantly reduced and liver metastases were almost undetectable. Laparoscopic distal gastrectomy and partial hepatectomy were performed as conversion surgery. The patient was discharged on the 9th day without any postoperative complications. Postoperative pathological findings showed no residual tumor in either gastric and hepatic specimens, and the therapeutic effect of chemotherapy was diagnosed as pathological complete response. We report a case of HER2-positive advanced gastric cancer with multiple liver metastases that achieved a pathologically complete response to chemotherapy followed by conversion surgery. Laparoscopic surgery would be one of an effective option for conversion surgery.

[Indications and Outcomes of Laparoscopic Endoscopic Cooperative Surgery(LECS)for Gastric Gastrointestinal Stromal Tumor].

Laparoscopic and endoscopic cooperative surgery(LECS)for gastric gastrointestinal stromal tumor(GIST)has become a popular surgery with both curability and functional preservation. In this study, we examined the outcomes of 14 patients who underwent classical LECS or CLEAN-NET in our hospital. Until March 2022, classical LECS was performed in patients with intraluminal growth tumors or tumors close to the gastroesophageal junction. After April 2022, classical LECS was performed in patients with intraluminal growth tumors without ulceration, and CLEAN-NET was performed in patients with ulceration or intramural growth tumors. There were 10 males and 4 females with a median age of 80.5 years. Intraluminal growth tumor were 8 patients, close to the gastroesophageal junction tumor were 3, and intramural growth tumor were 4, respectively. Five of these patients had tumors with ulceration. Classical LECS was performed in 10 patients and CLEAN-NET in 4 patients, and the median operative time was 165.5 minutes. All patients underwent R0 resection, and no postoperative complications or recurrences were observed. LECS was performed safely, and it is important to select the surgical procedure according to the tumor site and growth type.

[A Case of Local Recurrence of Esophageal Cancer after Chemoradiation Therapy Successfully Treated with Nivolumab].

We report a case of a patient with locally recurrent esophageal cancer after chemoradiation therapy(CRT)who responded to nivolumab. The patient was an 86-year-old man with advanced esophageal cancer. Upper gastrointestinal endoscopy (EGD)revealed a type 2 lesion in the middle thoracic esophagus, and biopsy revealed squamous cell carcinoma(SCC). Contrast- enhanced CT showed invasion of the left main bronchi. The patient was diagnosed as Stage Ⅳa advanced esophageal cancer, and was treated with 5-FU plus cisplatin chemotherapy, and 60 Gy of radiation therapy. The tumor disappeared by CT and EGD, and the patient was followed up for observation. The patient experienced a feeling of tightness again, and EGD revealed an ulcerative lesion in the middle thoracic esophagus, and a biopsy detected SCC. Because of the early recurrence after CRT, the patient was judged to be resistant to 5-FU plus cisplatin chemotherapy, and 8 courses of nivolumab were administered as second-line treatment. Follow-up EGD confirmed disappearance of ulcerative lesions, and no tumors have been observed to date.

A Case of Robotic Posterior Rectopexy for Full-thickness Rectal Prolapse.

We describe our experience with robotic posterior rectopexy for a patient with full-thickness rectal prolapse. To our knowledge, this is the first report of such a case in the literature. A 94-year-old woman presented with a history of gradually worsening rectal prolapse. On examination, we found that the rectum was completely prolapsed, and we observed a prolapsed intestinal tract. Surgery was indicated and robotic rectopexy was performed without intraoperative complications. The postoperative course was uneventful, and she was discharged 10 days after the operation. One year later, there were no signs of recurrence. Robotic surgery has become common in recent years. We used robotic surgery for rectopexy, including the suturing procedure. Suturing in robotic surgery is easier than that in laparoscopic surgery, and we demonstrated that robotic rectopexy could be safely and easily performed. The trial was registered in the UMIN clinical trial registry (number 000040378).

Design and Synthesis of Conformationally Constrained RORγt Inverse Agonists.

Retinoic-acid-related orphan receptor γt (RORγt) inverse agonists could be used for the treatment of autoimmune diseases. Previously, we reported a novel quinazolinedione 1 a with a flexible linear linker as a novel RORγt inverse agonist. A U-shaped conformation in the complex structure of 1 a with RORγt protein was confirmed. Further improvement of the pharmacokinetic (PK) profiles was required because of the low drug exposure in mice upon oral administration (mouse AUC of 1 a: 27 ng ⋅ h ⋅ mL-1 at 1 mg ⋅ kg-1 , p.o.). To improve the PK profiles, conformationally constrained U-shaped scaffolds were investigated. As a result, morpholine analogues with improved PK profiles and high potency were successfully identified. The substituent at the N1 position of the quinazoline moiety was also modified, leading to an enhancement of reporter activity. Consequently, compound 43 (N2 -(3-chloro-4-cyanophenyl)-N4 -(3-(cyclopropylmethyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-6-yl)morpholine-2,4-dicarboxamide) exhibited improved drug exposure (mouse AUC: 1289 ng ⋅ h ⋅ mL-1 at 1 mg ⋅ kg-1 , p.o.). In addition, suppression of IL-17A gene expression by IL-23 stimulation in a mouse pharmacodynamics model was observed for 43. The conformation of 43 with RORγt protein was also confirmed as U-shape by X-ray co-crystal structure analysis. The key interaction that boosts potency is also discussed.

Design, Synthesis, and Biological Evaluation of Retinoic Acid-Related Orphan Receptor γt (RORγt) Agonist Structure-Based Functionality Switching Approach from In House RORγt Inverse Agonist to RORγt Agonist.

Retinoic acid receptor-related orphan receptor γt (RORγt) agonists are expected to provide a novel class of immune-activating anticancer drugs via activation of Th17 cells and Tc17 cells. Herein, we describe a novel structure-based functionality switching approach from in house well-optimized RORγt inverse agonists to potent RORγt agonists. We succeeded in the identification of potent RORγt agonist 5 without major chemical structure change. The biochemical response was validated by molecular dynamics simulation studies that showed a helix 12 stabilization effect of RORγt agonists. These results indicate that targeting helix 12 is an attractive and novel medicinal chemistry strategy for switching existing RORγt inverse agonists to agonists.

Biochemical Properties of TAK-828F, a Potent and Selective Retinoid-Related Orphan Receptor Gamma t Inverse Agonist.

BACKGROUND/AIMS: Retinoid-related orphan receptor gamma t (RORγt) is a master regulator of T helper 17 cells that plays a pivotal role in the production of inflammatory cytokines including interleukin (IL)-17. Therefore, RORγt has attracted much attention as a target receptor for the treatment of inflammatory diseases including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, and psoriasis. This study aims to characterize TAK-828F, a potent and selective RORγt inverse agonist. METHODS: The biochemical properties of TAK-828F were evaluated using Time-Resolved Fluorescence Resonance Energy Transfer (TR-FRET) binding assay, surface plasmon resonance (SPR) biosensor assay, cofactor recruitment assay, reporter assay, and IL-17 expression assay. RESULTS: TR-FRET binding assay and SPR biosensor assay revealed rapid, reversible, and high affinity binding of TAK-828F to RORγt. The cofactor recruitment assay showed that TAK-828F inhibited the recruitment of steroid receptor coactivator-1 to RORγt. Furthermore, TAK-828F inhibited the transcriptional activity of human and mouse RORγt with selectivity against human RORα and RORß. TAK-828F also suppressed IL-17 production in Jurkat cells, overexpressing human RORγt. CONCLUSION: These favorable properties will be of advantage in the evaluation of TAK-828F in clinical studies for inflammatory diseases. Furthermore, these findings demonstrate that TAK-828F could serve as a pharmacological tool for further studies of RORγt and inflammatory diseases.

Discovery of [ cis-3-({(5 R)-5-[(7-Fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic Acid (TAK-828F) as a Potent, Selective, and Orally Available Novel Retinoic Acid Receptor-Related Orphan Receptor γt Inverse Agonist.

A series of tetrahydronaphthyridine derivatives as novel RORγt inverse agonists were designed and synthesized. We reduced the lipophilicity of tetrahydroisoquinoline compound 1 by replacement of the trimethylsilyl group and SBDD-guided scaffold exchange, which successfully afforded compound 7 with a lower log  D value and tolerable in vitro activity. Consideration of LLE values in the subsequent optimization of the carboxylate tether led to the discovery of [ cis-3-({(5 R)-5-[(7-fluoro-1,1-dimethyl-2,3-dihydro-1 H-inden-5-yl)carbamoyl]-2-methoxy-7,8-dihydro-1,6-naphthyridin-6(5 H)-yl}carbonyl)cyclobutyl]acetic acid, TAK-828F (10), which showed potent RORγt inverse agonistic activity, excellent selectivity against other ROR isoforms and nuclear receptors, and a good pharmacokinetic profile. In animal studies, oral administration of compound 10 exhibited robust and dose-dependent inhibition of IL-17A cytokine expression in a mouse IL23-induced gene expression assay. Furthermore, development of clinical symptoms in a mouse experimental autoimmune encephalomyelitis model was significantly reduced. Compound 10 was selected as a clinical compound for the treatment of Th17-driven autoimmune diseases.

Identification of novel quinazolinedione derivatives as RORγt inverse agonist.

Novel small molecules were synthesized and evaluated as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of inflammatory and autoimmune diseases. A hit compound, 1, was discovered by high-throughput screening of our compound library. The structure-activity relationship (SAR) study of compound 1 showed that the introduction of a chlorine group at the 3-position of 4-cyanophenyl moiety increased the potency and a 3-methylpentane-1,5-diamide linker is favorable for the activity. The carbazole moiety of 1 was also optimized; a quinazolinedione derivative 18i suppressed the increase of IL-17A mRNA level in the lymph node of a rat model of experimental autoimmune encephalomyelitis (EAE) upon oral administration. These results indicate that the novel quinazolinedione derivatives have great potential as orally available small-molecule RORγt inverse agonists for the treatment of Th17-driven autoimmune diseases. A U-shaped bioactive conformation of this chemotype with RORγt protein was also observed.

Pharmacological inhibitory profile of TAK-828F, a potent and selective orally available RORγt inverse agonist.

Retinoic acid-related orphan receptor γt (RORγt) is a key master regulator of the differentiation and activation of IL-17 producing CD4+ Th17, CD8+ Tc17 and IL-17/IFN-γ co-producing cells (Th1/17 cells). These cells play critical roles in the pathogenesis of autoimmune diseases such as inflammatory bowel disease and multiple sclerosis. Thus, RORγt is an attractive target for the treatment of these diseases. We discovered TAK-828F, an orally available potent and selective RORγt inverse agonist. The inhibitory effect on the activation and differentiation of Th17 cells by TAK-828F was evaluated in mouse and human primary cells. TAK-828F inhibited IL-17 production from mouse splenocytes and human peripheral blood mononuclear cells dose-dependently at concentrations of 0.01-10 µM without affecting the production of IFN-γ. Additionally, TAK-828F strongly inhibited Th17, Tc17 and Th1/17 cells' differentiation from naive T cells and memory CD4+ T cells at 100 nM without affecting Th1 cells' differentiation. In addition, TAK-828F improved Th17/Treg cells' population ratio by inhibiting Th17 cells' differentiation and up-regulating Treg cells. Furthermore, TAK-828F, at 100 nM, reduced the production of Th17-related cytokines (IL-17, IL-17F and IL-22) without affecting IFN-γ production in whole blood. These results demonstrate that TAK-828F has the potent and selective inhibitory activity against RORγt both in mouse and human cells. Additionally, oral administration of TAK-828F showed promising efficacy in naive T cell transfer mouse colitis model. TAK-828F may provide a novel therapeutic option to treat immune diseases by inhibiting Th17 and Th1/17 cells' differentiation and improving imbalance between Th17 and Treg cells.

Discovery of orally efficacious RORγt inverse agonists, part 1: Identification of novel phenylglycinamides as lead scaffolds.

A series of novel phenylglycinamides as retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists were discovered through optimization of a high-throughput screen hit 1. (R)-N-(2-((3,5-Difluoro-4-(trimethylsilyl)phenyl) amino)-1-(4-methoxyphenyl)-2-oxoethyl)-3-hydroxy-N-methylisoxazole-5-carboxamide (22) was identified as one of the best of these compounds. It displayed higher subtype selectivity and specificity over other nuclear receptors and demonstrated in vivo potency to suppress the transcriptional activity of RORγt in a mouse PD (pharmacodynamic) model upon oral administration.

Discovery of orally efficacious RORγt inverse agonists. Part 2: Design, synthesis, and biological evaluation of novel tetrahydroisoquinoline derivatives.

A series of tetrahydroisoquinoline derivatives were designed, synthesized, and evaluated for their potential as novel orally efficacious retinoic acid receptor-related orphan receptor-gamma t (RORγt) inverse agonists for the treatment of Th17-driven autoimmune diseases. We carried out cyclization of the phenylglycinamide core by structure-based drug design and successfully identified a tetrahydroisoquinoline carboxylic acid derivative 14 with good biochemical binding and cellular reporter activity. Interestingly, the combination of a carboxylic acid tether and a central fused bicyclic ring was crucial for optimizing PK properties, and the compound 14 showed significantly improved PK profile. Successive optimization of the carboxylate tether led to the discovery of compound 15 with increased inverse agonistic activity and an excellent PK profile. Oral treatment of mice with compound 15 robustly and dose-dependently inhibited IL-17A production in an IL23-induced gene expression assay.

Identification of 3,4-dihydro-2H-thiochromene 1,1-dioxide derivatives with a phenoxyethylamine group as highly potent and selective α1D adrenoceptor antagonists.

A series of phenoxyethylamine derivatives was designed and synthesized to discover potent and selective human α1D adrenoceptor (α1D adrenergic receptor; α1D-AR) antagonists. Compound 7 was taken from our internal compound collection as an attractive starting point and exhibited moderate binding affinity for α1D-AR and high selectivity against α1A- and α1B-ARs. We focused on modifying the 2-methylsulfonylbenzyl group of 7 to discover novel compounds structurally distinct from other reported α1-AR antagonists containing the phenoxyethylamine motif. Study of structure activity relationship guided by a targeted ligand-lipophilicity efficiency score led to the discovery of a novel scaffold of 3,4-dihydro-2H-thiochromene 1,1-dioxide for selective α1D-AR antagonists. Further optimization studies resulted in the identification of (4S)-N4-[2-(2,5-difluorophenoxy)ethyl]-N6-methyl-3,4-dihydro-2H-thiochromene-4,6-diamine 1,1-dioxide, (S)-41, as a novel, highly potent and selective α1D-AR antagonist. Herein, we provide details of the structure activity relationship of the phenoxyethylamine analog for the potency and selectivity.

[A Case of Long-Term Survival after Gastrectomy and Metachronous Brain Metastasis].

A30 -year-old woman underwent total gastrectomy with D2 lymph node dissection after being diagnosed with clinical T3, N2, M0, Stage III B gastric cancer. The postoperative pathological findings revealed a T3(SE), N2, M0, Stage III B tumor. Headache, dizziness, and vomiting occurred during chemotherapy for peritoneal recurrence, using weekly paclitaxel on days 1, 8, and 15. Head CT showed a solitary tumor with a diameter of 28mm in the cerebellum, as well as cerebellar swelling and hydrocephalus. She underwent an emergency craniotomy and tumor enucleation. Pathological examination revealed a metastatic brain tumor from the gastric cancer. She received 12 courses of CPT-11 plus cisplatin until discontinuation because of an adverse event. The patient is alive 6 years after the diagnosis of the cerebellar metastasis without recurrence.

Usefulness of Surgical Apgar Score on Predicting Survival After Surgery for Gastric Cancer.

BACKGROUND: Complete surgical resection is essential for a cure for most gastric cancer. Recently it was reported that surgical Apgar score (SAS) can predict postoperative complication and that postoperative complication is associated with poor long-term survival. The aim of this study is to assess whether SAS can predict overall survival (OS) after surgery for gastric cancer. METHODS: We retrospectively compared clinicopathological characteristics and survival between high and low SAS score groups in patients who underwent gastrectomy for gastric cancer. RESULTS: Low-scored SAS group (group L) was significantly more common among ASA-PS 2, open approach, total gastrectomy, D2 lymph node dissection, postoperative complication grade 2-4, deep tumor invasion, lymph node metastases, and advanced pathological TNM stage than high-scored SAS group (group H). The 5-year OS of group H and group L were 81.6 and 55.9 %, respectively (p < .001); OS of group L tended to be poorer than that of group H in stage III patients (p = .060) and in stage IV patients (p < .001). In multivariate analysis, pathological stage and SAS were identified as independent predictors for OS. CONCLUSIONS: SAS is useful for predicting survival after surgery for gastric cancer.

[A Case of Rectal Cancer with Unresectable Liver Metastasis Responding to Rechallenge with FOLFIRI].

A 63-year-old man underwent low anterior resection for rectal cancer.A synchronous liver metastasis located in segment 8 was 12 cm in diameter and unresectable due to its proximity to the inferior vena cava(IVC).The postoperative pathological findings revealed a T3(SS), N0, M1(liver)Stage IV tumor, and wild type K-RAS was expressed.We chose FOLFIRI plus cetuximab(Cmab)for first-line chemotherapy.After 6 courses, we changed the molecular target drug from Cmab to bevacizumab( Bmab)because the liver metastasis remained unresectable.The patient had long-term stable disease(SD)for approximately 30 months with the FOLFIRI-based regimen.We then changed the regimen to mFOLFOX6 plus Bmab for second-line, Cmab for third-line, and trifluridine/tipiracil hydrochloride for fourth-line chemotherapy to treat progressive disease(PD).After treatment with these chemotherapies, the patient wished to continue treatment.We restarted FOLFIRI plus Bmab for fifth-line chemotherapy as his general condition was still good.Consequently, his tumor markers levels decreased with stabilization of the disease on CT scans, and he continued therapy for 6 months while maintaining a good quality of life.This case suggested that rechallenge with anti-cancer agents could be effective and improve the prognosis of colorectal cancer patients after using all key drugs.

Easy method for fixation of the anvil using a one-handed sliding-knot technique after laparoscopic total gastrectomy.

INTRODUCTION: When esophagojejunostomy is performed using a circular stapler after laparoscopic total gastrectomy, fixing the anvil to the end of the esophagus is challenging. We describe an easy method for fixation of the anvil using a one-handed sliding-knot technique after the anvil has been inserted into the esophagus. MATERIALS AND SURGICAL TECHNIQUE: After removing the stomach, the main operator makes a whip stitch at the end of the esophagus using a long piece of monofilament string. Both ends of the string are pulled out from the port. A knot is then made and brought close the esophagus twice (sliding granny knots). After inserting the anvil into the esophagus, the main operator pulls the main standing string with one hand, applying vibration only. This causes the knots to tighten the anvil. Then, one or two knots are added to make sure that the anvil is firmly fixed in place. In addition, we routinely add one more ligation with a ready-made ligating loop. DISCUSSION: This method is easy and reliable, and does not require special devices or skills when performing reconstruction after laparoscopic total gastrectomy. Because of these factors, it has the potential to be widely used to perform esophagojejunostomy.

A methylene blue-assisted technique for harvesting lymph nodes after radical surgery for gastric cancer: a prospective, randomized, controlled study.

Harvesting lymph nodes (LNs) after gastrectomy is essential for accurate staging. This trial evaluated the efficiency and quality of a conventional method and a methylene blue-assisted method in a randomized manner. The key eligibility criteria were as follows: (i) histologically proven adenocarcinoma of the stomach; (ii) clinical stage I-III; (iii) R0 resection planned by gastrectomy with D1+ or D2 lymphadenectomy. The primary endpoint was the ratio of the pathologic number of harvested LNs per time (minutes) as an efficacy measure. The secondary endpoint was the number of harvested LNs, as a quality measure. Between August 2012 and December 2012, 60 patients were assigned to undergo treatment using the conventional method (n=29) and the methylene blue dye method (n=31). The baseline demographics were mostly well balanced between the 2 groups. The number of harvested LNs (mean±SD) was 33.6±11.9 in the conventional arm and 43.4±13.9 in the methylene blue arm (P=0.005). The ratio of the number of the harvested LNs per time was 1.12±0.46 LNs/min in the conventional arm and 1.49±0.59 LNs/min in the methylene blue arm (P=0.010). In the subgroup analyses, the quality and efficacy were both superior for the methylene blue dye method compared with the conventional method. The methylene blue technique is recommended for harvesting LNs during gastric cancer surgery on the basis of both the quality and efficacy.