Explainable artificial intelligence prediction-based model in laparoscopic liver surgery for segments 7 and 8: an international multicenter study.

BACKGROUND: Artificial intelligence (AI) is becoming more useful as a decision-making and outcomes predictor tool. We have developed AI models to predict surgical complexity and the postoperative course in laparoscopic liver surgery for segments 7 and 8. METHODS: We included patients with lesions located in segments 7 and 8 operated by minimally invasive liver surgery from an international multi-institutional database. We have employed AI models to predict surgical complexity and postoperative outcomes. Furthermore, we have applied SHapley Additive exPlanations (SHAP) to make the AI models interpretable. Finally, we analyzed the surgeries not converted to open versus those converted to open. RESULTS: Overall, 585 patients and 22 variables were included. Multi-layer Perceptron (MLP) showed the highest performance for predicting surgery complexity and Random Forest (RF) for predicting postoperative outcomes. SHAP detected that MLP and RF gave the highest relevance to the variables "resection type" and "largest tumor size" for predicting surgery complexity and postoperative outcomes. In addition, we explored between surgeries converted to open and non-converted, finding statistically significant differences in the variables "tumor location," "blood loss," "complications," and "operation time." CONCLUSION: We have observed how the application of SHAP allows us to understand the predictions of AI models in surgical complexity and the postoperative outcomes of laparoscopic liver surgery in segments 7 and 8.

Population Pharmacokinetic-Pharmacodynamic Target Attainment Analysis of Flomoxef in the Serum and Liver Tissue of Patients Undergoing Hepatic Resection.

The purpose of this study was to investigate the population pharmacokinetics of prophylactic flomoxef based on serum and liver tissue concentrations and to demonstrate a pharmacodynamic target concentration in the serum and liver tissue exceeding the MIC in order to design an effective dosing regimen. Serum samples (n = 210) and liver tissue samples (n = 29) from 43 individuals were analyzed using a nonlinear mixed-effects model. The pharmacodynamics index target value was regarded as the probability of maintaining flomoxef serum trough and liver tissue concentrations exceeding the MIC90 values, 0.5 mg/L and 1.0 mg/L, for Escherichia coli and methicillin-susceptible Staphylococcus aureus, respectively. The final population pharmacokinetic model was a two-compartment model with linear elimination. Creatinine clearance (CLCR) was identified as a significant covariate influencing total clearance when CLCR was less than 60 mL/min. The probability of achieving concentrations in the serum and liver tissue exceeding the MIC90 for E. coli or methicillin-susceptible S. aureus for a 1 g bolus dose was above 90% at 2 h after the initial dose. Our findings suggest that population pharmacokinetic parameters are helpful for evaluating flomoxef pharmacokinetics and determining intraoperative flomoxef redosing intervals.

Pancreas-contactless gastrectomy for gastric cancer prevents postoperative inflammation.

BACKGROUND: Pancreas-related complications after laparoscopic gastrectomy (LG) for gastric cancer can be fatal. We developed a gastrectomy procedure with no pancreas contact to prevent such complications and herein report the surgical outcomes. METHODS: We retrospectively reviewed 182 consecutive patients with gastric cancer who underwent LG at Kitasato University Hospital from January 2017 to January 2020. These patients were divided into a pancreas-contact group (C group) and pancreas-contactless group (CL group) for comparison of postoperative complications, and inflammatory parameters such as body temperature (BT) and C-reactive protein (CRP). RESULTS: Postoperative complications of CDc grade ≧ IIIa were significantly fewer in the CL group than in the C group [0/76 (0%) vs. 6/106 (5.7%), P = 0.035]. The median drain amylase (drain-AMY) on postoperative day 1 (POD1) was significantly lower in the CL group than in the C group (641 vs. 1162 IU/L, P = 0.02), as was BT at POD1 (37.4 °C vs. 37.7 °C, P = 0.04), the patient group with a BT above 37.5 °C at POD3 [5/76 (6.5%) vs. 18/106 (17%), P = 0.037], and those showing a CRP above 20.0 mg/dL at POD3 [5/76 (6.5%) vs. 20/106 (19%), P = 0.018]. CONCLUSIONS: Our technique to prevent pancreas contact during supra-pancreatic lymph node dissection during LG could minimize the inflammatory response and prevent further postoperative complications. Further large-scale, prospective studies are now required.

Promoter DNA Hypermethylation of the Cysteine Dioxygenase 1 (CDO1) Gene in Intraductal Papillary Mucinous Neoplasm (IPMN).

BACKGROUND: Intraductal papillary mucinous neoplasm (IPMN) involves adenoma (IPMA), a precancerous lesion, cancer (IPMC) including high-grade dysplasia (HGD), and invasive carcinoma (IC). DNA markers of IPMN are required for detection of invasive disease, and cysteine dioxygenase 1 (CDO1) gene promoter hypermethylation is a potential candidate. However, it has never been investigated in the context of IPMN. PATIENTS AND METHODS: A total of 107 IPMN tumor tissues, including 41 IPMC and 66 IPMA, were studied. CDO1 promoter methylation was quantified using TaqMan quantitative methylation-specific polymerase chain reaction (qMSP) in patients with IPMN and other pancreatic cystic disorders after pancreatectomy. RESULTS: The methylation values (TaqMeth Vs) of CDO1 increased when noncancerous pancreas tissues were compared with IPMA and HGD (p < 0.0001). Among IPMC, the TaqMeth Vs in IC were not significantly higher than in HGD. The TaqMeth Vs of the solid tumors were higher than those of the cystic tumors (p = 0.0016), which were in turn higher than the corresponding noncancerous tissues (p < 0.0001). Prognostic analysis revealed that high TaqMeth Vs (≥ 14.1) resulted in a poorer prognosis than low TaqMeth Vs (< 14.1) (p < 0.0001). In other pancreatic cystic diseases, only malignant mucinous cystic neoplasm showed DNA hypermethylation of its promoter. A pilot study in pancreatic juice confirmed methylation in all IPMN samples but not in benign pancreatic diseases (p = 0.0277). CONCLUSIONS: CDO1 promoter hypermethylation is extremely specific to IPMN and may accumulate with IPMN tumor progression during the adenoma-carcinoma sequence. It might be a promising candidate as a diagnostic marker of pancreatic cystic diseases.

Validation and performance of three-level procedure-based classification for laparoscopic liver resection.

BACKGROUND: A procedure-based laparoscopic liver resection (LLR) classification (IMM classification) stratified 11 different LLR procedures into 3 grades. IMM classification assessed the difficulty of LLR differently than an index-based LLR classification (IWATE criteria), which scored each procedure on an index scale of 12. We validated the difference of 3 IMM grades using an external cohort, evaluated the IMM classification using the scores of the IWATE criteria, and compared the performance of IMM classification with the IWATE criteria and the minor/major classification. METHODS: Patients undergoing LLR without simultaneous procedures were selected from a prospectively maintained database at the Institut Mutualiste Montsouris (IMM cohort) and from the database of 43 Japanese institutions (JMI cohort). Surgical and postoperative outcomes were evaluated according to the 3 IMM grades using the JMI cohort. The 11 LLR procedures included in the IMM classification were scored according to the IWATE criteria. The area under the curves (AUCs) for surgical and postoperative outcomes were compared. RESULTS: In the JMI (n = 1867) cohort, operative time, blood loss, conversion rate, and major complication rate were significantly associated with a stepwise increase in grades from I to III (all, P < 0.001). In the IMM (n = 433) and JMI cohorts, IMM grades I, II, and III corresponded to three low-scoring, two intermediate-scoring, and six high-scoring LLR procedures as per the IWATE criteria, respectively. Mean ± standard deviation among the IMM grades were significantly different: 3.7 ± 1.4 (grade I) versus 7.5 ± 1.7 (grade II) versus 10.2 ± 1.0 (grade III) (P < 0.001) in the IMM cohort and 3.6 ± 1.4 (grade I) versus 6.7 ± 1.5 (grade II) versus 9.3 ± 1.4 (grade III) (P < 0.001) in the JMI cohort. The AUCs for surgical and postoperative outcomes are higher for the 3-level IMM classification than for the minor/major classification. CONCLUSIONS: The difference of 3 IMM grades with respect to surgical and postoperative outcomes was validated using an external cohort. The 3-level procedure-based IMM classification was in accordance with the index-based IWATE criteria. The IMM classification performed better than the minor/major classification for stratifying LLR procedures.

Neoadjuvant chemotherapy plus surgery for high-risk advanced gastric cancer: long-term results of KDOG1001 trial.

PURPOSE: The purpose of this study is to evaluate the long-term survival outcomes of KDOG1001 trial after a minimum follow-up of 3 years. METHODS: Patients with bulky N2 lymph nodes, linitis plastica (type 4), or large ulcero-invasive-type tumors (type 3) received up to four 28-day cycles of DCS neoadjuvant chemotherapy (docetaxel at 40 mg/m2, cisplatin at 60 mg/m2 on day 1, and S-1 at 40 mg/m2 twice daily for 2 weeks) followed by gastrectomy with D2 lymphadenectomy plus adjuvant S-1 therapy for 1 year. The final preplanned analysis of long-term outcomes including overall survival and relapse-free survival was conducted after minimum follow-up of 3 years. This trial is registered with the University Hospital Medical Information Network Clinical Trials Registry, number UMIN 000003642, and has been completed. RESULTS: From May 2010 through January 2017, 40 patients were enrolled. All included patients underwent neoadjuvant chemotherapy with DCS followed by gastrectomy with D2 lymphadenectomy, and 32 (80%) completed adjuvant S-1 therapy for 1 year. After a median follow-up for surviving patients of 68 months at the last follow-up in January 2020, 3-year overall survival rate was 77.5% (95% confidence interval 62.1-87.9%), while 3-year relapse-free survival rate was 62.5% (95% confidence interval 46.8-76.0%). CONCLUSION: Neoadjuvant chemotherapy with 4 cycles of DCS followed by D2 gastrectomy plus adjuvant S-1 was associated with relatively good long-term oncologic outcomes for patients with the high-risk gastric cancer.

Diagnostic potential of hypermethylation of the cysteine dioxygenase 1 gene (CDO1) promoter DNA in pancreatic cancer.

DNA markers for pancreatic ductal adenocarcinoma (PDAC) are urgently needed for detection of minimally invasive disease. The epigenetic relevance of the cysteine dioxygenase 1 gene (CDO1) has been never investigated in PDAC. Three studies, including cellular experiments, tissue validation, and pilot testing for pancreatic cytology, were carried out. Promoter DNA methylation value (MV) of CDO1 was quantified by quantitative methylation-specific PCR. CDO1 expression was consistent with its promoter DNA methylation in 7 PDAC cell lines. In 160 retrospectively collected primary PDAC tumor tissues, MV was significantly higher compared to the corresponding noncancerous pancreas (area under the receiver operating characteristic curve [AUC] = 0.97, P < .0001), and CDO1 hypermethylation was highly specific to PDAC tumor tissues. CDO1 hypermethylation group (MV over 19) was significantly associated with diverse prognostic factors in PDAC. Surprisingly, it was significantly higher in prospectively collected PDAC cytology samples (n = 37), including both pancreatic juice (n = 12) and endoscopic ultrasound-fine needle aspiration (EUS-FNA) cytology (n = 25) compared to pancreatic benign diseases (AUC = 0.96, P < .0001). Detection of PDAC was confirmed by DNA testing in 35 of 37 patients (95% sensitivity); thus, it was more sensitive than cytology (33%) or EUS-FNA cytology (88%). Promoter DNA methylation of CDO1 is extremely specific for PDAC tumors, and accumulates with PDAC tumor progression. It could be a definitive diagnostic marker of PDAC in pancreatic juice or EUS-FNA cytology.

[Conversion Surgery for Initially Unresectable Locally Advanced Pancreatic Cancer Following Gemcitabine plus Nab-Paclitaxel - A Case Report].

We report a case of unresectable locally advanced pancreatic cancer successfully resected after gemcitabine(GEM)plus nab-paclitaxel(PTX)treatment. A 68-year-old man was referred to our institution with jaundice. We diagnosed pancreatic head cancer using computed tomography(CT)and endoscopic retrograde cholangiopancreatography. We initially diagnosed it as locally advanced unresectable pancreatic cancer because of extensive invasion to the portal vein. GEM plus nab- PTX was administered to the patient as systemic chemotherapy. After 9 courses of chemotherapy, a CT scan revealed that the tumor had significantly reduced in size and range of portal vein invasion. Therefore, we performed pancreaticoduodenectomy with resection of the portal vein and achieved R0 resection. Currently, the patient is alive without recurrence. Therefore, conversion surgery after treatment with GEM plus nab-PTX chemotherapy for unresectable pancreatic cancer should be considered.

Comparison of short-term outcomes of robotic-assisted and conventional laparoscopic surgery for rectal cancer: A propensity score-matched analysis.

INTRODUCTION: The advantages of robotic-assisted laparoscopic surgery (RALS) for rectal cancer remain controversial. This study clarified and compared the short-term outcomes of RALS for rectal cancer with those of conventional laparoscopic surgery (CLS). METHODS: The records of 303 consecutive patients who underwent RALS or CLS for rectal adenocarcinoma between November 2016 and November 2021 were analyzed using propensity score-matched analysis. After matching, 188 patients were enrolled in our study to compare short-term outcomes, such as operative results, postoperative complications, and pathological findings, in each group. RESULTS: After matching, baseline characteristics were comparable between groups. Although operative time in the RALS group was significantly longer than in the CLS group (p < 0.0001), the conversion rate to open laparotomy and the postoperative complication rate in the RALS group were significantly lower than in the CLS group (p = 0.0240 and p = 0.0109, respectively). Blood loss was comparable between groups. In the RALS group, postoperative hospital stay and days to soft diet were significantly shorter than those in the CLS group (p = 0.0464 and p < 0.0001, respectively). No postoperative mortality was observed in either group and significant differences were observed in resection margins and number of lymph nodes harvested. CONCLUSION: Robotic-assisted laparoscopic surgery for rectal cancer was safe, technically feasible, and had acceptable short-term outcomes. Further studies are required to validate long-term oncological outcomes.

Short- and long-term outcomes of robotic-assisted laparoscopic surgery for rectal cancer: A single-center retrospective cohort study.

INTRODUCTION: Whether rectal cancer surgery by robotic-assisted laparoscopic surgery provides beneficial advantages remains controversial. Although favorable outcomes in terms of the safety and technical feasibility of robotic-assisted laparoscopic surgery have been demonstrated for rectal cancer, long-term oncological outcomes for robotic-assisted laparoscopic surgery have only been examined in a few studies. This retrospective study of subjects who underwent robotic-assisted laparoscopic surgery evaluated short- and long-term outcomes of consecutive rectal cancer patients. METHODS: Between November 2016 and January 2020, we analyzed the records of 62 consecutive patients who underwent robotic-assisted laparoscopic surgery for rectal adenocarcinoma without distant metastasis to evaluate short- and long-term outcomes. RESULTS: Tumors were located in the lower or mid-rectum (88.7%) in most patients. The median operative time was 357 min. No patient received transfusions, and the median blood loss was 10.5 ml. Open laparotomy was not required in any patient. A Clavien-Dindo classification of all grades was observed in 12 patients (19.4%). Positive radial margin was not observed in any patient. Duration of median follow-up was 40.5 mo, while 3-y overall survival and 3-y relapse-free survival rates were 96.8% and 85.0%, respectively. The local recurrence rate was 3.4%. CONCLUSION: Favorable short- and long-term outcomes demonstrated robotic-assisted laparoscopic surgery was safe and technically feasible for rectal cancer.

An International Retrospective Observational Study of Liver Functional Deterioration after Repeat Liver Resection for Patients with Hepatocellular Carcinoma.

Whether albumin and bilirubin levels, platelet counts, ALBI, and ALPlat scores could be useful for the assessment of permanent liver functional deterioration after repeat liver resection was examined, and the deterioration after laparoscopic procedure was evaluated. For 657 patients with liver resection of segment or less in whom results of plasma albumin and bilirubin levels and platelet counts before and 3 months after surgery could be retrieved, liver functional indicators were compared before and after surgery. There were 268 patients who underwent open repeat after previous open liver resection, and 224 patients who underwent laparoscopic repeat after laparoscopic liver resection. The background factors, liver functional indicators before and after surgery and their changes were compared between both groups. Plasma levels of albumin (p = 0.006) and total bilirubin (p = 0.01) were decreased, and ALBI score (p = 0.001) indicated worse liver function after surgery. Laparoscopic group had poorer preoperative performance status and liver function. Changes of liver functional values before and after surgery and overall survivals were similar between laparoscopic and open groups. Plasma levels of albumin and bilirubin and ALBI score could be the indicators for permanent liver functional deterioration after liver resection. Laparoscopic group with poorer conditions showed the similar deterioration of liver function and overall survivals to open group.

Carbon monoxide induces hypothermia tolerance in Kupffer cells and attenuates liver ischemia/reperfusion injury in rats.

Ischemia/reperfusion (I/R) injury in liver grafts, which is initiated by cold preservation and is augmented by reperfusion, is a major problem that complicates graft quality, posttransplant patient care, and outcomes of liver transplantation (LT). Kupffer cells (KCs) play important roles in I/R injury; however, little is known about their changes during cold preservation. We examined whether a pretreatment with carbon monoxide (CO), a cytoprotective product of heme degradation, could influence KC activity during cold storage and protect liver grafts against LT-induced I/R injury. In vitro, primary rat KCs were stimulated for 24 hours under hypothermic conditions (4°C, 20% O(2)), with lipopolysaccharide, or under hypoxic conditions (37°C, 5% O(2)) with or without a CO pretreatment. When rat KCs were exposed to hypothermic conditions, they produced reactive oxygen species (ROS), but they did not produce tumor necrosis factor α (TNF-α) or nitric oxide. The preincubation of KCs with CO up-regulated heat shock protein 70 (HSP70) and inhibited ROS generation. When liver grafts from donor rats exposed to CO (250 ppm) for 24 hours were transplanted after 18 hours of cold preservation in University of Wisconsin solution, HSP70 expression increased in these grafts versus control grafts, and serum aspartate aminotransferase and alanine aminotransferase levels as well as necrotic areas and inflammatory infiltrates were significantly reduced after LT. CO-pretreated liver grafts showed less up-regulation of TNF-α and inducible nitric oxide synthase messenger RNA (mRNA) and reduced expression of proapoptotic B cell lymphoma 2-associated X protein mRNA, cleaved caspase-3, and poly(adenosine diphosphate ribose) polymerase. In conclusion, the pretreatment of donors with CO ameliorates LT-associated I/R injury with increased hepatic HSP70 expression, particularly in the KC population.

Multicenter Propensity Score-Based Study of Laparoscopic Repeat Liver Resection for Hepatocellular Carcinoma: A Subgroup Analysis of Cases with Tumors Far from Major Vessels.

Less morbidity is considered among the advantages of laparoscopic liver resection (LLR) for HCC patients. However, our previous international, multi-institutional, propensity score-based study of emerging laparoscopic repeat liver resection (LRLR) failed to prove this advantage. We hypothesize that these results may be since the study included complex LRLR cases performed during the procedure's developing stage. To examine it, subgroup analysis based on propensity score were performed, defining the proximity of the tumors to major vessels as the indicator of complex cases. Among 1582 LRLR cases from 42 international high-volume liver surgery centers, 620 cases without the proximity to major vessels (more than 1 cm far from both first-second branches of Glissonian pedicles and major hepatic veins) were selected for this subgroup analysis. A propensity score matching (PSM) analysis was performed based on their patient characteristics, preoperative liver function, tumor characteristics and surgical procedures. One hundred and fifteen of each patient groups of LRLR and open repeat liver resection (ORLR) were earned, and the outcomes were compared. Backgrounds were well-balanced between LRLR and ORLR groups after matching. With comparable operation time and long-term outcome, less blood loss (283.3±823.0 vs. 603.5±664.9 mL, p = 0.001) and less morbidity (8.7 vs. 18.3 %, p = 0.034) were shown in LRLR group than ORLR. Even in its worldwide developing stage, LRLR for HCC patients could be beneficial in blood loss and morbidity for the patients with less complexity in surgery.

Undifferentiated Embryonal Sarcoma of the Liver Identified after the Initial Diagnosis of a Hepatic Cyst.

Abdominal ultrasound in a 50-year-old Japanese man revealed a cystic lesion on the caudate lobe of the liver. Four-month follow-up imaging showed a rapid increase in the size of the cystic lesion. The patient underwent laparoscopic partial hepatectomy because of a suspicion and perceived risk that the lesion might be malignant. The initial histological diagnosis was a hepatic cyst. Eleven months later, computed tomography showed a giant cystic lesion in the abdominal cavity and multiple liver metastases. The patient underwent excision of the giant cystic lesion and a partial hepatectomy. Immunohistochemistry for the recurring lesion revealed undifferentiated embryonal sarcoma of the liver.

Dissected peripancreatic tissue margin is a critical prognostic factor and is associated with a K-ras gene mutation in pancreatic ductal adenocarcinoma.

We previously reported that the dissected pancreatic tissue margin (DPM) and the preoperative serum level of carbohydrate antigen 19-9 (preCA19-9) were independent prognostic factors in pancreatic ductal adenocarcinoma (PDAC). In the current study, the prognostic relevance of these factors, including their molecular associations, were validated. A total of 161 patients with PDAC underwent a pancreatectomy between 1986 and 2013, and a multivariate Cox proportional hazards model and a propensity score-based model validated the prognostic importance of DPM. The prognostic factors were compared with the mutation profiles of the K-ras and TP53 genes. Univariate prognostic analysis of disease-specific survival (DSS) demonstrated that DPM (P<0.0001), preCA19-9 (P<0.0001) and Union for International Cancer Control (UICC) stage (P<0.0001), were all significantly associated with poor outcome in PDAC. A multivariate Cox proportional hazards model confirmed that preCA19-9 (P=0.0002) and DPM (P=0.0002) remained as prognostic factors independent of UICC stage (P=0.0015). The combination of preCA19-9 and DPM to predict prognosis could accurately identify the long-term survivors of PDAC (70% 5-year DSS), and a multivariate logistic regression model identified that DPM was the most effective predictor of mortality. The prognostic relevance of DPM was also confirmed (P=0.0008) through propensity score-based background adjustment of patient bias. K-ras gene mutation was significantly associated with DPM (P=0.0002), and DPM-positive patients demonstrated recurrence of distant metastasis in 67% of cases. Therefore, DPM is a critical prognostic indicator in PDAC. In combination with preCA19-9, DPM may be useful to identify long-term survivors of PDAC. Furthermore, to the best of our knowledge, the current study was the first to discover that DPM can represent a poor prognosis based putatively on its association with the K-ras gene mutation.

Validation of index-based IWATE criteria as an improved difficulty scoring system for laparoscopic liver resection.

BACKGROUND: The original difficulty scoring system was revised after discussion at the 2nd International Consensus Conference on Laparoscopic Liver Resection held in Morioka (Iwate Prefecture) in Japan and renamed the IWATE criteria (a 4-level classification system involving 6 preoperative factors). We used Japanese and French cohorts to validate the IWATE criteria by evaluating their association with the procedure-based difficulty classification proposed by the Institut Mutualiste Montsouris. METHOD: Patients who had undergone laparoscopic liver resection at multiple Japanese multi-institutions or the Institut Mutualiste Montsouris were assigned to the multiple Japanese multi-institution (n = 1,867) or Institut Mutualiste Montsouris cohort (n = 433). We analyzed clinical characteristics and outcomes according to the 4-level IWATE criteria difficulties (low, intermediate, advanced, and expert) and evaluated their association with 11 laparoscopic liver resection procedures in the Institut Mutualiste Montsouris classification (low, intermediate, and high levels). RESULTS: We found significant differences in age, surgical indications, and the 4-level IWATE criteria difficulties between the cohorts (all, P < .001). Operation time and blood loss were significantly different among the 4-level difficulties in both cohorts (all, P < .001). The rates of conversion, postoperative complications, liver failure, and in-hospital deaths also increased significantly with increasing difficulty (all, P < .001). The IWATE criteria classified the three low-level Institut Mutualiste Montsouris procedures in the low-to-intermediate levels, the two intermediate-level procedures in the intermediate-to-advanced levels, and the six high-level procedures in the advanced-to-expert levels. CONCLUSION: We observed associations between the IWATE criteria and intraoperative and postoperative outcomes in the Japanese multi-institution and Institut Mutualiste Montsouris cohorts and thus validated the IWATE system.

Relative contribution of direct and indirect allorecognition in developing tolerance after liver transplantation.

The interaction of donor passenger leukocytes and host leukocytes in recipient secondary lymphoid tissues during the early posttransplantation period is crucial in directing host immune reactions toward allograft rejection or acceptance. Responsible T cell clones could be activated through the direct and indirect pathways of allorecognition. We examined the role of the indirect pathway in liver transplantation (LT) tolerance by depleting host antigen-presenting cells (APC) with phagocytic activity [e.g., cluster domain (CD)68+/CD163+ macrophages, CD11c+ dendritic cells (DC)] using liposome-encapsulating clodronate (LP-CL). After Lewis rat cell or liver graft transplantation, Brown Norway (BN) rat recipients pretreated with LP-CL showed a significantly reduced type 1 helper T cell cytokine up-regulation than control-LP-treated recipients. In the LT model, LP-CL treatment and host APC depletion abrogated hepatic tolerance; Lewis liver grafts in LP-CL-treated-BN recipients developed mild allograft rejection, failed to maintain donor major histocompatibility complex (MHC) class II+ leukocytes, and developed chronic rejection in challenged donor heart allografts, while control-LP-treated BN recipients maintained tolerance status and donor MHC class II+ hepatic leukocytes. Furthermore, in the BN to Lewis LT model, LP-CL recipient treatment abrogated spontaneous hepatic allograft acceptance, and graft survival rate was reduced to 43% from 100% in the control-LP group. In conclusion, the study suggests that host cells with phagocytic activity could play significant roles in developing LT tolerance.

Sinusoidal endothelial cell repopulation following ischemia/reperfusion injury in rat liver transplantation.

UNLABELLED: We evaluated the kinetics by which rat liver sinusoidal endothelial cells (LSECs) are repopulated in the reperfused transplanted liver after 18 hours of cold ischemic storage. We found that the majority of LSECs in livers cold-stored for 18 hours in University of Wisconsin solution are seriously compromised and often are retracted before transplantation. Sinusoids rapidly re-endothelialize within 48 hours of transplantation, and repopulation is coincident with up-regulation of hepatocyte vascular endothelial growth factor expression and vascular endothelial growth factor receptor-2 expression on large vessel endothelial cells and repopulating LSECs. Although re-endothelialization occurs rapidly, we show here, using several high-resolution imaging techniques and 2 different rat liver transplantation models, that engraftment of bone marrow-derived cells into functioning LSECs is routinely between 1% and 5%. CONCLUSION: Bone marrow plays a measurable but surprisingly limited role in the rapid repopulation and functional engraftment of bone marrow-derived LSECs after cold ischemia and warm reperfusion.

[A case of advanced gastric cancer with long-term survival treated by S-1/paclitaxel as neo-adjuvant chemotherapy].

A 61-year-old male presented with advanced gastric cancer with lymph node swelling around the root of superior mesenteric artery lymph nodes and invasion of pancreas. We thought a complete resection would be difficult, so he was given neo-adjuvant chemotherapy in combination with S-11 20 mg/body/day (3 weeks administration and 1 week rest) and paclitaxel (PTX) 80 mg/m(2) (day 1, 8, 15). After 2 courses of this neo-adjuvant chemotherapy, the tumor and lymph node swelling decreased in size. Total gastrectomy, Roux-en Y and D1+beta type nodal dissection were performed. Intraoperative findings included tumor exposure on the serous membrane and enlarged lymph nodes on the lesser curvature; however, no marked pancreatic invasion was observed and the lymph nodes had become scarred. The changes with neo-adjuvant chemotherapy were judged to be grade 2. After the operation, there was no side effect, though he received the same chemotherapy as an outpatient in three courses. Five years passed from the first medical examination. The patient remains alive, and the neo-adjuvant chemotherapy proved effective.