Satoshi Yasuda

Pathological and clinical impact of neoadjuvant chemoradiotherapy using full-dose gemcitabine and concurrent radiation for resectable pancreatic cancer

Background/purposeThe therapeutic options available as preoperative strategies for resectable pancreatic cancer have received worldwide attention. We have recently introduced neoadjuvant chemoradiotherapy (NACRT) to achieve local control and possibly complete cure. In this study, we have retrospectively evaluated its impact on pathology and the perioperative clinical course in addition to its safety.MethodsSixty-one patients who received full-dose gemcitabine (1000xa0mg/m2) preoperatively with concurrent radiation (50 or 54xa0Gy) were evaluated. Seventy-one patients who received no preoperative therapy served as controls. Perioperative outcomes, postoperative complications, immunonutritional status, and the performance of adjuvant chemotherapy were compared.ResultsFifty-nine patients (97xa0%) completed NACRT. Toxicity was acceptable and the regimen was feasible as outpatient treatment. The perioperative outcomes were closely comparable to control. The rate of pancreatic fistula was lower and hospital stay was shorter in the NACRT group. The rate of lymph node metastasis and stage was lower in the NACRT group. Furthermore, R0 resection could be achieved in 92xa0% of patients treated with NACRT. Nutritional status decreased after NACRT and further deteriorated during adjuvant chemotherapy. The initiation of postoperative chemotherapy was delayed in the NACRT group.ConclusionsOur current protocol of neoadjuvant chemoradiotherapy is feasible and substantially improves the pathology. However, it has some detrimental effects on postoperative nutritional status and performance of adjuvant chemotherapy. Furthermore, it should be noted that there is a possibility of arterial complications.

Simultaneous blockade of programmed death 1 and vascular endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour effect in vivo

Recent basic and clinical studies have shown that the programmed death ligand (PD‐L)/PD‐1 pathway has a significant role in tumour immunity, and its blockade has a therapeutic potential against several human cancers. We hypothesized that anti‐angiogeneic treatment might augment the efficacy of PD‐1 blockade. To this end, we evaluated combining the blockade of PD‐1 and vascular endothelial growth factor receptor 2 (VEGFR2) in a murine cancer model using Colon‐26 adenocarcinoma. Interestingly, simultaneous treatment with anti‐PD‐1 and anti‐VEGFR2 monoclonal antibodies (mAbs) inhibited tumour growth synergistically in vivo without overt toxicity. Blocking VEGFR2 inhibited tumour neovascularization significantly, as demonstrated by the reduced number of microvessels, while PD‐1 blockade had no impact on tumour angiogenesis. PD‐1 blockade might promote T cell infiltration into tumours and significantly enhanced local immune activation, as shown by the up‐regulation of several proinflammatory cytokine expressions. Importantly, VEGFR2 blockade did not interfere with T cell infiltration and immunological activation induced by PD‐1 blockade. In conclusion, simultaneous blockade of PD‐1 and VEGFR2 induced a synergistic in‐vivo anti‐tumour effect, possibly through different mechanisms that might not be mutually exclusive. This unique therapeutic strategy may hold significant promise for future clinical application.

PCA-1/ALKBH3 contributes to pancreatic cancer by supporting apoptotic resistance and angiogenesis.

The PCA-1/ALKBH3 gene implicated in DNA repair is expressed in several human malignancies but its precise contributions to cancer remain mainly unknown. In this study, we have determined its functions and clinical importance in pancreatic cancer. PCA-1/ALKBH3 functions in proliferation, apoptosis and angiogenesis were evaluated in human pancreatic cancer cells in vitro and in vivo. Further, PCA-1/ALKBH3 expression in 116 patients with pancreatic cancer was evaluated by immunohistochemistry. siRNA-mediated silencing of PCA-1/ALKBH3 expression induced apoptosis and suppressed cell proliferation. Conversely, overexpression of PCA-1/ALKBH3 increased anchorage-independent growth and invasiveness. In addition, PCA-1/ALKBH3 silencing downregulated VEGF expression and inhibited angiogenesis in vivo. Furthermore, immunohistochemical analysis showed that PCA-1/ALKBH3 expression was abundant in pancreatic cancer tissues, where it correlated with advanced tumor status, pathological stage and VEGF intensity. Importantly, patients with low positivity of PCA-1/ALKBH3 expression had improved postoperative prognosis compared with those with high positivity. Our results establish PCA-1/ALKBH3 as important gene in pancreatic cancer with potential utility as a therapeutic target in this fatal disease.

Clinical impact of herpesvirus entry mediator expression in human hepatocellular carcinoma.

BACKGROUNDnHerpes virus entry mediator (HVEM), also known as tumour necrosis factor receptor (TNFR) superfamily 14, regulates a variety of physiological and pathological responses in both innate and acquired immunity. Although HVEM is also suggested to be a critical regulator in tumours, actual roles in human cancer are largely unknown. This study aimed to clarify clinical importance of HVEM in human hepatocellular carcinoma (HCC).nnnPATIENTS AND METHODSnWe studied HVEM expression in 150 HCC patients to explore its clinical relevance, and we examined tumour infiltrating T cells and local immune status of them.nnnRESULTSnHVEM was expressed in HCC cells, while no or only limited expression was observed in normal tissues in the liver. Tumour HVEM expression was significantly correlated with age, serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) level, vascular invasion and tumour node metastasis (TNM) stage. Furthermore, tumour HVEM expression significantly correlated with postoperative recurrence and survival. Importantly, multivariate analysis indicated that the HVEM status had an independent prognostic value. Furthermore, HVEM status was inversely correlated with tumour-infiltrating CD4(+), CD8(+) and CD45RO(+) lymphocytes. In addition, it was also associated with reduced expression of perforin, granzyme B and interferon-γ (IFN-γ). Taken together, tumour-expressing HVEM plays a functionally important role in HCC.nnnCONCLUSIONnTumour-expressing HVEM plays a critical role in human HCC, possibly through regulating immune evasion. Therefore, targeting HVEM may be a novel promising therapeutic strategy for HCC.

Nectin-4 expression contributes to tumor proliferation, angiogenesis and patient prognosis in human pancreatic cancer

BackgroundNectin-4 belongs to the nectin family that has diverse physiological and pathological functions in humans. Recent studies have also suggested some roles for Nectin-4 in several human cancers. However, the precise roles and clinical relevance of Nectin-4 in tumors are largely unknown.MethodsNectin-4 expression was investigated in 123 patients with pancreatic cancer by immunohistochemistry. Furthermore, we investigated the association of Nectin-4 in pancreatic cancer with tumor proliferation, angiogenesis and immunity by using immunohistochemistry and siRNA interference method.ResultsPatients with high Nectin-4 expression had poorer postoperative prognosis than those with low expression. Importantly, multivariate analysis indicated that Nectin-4 expression had a significant independent prognostic value in pancreatic cancer (HRu2009=u20091.721, 1.085-2.730; Pu2009=u20090.021). Tumor Nectin-4 expression was significantly correlated with Ki67 expression. In addition, siRNA-mediated gene silencing of Nectin-4 significantly inhibited the cell proliferation in human pancreatic cancer cells, Capan-2 and BxPC-3. Furthermore, Nectin-4 expression was also positively correlated with VEGF expression and intratumoral microvessel density. However, there were no significant correlations of tumor Nectin-4 expression with tumor-infiltrating T cells.ConclusionNectin-4 is a significant prognostic predictor, and may play a critical role in pancreatic cancer. Nectin-4 may be novel therapeutic target for pancreatic cancer.

Significant involvement of herpesvirus entry mediator in human esophageal squamous cell carcinoma.

Herpesvirus entry mediator (HVEM) is known to regulate immune response and to be expressed in several human malignancies. However, to the authorss knowledge, the precise role of HVEM in human cancer biology remains unknown. The objective of the current study was to clarify the clinical significance of HVEM in human esophageal squamous cell carcinoma as well as its in vivo functions.

Impact of Mechanical Bowel Preparation on Postoperative Outcomes after Liver Resection for Patients with Hepatocellular Carcinoma: A Single-Center Retrospective Cohort Study.

Background: Despite the routine use of mechanical bowel preparation (MBP), the real impact of MBP for liver resection remains unclear. The aim of this study was to evaluate the postoperative outcomes of MBP after liver resection for hepatocellular carcinoma (HCC). Methods: This was a retrospective cohort study of all patients undergoing liver resection for patients with HCC between from April 2008 to March 2015. MBP was defined as a preoperative medication of polyethylene glycol lavage. We compared perioperative outcomes in patients who did or did not receive MBP before liver resection. Open and laparoscopic hepatectomy were analyzed separately. Results: A total of 227 patients underwent potentially curative liver resection for HCC during the study period. One hundred twenty-eight patients received MBP while 99 did not. In the open hepatectomy group, overall and major (Clavien-Dindo ≥3) complications were equivalent between the groups (31.9 vs. 25.8%, p = 0.840; 12.1 vs. 8.7%, p = 0.475). There were no meaningful differences in the incidence of liver failure (MBP: 22.4%, non-MBP: 13.0%, p = 0.116). Surgical-site infections occurred in 20 (17.2%) vs. 10 (14.5%) with no significant difference (p = 0.624). Similar results were obtained from the laparoscopic hepatectomy group. Conclusion: The use of MBP does not appear to impact the short outcomes after liver resection for patients with HCC. MBP might be omitted in liver surgery.

The Administration of Celecoxib as an Analgesic after Liver Resection Is Safe.

Background: There are a few studies that have evaluated postoperative analgesia. The aim of this study was to evaluate the safety of administering celecoxib to manage postoperative pain after liver surgery. Methods: The cases of patients who underwent liver resection at Nara Medical University from April 2008 to December 2015 were retrospectively analyzed. From January 2013 to December 2015, celecoxib was routinely administered (600 mg/day on postoperative day (POD) 2 and 400 mg/day from POD 3-7), whereas celecoxib was not administered from April 2008 to December 2012. The patients baseline characteristics, the operative procedures, and postoperative complications were analyzed. Results: In total, 207 patients were administered celecoxib (celecoxib group), whereas 246 were not (non-celecoxib group). The preoperative serum total bilirubin and creatinine levels and indocyanine green retention rate at 15 min values of the 2 groups were similar. Similar incidences of overall and major complications (Clavien-Dindo classification ≥grade IIIa) were seen in both groups (33.8 vs. 36.2%, p = 0.601 and 12.1 vs. 12.6%, p = 0.866, respectively). No significant differences in the incidences of gastrointestinal bleeding, acute renal failure, or portal vein thrombosis were observed between the groups. Conclusions: The use of celecoxib for postoperative analgesia in the early period after liver resection is safe.

The safety of the early removal of prophylactic drainage after liver resection based solely on predetermined criteria: a propensity score analysis

BACKGROUNDnProphylactic drainage after liver resection remains a common practice amongst hepatic surgeons. However, there is little information about the optimal timing of drain removal.nnnMETHODSnFrom April 2008 to December 2012 (conventional group), the drains were removed based on the treating surgeons view. From January 2013 to April 2016 (ERP group), the drains were removed on POD 3 if the bile concentration of the drain discharge was less than three times the serum bilirubin on POD 3, and the amount of drain discharge was <500xa0ml on POD 3. The postoperative outcomes of the two groups were compared using one-to-one propensity score-matching analysis.nnnRESULTSnOne hundred nine patients were extracted from ERP group (nxa0=xa0226) and conventional group (nxa0=xa0246). The time to drain removal was significantly shorter in the ERP group than in the conventional group (3 days vs. 5 days, Pxa0<xa00.001). The frequency of delayed bile leakage or the appearance of symptomatic abdominal fluid collection after drain removal did not differ between the two groups (3% vs. 4%, Pxa0=xa00.791).nnnCONCLUSIONnDrain removal on POD 3 based on the volume and bile concentration is safe.

The prognosis of liver resection for patients with four or more colorectal liver metastases has not improved in the era of modern chemotherapy

The impact of perioperative chemotherapy on patients with multiple colorectal liver metastases (CRLM) remains unclear. We attempted to examine whether the introduction of modern chemotherapies has improved the prognosis of patients that undergo liver resection for ≥4 CRLM.