A clinical trial of a unidirectional porous tricalcium phosphate filling for defects after resection of benign bone lesions: a prospective multicenter study.

Affinos (Kuraray, Japan) is a ß-tricalcium phosphate bone substitute with a unidirectional porous structure. This study aimed to investigate its efficacy on the healing process after filling for bone defects. Fifty-six patients who met the inclusion criteria were divided into cohort 1 (n = 30), including bones other than phalanges and metacarpal/tarsal bones, and cohort 2 (n = 26), including phalanges and metacarpal/tarsal bones. Semi-quantified scores for material resorption and trabeculation through the defect were evaluated with radiographs after surgery. In some patients, levels of bone metabolic markers were assessed. The values of resorption and trabeculation increased steadily with time, and trabeculation progressed compared with resorption in both cohorts. In cohort 1, multiple regression analyses showed that the diaphyseal lesion, smaller defect volume, and increased resorption values at 3 months were associated with increased values of resorption 12 months after surgery (R2 = 0.66, p < 0.001). The trabeculation values at 2 months were positively related to the trabeculation values 12 months after surgery (R2 = 0.35, p = 0.002). In cohort 2, the increased resorption values at 2 months and smaller defect volume significantly correlated with the increased resorption values 12 months after surgery (R2 = 0.58, p < 0.001). The ratio from the baseline of pyridinoline cross-linked carboxyterminal telopeptide of type I collagen at 3 months was negatively associated with the trabeculation values 12 months after surgery (R = - 0.791, p = 0.004). Evaluation of radiographic images and bone metabolic markers in the early postoperative period may predict the healing status at 12 months postoperatively in the defects followed by Affinos filling.

Tumor location and type affect local recurrence and joint damage in tenosynovial giant cell tumor: a multi-center study.

Osteochondral destruction and a high recurrence rate after surgery are major concerns that make difficult the treatment course of tenosynovial giant cell tumor. The aims of this study were to elucidate rates of postoperative local recurrence and osteochondral destruction, as correlated with various demographic factors. Eighty surgically treated patients with intra-articular tumors (knee: 49, ankle and foot: 12, hip: 10, others: 9) were included in this study. Factors including age, disease type (diffuse/localized), location, existence of osteochondral destruction were correlated with local recurrence or development/progression of osteochondral destruction. The 5-year local recurrence free survival rate was 71.4%. Diffuse type (n = 59, localized: n = 21) (P = 0.023) and knee location (P = 0.002) were independent risk factors for local recurrence. Diffuse type (P = 0.009) was a significant risk factor, and knee location (P = 0.001) was a negative factor for osteochondral destruction at the initial examination. Progression of osteochondral destruction was observed more often in cases with local recurrence (P = 0.040) and findings of osteochondral destruction at the initial examination (P = 0.029). Diffuse type is a factor that should be noted for both local recurrence and osteochondral destruction, while local recurrence occurs but osteochondral destruction is less observed in the knee.

Negative prognostic outcomes of percutaneous transhepatic biliary drainage in distal cholangiocarcinoma: a retrospective analysis using propensity score matching.

BACKGROUND: The efficacy of different types of preoperative biliary drainage for cholangiocarcinoma has been debated over the past two decades. Controversy concerning the use of percutaneous transhepatic biliary drainage (PTBD) versus endoscopic biliary drainage (EBD) still exists. This study aimed to compare the long-term outcomes between PTBD and EBD in patients with distal cholangiocarcinoma. METHODS: Data of patients diagnosed with distal cholangiocarcinoma who underwent preoperative PTBD or EBD from January 1999 to December 2017 were analyzed retrospectively. Post-surgical outcomes, including the incidence of post-operative complications, peritoneal metastasis, disease-free survival, and overall survival, were analyzed. Survival analyses were also performed after propensity score matching in the PTBD and EBD groups. RESULTS: The incidence of post-operative complications was similar in both groups. The 5-year estimated cumulative incidences for peritoneal metastasis were 14.7% and 7.2% in the PTBD and EBD groups, respectively (p = 0.192). The 5-year disease-free survival rates were 23.7% and 47.3% in the PTBD and EBD groups, respectively (p = 0.015). In the multi-variate analysis for overall survival, PTBD was an independent poor prognostic factor. The 5-year overall survival rates were 35.9% and 56.3% in the PTBD and EBD groups, respectively (hazard ratio 1.85, confidence interval 1.05-3.26, p = 0.035). The results after propensity score matching indicated a poorer prognosis in the PTBD group, with a 5-year survival rate of 35.9% in the PTBD group vs 56.0% in the EBD group (p = 0.044). CONCLUSION: PTBD should be considered as a negative prognostic factor in distal cholangiocarcinoma patients.

Resectional surgery in gallbladder cancer with jaundice-how to improve the outcome?

PURPOSE: To evaluate the surgical outcomes of patients with gallbladder cancer (GBC) with jaundice due to as-yet unelucidated prognostic factors. METHODS: A total of 348 GBC patients underwent resection at our institute between 1985 and 2016. Of these, 67 had jaundice (serum total bilirubin ≥ 2 mg/dL). Preoperative biliary drainage was performed, with portal vein embolization as required. All patients underwent radical surgery. We retrospectively evaluated the outcomes, performed multivariate analysis for overall survival, and compared our findings to those reported in the literature. RESULTS: The 5-year survival rate of M0 (no distant metastasis) GBC patients with jaundice, who underwent resectional surgery, was 21.9%, versus 68.3% in those without jaundice (p < 0.05). Since 2000, surgical mortality in GBC patients with jaundice has decreased from 12 to 6.8%. Patients with jaundice had more advanced disease and underwent major hepatectomies and vascular resections; however, preoperative jaundice alone was not a prognostic factor. Multivariate analysis of jaundiced patients revealed that percutaneous biliary drainage (PTBD) (vis-à-vis endoscopic drainage [EBD], hazard ratio [HR] 2.82), postoperative morbidity (Clavien-Dindo classification ≥ 3, HR 2.31), and distant metastasis (HR 1.85) were predictors of poor long-term survival. The 5-year survival and peritoneal recurrence rates in M0 patients with jaundice were 16% and 44%, respectively, for patients with PTBD and 39% (p < 0.05) and 13% (p = 0.07) for those with EBD. CONCLUSION: M0 GBC patients with jaundice should undergo surgery if R0 resection is possible. Preoperative EBD may be superior to PTBD in M0 GBC patients with jaundice, although further studies are needed.

Prognostic Factors for Surgically Resected Intraductal Papillary Neoplasm of the Bile Duct: A Retrospective Cohort Study.

BACKGROUND: To date, postoperative prognostic factors for intraductal papillary neoplasm of the bile duct (IPNB) have not been well-established. This study aimed to examine the histopathologic features and postoperative prognosis of the two IPNB subclassifications, as well as factors affecting prognosis, based on the authors' experience at a single institution. METHODS: The study enrolled 83 patients who underwent surgical resection for pathologically diagnosed IPNB at the authors' institution. The clinicopathologic features and postoperative outcomes for these patients were examined. The study also investigated postoperative prognostic factors for IPNB using uni- and multivariate analyses. RESULTS: More than half of the tumors (64%) diagnosed as IPNB were early-stage cancer (UICC Tis or T1). However, none were diagnosed as benign. The multivariate analysis showed that lymph node metastasis (hazard ratio [HR], 5.78; p = 0.002) and bile duct margin status with carcinoma in situ (D-CIS; HR, 5.10; p = 0.002) were independent prognostic factors, whereas MUC6 expression showed only a marginal influence on prediction of prognosis (HR, 0.32; p = 0.07). The tumor recurrence rate and the proportion of locoregional recurrence were significantly greater among the patients with D-CIS than among those with negative bile duct margins, including those patients with low-grade dysplasia. The patients with D-CIS showed a significantly poorer prognosis than those with negative bile duct margins (5-year survival, 38% versus 87%; p = 0.0002). CONCLUSIONS: Evaluation of resected IPNBs showed cancer in all cases. Avoiding positive biliary stumps during surgery, including resection of carcinoma in situ, would improve the prognosis for patients with IPNB.

Examination of Prognostic Factors Affecting Long-Term Survival of Patients with Stage 3/4 Gallbladder Cancer without Distant Metastasis.

In advanced gallbladder cancer (GBC) radical resection, if multiple prognostic factors are present, the outcome may be poor; however, the details remain unclear. To investigate the poor prognostic factors affecting long-term surgical outcome, we examined 157 cases of resected stage 3/4 GBC without distant metastasis between 1985 and 2017. Poor prognostic factors for overall survival and treatment outcomes of a number of predictable preoperative poor prognostic factors were evaluated. The surgical mortality was 4.5%. In multivariate analysis, blood loss, poor histology, liver invasion, and ≥4 regional lymph node metastases (LNMs) were independent prognostic factors for poor surgical outcomes; invasion of the left margin or the entire area of the hepatoduodenal ligament and a Clavien-Dindo classification ≥3 were marginal factors. The analysis identified outcomes of patients with factors that could be predicted preoperatively, such as liver invasion ≥5 mm, invasion of the left margin or the entire area of the hepatoduodenal ligament, and ≥4 regional LNMs. Thus, the five-year overall survival was 54% for zero factors, 34% for one factor, and 4% for two factors (p < 0.05). A poor surgical outcome was likely when two or more factors were predicted preoperatively; therefore, new treatment strategies are required for such patients.

Functional evaluation following deltoid muscle resection in patients with soft tissue sarcoma.

BACKGROUND: The present study aimed to determine functional outcomes in patients undergoing deltoid muscle resection for soft tissue sarcoma. METHODS: Between 2002 and 2014, 18 patients with soft tissue sarcoma of the shoulder who underwent wide resection including the deltoid muscle, and were followed up for more than 12 months, were retrospectively included in the study. In all, 11 patients were male and 7 were female. The median age was 59 years, median follow-up duration was 37 months. The extent of resection of deltoid muscle, with or without rotator cuff damage, reconstruction methods, adjuvant therapy, oncological outcomes, and the International Society of Limb Salvage (ISOLS) score as functional outcomes were analyzed. RESULTS: Six patients underwent total resection, and twelve underwent partial resections of deltoid muscle. The rotator cuff was resected in four patients. Soft tissue reconstruction was performed in 17 patients using a pedicled latissimus dorsi muscle flap. Two local recurrences and three distant metastases occurred during follow-up. Median overall survival was 72 months. The mean ISOLS score was 25.0 points (±4.6points). Univariate analysis revealed that there was no significant difference in ISOLS score regarding the extent of deltoid muscle resection. Multivariate analysis identified only combined resection of the rotator cuff as a significant prognostic factor for poor functional outcomes (P < 0.001). CONCLUSIONS: The extent of resection of the deltoid muscle might not affect the functional outcomes determined by ISOLS score. If the rotator cuff is resected concurrently, satisfactory functional outcomes might not be obtained.

Surgical Outcomes for Perihilar Cholangiocarcinoma with Vascular Invasion.

PURPOSE: To investigate short- and long-term surgical outcomes for patients with perihilar cholangiocarcinoma and vascular invasion. METHODS: Data from 249 patients who underwent perihilar cholangiocarcinoma surgery between 2000 and 2016 were retrospectively analyzed. Patient evaluations included short-term surgical outcomes following vascular resection and long-term outcomes in cases with histopathological vascular invasion. RESULTS: Mortality was 3.6% overall; 16% for hepatic artery resections, 5.4% for portal vein resections, and 1.7% in the absence of vascular resection (p = 0.029). No between-group differences were observed in the incidence of Clavien-Dindo grade ≥ 3 complications. The factors related to perioperative mortality were hepatic artery resection (odds ratio [OR] = 25.5), right trisectionectomy (OR = 13.0), and central bisectionectomy (OR = 13.8). Multivariate analysis for overall survival identified several prognostic factors: carcinoembryonic antigen level ≥ 5 ng/mL (hazard ratio [HR] = 1.68), poor differentiation (HR = 2.39), distant metastasis (HR = 1.97), and R1 invasive resection (HR = 2.13). Five-year overall survival for patients with portal vein invasion and M0R0/1cis was 35.6%, significantly worse than the 53.4% for patients with no portal vein invasion and M0R/1cis but better than the 0% for patients with portal vein invasion and M1 or R1. Those with hepatic arterial invasion and M0R0/1cis were 24.7%, significantly worse than the 53.4% for patients with no hepatic arterial invasion and M0R0/1cis but significantly better than the 0% for patients with hepatic arterial invasion and M1 or R1. CONCLUSION: Short-term outcomes for patients with perihilar cholangiocarcinoma and undergoing vascular resection were poor compared to those without vascular resection. Long-term survival in R0M0 disease was more favorable; aggressive surgery is recommended.

Single metastasis of myxoid liposarcoma from the thigh to thyroid gland: a case report.

BACKGROUND: Thyroid metastasis of soft tissue sarcoma is very rare, and the diagnosis is especially difficult when only a single lesion is present. CASE PRESENTATION: A 50-year-old man was diagnosed with myxoid liposarcoma of the right thigh and treated with wide resection. Two and a half years after the surgery, a growing low-density area was incidentally observed in the right lobe of his thyroid gland on follow-up chest computed tomography. Fine needle aspiration biopsy was performed twice, and the thyroid mass was suspected of being a sarcoma metastasis. He was treated by hemithyroidectomy, and the lesion was pathologically confirmed as a metastasis of myxoid liposarcoma. CONCLUSION: We experienced single thyroid gland metastasis in patients with myxoid liposarcoma in whom a growing mass is observed in the thyroid gland after radical surgery of the primary site.

de Garengeot hernia with appendicitis treated by two-way-approach surgery: a case report.

de Garengeot hernia is a rare subtype of a femoral hernia with incarceration of the appendix. This type of hernia usually presents with therapeutic dilemmas, especially because of the risk of surgical site infection (SSI). Our patient was a 74-year-old woman with a bulging mass and tenderness in the right inguinal area. Computed tomography revealed an incarcerated appendix, with appendicitis in the femoral hernia. Laparoscopic appendectomy was initially performed, followed by hernioplasty via the anterior approach to prevent properitoneal contamination. Some authors have recently reported cases successfully treated by laparoscopy. However, this type of hernia has a higher risk for SSI, compared with the risk involved in usual hernioplasty. Therefore, selection of the appropriate surgical approach to prevent wound infection is important, especially in the presence of appendicitis. We would like to highlight the usefulness of hybrid surgery, laparoscopic appendectomy and hernioplasty via the anterior approach to prevent SSIs.

Immunohistochemical staining with non-phospho ß-catenin as a diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with extra-peritoneal desmoid-type fibromatosis.

BACKGROUND: Immunohistochemical staining with conventional anti-ß-catenin antibody has been applied as a diagnostic tool for desmoid-type fibromatosis (DF). This study aimed to evaluate the diagnostic and prognostic value of immunohistochemical staining with anti-non-phospho ß-catenin antibody, which might more accurately reflect the aggressiveness of DF, in comparison to the conventional anti-ß-catenin antibody. METHODS: Between 2003 and 2015, 40 patients with extra-peritoneal sporadic DF were prospectively treated with meloxicam or celecoxib, a COX-2 inhibitor, therapy. The efficacy of this treatment was evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST). Immunohistochemical staining was performed on formalin-fixed material to evaluate the expression of ß-catenin and non-phospho ß-catenin, and the positivity was grouped as negative, weak, moderate, and strong. DNA was isolated from frozen tissue or formalin-fixed materials, and the CTNNB1 mutation status was determined by direct sequencing. RESULTS: Of the 40 patients receiving COX-2 inhibitor treatment, there was one with complete remission, 12 with partial remission, 7 with stable disease, and 20 with progressive disease. The mutation sites in CTNNB1 were detected in 22 (55%) of the 40 cases: T41A (17 cases), S45F (3 cases), and T41I and S45P (1 each). The positive nuclear expression of non-phospho ß-catenin showed a significant correlation with positive CTNNB1 mutation status detected by Sanger method (p = 0.025), and poor outcome in COX-2 inhibitor therapy (p = 0.022). In contrast, nuclear expression of ß-catenin did not show a significant correlation with either CTNNB1 mutation status (p = 0.43) or outcome of COX-2 inhibitor therapy (p = 0.38). CONCLUSIONS: Nuclear expression of non-phospho ß-catenin might more appropriately reflect the biological behavior of DF, and immunohistochemical staining with non-phospho ß-catenin could serve as a more useful diagnostic and prognostic tool of COX-2 inhibitor therapy for patients with DF.

Heat-stimuli-enhanced osteogenesis using clinically available biomaterials.

A recent study reported that heat stress stimulates osteogenesis in an in vivo rat model using alginate gel and magnetite cationic liposomes. However, for clinical use, the efficacy for promoting osteogenesis needs to be investigated using clinically approved materials, and preferably with animals larger than rats. The aim of this study was to evaluate multiple heat stimuli-triggered osteogenesis in rat tibial defect models using already clinically applicable materials (Resovist® and REGENOS®) and determine the efficacy also in the rabbit. Fifty-eight rats and 10 rabbits were divided into two groups, respectively, with or without hyperthermia treatment at 45°C for 15 min. (hyperthermia; 20 rats once a week, 8 rats three times a week, 5 rabbits once a week, control; 30 rats and 5 rabbits). Micro-CT assessment at 4 weeks revealed that a significantly stimulated osteogenesis was observed in the once a week group of both rats and rabbits as compared to the control group (p = 0.018 and 0.036, respectively). In contrast, the three times a week group did not show enhanced osteogenesis. Histological examination and image analysis showed consistent results in which the area of mineralized bone formation in the once a week hyperthermia group was significantly increased compared with that in the control group at four weeks (rat; p = 0.026, rabbit; p = 0.031). Newly formed bone was observed in the grafted materials from the periphery toward the center, and more osteoclasts were found in the once a week group. Heat stress also induced enhanced alkaline phosphatase expression in cultured osteoblastic cells, MC3T3, in vitro (p = 0.03). On the other hand, heat stress had no obvious effects on chondrogenic differentiation using ATDC5 cells. Our study demonstrates that heat-stimuli with clinically applicable novel heating materials can promote significant osteogenesis, and may thus be a promising treatment option for diseases associated with bone defects.

Safety-related outcomes of the Japanese Society of Hepato-Biliary-Pancreatic Surgery board certification system for expert surgeons.

BACKGROUND: We investigated safety-related outcomes of hepatobiliary pancreatic (HBP) surgeries performed after establishment of the Japanese Society of Hepato-Biliary-Pancreatic Surgery (JSHBPS) board certification system for expert surgeons. METHODS: We analyzed post-HBP surgery mortality data obtained from annual safety reports provided by board-certified training institutions between 2012 and 2015. RESULTS: The 90-day mortality rate for the 53,929 high-level HBP surgeries performed at board-certified training institutions was 1.7%. The 30-day mortality rates for 2012, 2013, 2014, and 2015 were 0.9%, 0.7%, 0.6%, and 0.6%, respectively, and the 90-day mortality rates were 2.1%, 1.8%, 1.6%, and 1.3%, respectively, with significant decreases in both. The surgeries with high 4-year cumulative mortality rates were left hepatic trisectionectomy (10.3%), hepatopancreatectomy (7.6%), liver transplant recipient surgery (6.7%), hepatectomy with extrahepatic bile duct resection (4.6%), and right hepatic trisectionectomy (4.5%). Over the 4-year period, the number of operations increased, but the 90-day mortality rates for these surgeries, with the exception of right trisectionectomy, decreased. CONCLUSIONS: The JSHBPS board certification system for expert surgeons has significantly decreased mortality subsequent to high-level HBP surgeries. Reducing mortality associated with high-risk HBP surgeries will be our next challenge.

Antitumor effects of 4-methylumbelliferone, a hyaluronan synthesis inhibitor, on malignant peripheral nerve sheath tumor.

Hyaluronan (HA) has been shown to play important roles in the growth, invasion and metastasis of malignant tumors. Our previous study showing that high HA expression in malignant peripheral nerve sheath tumors (MPNST) is predictive of poor patient prognosis, prompted us to speculate that inhibition of HA synthesis in MPNST might suppress the tumorigenicity. The aim of our study was to investigate the antitumor effects of 4-methylumbelliferone (MU), an HA synthesis inhibitor, on human MPNST cells and tissues. The effects of MU on HA accumulation and tumorigenicity in MPNST cells were analyzed in the presence or absence of MU in an in vitro as well as in vivo xenograft model using human MPNST cell lines, sNF96.2 (primary recurrent) and sNF02.2 (metastatic). MU significantly inhibited cell proliferation, migration and invasion in both MPNST cell lines. HA binding protein (HABP) staining, particle exclusion assay and quantification of HA revealed that MU significantly decreased HA accumulation in the cytoplasms and pericellular matrices in both MPNST cell lines. The expression levels of HA synthase2 (HAS2) and HA synthase3 (HAS3) mRNA were downregulated after treatment with MU. MU induced apoptosis of sNF96.2 cells, but not sNF02.2 cells. MU administration significantly inhibited the tumor growth of sNF96.2 cells in the mouse xenograft model. To the best of our knowledge, our study demonstrates for the first time the antitumor effects of MU on human MPNST mediated by inhibition of HA synthesis. Our results suggest that MU may be a promising agent with novel antitumor mechanisms for MPNST.

Improved surgical outcomes for hilar cholangiocarcinoma: changes in surgical procedures and related outcomes based on 40 years of experience at a single institution.

PURPOSE: This study aimed to examine the changes in procedures for hilar cholangiocarcinoma (HC) surgery and patient survival following HC surgery over a 40-year period. METHODS: Between 1974 and 2014, 239 consecutive patients underwent surgery for HC. The changes in perioperative therapy and short- and long-term surgical outcomes were evaluated. RESULTS: The rates of major hepatectomy (in particular, right hepatectomy) and R0 resection significantly increased. Blood loss, transfusion rate, morbidity, and surgical mortality all significantly decreased. The 5-year disease-specific survival was 9.29 % (n = 38) in 1974-1988, 41.1 % (n = 88) in 1989-2003 and 55.6 % (n = 57) in 2004-2008 (p = 0.0001: 1974-1988 vs 1989-2003, p < 0.0001:1974-1988 vs 2004-2008, p = 0.076: 1989-2003 vs 2004-2008). According to a multivariate analysis, Bismuth classification IV (HR vs I, 2.86), period 1989-2003 (HR vs 1974-1988, 0.31), 2004-2008 (HR vs 1974-1988, 0.26), and R1 or R2 resection (HR vs R0, 2.22) were independent prognostic factors. CONCLUSION: The surgical outcomes for HC over the 40-year period clearly improved as a result of aggressive surgery and progress in surgical techniques, perioperative management, and diagnostic tools.

Expression of colony-stimulating factor 1 is associated with occurrence of osteochondral change in pigmented villonodular synovitis.

Pigmented villonodular synovitis (PVNS) is a benign, translocation-derived neoplasm. Because of its high local recurrence rate after surgery and occurrence of osteochondral destruction, a novel therapeutic target is required. The present study aimed to evaluate the significance of protein expression possibly associated with the pathogenesis during the clinical course of PVNS. In 40 cases of PVNS, positivity of colony-stimulated factor 1 (CSF1), its receptor (CSF1R), and receptor activator of nuclear factor kappa-B ligand (RANKL) were immunohistochemically determined. The relationship between the positivity and clinical outcomes was investigated. High positivity of CSF1 staining intensity was associated with an increased incidence of osteochondral lesions (bone erosion and osteoarthritis) (p = 0.009), but not with the rate of local recurrence. Positivity of CSF1R and RANKL staining was not associated with any clinical variables. The number of giant cells was not correlated with positivity of any of the three proteins, or with the clinical outcome. Focusing on knee cases, CSF1 positivity was also associated with the incidence of osteochondal change (p = 0.02). CSF1R positivity was high in cases which had local recurrence, but not significantly so (p = 0.129). Determination of CSF1 and CSF1R expression may be useful as a prognosticator of the clinical course and/or outcomes of PVNS.

Clinical practice guidelines for the management of biliary tract cancers 2015: the 2nd English edition.

BACKGROUND: The Japanese Society of Hepato-Biliary-Pancreatic Surgery launched the clinical practice guidelines for the management of biliary tract and ampullary carcinomas in 2008. Novel treatment modalities and handling of clinical issues have been proposed after the publication. New approaches for editing clinical guidelines, such as the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, also have been introduced for better and clearer grading of recommendations. METHODS: Clinical questions (CQs) were proposed in seven topics. Recommendation, grade of recommendation and statement for each CQ were discussed and finalized by evidence-based approach. Recommendation was graded to grade 1 (strong) and 2 (weak) according to the concept of GRADE system. RESULTS: The 29 CQs covered seven topics: (1) prophylactic treatment, (2) diagnosis, (3) biliary drainage, (4) surgical treatment, (5) chemotherapy, (6) radiation therapy, and (7) pathology. In 27 CQs, 19 recommendations were rated strong and 11 recommendations weak. Each CQ included the statement of how the recommendation was graded. CONCLUSIONS: This guideline provides recommendation for important clinical aspects based on evidence. Future collaboration with cancer registry will be a key for assessment of the guidelines and establishment of new evidence. Free full-text articles and a mobile application of this guideline are available via http://www.jshbps.jp/en/guideline/biliary-tract2.html.

In vivo heat-stimulus-triggered osteogenesis.

Several studies have reported that heat stress stimulates the activity of osteoblastic cells in vitro. However, few have addressed the effects of heat stress on osteogenesis in vivo, nor have the optimal temperatures for bone formation been determined. The aim of the present study was to investigate the effects of hyperthermia treatment on osteogenesis in a rat tibial defect model. Forty-four Sprague Dawley rats were divided into two groups with or without hyperthermia treatment. A 3-mm circular defect in the proximal tibia filled with magnetite cationic liposomes embedded in alginate beads was subjected to hyperthermia treatment (43-46 °C). Radiological assessment at 2 weeks after the treatment showed that significantly stimulated osteogenesis was observed in the hyperthermia group as compared to the control group (p = 0.003). Histomorphometrical analysis at 2 weeks revealed a significant increase of newly formed bone in the hyperthermia group, compared with the control group (p < 0.001). Area of newly formed bone in each hyperthermia group was significantly increased as compared with the control group (43 °C; p = 0.005, 44 °C; p = 0.019, 45 °C; p = 0.003, and 46 °C; p = 0.003, respectively). Alkaline phosphatase was overexpressed at the surfaces of newly formed bone adjacent to magnetite cationic liposome implantation. Our results demonstrate for the first time that heat stimulus accelerates osteogenesis in vivo, and may thus be of interest as a novel and promising tool to induce osteogenesis clinically as well.