Robotic surgery after total neoadjuvant therapy for rectal cancer: pitfalls of beyond total mesorectal excision for patients with sidewall invasion.

AIM: Total neoadjuvant therapy (TNT) for locally advanced rectal cancer (LARC) is rapidly spreading. The robotic surgical techniques to approach lateral invasion, such as that of the pelvic plexus, have not yet been established. In this technical note, we present a video illustrating a surgical technique for lateral invasion using our novel technique and discuss its pitfalls. METHOD: We present the case of a 65-year-old man with LARC. Robotic surgery was performed after TNT using the da Vinci Xi Surgical System (Intuitive Surgical Inc., Sunnyvale, CA, USA). The surgical procedure was as follows: (1) D3 lymph node dissection around the inferior mesenteric artery using a medial-to-lateral approach; (2) rectal mobilization; (3) dissection of the ureterohypogastric fascia and ureter; and (4) combined resection of the hypogastric nerve and pelvic plexus. The key surgical point for sidewall invasion is the resection extent. Dividing the resection extent into three areas is important: zone A, which contains the pelvic plexus and is closest to the tumour; zone B, which contains the iliac vessels; and zone C, the most lateral zone, which contains the obturator nerves. This allows organ and function preservation by resecting only the smallest organ that truly requires R0 resection. RESULTS: The operating time was 333 min, console time was 232 min, and blood loss was 0 mL. The circumferential resection margin was 10 mm, and an R0 resection was achieved. CONCLUSION: We introduced a novel approach for robotic surgery after TNT for LARC with sidewall invasion. This technique can be performed safely and may help standardize 'beyond total mesorectal excision'.

[A Case of Desmoid-Type Fibromatosis of the Mesentery of Small Intestine].

Desmoid-type fibromatosis is a relatively rare disease, often associated with familial adenomatous polyposis and a history of abdominal surgery. A 43-year-old male patient presented with abdominal pain and contrast-enhanced CT showed a mass in the lower abdomen. The mass was a 4×4×3 cm white, dense tumor with a wreath-like arrangement of eosinophilic spindle-shaped cells. Immunostaining showed KIT(-), CD34(-), desmin(-), ß-catenin(+), SMA(few+), and the diagnosis was desmoid-type fibrosis. Six months after surgery, there was no apparent recurrence.

Insights on hazardous metal bioaccessibility, and groundwater impacted by Zn residues from a legacy mine and risk evaluation of adjacent soils.

This study explored the legacy impact of Zinc plant residues (ZPRs) in Kabwe, Zambia, on the environment and human health, particularly in light of the town's reputation for Pb pollution. ZPRs solid samples and groundwater within and around ZPRs zone were collected from the legacy mine, along with soils in a 10 km radius from the mine site. Bioaccessible fractions of Pb and Zn were elucidated by Japanese leaching test (JLT) and simple bioaccessibility extraction test (SBET). Cationic speciation of Pb and Zn from inhalable and ingestible ZPRs particles was investigated via sequential extraction. Groundwater in the ZPRs area showed higher Zn levels (1490 mg/L) compared to Pb (1.7 mg/L). Elevated Zn concentration were facilitated by the presence of soluble Zn sulfates while Pb was constrained due to its precipitation as anglesite. Groundwater sampled outside the ZPRs area was within the Zambia regulatory limits (< 0.5 mg/L for Pb and < 1 mg/L for Zn). Inhalation exposure to < 30 µm dust particles from ZPRs and soils near the mine indicated negligible risk, with < 3% of bioaccessible Pb in artificial lysosomal fluid. Meanwhile, oral intake of ZPRs particles < 250 µm revealed elevated bioaccessible fractions (36% for Pb and 70% for Zn). ZPRs cationic speciation of ingestible particles < 30 µm, 30-75 µm, 75-150 µm and 150-250 µm indicated that the bioaccessible Pb predominantly emanated from labile Pb fractions under gastric conditions with pH < 1. This was due to the dissolution of Pb associated with the exchangeable phase, carbonates and iron/manganese oxides; however, only exchangeable/carbonate Pb was bioaccessible at pH < 2. Hazard quotients indicated increased risks of Pb intoxication through the ingestion of ZPRs and soils near the legacy mine, with higher risks observed in children, emphasizing the need to remediate legacy mine wastes to reduce health risks and protect groundwater through monitoring in mining-affected regions.

Establishing Monoclonal Gammopathy of Undetermined Significance as an Independent Pre-Disease State of Multiple Myeloma Using Raman Spectroscopy, Dynamical Network Biomarker Theory, and Energy Landscape Analysis.

Multiple myeloma (MM) is a cancer of plasma cells. Normal (NL) cells are considered to pass through a precancerous state, such as monoclonal gammopathy of undetermined significance (MGUS), before transitioning to MM. In the present study, we acquired Raman spectra at three stages-834 NL, 711 MGUS, and 970 MM spectra-and applied the dynamical network biomarker (DNB) theory to these spectra. The DNB analysis identified MGUS as the unstable pre-disease state of MM and extracted Raman shifts at 1149 and 1527-1530 cm-1 as DNB variables. The distribution of DNB scores for each patient showed a significant difference between the mean values for MGUS and MM patients. Furthermore, an energy landscape (EL) analysis showed that the NL and MM stages were likely to become stable states. Raman spectroscopy, the DNB theory, and, complementarily, the EL analysis will be applicable to the identification of the pre-disease state in clinical samples.

Analysis of vitamin D receptor binding affinities of enzymatically synthesized triterpenes including ambrein and unnatural onoceroids.

Onoceroids are a rare family of triterpenes. One representative onoceroid is ambrein, which is the main component of ambergris used as a traditional medicine. We have previously identified the onoceroid synthase, BmeTC, in Bacillus megaterium and succeeded in creating ambrein synthase by introducing mutations into BmeTC. Owing to the structural similarity of ambrein to vitamin D, a molecule with diverse biological activities, we hypothesized that some of the activities of ambergris may be induced by the binding of ambrein to the vitamin D receptor (VDR). We demonstrated the VDR binding ability of ambrein. By comparing the structure-activity relationships of triterpenes with both the VDR affinity and osteoclastic differentiation-promoting activity, we observed that the activity of ambrein was not induced via the VDR. Therefore, some of the activities of ambergris, but not all, can be attributed to its VDR interaction. Additionally, six unnatural onoceroids were synthesized using the BmeTC reactions, and these compounds exhibited higher VDR affinity than that of ambrein. Enzymatic syntheses of onoceroid libraries will be valuable in creating a variety of bioactive compounds beyond ambergris.

Simultaneous XIAP and cIAP1/2 inhibition by a dimeric SMAC mimetic AZD5582 induces apoptosis in multiple myeloma.

Overexpression of inhibitor of apoptosis (IAP) proteins is associated with poor prognosis. In multiple myeloma (MM), the IAP inhibitors (IAPi), LCL161, have been evaluated in preclinical and clinical settings but are not fully effective. Among IAPs, XIAP has the strongest anti-apoptotic function with direct binding activity to caspases and cIAP1 and cIAP2 are positive regulator of NF-κB signaling. Prior IAPi such as LCL161 has high affinity to cIAP1 and cIAP2 resulting in inferior inhibiting activity against XIAP. A novel dimeric IAPi, AZD5582 (C58H78N8O8), have high binding potency to XIAP with EC50 dose of 15 nM, enabling to simultaneous inhibit XIAP and cIAP1/2. AZD5582 monotherapy showed cell growth inhibition for all MM cell lines, MM1S, RPMI8226, U266 and KMS-5 and induced apoptosis. AZD5582 further showed anti-proliferation effect under the IL-6 additional condition and inhibited JAK-STAT signaling triggered by IL-6. AZD5582 combined with carfilzomib therapy showed a synergistic effect. Enhanced apoptosis was also observed in combination therapy. Synergistic effect was further observed with other conventional therapeutics. Simultaneous XIAP and cIAP1/2 inhibition by the dimeric IAPi AZD5582 is promising. This study provides a rationale of AZD5582 as a new treatment strategy in monotherapy and in combination therapy.

Ramucirumab Plus Paclitaxel as a Second-line Chemotherapy in Older Adults With Advanced Gastric Cancer (YCOG1601).

BACKGROUND/AIM: Ramucirumab plus paclitaxel has been widely used as a second-line chemotherapy for treating advanced gastric cancer. However, the real-world data of this regimen for older patients with gastric cancer (GC) remains unrevealed. The aim of this study was to clarify the feasibility and efficacy of this regimen for older patients with GC in a single-arm, phase II study. PATIENTS AND METHODS: Patients aged ≥70 years having unresectable or recurrent GC who met the eligible criteria were enrolled. Paclitaxel was administered at a dose of 80 mg/m2 on days 1, 8, and 15, and ramucirumab was administered at a dose of 8 mg/kg on day 1 and day 15 of a 4-week cycle. Primary endpoint was the incidence of adverse events and secondary endpoints were response rate, progression-free survival, and overall survival. A total of 25 patients were enrolled in the full-set analysis. RESULTS: Grade 3 or more adverse events were observed in 21 patients (84.0%). Neutropenia was most frequently observed (68.0%), followed by peripheral sensory neuropathy (12.0%), and febrile neutropenia (12.0%). Median progression-free survival and overall survival were 6.9 months and 13.4 months, respectively. Disease control rate was 88.0%, and response rate of patients with measurable lesions was 52.9%. Notably, no treatment-related deaths occurred. CONCLUSION: Ramucirumab plus paclitaxel as a second-line chemotherapy demonstrated acceptable oncological outcomes, despite the occurrence of frequent adverse events. It is necessary to carefully select patients and adjust treatment regimens in older patients with GC to safely administer chemotherapy and subsequently achieve satisfactory long-term outcomes.

Health literacy in older patients with abdominal tumours and its association with clinical characteristics: A cross-sectional study.

PURPOSE: Health literacy (HL) is pivotal in managing patients with abdominal cancer and is associated with treatment outcomes and care experience. However, detailed characteristics of HL and their associations with clinical features remain uncertain in the population. Therefore, we aimed to comprehensively investigate HL and its associations with clinical characteristics in older patients with abdominal tumours. METHODS: We analysed 103 older patients with abdominal tumours prescribed perioperative rehabilitation programs in an acute care hospital. The Japanese version of the European Health Literacy Survey Questionnaire was used to measure comprehensive HL. Multivariate ordinal or linear regression analyses were used to explore the associations between HL and the following clinical characteristics: physical status, physical function, cardiopulmonary function, levels of activities of daily living (ADL), physical activity level, and health-related quality of life (HR-QoL). All regression analyses included patient demographics as covariates. RESULTS: Approximately 50%-70% of the participants had difficulty accessing and appraising health-related information, and 20%-45% thought it was difficult to understand and apply the information. The percentage of limited HL levels in general HL, three health-relevant domains, and four competencies ranged from 62% to 83%. Moreover, regression analyses revealed that lower HL was associated with worse physical status/function, lower ADL, and poorer HR-QoL. CONCLUSION: Most older patients with abdominal tumours have limited HL, which may lead them to make treatment decisions without fully understanding what healthcare providers advise. Furthermore, patients with lower HL are at a higher risk of poor treatment outcomes because of their worse clinical characteristics.

Development of a Novel CD26-Targeted Chimeric Antigen Receptor T-Cell Therapy for CD26-Expressing T-Cell Malignancies.

Chimeric-antigen-receptor (CAR) T-cell therapy for CD19-expressing B-cell malignancies is already widely adopted in clinical practice. On the other hand, the development of CAR-T-cell therapy for T-cell malignancies is in its nascent stage. One of the potential targets is CD26, to which we have developed and evaluated the efficacy and safety of the humanized monoclonal antibody YS110. We generated second (CD28) and third (CD28/4-1BB) generation CD26-targeted CAR-T-cells (CD26-2G/3G) using YS110 as the single-chain variable fragment. When co-cultured with CD26-overexpressing target cells, CD26-2G/3G strongly expressed the activation marker CD69 and secreted IFNgamma. In vitro studies targeting the T-cell leukemia cell line HSB2 showed that CD26-2G/3G exhibited significant anti-leukemia effects with the secretion of granzymeB, TNFα, and IL-8, with 3G being superior to 2G. CD26-2G/3G was also highly effective against T-cell lymphoma cells derived from patients. In an in vivo mouse model in which a T-cell lymphoma cell line, KARPAS299, was transplanted subcutaneously, CD26-3G inhibited tumor growth, whereas 2G had no effect. Furthermore, in a systemic dissemination model in which HSB2 was administered intravenously, CD26-3G inhibited tumor growth more potently than 2G, resulting in greater survival benefit. The third-generation CD26-targeted CAR-T-cell therapy may be a promising treatment modality for T-cell malignancies.

A resected case of acinar cell carcinoma of the pancreas with liver metastasis following chemotherapy using modified FOLFIRINOX.

BACKGROUND: Acinar cell carcinoma of the pancreas is a rare exocrine malignancy representing less than 1% of all pancreatic neoplasms. It has been reported that it responds to treatment differently from pancreatic ductal adenocarcinoma and the treatment algorithm for acinar cell carcinoma usually depends on the stage of the respective tumor and the patient's current status. CASE PRESENTATION: A 60-year-old man presented with upper abdominal pain and anorexia. Abdominal ultrasonography showed a large-sized hepatic mass and he was referred to our hospital. Contrast-enhanced computed tomography demonstrated a 110-mm low-density area occupying the right hemi-liver and an enhanced mass of 70 × 56 mm in the tail of the pancreas, which seemed to directly infiltrate into the spleen. The case was diagnosed as acinar cell carcinoma with a simultaneous liver metastasis identified by liver biopsy. Upfront resection of pancreatic cancer with distant metastasis might not be considered as an optimal choice, and in this case chemotherapy was administered prior to curative resection. Chemotherapy using the modified FOLFIRINOX regimen was undertaken, resulting in a partial remission; the liver tumor reduced in size from 110 to 47 mm and the pancreatic tumor from 70 to 40 mm. The patient then safely underwent curative hepatic resection with distal pancreato-splenectomy. Histological examinations revealed small-sized atypical cells with large nuclei that had formed acinar patterns, and immunostaining with trypsin was positive in tumor cells, which was in accordance with acinar cell carcinoma. More than 3 years later, the patient is doing well without any recurrence. CONCLUSION: Aggressive and curative surgery in combination with chemotherapy such as FOLFIRINOX could be a treatment option to achieve long-term survival in cases of acinar cell carcinoma with liver metastases.

Endoscopic Resection with One-Port Placement: A Newly Developed Technique for the Safe Management of Advanced Endoscopic Resection for Gastric Gastrointestinal Stromal Tumors.

INTRODUCTION: Endoscopic full-thickness resection (EFTR) without laparoscopic assistance (pure EFTR) is an emerging, less invasive treatment for gastrointestinal stromal tumors (GISTs). However, the technique has seldom been performed outside China because of concerns regarding pneumoperitoneum, maintenance of endoscopic view, and endoscopic suturing. This study aimed to evaluate the efficacy and safety of endoscopic resection with one-port placement (EROPP) for gastric GISTs. METHODS: This retrospective study included 17 patients with gastric GISTs originating from the muscularis propria who underwent EROPP between 2019 and 2022. One camera port was inserted in the umbilicus before initiating the endoscopic procedure to maintain intra-abdominal pressure, which was monitored and adjusted via this port. While allowing for conversion to laparoscopic surgery if needed, EFTR was performed as follows: (1) circumferential incision of the mucosal and submucosal layers around the lesion was performed by typical endoscopic submucosal dissection; (2) an intentional perforation and subsequent seromuscular resection was made using dental floss and an endo-clip for traction; and (3) closure of the gastric full-thickness defect was performed with an over-the-scope clip (OTSC) after peroral retrieval of the specimen. We retrospectively assessed the short-term outcomes and safety. RESULTS: All procedures were completed successfully without conversion to laparoscopic surgery. The median size of the resected tumors was 23 mm (range, 8-35 mm), the median resection time was 36 min (range, 22-95 min), and closure time was 18 min (range, 10-45 min). The rates of en bloc and complete resection were 100% and 88%, respectively. In 2 cases, another port was added to aspirate the leaking fluid or check the condition of the endoscopic closure. All gastric defects were endoscopically closed, mainly using OTSCs. The recovery course for all patients was uneventful, and no adverse events were reported. CONCLUSIONS: EROPP is a safe and minimally invasive treatment for gastric GISTs and appears to be suitable for introducing EFTR procedures.

A Novel Mechanism for Bone Loss: Platelet Count Negatively Correlates with Bone Mineral Density via Megakaryocyte-Derived RANKL.

A potential association between hematopoietic stem cell status in bone marrow and surrounding bone tissue has been hypothesized, and some studies have investigated the link between blood count and bone mineral density (BMD), although their exact relationship remains controversial. Moreover, biological factors linking the two are largely unknown. In our present study, we found no clear association between platelet count and BMD in the female group, with aging having a very strong effect on BMD. On the other hand, a significant negative correlation was found between platelet count and BMD in the male group. As a potential mechanism, we examined whether megakaryocytes, the source of platelet production, secrete cytokines that regulate BMD, namely OPG, M-CSF, and RANKL. We detected the production of these cytokines by megakaryocytes derived from bone marrow mononuclear cells, and found that RANKL was negatively correlated with BMD. This finding suggests that RANKL production by megakaryocytes may mediate the negative correlation between platelet count and BMD. To our knowledge, this is the first report to analyze bone marrow cells as a mechanism for the association between blood count and BMD. Our study may provide new insights into the development and potential treatment of osteoporosis.

Identification of CgeA as a glycoprotein that anchors polysaccharides to the spore surface in Bacillus subtilis.

The Bacillus subtilis spore is composed of a core, containing chromosomal DNA, surrounded by a cortex layer made of peptidoglycan, and a coat composed of concentric proteinaceous layers. A polysaccharide layer is added to the spore surface, and likely anchored to the crust, the coat outermost layer. However, the identity of the coat protein(s) to which the spore polysaccharides (SPS) are attached is uncertain. First, we showed that the crust proteins CotVWXYZ and CgeA were all contained in the peeled SPS layer obtained from a strain missing CotE, the outer coat morphogenetic protein, suggesting that the SPS is indeed bound to at least one of the spore surface proteins. Second, CgeA is known to be located at the most downstream position in the crust assembly pathway. An analysis of truncated variants of CgeA suggested that its N-terminal half is required for localization to the spore surface, while its C-terminal half is necessary for SPS addition. Third, an amino acid substitution strategy revealed that SPS was anchored at threonine 112 (T112), which constitutes a probable O-glycosylation site on CgeA. Our results indicated that CgeA is a glycoprotein required to initiate SPS assembly and serves as an anchor protein linking the crust and SPS layers.

Novel approach toward minimally invasive surgery for mid-transverse colon cancer: 'moving the left colon' technique.

AIM: During surgery for mid-transverse colon cancer (MTC), surgeons often face the dilemma of whether to mobilize the hepatic or splenic flexure. There is no established optimal minimally invasive surgical procedure for MTC. METHODS: We present our novel minimally invasive surgical technique, called the 'moving the left colon' technique for MTC, along with a video demonstration. The procedure involves four main steps: (i) mobilization of the splenic flexure using a medial-to-lateral approach, (ii) dissection of lymph nodes around the middle colic artery from the left side of the superior mesenteric artery approach, (iii) separation of the pancreas and transverse mesocolon and (iv) 'moving the left colon' and performing an intracorporeal anastomosis. By mobilizing the splenic flexure, anatomical landmarks are revealed, which enables safer dissection. Combining this technique with intracorporeal anastomosis allows for a safe and easy anastomosis. RESULTS: Between April 2021 and January 2023, a single-skilled colorectal surgeon performed laparoscopic transverse colectomies using our new approach on three consecutive patients with MTC. The patients had a median age of 75 years (range 46-89 years). The median operative time was 194 min (range 193-228 min) and blood loss was 8 mL (range 0-20 mL). None of the patients experienced any perioperative complications and the median postoperative hospital stay was 6 days. CONCLUSION: We introduced a novel approach for laparoscopic surgery for MTC. This technique can be performed safely and may help standardize minimally invasive surgery for MTC.

Adverse Events in Patients With Esophageal Cancer Treated With Nivolumab in Combination With Radiotherapy.

BACKGROUND/AIM: When nivolumab is administered as second-line therapy for esophageal cancer, radiotherapy may also be provided in cases either concurrently or sequentially. The aim of this study was to retrospectively examine whether the incidence of adverse events increases in such cases. PATIENTS AND METHODS: Twenty-two esophageal cancer patients [17 males and 5 females; mean age 71 years (range=58-87 years)] treated with nivolumab were included. Patients were divided into two treatment groups: nivolumab alone (N group) (12 patients) and nivolumab combined with radiotherapy (R group) (10 patients). All patients had squamous cell carcinoma. The primary outcomes measured were the severity and frequency of adverse events. RESULTS: Adverse events were seen in 6 of the 12 patients in the N group and 8 of the 10 in the R group. There were significantly more adverse events in the R group (p=0.035), but no difference in Grade 3 or higher adverse events (p=0.781), indicating that the adverse events were controllable. There was no significant difference in treatment effect between the N and R groups. CONCLUSION: In this report, 50% of adverse events in the N group were grade 3-4, 25% of which were grade 4, as seen in previous reports. In the present study, the side effects were not enhanced by treatment with immune checkpoint inhibitors plus radiotherapy. Immune checkpoint inhibitors plus radiation therapy would be a relatively safe treatment and may become an option for esophageal cancer treatment in the future.

Does Intestinal Peristalsis Cause Suture Failure After Instrument Suture?

BACKGROUND/AIM: Gastrectomy with lymphadenectomy is a standard treatment for gastric cancer. Anastomotic leakage remains a potentially fatal complication of gastrectomy. Forceful stapler extraction may cause anastomotic complications. We focused on the duodenal peristalsis, as we hypothesized that it might cause forceful stapler extraction. We then retrospectively investigated duodenal peristalsis and reviewed videos of Da Vinci system cases to clarify the relationship between peristalsis and anastomotic complications. PATIENTS AND METHODS: Forty-nine cases with stored videos of laparoscopic surgery using the Da Vinci system from 2015 to March 2021 were included. Peristalsis was defined by repeated contraction and expansion that was clearly visible three or more times in a row. The duodenum was investigated because it is frequently observed during gastrectomy. Suture failure was evaluated in cases with and without peristalsis. RESULTS: The study population included 49 patients [male, n=32; female, n=17; median age, 71 (42-82) years]. Duodenal peristalsis was observed in 14 (28.6%) cases. Three patients experienced complications. A comparative study of cases with and without complications showed significant peristalsis in cases with complications (p=0.0198). CONCLUSION: A new definition to evaluate duodenal peristalsis was established. Anastomotic complications were significantly more frequent in cases with peristalsis (p=0.0198). Our results suggest the utility of manual over-sewing or the use of reinforcement material.

Repetitive administration of cultured human CD34+ cells improve adenine-induced kidney injury in mice.

BACKGROUND: There is no established treatment to impede the progression or restore kidney function in human chronic kidney disease (CKD). AIM: To examine the efficacy of cultured human CD34+ cells with enhanced proliferating potential in kidney injury in mice. METHODS: Human umbilical cord blood (UCB)-derived CD34+ cells were incubated for one week in vasculogenic conditioning medium. Vasculogenic culture significantly increased the number of CD34+ cells and their ability to form endothelial progenitor cell colony-forming units. Adenine-induced tubulointerstitial injury of the kidney was induced in immunodeficient non-obese diabetic/severe combined immunodeficiency mice, and cultured human UCB-CD34+ cells were administered at a dose of 1 × 106/mouse on days 7, 14, and 21 after the start of adenine diet. RESULTS: Repetitive administration of cultured UCB-CD34+ cells significantly improved the time-course of kidney dysfunction in the cell therapy group compared with that in the control group. Both interstitial fibrosis and tubular damage were significantly reduced in the cell therapy group compared with those in the control group (P < 0.01). Microvasculature integrity was significantly preserved (P < 0.01) and macrophage infiltration into kidney tissue was dramatically decreased in the cell therapy group compared with those in the control group (P < 0.001). CONCLUSION: Early intervention using human cultured CD34+ cells significantly improved the progression of tubulointerstitial kidney injury. Repetitive administration of cultured human UCB-CD34+ cells significantly improved tubulointerstitial damage in adenine-induced kidney injury in mice via vasculoprotective and anti-inflammatory effects.

Redo laparoscopic colorectal resection: a retrospective analysis with propensity score matching.

PURPOSE: Reports of redo laparoscopic colorectal resection (Re-LCRR) are scarce. In order to evaluate the safety and short-term outcomes of Re-LCRR, we performed a matched case-control analysis of patients who underwent this procedure for colorectal cancer. METHOD: This was a retrospective, monocentric study that included patients who underwent Re-LCRR for colorectal cancer between January 2011 and December 2019 at our institution. The patients were compared to a 2:1 matched sample. Matching was conducted based on age, sex, BMI, surgical procedure, and clinical stage. RESULT: Twenty-nine patients underwent Re-LCRR (RCRR group) and were compared to 58 patients selected by matching who underwent LCRR as primary resection (PCRR group). The median of age of the 29 patients of RCRR group was 75 (IQR 56-81) years and the RCRR group included 14 males. The median operative time of the RCRR group was 167 (IQR 126-232) minutes, and the median intraoperative blood loss was 5 (IQR 2-35) ml. In the RCRR group, there were no cases that required conversion to laparotomy. The short-term outcomes of the two groups did not differ to a statistical extent with respect to operative time (p = 0.415), intraoperative blood loss (p = 0.971), rate of conversion to laparotomy (p = 0.477), comorbidity (p = 0.215), and postoperative hospital stay (p = 0.809). No patients in either group experienced postoperative anastomotic leakage or required re-operation due to postoperative complications, and there was no procedure-related death. However, in terms of oncological factors, although there was no difference in the number of cases with a positive radical margin between the two groups (p = 1.000), the number of harvested lymph nodes in the RCRR group was significantly lower than that in the PCRR group (p = 0.015) and the RCRR group included 10 cases with less than 12 harvested lymph nodes. CONCLUSION: Re-LCRR is associated with good short-term results and can be safely performed; however, the number of harvested lymph nodes is significantly reduced in comparison to primary resection cases, and further studies are needed to evaluate its long-term prognosis.

Tumor DNA in Peritoneal Lavage as a Novel Biomarker for Predicting Peritoneal Recurrence in Patients With Gastric Cancer.

BACKGROUND: Peritoneal lavage cytology positivity (CY1) has been identified as a prognostic factor for distant metastases that is equivalent to peritoneal dissemination in Japan. Peritoneal lavage cytology is usually diagnosed by microscopic findings; a diagnostic procedure using a liquid biopsy (LB) technique has not yet been established. PATIENTS AND METHODS: We evaluated the feasibility of a LB approach using peritoneal lavage samples from 15 patients with gastric cancer. Samples were collected from both the Douglas pouch and the left subdiaphragmatic area, and cell-free DNA was extracted for analysis of TP53 mutations using droplet digital polymerase chain reaction. RESULTS: All 10 patients with CY1 had positive cytology for the left subdiaphragmatic specimen. However, only six out of the 10 patients had positive cytology for their Douglas pouch specimens, and these six patients had peritoneal tumor DNA (ptDNA) in these specimens. In all five patients with CY0, ptDNA was not detected. The overall survival was significantly shorter in the ptDNA-positive group than in the ptDNA-negative group. The survival of the group with a high amount of DNA from free intraperitoneal cells (ficDNA) was significantly worse than that of those with a low amount. In contrast, the group with a high amount of DNA from peritoneal cell-free DNA (pcfDNA) had significantly better survival than the group with a low amount. CONCLUSION: LB cytology showed equivalent utility to that of conventional microscopic examinations regarding its diagnostic ability. Therefore ptDNA, pcfDNA and ifcDNA are expected to be useful as prognostic factors.

DPP8 Selective Inhibitor Tominostat as a Novel and Broad-Spectrum Anticancer Agent against Hematological Malignancies.

DPP8/9 inhibition induces either pyroptotic or apoptotic cell death in hematological malignancies. We previously reported that treatment with the DPP8/9 inhibitor 1G244 resulted in apoptotic cell death in myeloma, and our current study further evaluates the mechanism of action of 1G244 in different blood cancer cell lines. Specifically, 1G244 inhibited DPP9 to induce GSDMD-mediated-pyroptosis at low concentrations and inhibited DPP8 to cause caspase-3-mediated-apoptosis at high concentrations. HCK expression is necessary to induce susceptibility to pyroptosis but does not participate in the induction of apoptosis. To further characterize this DPP8-dependent broad-spectrum apoptosis induction effect, we evaluated the potential antineoplastic role for an analog of 1G244 with higher DPP8 selectivity, tominostat (also known as 12 m). In vitro studies demonstrated that the cytotoxic effect of 1G244 at high concentrations was enhanced in tominostat. Meanwhile, in vivo work showed tominostat exhibited antitumor activity that was more effective on a cell line sensitive to 1G244, and at higher doses, it was also effective on a cell line resistant to 1G244. Importantly, the weight loss morbidity associated with increasing doses of 1G244 was not observed with tominostat. These results suggest the possible development of novel drugs with antineoplastic activity against selected hematological malignancies by refining and increasing the DPP8 selectivity of tominostat.