Feasibility of robotic-assisted surgery in advanced rectal cancer: a multicentre prospective phase II study (VITRUVIANO trial).

BACKGROUND: The potential benefits of robotic-assisted compared with laparoscopic surgery for locally advanced cancer have not been sufficiently proven by prospective studies. One factor is speculated to be the lack of strict surgeon criteria. The aim of this study was to assess outcomes for robotic surgery in patients with locally advanced rectal cancer with strict surgeon experience criteria. METHODS: A criterion was set requiring surgeons to have performed more than 40 robotically assisted operations for rectal cancer. Between March 2020 and May 2022, patients with rectal cancer (distance from the anal verge of 12 cm or less, cT2-T4a, cN0-N3, cM0, or cT1-T4a, cN1-N3, cM0) were registered. The primary endpoint was the rate positive circumferential resection margin (CRM) from the pathological specimen. Secondary endpoints were surgical outcomes, pathological results, postoperative complications, and longterm outcomes. RESULTS: Of the 321 registered patients, 303 were analysed, excluding 18 that were ineligible. At diagnosis: stage I (n = 68), stage II (n = 84) and stage III (n = 151). Neoadjuvant therapy was used in 56 patients. There were no conversions to open surgery. The median console time to rectal resection was 170 min, and the median blood loss was 5 ml. Fourteen patients had a positive CRM (4.6%). Grade III-IV postoperative complications were observed in 13 patients (4.3%). CONCLUSION: Robotic-assisted surgery is feasible for locally advanced rectal cancer when strict surgeon criteria are used.

Recurrence of rectal cancer on the pelvic sidewall after lateral lymph node dissection.

PURPOSE: Although lateral lymph node dissection has been performed to prevent lateral pelvic recurrence in locally advanced lower rectal cancer, the incidence of lateral pelvic recurrence after this procedure has not been investigated. Therefore, this study aimed to investigate the long-term outcomes of patients who underwent lateral pelvic lymph node dissection, with a particular focus on recurrence patterns. METHODS: This was a retrospective study conducted at a single high-volume cancer center in Japan. A total of 493 consecutive patients with stage II-III rectal cancer who underwent lateral lymph node dissection between January 2005 and August 2022 were included. The primary outcome measures included patterns of recurrence, overall survival, and relapse-free survival. Patterns of recurrence were categorized as lateral or central pelvic. RESULTS: Among patients who underwent lateral lymph node dissection, 18.1% had pathologically positive lateral lymph node metastasis. Lateral pelvic recurrence occurred in 5.5% of patients after surgery. Multivariate analysis identified age > 75 years, lateral lymph node metastasis, and adjuvant chemotherapy as independent risk factors for lateral pelvic recurrence. Evaluation of the recurrence rate by dissection area revealed approximately 1% of recurrences in each area after dissection. CONCLUSION: We demonstrated the prognostic outcome and limitations of lateral lymph node dissection for patients with advanced lower rectal cancer, focusing on the incidence of recurrence in the lateral area after the dissection. Our study emphasizes the clinical importance of lateral lymph node dissection, which is an essential technique that surgeons should acquire.

Hazard function analysis of prognosis after recurrent colorectal cancer.

BACKGROUND AND OBJECTIVES: Mean survival time (MST) is used as the indicator of prognosis in patients with a colorectal cancer (CRC) recurrence. The present study aimed to visualize the changes in death risk after a CRC recurrence using hazard function analysis (HFA) to provide an alternative prognostic indicator to MST. METHODS: The medical records of 725 consecutive patients with a recurrence following R0 radical surgery for CRC were retrospectively reviewed. RESULTS: The five-year, post-recurrence survival rate was 37.8%, and the MST was 3.5 years while the risk of death peaked at 2.9 years post-recurrence. Seven variables were found to predict short-term survival, including the number of metastatic organs ≥ 2, non-surgical treatment for the recurrence, and a short interval before recurrence. In patients with a recurrence in one organ, the MST was four years, the peak time of death predicted by HFA was 2.9 years, and the five-year survival rate was 45.8%. In patients with a surgical resection of the recurrence, the MST was 8 years, the peak time of death was 3.3 years, and the five-year survival rate was 62%. CONCLUSIONS: The present study established a novel method of assessing changes in mortality risk over time using HFA in patients with a CRC recurrence.

Modified neoadjuvant rectal score as a novel prognostic model for rectal cancer patients who underwent chemoradiotherapy.

BACKGROUND: The neoadjuvant rectal score (NAR score) has recently been proposed as a better prognostic model than the conventional TNM classification for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy. We recently developed an apoptosis-detection technique for assessing the viability of residual tumors in resected specimens after chemoradiotherapy. This study aimed to establish an improved prognostic classification by combining the NAR score and the assessment of the apoptosis of residual cancer cells. METHODS: We retrospectively enrolled 319 rectal cancer patients who underwent chemoradiotherapy followed by radical surgery. The recurrence-free survival and overall survival of the four models were compared: TNM stage, NAR score, modified TNM stage by re-staging according to cancer cell viability, and modified NAR score also by re-staging. RESULTS: Downstaging of the ypT stage was observed in 15.5% of cases, whereas only 4.5% showed downstaging of ypN stage. C-index was highest for the modified NAR score (0.715), followed by the modified TNM, TNM, and NAR score. Similarly, Akaike's information criterion was smallest in the modified NAR score (926.2), followed by modified TNM, TNM, and NAR score, suggesting that the modified NAR score was the best among these four models. The overall survival results were similar: C-index was the highest (0.767) and Akaike's information criterion was the smallest (383.9) for the modified NAR score among the four models tested. CONCLUSION: We established a novel prognostic model, for rectal cancer patients that have undergone neoadjuvant chemoradiotherapy, using a combination of apoptosis-detecting immunohistochemistry and neoadjuvant rectal scores.

Clinicopathological characteristics of Lynch-like syndrome.

BACKGROUND: Lynch-like syndrome (LLS) has recently been proposed as a third type of microsatellite instability (MSI) tumor after Lynch syndrome (LS) and sporadic MSI colorectal cancer (CRC) without either a germline variant of mismatch repair (MMR) genes or hypermethylation of the MLH1 gene. The present study aimed to clarify and compare the clinicopathological characteristics of LLS with those of the other MSI CRC subtypes. METHODS: In total, 2634 consecutive patients with CRC who underwent surgical resection and subsequently received universal tumor screening (UTS), including MSI analysis were enrolled between January 2008 and November 2019. Genetic testing was performed in patients suspected of having Lynch syndrome. RESULTS: UTS of the cohort found 146 patients with MSI CRC (5.5%). Of these, excluding sporadic MSI CRC, 30 (1.1%) had a diagnosis of LS, and 19 (0.7%) had no germline pathogenic variants of the MMR gene. The CRC type in the latter group was identified as LLS. LLS occurred significantly more often in young patients, was left-sided, involved a KRAS variant and BRAF wild-type, and had a higher concordance rate with the Revised Bethesda Guidelines than sporadic MSI CRC. No significant differences were observed in terms of the clinicopathological factors between LLS and LS-associated MSI CRC; however, LLS had a lower frequency of LS-related neoplasms compared with LS. CONCLUSIONS: Distinguishing clinically between LS and LLS was challenging, but the incidence of neoplasms was higher in LS than in LLS, suggesting the need for different screening and surveillance methods for the two subtypes.

A rare case of localized peliosis hepatis during adjuvant chemotherapy including oxaliplatin mimicking a liver metastasis of colon cancer.

BACKGROUND: Oxaliplatin-based regimens are commonly used as adjuvant chemotherapy following surgery for colorectal cancer. Adverse events associated with oxaliplatin include blue liver, which is caused by sinusoidal dilation and diffuse peliosis hepatis. We report herein a case of localized peliosis hepatis closely resembling a metastatic liver tumor. CASE PRESENTATION: The patient, a 50-year-old male, underwent a robotically assisted colectomy for rectosigmoid colon cancer, which was discovered when hematochezia occurred. The patient received a diagnosis of pStage IIIb and was treated with four courses of CAPOX as adjuvant chemotherapy starting at postoperative month 1. At postoperative month 4, contrast-enhanced computed tomography (CT) of the abdomen revealed a 20-mm, low-density area with heterogeneous internal structure in S6/7 of the liver. Abdominal ultrasound and gadolinium ethoxybenzyl-diethylenetriaminepentaacetic acid-enhanced magnetic resonance imaging (EOB-MRI) findings led to a diagnosis of metastatic liver tumor, for which a laparoscopic partial hepatectomy was performed. The resected lesion was a dark reddish-brown nodule with indistinct margins that appeared to be continuous with the surrounding area. Histopathological analysis revealed severe, localized dilatation of the sinusoids and congestion consistent with the gross nodule. Based on these findings, localized peliosis hepatis associated with oxaliplatin-induced sinusoidal damage was diagnosed. CONCLUSIONS: Localized peliosis hepatis associated with oxaliplatin use can be difficult to distinguish from a metastatic liver tumor on imaging studies.

Screening of promising chemotherapeutic candidates from plants against human adult T-cell leukemia/lymphoma (VIII): six new withanolides from Physalis philadelphica.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature peripheral T-lymphocytes caused by human T-cell leukemia virus type I (HTLV-I). There are an estimated 5-20 million HTLV-1-infected individuals worldwide. Conventional chemotherapeutic regimens used against other malignant lymphomas have been administered to patients with ATL, but the therapeutic outcomes of acute and lymphoma-type ATL remain extremely poor. In the course of our screening program for novel chemotherapeutic candidate compounds from plants against two human T-cell leukemia virus I-infected T-cell lines (MT-1 and MT-2), we screened 16 extracts obtained from different parts of 7 Solanaceae plants. We identified that the extracts of Physalis pruinosa and P. philadelphica showed potent anti-proliferative activity in MT-1 and MT-2 cells. In our previous study, we have isolated withanolides from extract of aerial parts of P. pruinosa and examined their structure-activity relationships. In addition, we are also investigating further structure-activity relationships about other withanolides from Solanaceae plants (Withania somnifera, Withania coagulans, Physalis angulate, Nicandra physalodes, Petunia hybrida, and Solanum cilistum). In this study, we attempted to isolate their active compounds against MT-1 and MT-2 from extracts of P. philadelphica. We identified 13 withanolides, including six newly isolated compounds [24R, 25S-4ß, 16ß, 20R-trihydroxy-1-oxowitha-2-en-5ß, 6 ß -epoxy-22,26-olide (1), 4ß, 7ß,20R-trihydroxy-1-oxowitha-2-en-5ß, 6ß -epoxy-22,26-olide (2), 17ß,20 S-dihydroxywithanone (3), 2,3-dihydro-3ß-methoxy-23ß-hydroxywithaphysacarpin (4), 3-O-(4-rhamnosyl)glucosyl-physalolactone B (5), and 17R, 20R, 22S, 23S, 24R, 25R-4ß, 5α, 6ß, 20ß, 22α -tetrahydroxy-16ß, 23-diepoxy-1-oxowitha-2-en-26, 23-olide (6)], from the extract and examined the structure-activity relationships. The 50% effective concentration of withaphysacarpin (compound 7) [MT-1: 0.10 µM and MT-2: 0.04 µM] was comparable to that of etoposide [MT-1: 0.08 µM and MT-2: 0.07 µM]. Therefore, withanolides might be promising candidates for the treatment of ATL.

Vasoactive intestinal peptide blockade suppresses tumor growth by regulating macrophage polarization and function in CT26 tumor-bearing mice.

Macrophages are a major population of immune cells in solid cancers, especially colorectal cancers. Tumor-associated macrophages (TAMs) are commonly divided into M1-like (tumor suppression) and M2-like (tumor promotion) phenotypes. Vasoactive intestinal peptide (VIP) is an immunoregulatory neuropeptide with a potent anti-inflammatory function. Inhibition of VIP signaling has been shown to increase CD8+ T cell proliferation and function in viral infection and lymphoma. However, the role of VIP in macrophage polarization and function in solid tumors remains unknown. Here, we demonstrated that conditioned medium from CT26 (CT26-CM) cells enhanced M2-related marker and VIP receptor (VPAC) gene expression in RAW264.7 macrophages. VIP hybrid, a VIP antagonist, enhanced M1-related genes but reduced Mrc1 gene expression and increased phagocytic ability in CT26-CM-treated RAW264.7 cells. In immunodeficient SCID mice, VIP antagonist alone or in combination with anti-PD-1 antibody attenuated CT26 tumor growth compared with the control. Analysis of tumor-infiltrating leukocytes found that VIP antagonist increased M1/M2 ratios and macrophage phagocytosis of CT26-GFP cells. Furthermore, Vipr2 gene silencing or VPAC2 activation affected the polarization of CT26-CM-treated RAW264.7 cells. In conclusion, the inhibition of VIP signaling enhanced M1 macrophage polarization and macrophage phagocytic function, resulting in tumor regression in a CT26 colon cancer model.

Simultaneous SGLT2 inhibition and caloric restriction improves insulin resistance and kidney function in OLETF rats.

SGLT2 inhibitors (SGLT2i) are emerging as a novel therapy for type 2 diabetes due to their effective hypoglycemic and potential cardio- and nephroprotective effects, while caloric restriction (CR) is a common behavioral modification to improve adiposity and insulin resistance. Therefore, both interventions simultaneously may potentially further improve metabolic syndrome by enhancing carbohydrate metabolism. To test this hypothesis, cohorts of 10-week old, male Long Evans Tokushima Otsuka (LETO) and Otsuka Long Evans Tokushima Fatty (OLETF) rats were treated with SGLT2i (10 mg luseoglifozin/kg/day x 4 wks) (OLETF only) and/or 30% CR (2 wks at 12 weeks of age). CR maintained body mass in both strains while SGLT2i alone did not have any effect on body mass. Simultaneous treatments decreased SBP in OLETF vs SGLT2i alone, decreased insulin resistance index (IRI), and increased creatinine clearance vs OLETF ad lib. Conversely, CR decreased albuminuria independent of SGLT2i. In conclusion, SGLT2i treatment by itself did not elicit significant improvements in insulin resistance, kidney function or blood pressure. However, when combined with CR, these changes where more profound than with CR alone without inducing chronic hypoglycemia.

Contributions of renal water loss and skin water conservation to blood pressure elevation in spontaneously hypertensive rats.

We recently reported that skin vasoconstriction to suppress transepidermal water loss (TEWL) leads to hypertension in renal injury model rats with impaired urine concentration ability. In this study, we investigated the pathogenesis of hypertension in spontaneously hypertensive rats (SHRs) from the perspective of renal water loss and skin water conservation. We compared the urinary concentration ability, body sodium and water balance, blood pressure, and TEWL in SHRs and control normotensive Wistar-Kyoto rats (WKYs). SHRs showed significantly higher urine volume and lower urinary osmolality than those of WKYs, while there were no significant differences in water intake, urinary osmolyte excretion, and plasma osmolarity between the groups. SHRs exhibited significantly higher blood pressure, skin sodium content, and lower TEWL compared with those is WKYs. Skin vasodilation, induced by elevating body temperature, increased TEWL in both SHRs and WKYs, and significantly reduced blood pressure in SHRs but not WKYs. These findings suggest that physiological adaptation can reduce dermal water loss in SHRs to compensate for renal water loss. Vasoconstriction required for successful cutaneous water conservation explains SHR hypertension. Renal concentration ability and skin barrier function for water conservation may become a novel therapeutic target for essential hypertension.

Multicentre single-arm phase II trial evaluating the safety and effiCacy of Panitumumab and iRinOtecan in NeoRAS Wild-type mEtaStatic colorectal cancer patientS (C-PROWESS trial): study protocol.

INTRODUCTION: A new concept of 'NeoRAS wild-type (WT)', which means conversion of RAS status from RAS mutant to RAS WT after treatment, has been reported. Previous observational and proof-of-concept studies have demonstrated the efficacy of epidermal growth factor receptor inhibitors in patients with NeoRAS WT metastatic colorectal cancer (mCRC). Moreover, posthoc biomarker analyses of these studies have suggested that not only the RAS status in the circulating tumour DNA (ctDNA) but also other gene mutational status may be useful as biomarkers of epidermal growth factor receptor inhibitors for NeoRAS WT mCRC. METHODS AND ANALYSIS: This trial is a multicentre, single-arm, phase II trial to assess the efficacy and safety of panitumumab plus irinotecan therapy for patients with NeoRAS mCRC. The key eligibility criteria include RAS mutant mCRC initially proven in tumour tissue refractory or intolerant to fluoropyrimidine, oxaliplatin and irinotecan; RAS WT in ctDNA (defined as plasma mutant allele frequencies of all RAS ≤0.1%) within 28 days before enrolment and Eastern Cooperative Oncology Group performance status ≤2. The primary endpoint is the response rate. The target sample size is 30 patients. Biomarker analyses are planned to be performed using next-generation sequencing-based ctDNA analysis. ETHICS AND DISSEMINATION: This study was approved by the certified review board of National Cancer Center Hospital. The main results of the trial will be presented in international meetings and in medical journals. TRIAL REGISTRATION NUMBER: s031210565.

Japanese multicenter prospective study investigating laparoscopic surgery for locally advanced rectal cancer with evaluation of CRM and TME quality (PRODUCT trial).

Aim: In Japan, we have not been able to validate the results of laparoscopic surgery for locally advanced rectal cancer using the universal index "circumferential resection margin (CRM)." Previously, we established a semi-opened circular specimen processing method and validated its feasibility. In the PRODUCT trial, we aimed to assess CRM in patients with locally advanced rectal cancer who underwent laparoscopic rectal resection. Methods: This was a multicenter, prospective, observational study. Eligible patients had histologically confirmed rectal adenocarcinoma located at or below 12 cm above the anal verge with clinical stage II or III and were scheduled for laparoscopic or robotic surgery. The primary endpoint was pathological CRM. CRM ≤1 mm was defined as positive. Results: A total of 303 patients operated on between August 2018 and January 2020 were included in the primary analysis. The number of patients with clinical stage II and III was 139 and 164, respectively. Upfront surgery was performed for 213 patients and neoadjuvant therapy for 90 patients. The median CRM was 4.0 mm (IQR, 2.1-8.0 mm), and CRM was positive in 26 cases (8.6%). Univariate and multivariate analyses demonstrated that a predicted CRM from the mesorectal fascia of ≤1 mm on MRI was the significant factor for positive CRM (P = .0012 and P = .0045, respectively). Conclusion: This study showed the quality of laparoscopic rectal resection based on the CRM in Japan. Preoperative MRI is recommended for locally advanced rectal cancer to prevent CRM positivity.

Glucose Increases Hepatic Mitochondrial Antioxidant Enzyme Activities in Insulin Resistant Rats Following Chronic Angiotensin Receptor Blockade.

Non-alcoholic fatty liver disease (NAFLD) affects up to 20% of the world's population. Overactivation of the angiotensin receptor type 1 (AT1) contributes to metabolic dysfunction and increased oxidant production, which are associated with NAFLD and impaired hepatic lipid metabolism. Nuclear factor erythroid-2-related factor 2 (Nrf2) regulates the expression of antioxidant phase II genes by binding to the antioxidant response element (ARE); however, the mechanisms by which AT1 contributes to this pathway during the progression of NAFLD remain unresolved. To investigate hepatic Nrf2 response to a hyperglycemic challenge, we studied three groups of rats (male, 10-weeks-old): (1) untreated, lean Long Evans Tokushima Otsuka (LETO), (2) untreated, obese Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + angiotensin receptor blocker (OLETF + ARB; 10 mg olmesartan/kg/d × 6 weeks). Livers were collected after overnight fasting (T0; baseline), and 1 h and 2 h post-oral glucose load. At baseline, chronic AT1 blockade increased nuclear Nrf2 content, reduced expression of glutamate-cysteine ligase catalytic (GCLC) subunit, glutathione peroxidase 1 (GPx1), and superoxide dismutase 2 (SOD2), mitochondrial catalase activity, and hepatic 4-hydroxy-2-nonenal (4-HNE) content. The expression of hepatic interleukin-1 beta (IL-1ß) and collagen type IV, which are associated with liver fibrosis, were decreased with AT1 blockade. Glucose increased Nrf2 translocation in OLETF but was reduced in ARB, suggesting that glucose induces the need for antioxidant defense that is ameliorated with ARB. These results suggest that overactivation of AT1 promotes oxidant damage by suppressing Nrf2 and contributing to hepatic fibrosis associated with NAFLD development.

Improved lipogenesis gene expression in liver is associated with elevated plasma angiotensin 1-7 after AT1 receptor blockade in insulin-resistant OLETF rats.

Increased angiotensin II (Ang II) signaling contributes to insulin resistance and liver steatosis. In addition to ameliorating hypertension, angiotensin receptor blockers (ARBs) improve lipid metabolism and hepatic steatosis, which are impaired with metabolic syndrome (MetS). Chronic blockade of the Ang II receptor type 1 (AT1) increases plasma angiotensin 1-7 (Ang 1-7), which mediates mechanisms counterregulatory to AT1 signaling. Elevated plasma Ang 1-7 is associated with decreased plasma triacylglycerol (TAG), cholesterol, glucose, and insulin; however, the benefits of RAS modulation to prevent non-alcoholic fatty liver disease (NAFLD) are not fully investigated. To better address the relationships among chronic ARB treatment, plasma Ang 1-7, and hepatic steatosis, three groups of 10-week-old-rats were studied: (1) untreated lean Long Evans Tokushima Otsuka (LETO), (2) untreated Otsuka Long Evans Tokushima Fatty (OLETF), and (3) OLETF + ARB (ARB; 10 mg olmesartan/kg/d × 6 weeks). Following overnight fasting, rats underwent an acute glucose load to better understand the dynamic metabolic responses during hepatic steatosis and early MetS. Tissues were collected at baseline (pre-load; T0) and 1 and 2 h post-glucose load. AT1 blockade increased plasma Ang 1-7 and decreased liver lipids, which was associated with decreased fatty acid transporter 5 (FATP5) and fatty acid synthase (FASN) expression. AT1 blockade decreased liver glucose and increased glucokinase (GCK) expression. These results demonstrate that during MetS, overactivation of AT1 promotes hepatic lipid deposition that is stimulated by an acute glucose load and lipogenesis genes, suggesting that the chronic hyperglycemia associated with MetS contributes to fatty liver pathologies via an AT1-mediated mechanism.

Safety, efficacy, and operability of a newly developed absorbable adhesion barrier (GM142) in patients with primary rectal cancer scheduled for diverting ileostomy during laparoscopic surgery: Randomized controlled trial.

Aim: The aim of this study was to compare the outcomes of GM142, a newly developed gelatin film with a concave and convex structure to a commercially available conventional film, hyaluronate-carboxymethylcellulose. Methods: Patients with primary rectal cancer who were scheduled for diverting ileostomy during laparoscopic surgery were eligible for this study. Patients were randomized before surgery and an antiadhesion film was applied under the umbilical incision. The primary outcome was the incidence of adhesion under the midline incision confirmed by second-look surgery for diverting ileostomy closure. The secondary outcomes were the adhesion severity score, the extent of adhesion score, the presence of intestinal obstruction, and the success of all patching. Results: A total of 146 patients were enrolled. A total of 123 patients were included in the full analysis set. The primary outcome of "no adhesion" was observed in 66.1% in the GM142 group and 55.7% in the conventional film group. The noninferiority of GM142 to conventional film was confirmed (P = .0005). The secondary outcomes were similar between the groups. For the safety evaluation, there were no safety concerns regarding allergic reactions to gelatin or increased gelatin-specific IgE antibody titers. Conclusions: The noninferiority of GM142 to conventional film was shown. GM142 showed no major safety issues. The clinical safety profiles of GM142 suggested certain physiological benefits of the gelatin film as an adhesion barrier.

Glomerular deposition of galactose-deficient IgA1-containing immune complexes via glomerular endothelial cell injuries.

BACKGROUND: Galactose-deficient immunoglobulin A1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathological role of Gd-IgA1-containing immune complexes (ICs) and the mechanism of deposition in the mesangial region remain unclear. METHODS: To examine the deposition of Gd-IgA1-containing ICs in the mesangial region through glomerular endothelial cell injury, we evaluated the alteration of renal microvascular endothelial glycocalyx in nude mice injected with Gd-IgA1-IgG ICs. Human renal glomerular endothelial cells (HRGECs) were used to assess the potential capacity of Gd-IgA1-IgG ICs to activate endothelial cells. RESULTS: Nude mice injected with Gd-IgA1-containing ICs showed podocyte and endothelial cell injuries, with IgA, IgG and C3 depositions in glomerular capillaries and the mesangium. Moreover, albuminuria and hematuria were induced. Real-time glycocalyx imaging showed that renal microvascular glycocalyx was decreased immediately after injection of Gd-IgA1-containing ICs and then mesangial IgA deposition was increased. After coculture of Gd-IgA1-containing ICs with HRGECs, messenger RNA expression levels of endothelial adhesion molecules and proinflammatory mediators were upregulated significantly. CONCLUSION: Gd-IgA1-IgG ICs had a high affinity for glomerular endothelial cells, which resulted in glomerular filtration barrier dysfunction mediated by glycocalyx loss. Furthermore, Gd-IgA1-IgG ICs accelerated the production of adhesion factors and proinflammatory cytokines in glomerular endothelial cells. The glomerular endothelial cell injury induced by Gd-IgA1-containing ICs may enhance the permeability of Igs in the mesangial region and subsequent inflammatory responses in the pathogenesis of IgAN.

Tolvaptan induces body fluid loss and subsequent water conservation in normal rats.

We have recently reported that the urea osmolyte-associated water conservation system is activated in fluid loss models such as high salt-induced natriuresis, renal injury-induced impaired renal concentrating ability, or skin barrier dysfunction-induced transepidermal water loss. The system consists of the interaction of multiple organs including renal urea recycling, hepato-muscular ureagenesis, and suppression of cardiovascular energy expenditure. Here, we determined the effect of pharmacological fluid loss induced by tolvaptan, a selective vasopressin V2 receptor antagonist, on water conservation. We evaluated the water conservation system in rats that consumed a control diet or a diet containing 0.1% tolvaptan. Tolvaptan increased urine volume on day 1, but this renal water loss then gradually decreased. Body water and osmolyte content were decreased by tolvaptan on day 1 but had normalized by day 7. Tolvaptan induced fluid loss on day 1, and the following restoration of body fluid on day 7 was associated with an increase in urea transporter A1-associated renal urea recycling. Tolvaptan did not affect hepato-muscular ureagenesis on day 1 and day 7, or cardiovascular energy expenditure during treatment. Thus, tolvaptan-induced fluid loss leads to activation of the water conservation system via renal urea recycling.

Hepatocellular carcinoma induces body mass loss in parallel with osmolyte and water retention in rats.

AIMS: The number of cancer survivors with cardiovascular disease is increasing. However, the effect of cancer on body fluid regulation remains to be clarified. In this study, we evaluated body osmolyte and water imbalance in rats with hepatocellular carcinoma. MAIN METHODS: Wistar rats were administered diethylnitrosamine, a carcinogenic drug, to establish liver cancer. We analyzed tissue osmolyte and water content, and their associations with aldosterone secretion. KEY FINDINGS: Hepatocellular carcinoma rats had significantly reduced body mass and the amount of total body sodium, potassium, and water. However, these rats had significantly increased relative tissue sodium, potassium, and water content per tissue dry weight. Furthermore, these changes in sodium and water balance in hepatocellular carcinoma rats were significantly associated with increased 24-h urinary aldosterone excretion. Supplementation with 0.25% salt in drinking water improved body weight reduction associated with sodium and water retention in hepatocellular carcinoma rats, which was suppressed by treatment with spironolactone, a mineralocorticoid receptor antagonist. Additionally, the urea-driven water conservation system was activated in hepatocellular carcinoma rats. SIGNIFICANCE: These findings suggest that hepatocellular carcinoma induces body mass loss in parallel with activation of the water conservation system including aldosterone secretion and urea accumulation to retain osmolyte and water. The osmolyte and water retention at the tissue level may be a causative factor for ascites and edema formation in liver failure rats.

Guidewire-assisted over-the-scope clip delivery method into the distal intestine: a case series.

BACKGROUND: The Over-the-scope clip (OTSC) has been recently introduced for multiple purposes, including refractory bleeding, perforation, fistula, and anastomotic dehiscence of the gastrointestinal tract. However, no easy access techniques for delivering OTSCs to distant sites have been described. Therefore, we have developed a simple and safe guidewire-assisted OTSC delivery (GOD) method for use on the distal intestine. This study aimed to investigate the technical feasibility and safety of the method. MATERIAL AND METHODS: Between June 2018 and April 2019, all eight patients who underwent the GOD method were retrospectively examined. The primary outcome was the successful rate of OTSC delivery to the lesion without complications. The secondary outcomes were GOD procedure time, total procedure time, technical and clinical OTSC success rates, and GOD- and OTSC-associated complications. RESULTS: The rate of successful OTSC delivery was 100%. The median procedure time of GOD was 21 min (range 8-29). The median total procedure time was 38.5 min (range 26-41). The technical and clinical success rates of OTSC were 100% and 75% (6/8), respectively. No GOD- or OTSC-associated complications occurred. CONCLUSIONS: The GOD method is a feasible and safe technique for delivering OTSC toward the small and proximal large intestine.

Long-term outcomes of over-the-scope clip for refractory gastrointestinal diseases.

BACKGROUND: The Over-The-Scope Clip (OTSC) can effectively treat refractory gastrointestinal diseases. However, most reports have focused on short-term effectiveness. We examined clinical outcomes of the deployed clips and long-term characteristics. MATERIAL AND METHODS: Of 47 patients with OTSC treatment, 35 with follow-up periods of ≥3 months were retrospectively examined. The indications were 11 bleedings, 17 perforations, and seven fistulas. The observation period was defined as medium-term (3 to <12 months) or long-term (≥12 months). The primary outcome was the clinical success rate without disease recurrence. The secondary outcomes were the complication rate, survival duration, and clip retention rate. RESULTS: The medium- and long-term clinical success rates were 100% during the observation period (median, 44 months; range, 3-78 months). The complication rate was 2.9% (n = 1). The median survival time was 1,634 days for bleeding, 1,757 days for perforation, and 444 days for fistulas. The overall clip retention rates were 56.4%, 38.1%, 30.9%, and 25.9% after one, six, and 12 months and at the final follow-up, respectively. The average clip retention duration was 244 days in bleeding, 656 days in perforations, and 188 days in fistulas. CONCLUSIONS: Regardless of clip detachment, the OTSC can be effective in long-term.