Downregulated expression of PBRM1 in sarcomatoid hepatocellular carcinoma.

Sarcomatoid hepatocellular carcinoma (SHCC) is a rare and highly lethal subtype of HCC. The present study aimed to explore the unique markers of SHCC using whole gene expression analysis. Subsequently, gene expression analysis was performed using five sarcomatoid and seven carcinomatoid components of seven tissues from patients with SHCC. The results demonstrated a significant downregulation of polybromo 1 (PBRM1) gene expression in the sarcomatoid components. Immunohistochemical staining also indicated a decreased expression of PBRM1 in the sarcomatoid components. Moreover, gene ontology enrichment analysis revealed that most of the 336 differentially expressed genes between the sarcomatoid and carcinomatoid components were involved in functions associated with DNA replication and histone methylation, which was consistent with the loss of function of PBRM1 which encodes Switch/sucrose-non-fermentable chromatin remodeling complex protein. Therefore, the results of the present study suggested that PBRM1 may be a candidate biomarker for the evaluation of SHCC.

The Prognostic Impact of ABO Blood Group in Hepatocellular Carcinoma Following Hepatectomy.

BACKGROUND/PURPOSE: The effect of the ABO blood group on the survival of patients with hepatocellular carcinoma (HCC) is unclear. The aim of the present study is to determine the prognostic impact of ABO blood types on the survival of a Japanese population of patients with HCC who underwent surgical resection. METHODS: Patients with HCC (n = 480) who underwent an R0 resection between 2010 and 2020 were retrospectively analyzed. Survival outcomes were investigated according to ABO blood type (A, B, O, or AB). Outcomes for type A (n = 173) and non-type A (n = 173) groups after surgery were compared using 1-to-1 propensity score matching to control for variables. RESULTS: In the study cohort, 173 (36.0%), 133 (27.7%), 131 (27.3%), and 43 (9.0%) of participants had Type A, O, B, and AB, respectively. Type A and non-type A patients were successfully matched based on liver function and tumor characteristics. Recurrence-free survival (RFS; hazard ratio [HR] 0.75, 95% confidence interval [Cl] 0.58-0.98, p = 0.038) and overall survival (OS; HR: 0.67, 95% Cl: 0.48-0.95, p = 0.023) for patients with blood type A were both significantly decreased relative to non-type A patients. Cox proportional hazard analysis demonstrated that patients with HCC who have blood type A had a worse prognosis than those with non-type A blood. CONCLUSION: ABO blood type may have a prognostic impact on patients with HCC after hepatectomy. Blood type A is an independent unfavorable prognostic factor for recurrence-free and overall survival (RFS and OS) after hepatectomy.

Efficacy and Safety of Liver Resection in Super Elderly Patients with Hepatocellular Carcinoma.

OBJECTIVE: Liver resection in the super elderly patients remains challenging because of comorbidities and operative tolerability. METHODS: In this study, we compared postoperative complications and survival in patients aged ≥85 yr included five patients aged ≥90 yr with those aged 70-79 and 80-84 yr at a single institution. RESULTS: Three hundred sixty-seven patients aged ≥70 yr underwent liver resection and were divided into three groups based on age at operation between 2010 and 2022; (a) 70-79 yr (median of 74 yr, n=245), (b) 80-84 yr (median of 82 yr, n=81), and (c) ≥85 yr (median of 87 yr, n=41). In the ≥85 yr group (90-yr-old group), twenty-five patients (four) had hypertension, fourteen (one) had diabetes mellitus, seven (one) had cardiovascular disease, and five patients (one) had dementia. The rate of comorbidities did not differ significantly among three groups. The rate of postoperative complications (Clavien-Dindo grade 3a≤) was 25% in the 70- to 79-yr-old group, 27% in the 80- to 84-yr-old group, and 17% in the ≥85-yr-old group (20% in the ≥90-yr-old group) (N.S.). The 1- and 5-yr patient survival rates in the ≥85-yr-old group were 90.1% and 48.5% respectively, compared with 86.7% and 60.9% in the 70- to 79-yr-old group and 83.8% and 66.3% in the 80- to 84-yr-old group, respectively (N.S.). CONCLUSION: Despite the management of comorbidities, liver resection for well-selected super elderly patients, such as those aged ≥85 yr included ≥90yr, has acceptable outcomes. The age of patient is not an absolute contraindication to liver resection.

Modified Albumin-Bilirubin Grade and Alpha-Fetoprotein Score (mALF Score) for Predicting the Prognosis of Hepatocellular Carcinoma after Hepatectomy.

We developed and evaluated a modified albumin-bilirubin grade and α-fetoprotein (mALF) score, a nutritional and oncological assessment tool for patients with hepatocellular carcinoma (HCC) after surgical resection. Patients (n = 480) who underwent R0 resection between 2010 and 2020 were analyzed retrospectively. The mALF score assigned one point for a modified albumin-bilirubin (mALBI) grade 2b or 3 and one point for an α-fetoprotein (AFP) level ≥ 100 ng/mL. Patients were classified by mALF scores of 0 (mALBI grade 1/2a, AFP < 100 ng/mL), 1 (mALBI grade 2b/3 or AFP ≥ 100 ng/mL), or 2 (mALBI grade 2b/3, AFP ≥ 100 ng/mL) points. Liver reserve deteriorated and cancer progressed with increasing score. Postoperative complications (Clavien−Dindo classification ≥ 3) differed significantly among groups. The 5-year recurrence-free survival (RFS) rates were 34.8%, 11.2%, and 0.0% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The 5-year overall survival (OS) rates were 66.0%, 29.7%, and 17.8% for 0, 1, and 2 points, respectively (1 or 2 versus 0 points, p < 0.001). The mALF score was an independent prognostic predictor of RFS and OS. In HCC, the mALF score was effective for predicting postoperative complications and long-term survival.

Efficacy of a third-generation oncolytic herpes simplex virus in refractory soft tissue sarcoma xenograft models.

Malignant soft tissue tumors, particularly highly malignant leiomyosarcomas, are resistant to chemotherapy and associated with a poor prognosis. T-01, a third-generation genetically modified herpes simplex virus type 1, replicates in tumor cells alone and exerts a cell-killing effect. The current study aimed to investigate the antitumor effect of T-01, which is a novel treatment for leiomyosarcoma. In vitro, six human cell lines and one mouse sarcoma cell line were assessed for T-01 cytotoxicity. In vivo, the efficacy of T-01 was examined in subcutaneously transplanted leiomyosarcoma (SK-LMS-1) cells and subcutaneously or intraperitoneally transplanted mouse sarcoma (CCRF S-180II) cells. Cytokines were assessed using ELISpot assay with splenocytes from the allogeneic models for immunological evaluation. T-01 showed cytotoxicity in all seven cell lines (p < 0.001). In the SK-LMS-1 xenotransplantation model, tumor growth was suppressed by T-01 administration (p = 0.02). In the CCRF S-180II subcutaneous tumor model, bilateral tumor growth was significantly suppressed in the T-01-treated group compared with the control group (p < 0.001). In the peritoneal dissemination model, T-01 treatment caused significant survival prolongation compared with the control (p < 0.01). In conclusion, third-generation genetically modified herpes simplex virus type 1 may be an effective novel therapy against refractory sarcomas.

A case of undifferentiated carcinoma of the gallbladder with severe inflammation and difficult preoperative chemotherapy.

Undifferentiated carcinoma (UC) is relatively rare among gallbladder cancers, and the prognosis is poor compared to gallbladder adenocarcinoma. We report a 64-year-old man with gallbladder UC who underwent radical surgery and achieved long-term survival. He presented with a chief complaint of abdominal distension and loss of appetite. An abdominal computed tomography (CT) scan revealed a gallbladder tumor with a major axis of 120 mm that appeared to directly infiltrate the hepatic bed. No major vascular infiltration was noted, but the left and right intrahepatic bile ducts were dilated. On admission, the serum CRP level was 16.5 mg/dL; cholangitis and cholecystitis were suspected. He was hospitalized, treated with antibiotics, and underwent bile duct drainage; however, inflammation recurred and chemotherapy was not possible. Thus, three right liver areas, the caudate lobe, and the gallbladder were extirpated. Histopathologic examination showed a 130 × 90 mm tumor with extensive infiltration, hemorrhage, and necrosis in the liver. In the area occupied by the tumor, multinucleated cell proliferation, and polygonal and spindle-shaped tumor cells were noted. Based on the above findings, a diagnosis of UC was established. Postoperatively, gemcitabine and cisplatin were continued as adjuvant chemotherapy. No tumor recurrence has been detected after 24 months of follow-up care.

Predicting Complications following Surgical Resection of Hepatocellular Carcinoma Using Newly Developed Neo-Glasgow Prognostic Score with ALBI Grade: Comparison of Open and Laparoscopic Surgery Cases.

Background/Aim: Nutritional assessment is known to be important for predicting prognosis in patients with malignant diseases. This study examined the usefulness of a prognostic predictive nutritional assessment tool for hepatocellular carcinoma (HCC) patients treated with surgical resection. Materials/Methods: HCC patients (n = 429) classified as Child−Pugh A who underwent an R0 resection between 2010 and 2020 were retrospectively analyzed (median age 73 years, males 326 (76.0%), Child−Pugh score 5:6 = 326:103, single tumor 340 (79.2%), median tumor size 3.5 cm, open:laparoscopic = 304:125). Glasgow prognostic score (GPS) and the newly developed neo-GPS method, which uses albumin−bilirubin grade 1 instead of albumin, were evaluated to compare their usefulness for prognosis prediction. Results: Median survival time for patients with a GPS score of 0, 1, and 2 was 120, 51, and 20 months, respectively. As for neo-GPS, that for those with a score of 0, 1, and 2 was not applicable (NA), 53 months, and 35 months, respectively (each p < 0.001; c-index: 0.556 and 0.611, respectively). Furthermore, median progression-free survival was 33, 22, and 9 months, and 41, 24, and 15 months, respectively (each p < 0.001; c-index: 0.539 and 0.578, respectively). As compared to patients with a high GPS (≥1), those with a high neo-GPS (≥1) showed a greater rate of high Clavien−Dindo classification (≥3) (39.2% vs. 65.1%). A comparison of patients with a high GPS (≥1) with those with a high neo-GPS (≥1) showed no significant difference regarding frequency of open or laparoscopic hepatectomy (17.4% vs. 15.2%, p = 0.670; 44.7% vs. 43.2%, p = 0.831, respectively), while the frequency of high Clavien−Dindo classification (≥3) was lower in patients who underwent a laparoscopic hepatectomy (11.2% vs. 22.7%, p = 0.007). Conclusion: The present findings suggest that the newly developed neo-GPS based on ALBI grade is an effective prognostic nutritional assessment tool and can be used for prediction of postoperative complications.

Patients with polyclonal hepatocellular carcinoma are at a high risk of early recurrence and have a poor recurrence-free survival period.

BACKGROUND/PURPOSE OF THE STUDY: Tumor heterogeneity based on copy number variations is associated with the evolution of cancer and its clinical grade. Clonal composition (CC) represents the number of clones based on the distribution of B-allele frequency (BAF) obtained from a genome-wide single nucleotide polymorphism (SNP) array. A higher CC number represents a high degree of heterogeneity. We hypothesized and evaluated that the CC number in hepatocellular carcinoma (HCC) tissues might be associated with the clinical outcomes of patients. METHODS: Somatic mutation, whole transcriptome, and CC number based on copy number variations of 36 frozen tissue samples of operably resected HCC tissues were analyzed by targeted deep sequencing, transcriptome analysis, and SNP array. RESULTS: The samples were classified into the heterogeneous tumors as poly-CC (n = 26) and the homogeneous tumors as mono-CC (n = 8). The patients with poly-CC had a higher rate of early recurrence and a significantly shorter recurrence-free survival period than the mono-CC patients (7.0 months vs. not reached, p = 0.0084). No differences in pathogenic non-synonymous mutations, such as TP53, were observed between the two groups when targeted deep sequencing was applied. A transcriptome analysis showed that cell cycle-related pathways were enriched in the poly-CC tumors, compared to the mono-CC tumors. Poly-CC HCC is highly proliferative and has a high risk of early recurrence. CONCLUSION: CC is a possible candidate biomarker for predicting the risk of early postoperative recurrence and warrants further investigation.

The Impact of Sorafenib in Combination with Intermittent Hepatic Arterial Infusion Chemotherapy for Unresectable Hepatocellular Carcinoma with Major Vascular Invasion.

The aim of the current study was to investigate the efficacy and safety of sorafenib and intermittent hepatic arterial infusion chemotherapy with cisplatin for unresectable hepatocellular carcinoma (HCC) with severe portal vein invasion. The antitumor effect was a complete response in 1 of 38 patients, a partial response in 12 patients, stable disease in 16 patients, and progressive disease in 9 patients, for a 34.2% response rate and a 76.3% disease control rate. This regimen had favorable efficacy and acceptable safety and may be feasible for unresectable HCC with severe portal vein invasion.

Superiority of CRP-albumin-lymphocyte index (CALLY index) as a non-invasive prognostic biomarker after hepatectomy for hepatocellular carcinoma.

BACKGROUND: We aimed to investigate whether a novel biomarker incorporating albumin, lymphocytes, and CRP can predict the prognosis for hepatocellular carcinoma (HCC) after hepatectomy. METHODS: Between January 2011 and December 2013, 384 patients who underwent hepatectomy in four university hospitals in Japan were investigated as a discovery cohort. The CRP-Albumin-Lymphocyte (CALLY index) was defined as (Albumin × Lymphocyte)/(CRP × 104). Patients with a CALLY index ≥5 (n = 200) were compared to those with an index <5 (n = 184). Next, validation was performed using 267 patients from three other university hospitals (external validation cohort). RESULTS: The number of TNM Stage III and IV patients was significantly higher in the CALLY <5 group than the ≥5 group (p = 0.003). There was a significant difference in the 5-year survival rate (CALLY ≥5: 71% vs. <5: 46%; p < 0.001). Multivariate analysis identified the CALLY index as an independent factor of overall survival. Similarly, there was a significant difference in the 5-year survival rate between the CALLY ≥5 (73%) and <5 (48%) groups (p < 0.001), and the CALLY index was identified as an independent prognostic factor in the external validation cohort. CONCLUSION: The CALLY index derived from CRP, albumin, and lymphocyte values is a promising predictive biomarker for postoperative prognosis of patients with HCC.

Prospective Study to Evaluate the Safety and Efficacy of a New Surgical Tube Fixation Method: A Pilot Study.

BACKGROUND: Various tubes may be fixed to the skin by ligation using silk sutures after gastrointestinal surgery. We investigated the effects of a skin substitute, "Nonaht®," on pain and skin inflammation at the fixation sites of various tubes. METHODS: The effects of tubes (abdominal drains, small intestinal feeding tubes, and bile duct drainage tubes) fixed in place using either silk sutures or Nonaht were compared for 1-3 months. RESULTS: The median pain scores at the fixation site when abdominal drains were removed were 1.0 with silk sutures and 0 with Nonaht (p < 0.001). Scarring at the fixation site at postoperative month (POM) 1 occurred in 13 of 28 cases in the silk suture group and in no cases in the Nonaht group (p < 0.001). The median pain scores at the fixation site with long-term tubes on postoperative day (POD) 14 and POM 1 were 2.0 and 1.0, respectively, with silk sutures, and none at all time points with Nonaht (p < 0.001). Scarring at the fixation site at POM 3 occurred in all 10 cases in the silk suture group and in no cases in the Nonaht group (p < 0.001). CONCLUSIONS: Patients with conventional skin fixation of tubes using silk sutures were continuously aware of pain at the fixation site and developed skin damage and subsequent scar formation, especially for tubes inserted for ≥ 1 month. The use of Nonaht may reduce the incidence of dermatitis and wound infections at tube fixation sites, thereby promoting early postoperative recovery.

Long-term complete response to lenvatinib in a patient with unresectable hepatocellular carcinoma.

A 36-year-old man had been diagnosed with a solitary hepatocellular carcinoma in the right lobe of the liver by computed tomography, and right hemihepatectomy was performed 16 years previously. Approximately 13 years later, he underwent partial hepatectomy because of intrahepatic recurrence in segment 4. Multinodular intrahepatic recurrences in the remnant liver were identified 19 months after repeat hepatectomy, and he underwent transcatheter arterial chemoembolization therapy. Ultimately, six transcatheter arterial chemoembolization therapies were required because of multiple repeat multinodular intrahepatic recurrences. The patient was refractory to transcatheter arterial chemoembolization, and therefore, he participated in a trial of lenvatinib monotherapy. At lenvatinib initiation, his liver function was Child-Pugh class A. Enhanced abdominal computed tomography detected four tumors in the remnant liver. Enhanced abdominal computed tomography findings at the first evaluation showed no residual contrast uptake on arterial phase images, corresponding to a complete response according to Response Evaluation Criteria in Solid Tumors at 4 months after initiation of lenvatinib. The patient was able to continue long-term lenvatinib therapy with well-controlled general health, and he maintained a complete response for two years and three months. Here, we describe his clinical course and radiological results during lenvatinib monotherapy.

The percutaneous tandem drainage technique for radical treatment of intractable hepaticojejunostomy leakage.

The principal concept of the percutaneous tandem drainage procedure for an intractable hepaticojejunostomy (HJ) leakage is to decrease the amount of fluid and divide the fluid-filled cavity into several small cavities, which can then be drained individually. Percutaneous abscess drainage (PAD) has a role in drainage of the fluid cavity, whereas percutaneous trans-anastomotic jejunum drainage (PTAJD) has a role in drainage to reduce the bile fluid and digestive juices. A decrease in fluid induces effective drainage of the fluid cavity by PAD. A negative pressure suction drain accelerates reduction of the fluid cavity. PAD is removed when the localized fluid cavity has collapsed. PTAJD is finally removed after a clamping test is performed. Since 2020, we performed the percutaneous tandem drainage for two patients, and an intractable HJ leakage was gently resolved within 3 months without any adverse event. The percutaneous tandem drainage technique is safe for steady drain management of an intractable HJ leakage.

Investigation of a Tumor Location-Specific Therapeutic Strategy for Intrahepatic Cholangiocarcinoma.

OBJECTIVE: An optimal therapeutic strategy for intrahepatic cholangiocarcinoma (ICC) has not yet been determined. Herein we focused on intrahepatic tumor location and retrospectively analyzed tumor characteristics depending on location to elucidate a location-specific therapeutic strategy for ICC. METHODS: Sixty-five ICC patients were divided into three groups based on the distance between the innermost portion of the tumor and portal vein branches observed on preoperative imaging: peripheral, intermediate and central ICC. RESULTS: Median disease-specific survival (DSS) of the peripheral ICC was not reached, whereas median DSS was 32.9 months in intermediate ICC and 25.2 months in central ICC (p <0.05). Vascular invasion was observed in all groups (56-92%). Bile duct invasion to the first branch of the hepatic duct was more commonly observed in central ICC (43%) compared with the peripheral and intermediate ICC (0-8%). Lymph node metastasis was not observed in peripheral ICC, whereas it was frequently observed in intermediate and central ICC (39-44%). A Cox regression analysis revealed sufficient RDI (≥58.3%) of adjuvant chemotherapy (AC) significantly increased the length of DSS (HR: 0.205). Based on these data, we have proposed a location-specific therapeutic strategy as follows: peripheral ICC requires anatomical resection without lymphadenectomy; intermediate ICC requires anatomical resection with lymphadenectomy and sufficient doses of AC; and central ICC requires anatomical resection with extrahepatic bile duct resection, caudate lobectomy, lymphadenectomy, and sufficient doses of AC. CONCLUSION: We propose an intrahepatic tumor location-specific therapeutic strategy for ICC. This information could contribute to the appropriate therapeutic management of patients with ICC.

The Impact of Sorafenib in Combination with Transarterial Chemoembolization on the Outcomes of Intermediate-Stage Hepatocellular Carcinoma.

BACKGROUND: We investigated the treatment outcomes and hepatic reserve of transarterial chemoembolization (TACE)-refractory patients with recurrent advanced hepatocellular carcinoma (HCC) treated with TACE plus sorafenib. METHODS: Forty-one patients with intermediate-stage HCC defined as being TACE refractory on imaging were treated with sorafenib and TACE between 2009 and 2012 and comprised the combination treatment group. Twenty-nine patients who received repeated TACE after becoming refractory to TACE between 2005 and 2008 comprised the TACE continuation group. RESULTS: Although the interval between successive rounds of TACE was significantly shorter before the patients developed TACE refractoriness, it was significantly longer after the development of TACE refractoriness, in the combination treatment group compared with the TACE continuation group. The appearance of extrahepatic spread and/or vascular invasion differed significantly between the two groups. The median overall survival was significantly longer in the combination treatment group than in the TACE continuation group (20.5 vs. 15.4 months, respectively; hazard ratio = 2.04; 95% confidence interval = 1.20-3.48). The 3-year overall survival rate was 33.4% in the combination treatment group and 3.5% in the TACE continuation group. Downstaging of the Child-Pugh class was significantly less frequent in the combination treatment group than in the TACE continuation group. In COX proportional hazards analyses, sorafenib plus TACE resulted in a better prognosis compared with repeated TACE. CONCLUSIONS: Treatment with sorafenib plus TACE in TACE-refractory patients with intermediate-stage HCC resulted in longer intervals between TACE rounds, better maintenance of hepatic reserve, and significantly longer OS compared with repeated TACE.

Near-Infrared Fluorescence Imaging and Photodynamic Therapy for Liver Tumors.

Surgery with fluorescence equipment has improved to treat the malignant viscera, including hepatobiliary and pancreatic neoplasms. In both open and minimally invasive surgeries, optical imaging using near-infrared (NIR) fluorescence is used to assess anatomy and function in real time. Here, we review a variety of publications related to clinical applications of NIR fluorescence imaging in liver surgery. We have developed a novel nanoparticle (indocyanine green lactosome) that is biocompatible and can be used for imaging cancer tissues and also as a drug delivery system. To date, stable particles are formed in blood and have an ~10-20 h half-life. Particles labeled with a NIR fluorescent agent have been applied to cancer tissues by the enhanced permeability and retention effect in animals. Furthermore, this article reviews recent developments in photodynamic therapy with NIR fluorescence imaging, which may contribute and accelerate the innovative treatments for liver tumors.

Perioperative Geriatric Assessment as A Predictor of Long-Term Hepatectomy Outcomes in Elderly Patients with Hepatocellular Carcinoma.

This retrospective study recorded pertinent baseline geriatric assessment variables to identify risk factors for recurrence-free survival (RFS) and overall survival (OS) after hepatectomy in 100 consecutive patients aged ≥70 years with hepatocellular carcinoma. Patients had geriatric assessments of cognition, nutritional and functional statuses, and comorbidity burden, both preoperatively and at six months postoperatively. The rate of change in each score between preoperative and postoperative assessments was calculated by subtracting the preoperative score from the score at six months postoperatively, then dividing by the score at six months postoperatively. Patients with score change ≥0 comprised the maintenance group, while patients with score change <0 comprised the reduction group. The change in Geriatric 8 (G8) score at six months postoperatively was the most significant predictive factor for RFS and OS among the tested geriatric assessments. Five-year RFS rates were 43.4% vs. 6.7% (maintenance vs. reduction group; HR, 0.19; 95%CI, 0.11-0.31; p < 0.001). Five-year OS rates were 73.8% vs. 17.8% (HR, 0.12; 95%CI, 0.06-0.25; p < 0.001). Multivariate Cox proportional hazards analysis showed that perioperative maintenance of G8 score was an independent prognostic indicator for both RFS and OS. Perioperative changes in G8 scores can help forecast postoperative long-term outcomes in these patients.

Levosimendan pretreatment improves survival of septic rats after partial hepatectomy and suppresses iNOS induction in cytokine-stimulated hepatocytes.

We evaluated the survival effects and biochemical profiles of levosimendan in septic rats after partial hepatectomy and investigated its effects in cultured hepatocytes. Thirty-two rats underwent 70% hepatectomy and were randomised equally into four groups, followed by lipopolysaccharide (LPS) injection (250 µg/kg, i.v.) after 48 h. Levosimendan was given (i.p.) 1 h before LPS injection [group (A) levosimendan 2 mg/kg; (B) 1; (C) 0.5; (D) vehicle]. Survival at 7 days was increased significantly in group A compared with that in group D [A: 63%; B: 38%; C: 13%; D: 0%]. In serum, levosimendan decreased the level of tumour necrosis factor-α, interleukin (IL)-1ß, IL-6 and nitric oxide (NO). In remnant livers, levosimendan inhibited inducible nitric oxide synthase (iNOS) gene expression. In primary cultured rat hepatocytes stimulated by IL-1ß, levosimendan suppressed NO production by inhibiting iNOS promoter activity and stability of its mRNA.

Efficacy of a third-generation oncolytic herpes simplex virus in neuroendocrine tumor xenograft models.

BACKGROUND: Few chemotherapies are available for neuroendocrine tumors, especially for highly malignant neuroendocrine cancers. The third-generation oncolytic herpes simplex virus type 1 (HSV-1) T-01 selectively replicates in tumor cells and shows cytotoxicity against tumor cells without damaging surrounding normal tissues. We examined the antitumor effect of T-01 to explore novel treatments for patients with neuroendocrine tumors. METHODS: The cytotoxicity of T-01 was tested in two human and one murine neuroendocrine tumor cell lines in vitro. Mouse models with subcutaneously implanted human neuroendocrine tumor QGP1 cells were used to investigate T-01 efficacy in vivo. RESULTS: T-01 showed cytotoxicity against the three cell lines in vitro. In xenograft models, the growth of tumors derived from QGP1 cells was inhibited by T-01 compared with control group. Although weight loss of mice was observed with tumor growth in the control group, it was suppressed by T-01 administration. The antitumor effects of T-01 were dependent on virus concentration and frequency of administration. CONCLUSIONS: T-01 effectively inhibits tumor cell proliferation in a poorly differentiated NEC mouse model. These results suggest that the third-generation oncolytic HSV-1 may serve as a novel treatment for patients with neuroendocrine tumors.

Efficacy and safety of thromboembolism prophylaxis with fondaparinux in Japanese colorectal cancer patients undergoing laparoscopic surgery: A phase II study.

PURPOSE: We aimed to assess the safety and efficacy of fondaparinux (FPNX) for patients undergoing laparoscopic colorectal surgery (LAC). METHODS: Patients scheduled for LAC received once-daily subcutaneous injections of FPNX 1.5-2.5 mg for 4-8 days. The primary endpoint was the incidence of bleeding events. The secondary endpoint was the incidence of deep vein thrombosis (DVT) and pulmonary embolism (PE). RESULTS: Among 128 patients evaluable for efficacy, 119 patients were administered FPNX. Nine patients were excluded owing to intraoperative events, including conversion to open surgery among others. Thirteen patients discontinued treatment owing to anastomotic bleeding (n = 5), anastomotic leakage (n = 3), bleeding at drain insertion site (n = 2), subcutaneous bleeding (n = 1), drug-induced rash (n = 1), and sepsis (n = 1). Among the FPNX discontinuations, there were eight cases of bleeding (6.7%), and two cases of major bleeding (1.7%). In multivariate analysis, operative time >300 min was identified as a risk factor for bleeding events (p = 0.001) secondary to FPNX. The incidence rate of DVT was 2.5% (3/119 cases); these patients were asymptomatic. CONCLUSION: There were no cases of PE. It is necessary to establish strict criteria for VTE prophylaxis with FPNX after LAC for Japanese patients considering the incidence of bleeding events.