Search

Cancer is a leading cause of death worldwide, and the incidence continues to increase. Despite major research aimed at discovering and developing novel and effective anticancer drugs, oncology drug development is a lengthy and costly process, with high attrition rates. Drug repositioning (DR, also referred to as drug repurposing), the process of finding new uses for approved noncancer drugs, has been gaining popularity in the past decade. DR has become a powerful alternative strategy for discovering and developing novel anticancer drug candidates from the existing approved drug space. Indeed, the availability of several large established libraries of clinical drugs and rapid advances in disease biology, genomics/transcriptomics/proteomics and bioinformatics has accelerated the pace of activity‐based, literature‐based and in silico DR, thereby improving safety and reducing costs. However, DR still faces financial obstacles in clinical trials, which could limit its practical use in the clinic. Here, we provide a brief review of DR in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan., We provide a brief review of drug repositioning (DR) in cancer and discuss difficulties in the development of DR for clinical use. Furthermore, we introduce some promising DR candidates for anticancer therapy in Japan.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, operative procedures have been standardized, and the safety and efficacy of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less invasive type of surgery, the number of endoscopic procedures performed has increased in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. Notably, a technical skills certification system for surgeons was established by the JSES to train instructors on how to teach safe endoscopic surgery. Furthermore, the JSES has conducted a national survey every two years to evaluate the status of endoscopic surgery over time. In 2017, 248 743 patients underwent endoscopic surgery in all surgical domains, such as abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The 14th National Survey of Endoscopic Surgery conducted by the JSES demonstrated the status of laparoscopic surgery in Japan in 2016-2017.

Chemotherapy after hepatectomy for colorectal liver metastasis has not been established, due to the toxic side effects, which are likely related to impaired drug clearance during liver regeneration. We investigated the pharmacokinetic and toxicodynamic evaluation of 5-fluorouracil (5-FU) during liver regeneration after major hepatectomy in a rat model. Thirty-six male Wistar rats were divided into control (C), control with chemotherapy (CC), hepatectomy (H), and hepatectomy with chemotherapy (HC) groups. The CC and HC groups were administered 5-FU for 4 days. Plasma 5-FU, liver weight, and liver dihydropyrimidine dehydrogenase (DPD) were measured. The ileal villous height was measured to determine adverse effects. The area under the curve and maximum plasma concentration of 5-FU increased by up to 51% and 32%, respectively, in the HC group compared to the CC group. The liver regeneration rate was significantly lower in the HC group than in the H group (67.3 ± 7.4 vs 33.0 ± 5.7%, p

Rationale: Cerebrovascular function is critical for brain health, and endogenous vascular protective pathways may provide therapeutic targets for neurological disorders. S1P (Sphingosine 1-phosphate) signaling coordinates vascular functions in other organs, and S1P 1 (S1P receptor-1) modulators including fingolimod show promise for the treatment of ischemic and hemorrhagic stroke. However, S1P 1 also coordinates lymphocyte trafficking, and lymphocytes are currently viewed as the principal therapeutic target for S1P 1 modulation in stroke. Objective: To address roles and mechanisms of engagement of endothelial cell S1P 1 in the naive and ischemic brain and its potential as a target for cerebrovascular therapy. Methods and Results: Using spatial modulation of S1P provision and signaling, we demonstrate a critical vascular protective role for endothelial S1P 1 in the mouse brain. With an S1P 1 signaling reporter, we reveal that abluminal polarization shields S1P 1 from circulating endogenous and synthetic ligands after maturation of the blood-neural barrier, restricting homeostatic signaling to a subset of arteriolar endothelial cells. S1P 1 signaling sustains hallmark endothelial functions in the naive brain and expands during ischemia by engagement of cell-autonomous S1P provision. Disrupting this pathway by endothelial cell-selective deficiency in S1P production, export, or the S1P 1 receptor substantially exacerbates brain injury in permanent and transient models of ischemic stroke. By contrast, profound lymphopenia induced by loss of lymphocyte S1P 1 provides modest protection only in the context of reperfusion. In the ischemic brain, endothelial cell S1P 1 supports blood-brain barrier function, microvascular patency, and the rerouting of blood to hypoperfused brain tissue through collateral anastomoses. Boosting these functions by supplemental pharmacological engagement of the endothelial receptor pool with a blood-brain barrier penetrating S1P 1 -selective agonist can further reduce cortical infarct expansion in a therapeutically relevant time frame and independent of reperfusion. Conclusions: This study provides genetic evidence to support a pivotal role for the endothelium in maintaining perfusion and microvascular patency in the ischemic penumbra that is coordinated by S1P signaling and can be harnessed for neuroprotection with blood-brain barrier-penetrating S1P 1 agonists.

Background and Aims Calcimimetic agent is used for secondaryhyperparathyroidism (SHPT), but it might cause gastrointestinal side-effects. These side effects are severe problem for PD patients with gastrointestinal symptoms due to dialysis fluid storage. Evocalcet is a new calcimimetic agent for SHPT, and expected to reduce gastrointestinal related symptoms. There have been some reports about switching from cinacalcet to evocalcet or administered for HD patients. However, there have been few reports on PD patients. Here, we reported the efficiency and safety of evocalcet in PD patients. Method PD patients who had newly started to treat for SHPT with evocalcet, between August 2018 to August 2019 were selected. Patients who died or transferred to HD within 6 months after administered evocalcet were excluded. We compared the changes in whole PTH level, serum phosphorus level and serum corrected calcium level with baseline and after administration. Moreover, we investigated adverse events of gastrointestinal related symptoms. Results Overall, 34 PD patients were included, (mean age: 67.5 years old, male/female: 23/11, average PD vintage: 39.6 months, serum phosphorus level: 5.1 ± 1.0 mg/dl). There was a significant reduction in whole PTH at week 16 from baseline (346 ± 187 pg/ml vs 258 ± 196 pg/ml, p Conclusion These results suggested that evocalcet might be efficient and safety in PD patients with SHPT.

In Japan, the first endoscopic surgery, a laparoscopic cholecystectomy, was performed in 1990. Since then, the operative procedure has been standardized, and the safety and usefulness of endoscopic surgery have been evaluated. In accordance with the social acceptance of endoscopic surgery as a less-invasive surgery, the number of endoscopic procedures has been increasing in all surgical domains. The Japan Society for Endoscopic Surgery (JSES) has played an important role in the development of endoscopic surgery in Japan. For example, JSES established a technical skills certification system for surgeons to train instructors how to teach safe endoscopic surgery, and the organization performs a national survey every 2 years. In 2015, a total of 211 953 patients underwent endoscopic surgery in all surgical domains, including abdominal, thoracic, mammary and thyroid gland, cardiovascular, obstetrics and gynecology, urologic, orthopedic, and plastic surgery. The course of laparoscopic surgery's development and its current status are reported here based on the results of the most recent questionnaire survey conducted by JSES.

This study reported 5-year data on the safety and effectiveness of prolonged-release tacrolimus (PR-T) in de novo kidney transplant recipients (KTRs) in Japanese routine clinical practice. Methods This was an open-label, prospective, noncomparative, observational, postmarketing surveillance study of de novo KTRs who initiated PR-T as part of routine clinical practice in 43 sites in Japan between March 2009 and March 2011. Follow-up period was March 2010 to March 2016. Effectiveness outcomes included Kaplan-Meier estimated patient survival, graft survival, graft rejection, estimated glomerular filtration rate (eGFR; Modification of Diet in Renal Disease-4), and creatinine clearance. Adverse drug reactions (ADRs) were recorded. Results The safety analysis set comprised 250 de novo KTRs (mean age 45.9 [SD, 14.2] years); 249 patients formed the efficacy analysis set. Mean PR-T daily dose decreased during the study (0.14 [SD, 0.05], 0.09 [SD, 0.05], and 0.05 [SD, 0.03] mg/kg at day 0 [transplant], week 24, and year 5, respectively), as did tacrolimus trough levels (15.9 [SD, 13.4] to 4.0 [SD, 1.4] ng/mL between day 1 and year 5). Year 5 Kaplan-Meier estimated patient survival, graft survival, and rejection rates were 96.7%, 93.4%, and 26.9%, respectively. Mean eGFR and serum creatinine levels remained stable from week 4 to year 5 post transplant (eGFR, 48.3 [SD, 16.9] vs 48.7 [SD, 13.8] mL/min/1.73 m2, respectively; serum creatinine, 1.39 [SD, 0.89] vs 1.25 [SD, 0.50] mg/dL). Overall, 230 ADRs were reported in 129 (51.6%) patients. Eight patients died during follow-up. Conclusion PR-T–based immunosuppression was effective, and renal function remained stable up to 5 years post transplant in routine clinical practice in Japan. Incidence of ADRs was low, and no new safety signals were identified.

Background Non-ampullary duodenal adenocarcinoma, excluding carcinoma in the ampulla of Vater, is a rare disease. Although several prognostic factors have been reported, they remain controversial due to the rarity of non-ampullary duodenal adenocarcinoma. The aims of this study were to investigate prognostic factors in patients with non-ampullary duodenal adenocarcinoma and to assess chemotherapy in patients with recurrence. Patients and methods Records of 25 patients who underwent surgical treatment for non-ampullary duodenal adenocarcinoma from 2004 to 2016 were retrospectively reviewed. The relationship between the clinicopathological factors and outcomes was investigated. Results Serum level of CA19-9, gross appearance, tumor size, tumor invasion, lymph node metastases, TNM stage and lymphatic and vascular invasion were significant risk factors of recurrence. Patients with recurrence who received chemotherapy according to regimens used to treat colorectal cancer had a better prognosis than those without chemotherapy (P = 0.016). Conclusion Advanced non-ampullary duodenal adenocarcinoma has a poor prognosis, but chemotherapy possibly improves the prognosis in the patients with recurrent non-ampullary duodenal adenocarcinoma.

Idiopathic hypertrophic pachymeningitis (HP) is a rare clinical entity characterized by thickening of the dura mater without obvious underlying disease. High-dose steroid therapy is considered to be the first line for idiopathic HP, but half of patients show resistance for steroid therapy and suffer progressive clinical course. We describe low-dose methotrexate (MTX) administration for recurrent and steroid-resistant idiopathic HP resulting in noticeable improvement without severe adverse effects. A 51-year-old Japanese woman with dermatomyositis first presented with right retro-orbital pain caused by dural thickening in the sella and upper clivus involving the right trigeminal nerve, which was diagnosed as idiopathic HP by transsphenoidal biopsy. High-dose methylprednisolone therapy led to remission, and she remained healthy with low-dose dexamethasone. Three years after the initial therapy she presented with right facial nerve and lower cranial nerve palsies caused by diffuse and significant dural thickening in the posterior cranial fossa. Second highdose methylprednisolone therapy was introduced, but the effect was transient and she suffered aspiration pneumonia. Low-dose oral MTX therapy was begun, and her symptoms were almost resolved and dural thickening was remarkably improved without severe adverse effects. Lowdose MTX may be a more appropriate choice for idiopathic HP than steroid administration. Randomized controlled clinical trials are now needed.

Laparoscopic liver resection is widely used for liver tumors, but its utility in patients with cirrhosis remains controversial. The aim of this study was to assess the surgical outcomes of laparoscopic liver resection in patients with liver cirrhosis with specific reference to a difficulty scoring system. From January 2010 to March 2016, the outcomes of laparoscopic liver resection in 95 patients were retrospectively reviewed. Surgical outcomes were analyzed to identify differences between the liver cirrhosis and non-liver cirrhosis groups; these groups were further stratified to high and low difficulty scores. The surgical outcomes of both groups were compared according to the difficulty scores. Overall, 53/95 (55.8%) patients were diagnosed with liver cirrhosis. There were no significant differences in surgical duration, blood loss, postoperative hospital stay, and morbidity between groups, although liver function was worse in the liver cirrhosis group than in the non-liver cirrhosis group. Multivariate analysis showed that the difficulty score was an independent predictor of increased blood loss. In particular, blood loss in cirrhotic patients was significantly greater with a high difficulty score than with a low difficulty score. The safety profile of laparoscopic liver resection was the same in patients with and without liver cirrhosis. However, patients with liver cirrhosis and a high difficulty score require extra attention, because of a higher risk for perioperative blood loss.

Splenectomy is the standard therapy for medically refractory immune thrombocytopenia (ITP). Laparoscopic splenectomy (LS) has gained wide acceptance; however, the long-term outcomes of LS versus open splenectomy (OS) for patients with ITP remain unclear. We analyzed, retrospectively, 32 patients who underwent splenectomy, as LS in 22 and OS in 10, for refractory ITP at our institute. Data were evaluated based on the American Society of Hematology 2011 evidence-based practice guidelines for ITP. Although the operation time was significantly longer in the LS group (p

To evaluate the efficacy and safety of gemcitabine plus cisplatin in Japanese patients with unresectable gallbladder cancer (GBC). Chemo-naive patients with histologically proven unresectable GBC were enrolled in this study. The patients received gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on days 1 and 8, every 21 days. A response assessment was done by CT scan every 4 weeks. The primary end points were to determine the response rates [RR; complete response (CR) + partial response (PR)] and the disease control rate [DCR; CR + PR + stable disease (SD)]. The secondary end points were to evaluate toxicity, progression-free survival (PFS), and overall survival (OS). From March 2012 to February 2015, 14 patients from seven different institutions were enrolled in the study, and 13 cases were evaluable for assessment. Eleven cases (84.6%) had distant metastases, and 8 cases (61.5%) had obstructive jaundice. There was no CR, 1 PR (7.7%), 11 SD (84.6%), and 1 progressive disease (PD) (7.7%). The RR was 7.7%, whereas the DCR was 92.3%. The median PFS was 3.1 months, the median OS was 6.2 months, and the one-year survival rate was 0%. Grade 3 hematologic toxicity was observed in three cases (23%), but all of them recovered upon drug withdrawal, and there was no treatment-related death. Although gemcitabine plus cisplatin has a high DCR (92.3%) and relatively low toxicity, the RR is less than 10%, and development of new therapies is desired for the treatment of unresectable GBC.

Background and Purpose— Multilineage-differentiating stress-enduring (muse) cells are endogenous nontumorigenic stem cells with pluripotency harvestable as pluripotent marker SSEA-3 + cells from the bone marrow from cultured bone marrow-mesenchymal stem cells. After transplantation into neurological disease models, muse cells exert repair effects, but the exact mechanism remains inconclusive. Methods— We conducted mechanism-based experiments by transplanting serum/xeno-free cultured-human bone marrow-muse cells into the perilesion brain at 2 weeks after lacunar infarction in immunodeficient mice. Results— Approximately 28% of initially transplanted muse cells remained in the host brain at 8 weeks, spontaneously differentiated into cells expressing NeuN (≈62%), MAP2 (≈30%), and GST-pi (≈12%). Dextran tracing revealed connections between host neurons and muse cells at the lesioned motor cortex and the anterior horn. Muse cells extended neurites through the ipsilateral pyramidal tract, crossed to contralateral side, and reached to the pyramidal tract in the dorsal funiculus of spinal cord. Muse-transplanted stroke mice displayed significant recovery in cylinder tests, which was reverted by the human-selective diphtheria toxin. At 10 months post-transplantation, human-specific Alu sequence was detected only in the brain but not in other organs, with no evidence of tumor formation. Conclusions— Transplantation at the delayed subacute phase showed muse cells differentiated into neural cells, facilitated neural reconstruction, improved functions, and displayed solid safety outcomes over prolonged graft maturation period, indicating their therapeutic potential for lacunar stroke.

Inferior vena cava (IVC) syndrome results from obstruction of the IVC. Occlusion of the IVC caused by external pressure is a well-recognized complication of malignancy; meanwhile, benign causes of IVC obstruction are not frequently encountered without deep vein thrombosis. There have been a few reports of benign external compression of the IVC. We here show a rare and unique case of benign IVC syndrome in a 47-year-old woman, which was caused by hemorrhage as a complication of laparoscopic adrenalectomy on postoperative day 1. She had undergone laparoscopic adrenalectomy, performed successfully for primary aldosteronism, but she lost consciousness for about 10 seconds on postoperative day 1. After emergency medical care, her sinus rhythm and stable hemodynamic status were restored. At that time, computed tomography showed retroperitoneal hematoma caused by port site bleeding with the IVC compressed excessively, and we considered that drastic IVC syndrome may have occurred. Hemostatics and complete rest improved her general condition gradually, and she left the hospital on postoperative day 20. Laparoscopic adrenalectomy is technically feasible and has several advantages over open adrenalectomy, such as less intraoperative blood loss and a shorter hospital stay. However, surgeons must be careful of potential critical complications.

Resection of a tumor located in the paracaval portion of the liver, without sacrificing other parts of the liver, is surgically challenging. Here, we describe using a laparoscopic caudal approach for a small hepatocellular carcinoma located in the paracaval portion. It is the first case using the laparoscopic caudal approach to be reported in the literature. Compared with the conventional approaches, this procedure can minimize both surgical invasiveness and the volume of liver parenchyma to be resected. In addition, the laparoscopic view is suitable for this procedure. The laparoscopic caudal approach can be a safe procedure with minimal invasiveness for a small paracaval tumor, particularly in patients with liver cirrhosis.

Small subcortical infarcts account for 25% of all ischemic strokes. Although once considered to be a small vessel disease with a favorable outcome, recent studies have reported relatively poor long-term prognoses following small subcortical infarcts. Limited pre-clinical modeling has hampered understanding of the etiology and development of treatments for this disease. Therefore, we attempted to develop a new experimental model of small subcortical infarcts in mice to investigate pathophysiological changes in the corticospinal tract and assess long-term behavioral performance. The vasoconstrictor peptide, endothlin-1 (ET-1), in combination with the nitric oxide synthase inhibitor, N(G)-nitro-l-arginine methyl ester (l-NAME), were injected into the internal capsule of mice. Histological and behavioral tests were performed 0-8 weeks after the injection. The ET-1/l-NAME injection resulted in severe neurological deficits that continued for up to 8 weeks. The loss of axons and myelin surrounded by reactive gliosis was identified in the region of the injection, in which the vasoconstriction of microvessels was also observed. Moreover, a tract-tracing study revealed an interruption in axonal flow at the internal capsule. The present model of small subcortical infarcts is unique and novel due to the reproduction of neurological deficits that continue for a long period, up to 8 weeks, as well as the use of mice as experimental animals. The reproducibility, simplicity, and easy adoptability make the present model highly appealing for use in further pre-clinical studies on small subcortical infarcts.

Objective: Muse cells reside as pre-existing pluripotent-like stem cells within the fibroblasts, are nontumorigenic, exhibit differentiation capacity into triploblastic-lineage cells, and replenish lost cells when transplanted in injury models. Cell fate and function of human skin fibroblast-derived Muse cells were evaluated in a rat stroke model. Methods: Muse cells (30,000), collected by pluripotent surface marker stage-specific embryonic antigen-3, were injected stereotaxically into three deposits within the rat ischemic cortex at 2 days after transient middle cerebral artery occlusion, and the cells' biological effects were examined for more than 84 days. Results: Muse cells spontaneously and promptly committed to neural/neuronal-lineage cells when cocultured with stroke brain slices. Muse-transplanted stroke rats exhibited significant improvements in neurological and motor functions compared to control groups at chronic days 70 and 84, without a reduction in the infarct size. Muse cells survived in the host brain for up to 84 days and differentiated into NeuN (∼65%), MAP-2 (∼32%), calbindin (∼28%), and GST-π (∼25%)-positive cells in the cortex, but glial fibrillary acidic protein-positive cells were rare. Tumor formation was not observed. Muse cells integrated into the sensory-motor cortex, extended their neurites into cervical spinal cord, and displayed normalized hind limb somatosensory evoked potentials. Interpretation: Muse cells are unique from other stem cells in that they differentiate with high ratio into neuronal cells after integration with host brain microenvironment, possibly reconstructing the neuronal circuit to mitigate stroke symptoms. Human fibroblast-derived Muse cells pose as a novel source of transplantable stem cells, circumventing the need for gene manipulations, especially when contemplating autologous cell therapy for stroke.

The choice between performing routine and selective upper gastrointestinal endoscopy (UGE) before bariatric surgery remains controversial. This study aimed to evaluate the clinical significance of UGE before laparoscopic bariatric procedures. We enrolled 155 obese Japanese patients who underwent laparoscopic bariatric procedures at our institute and evaluated their endoscopic findings, such as reflux esophagitis (RE), hiatal hernia (HH), Barrett’s esophagus, gastritis, duodenitis, gastroduodenal ulcer, gastric cancer, and polyps. Preoperative endoscopy revealed abnormal findings in 102 patients (66%), including gastritis in 57 (37%), HH in 51 (32%), RE in 27 (17%), benign gastric polyps in 16 (10%), duodenitis in 6 (4%), and Barrett’s esophagus in 1 (0.6%). Two patients with definite HH were treated with simultaneous crural repair at the time of bariatric surgery. Duodenitis was graded as severe in three of these six patients and treated with a proton pump inhibitor before surgery. Eleven patients received therapy to eradicate Helicobacter pylori (H. pylori), either before or after the surgery. In summary, preoperative endoscopy changed the perioperative management for 16 of the 155 patients (10%). Routine UGE may be necessary before bariatric procedures in obese Japanese patients.

Background Postoperative pancreatic fistula (POPF) is a major complication of distal pancreatectomy (DP). Several procedures for resection and closure of the pancreas have been proposed; however, the rate of POPF remains high. The aims of this study were to investigate the relationship between perioperative factors and POPF and to clarify the advantages of pre-firing compression of the pancreas in the DP. Patients and method From 2008 to 2016, records of 75 patients who underwent DP were retrospectively reviewed. The relationship between the perioperative factors and clinically relevant POPF was investigated. Results Univariate analysis showed that body mass index, thickness of the pancreas, and pre-firing compression were significantly related with clinically relevant POPF. Multivariate analysis showed that the pre-firing compression was an independent factor of clinically relevant POPF (OR = 44.31, 95%CI = 3.394–578.3, P = 0.004). Conclusions Pre-firing compression of the pancreas can prevent clinically relevant POPF in DP.

Hemorrhagic complication is one of the notable surgical complications of the revascularization surgery for moyamoya disease (MMD). Cerebral hyperperfusion (CHP) has been considered as the underlying cause of this complication. It mostly occurs several days after surgery, but the intra-operative hemorrhage immediately after bypass has not been reported previously. A 21-year-old woman presented right thalamic hemorrhage and was diagnosed as having MMD by cerebral angiography. In light of the location of the hemorrhage at the vascular territory of posterior circulation and the manifestation of transient ischemic attack during the follow-up period, she underwent revascularization surgery to prevent future ischemic attack and rebleeding. Superficial temporal artery (STA) was uneventfully anastomosed to the temporal M4 branch of the middle cerebral artery in an end-to-side manner. A few minutes after the completion of the anastomosis, hemorrhage occurred in the fissure adjacent to the site of anastomosis. Indocyanine green (ICG) video angiography just before hemorrhage showed focal early filling through the STA graft with early venous filling around the site of the anastomosis. The bleeding was controlled by immediate hypotensive therapy (systolic blood pressure 117 to 91 mmHg). The mean blood flows of the STA graft measured by ultrasonic flowmetry before and after hypotensive therapy were 52.8 and 24.2 ml/min, respectively. Single-photon emission computed tomography (SPECT) on the next day after surgery showed focal hyperperfusion in the surgical side. Intra-operative ultrasonic flowmetry, ICG, and postoperative SPECT would explain that CHP was the potential cause of the hemorrhagic complication. This is the first case describing intra-operative hemorrhagic complication during revascularization surgery for MMD. Surgeons need to be aware of this rare complication and its management method.

Traumatic acute subdural hematoma (ASDH) is generally addressed by craniotomy under general anesthesia. We report a patient whose traumatic ASDH was treated under local anesthesia by one-burr-hole endoscopic surgery. This 87-year-old woman had undergone coil embolization for a ruptured right middle-cerebral artery aneurysm and placement of a ventriculoperitoneal shunt for normal pressure hydrocephalus 5 years earlier. Upon admission, she manifested consciousness disturbance after suffering head trauma and right hemiplegia. Her Glasgow Coma Scale score was 8 (E2V2M4). Computed tomography (CT) demonstrated a thick, left-frontotemporal ASDH. Due to her advanced age and poor condition, we performed endoscopic surgery rather than craniotomy to evacuate the ASDH. Under local anesthesia, we made a burr hole in her left forehead and increased its size to 15 mm in diameter. After introducing a transparent sheath into the hematoma cavity with a rigid endoscope, the clot was evacuated with a suction tube. The arterial bleeding point was electrically coagulated. A postoperative CT scan confirmed the reduction of the hematoma. There was neither brain compression nor brain swelling. Her consciousness disturbance and right hemiplegia improved immediately. Endoscopic surgery may represent a viable method to address traumatic intracranial hematomas in some patients.

Lactococcus lactis cremoris (L. lactis cremoris) infections are very rare in humans. Only three case reports of brain abscess have been reported and the infectious routes and pathological features are still unknown. We experienced a subdural empyema due to L. lactis cremoris in an immunocompetent adult. A 33-year-old man was admitted with fever, right facial pain, left hemiparesis, and left hemianopsia. Computed tomography demonstrated low density fluid collection in the right falcotentorial subdural space. Magnetic resonance (MR) images revealed a high signal lesion on a diffusion-weighted image (DWI) and fluid attenuated inversion recovery (FLAIR) images in the right paratentorial and parafalcine subdural space, right maxillary sinus, and bilateral ethmoidal sinus. He underwent two sequential open surgeries for removal and drainage of empyema and was treated with antibiotics including meropenem and ampicillin. To our knowledge, this is the first report of subdural empyema caused by L. lactis cremoris infection. We report the case and discuss the pathological features with the previous literature.

Background Splenopancreatic fusion is a rare anomaly that is often associated with trisomy 13. Its diagnosis can be important in patients scheduled to undergo distal pancreatectomy or splenectomy, to avoid possible intraoperative or postoperative complications. Case presentation An 82-year-old Japanese man was referred to our hospital for further evaluation and treatment for a solitary hepatocellular carcinoma based on liver cirrhosis. Triple-phase contrast-enhanced multidetector-row computed tomography and magnetic resonance imaging showed a splenopancreatic fusion as well as a solitary hepatocellular carcinoma in segment VIII of his liver. Conclusions Fusion of the pancreatic tail and spleen is a rare and asymptomatic anomaly. Its detection can be improved by the use of multidetector computed tomography or magnetic resonance imaging.

Introduction: Primary hyperparathyroidism (PHP) is a curable disease because most patients have only one adenoma and can fully recover after adenoma removal at the location determined by preoperative imaging. However, many Japanese surgeons believe that intraoperative intact PTH measurement (IOPM) is essential to the surgery. Hence, many general surgeons in Japan are unable to perform surgeries for PHP in their local hospitals and must refer the patients to urban high volume centers that have introduced IOPM, even though they are experienced in general surgery and the surgery for PHP is technically simple and related to general surgery. So, we analyzed the relationship of surgical outcomes, with and without IOPM. Method: Between January 2007 and December 2016, 183 consecutive patients with PHP underwent surgery in our institution. We performed the surgery between 2007 and 2012 without IOPM, and starting from 2013 we performed the surgery with IOPM. We compared and evaluated the cure rate and surgical complications between patients who underwent unilateral neck exploration without IOPM with clear preoperative localization of the affected adenoma, and those who underwent any surgery with IOPM. Result: There was no significant difference in cure rate between the two groups and there were no surgical complication in either group. Conclusion: In cases where preoperative imaging is able to clearly localize the affected adenoma and an experienced general or endocrine surgeon performs the surgery, there is no significant difference in overall cure rate and surgical complications with or without IOPM. Though many hospitals in Japan currently do not perform IOPM routinely, our study may encourage many general surgeons to perform the surgery without IOPM.

We herein report a case of sarcomatoid carcinoma that developed in a remnant stomach. A 76-year-old male with a history of distal gastrectomy for a duodenal ulcer 28 years earlier underwent investigation for a tumor in the remnant stomach. An endoscopic survey showed a round elevated tumor measuring 6 cm in diameter, and a biopsy specimen suggested carcinosarcoma. A total gastrectomy of the remnant stomach was performed, and the excised tumor was identified to be a malignant neoplasm consisting of both carcinomatous and sarcomatous components. A diagnosis of sarcomatoid carcinoma was made since the epithelial markers were positive even in the mesenchymal elements of the tumor. To our knowledge, only 4 cases of sarcomatoid carcinoma of the stomach have been reported in the English literature so far.

There are no current guidelines for the management of familial pheochromocytoma (FP). We tried to determine the optimal management of patients with FP. Among 191 patients with pheochromocytoma who underwent surgical resection between 1979 and 2010, there were 18 FP (13 different kindreds; 11 females/7 males; mean age at initial operation: 38.7 years). The 18 FP cases comprised 10 with MEN2A, 2 with MEN2B, 4 with von Hippel-Lindau disease, and 2 with FP only, and all pheochromocytomas were of adrenal origin. The number of probands and family members was 9 and 9 respectively. Mean tumor size was 6.4 cm in diameter. Simultaneous bilateral adrenalectomy was performed in 6 patients, and unilateral adrenalectomy was performed as the initial surgery in 12 patients. A metachronous contralateral adrenalectomy was performed in 3 patients, 90, 236 and 312 months after the primary operation, respectively. None of the patients received partial adrenalectomy. Among another 9 patients with unilateral adrenalectomy, contralateral pheochromocytomas were suspected in 4 cases at the initial operation. However, none of these contralateral lesions developed severe symptoms or tumor enlargement during a median follow-up of 116 months. In the remaining 5 patients, pheochromocytoma did not develop in the contralateral adrenals over a median follow-up of 80.5 months. Bilateral lesions of adrenal pheochromocytoma in familial cases occurred in 78% of cases (14/18); 9 patients (including 4 with contralateral pheochromocytoma) did not require a contralateral adrenalectomy during a median follow-up of 119 months. No patients have suffered from Addisonian crisis. The ipsilateral adrenalectomy and follow-up of contralateral small pheochromocytoma is one of the management options to preserve adrenocortical function in FP patients.

Background: Tamoxifen (TAM) and toremifene (TOR) prevent estrogen from stimulating breast cancer growth and also have agonistic effects in a number of physiological systems. TAM is known to increase intracellular triglyceride, but the action of TOR on lipid metabolism in vitro has not yet been determined. Aim: To compare the effect of TOR on lipid metabolism with that of TAM in vitro, using HepG2 cell lines. Methods: Intracellular concentrations of total cholesterol and triglyceride in HepG2 cells were measured by an enzymatic method after TAM or TOR treatment. Results: Intracellular concentrations of total cholesterol were decreased by both TAM and TOR, but not significantly different from the control level. TOR produced no changes in the intracellular concentrations of triglyceride, whereas TAM increased the intracellular concentrations of triglyceride at concentrations ranging from 10–7 to 10–5 mol/l of TAM (p < 0.05). Moreover, significant differences were noted between the two treated groups at concentrations ranging from 10–9 to 10–5 mol/l (p < 0.05). Conclusion: TOR treatment did not increase intracellular concentrations of triglyceride, although TAM treatment did so.

When a patient with a ventriculoperitoneal shunt (VPS) undergoes laparoscopic surgery, there is the concern about possible problems with the shunt due to increased intra-abdominal pressure. We conducted a simplified reflux experiment on VPS valves to demonstrate safety. Each of five different VPS valves was connected via tubes to a glass vessel of our own making. Carbon-dioxide gas was consecutively insufflated into the vessel at 3-25 mm Hg pressure to determine whether reflux occurred when the valves and tubes were empty (opened test) and when filled with physiologic saline (closed test). Reflux occurred for two of five valves at an insufflation pressure of 5 mm Hg or more in the opened test, while not for any valves until 25 mm Hg in the closed test. In clinical settings, there would be no possibility of reflux under the pneumoperitoneum in VPS systems draining cerebrospinal fluid. Laparoscopic surgery in patients with VPS would be performed safely if characteristics of VPS valves are taken advantage of.

Aims Hepatic resection is the most effective therapy for hepatocellular carcinoma (HCC); however, intrahepatic recurrence is common. Predictors of survival after intrahepatic recurrence have not been fully investigated. To clarify the prognosis and choice of treatment of intrahepatic recurrence after hepatic resection, we conducted a comparative retrospective analysis of 147 patients with HCC who underwent hepatic resection. Methods We retrospectively examined the relations between clinicopathologic factors, including the number of recurrent intrahepatic tumors and long-term prognosis after recurrence in 147 HCC patients who underwent resection. We also examined long-term survival after recurrence based on treatment types and recurrence pattern. Results Patients with multiple tumors ( n = 83) showed less tumor differentiation, more frequent portal invasion, a higher alpha-fetoprotein level, and larger tumors than did patients with solitary tumor ( n = 64). In the solitary tumor group, local ablation therapy and repeat hepatic resection were performed in 25 and 10, respectively. In the multiple tumor group, 59 were treated by transarterial chemoembolization. Multivariate analysis showed intraoperative blood transfusion and multiple tumors to be independent risk factors for poor cancer-related survival after recurrence. By subset analysis based on treatment types and recurrence pattern, survival after recurrence was significantly better in patients treated by local ablation therapy than those treated by other therapies in both solitary and multiple tumor groups. Conclusions For patients with solitary recurrence, a good prognosis is predicted. Local ablation therapy is a best candidate for treatment of solitary and multiple intrahepatic recurrences after hepatic resection.

We investigated the feasibility of using real-time tissue elastography (EG) with transcutaneous ultrasonography (EG-US) for pancreatic diseases.A preliminary study (phase I) and a prospective (phase II) study were conducted. Phase I: subjects were 10 volunteers, 5 with cancer, 2 with endocrine tumor, 5 with chronic pancreatitis, 14 with intraductal papillary-mucinous neoplasm. To determine the characteristic EG images (diagnostic criteria for phase II), B-mode images were compared with EG images and histopathologic findings. Phase II: 53 consecutive patients were enrolled. The visualization rate by EG-US in lesions visualized by B mode was assessed, and the correct diagnosis rate by B mode alone (B diagnosis) or in combination with EG-US was evaluated.Phase I: normal parenchyma was a homogeneous color. In cancer, EG-US showed a markedly hard area with soft spots inside. Endocrine tumor was uniform and soft comparable to parenchyma. Chronic pancreatitis showed a mixture of various colors. Phase II: we identified 77.4% (41/53) of the lesions and observed 60.0% (15/25) of the cancers, 100% (3/3) of the endocrine tumor, 92.0% (23/25) of the cases of chronic pancreatitis cases on EG-US. The B-diagnosis rates ranged from about 70% to 80%. The diagnosis rates of the combination were more than 90% of lesions of each type.The EG-US is feasible in the diagnosis of pancreatic diseases.

A 45-year-old woman with previously diagnosed chronic type adult T-cell leukemia (ATL) presented with abdominal discomfort and red eruptions on her arms and legs. Anemia, thrombocytopenia, hypercalcemia, and splenomegaly indicated progression to acute-type ATL. Combined chemotherapy resulted in normalization of the serum calcium level and improvement in her symptoms. However, the severe anemia and thrombocytopenia persisted, necessitating transfusions of red blood cells (RBC) and platelets three times a week. We performed splenectomy in an attempt to reduce the total volume of malignant cells and improve the hypersplenism. After the operation, the RBC and platelet counts increased gradually, and the transfusions were stopped on postoperative day (POD) 3. Splenectomy should be considered as an optional treatment for hypersplenism caused by ATL when hypersplenism cannot be controlled by chemotherapy in patients without a high surgical risk.

Although laparoscopic distal pancreatectomy (LDP) is technically feasible, its benefits remain uncertain. The purpose of this study was to compare the clinical results of LDP and open distal pancreatectomy (ODP). The medical records of 14 consecutive patients who underwent LDP were reviewed and compared with those of 19 patients who underwent ODP. All patients were treated for benign or borderline malignant disease of the pancreas. Operation time was longer for LDP than for ODP (290.7 vs. 213.8 min, P=0.0022), and postoperative analgesics were administered less frequently for patients who underwent LDP. Patients treated by LDP had earlier recovery of bowel function, shorter time to oral intake, and shorter postoperative hospital stay than those treated by ODP. No difference in morbidity or inflammatory response was observed between the 2 groups. LDP for benign or borderline malignant disease of the pancreas provides benefits without increasing morbidity.

はじめに: 我々が我が国に導入した腹腔鏡下調節性胃バンディング術 (laparoscopic adjustable gastric banding; 以下, LAGB) の体重減少効果と肥満関連健康障害に対する改善効果について検討したので報告する. 方法: 2005年8月からの2年間に21例の内科治療無効の肥満症例にLAGBを施行した. 平均年齢38歳, BMI 44kg/m2であり, 肥満関連健康障害を平均3.1疾患有していた. LAGBは全例, Pars flaccida法で行い, バンドの逸脱予防のために胃-胃縫合を3～5針行った. 結果 LAGBの周術期に1例も合併症を認めず, 術後の平均在院期間は平均3.4日であった. LAGB後の平均体重減少は12か月25kg, 18か月29kgであり, 過剰体重減少率は12か月41%, 18か月49%であった. 良好な体重減少により, 高血圧91%, 高脂血症94%, 糖尿病100%と高率に改善した. 考察: LAGBは安全性と有効性を兼ね備えた術式であり, 今後我が国においても普及していくものと思われた.

Although extrahepatic metastasis occurs rarely after hepatic resection for hepatocellular carcinoma (HCC), the prognosis of these patients is extremely poor. Predictors of extrahepatic metastasis have not been fully investigated.To identify predictors of extrahepatic metastasis after resection, we retrospectively investigated 77 patients with HCC tumors50 mm in diameter who underwent hepatic resection. We investigated correlations between postoperative extrahepatic metastasis and clinicopathologic factors as well as extrahepatic metastasis-free survival rate by log rank test and predictors of extrahepatic metastasis by univariate and multivariate logistic regression models.Hepatitis B surface antigen (HBs-Ag) was found in 25 (32.5%) of 77 patients, and extrahepatic metastasis occurred in 26 (33.8%). Patients with extrahepatic metastasis showed better liver function and a high occurrence of HBs-Ag positivity than those without. The 5-year extrahepatic metastasis-free survival rate was worse in patients with HBs-Ag positivity, larger tumors (or = 70 mm), higher alfa-fetoprotein level (or = 300 ng/mL), and lower indocyanine green retention rate at 15 minutes (ICGR15) (15%) than in those without. By univariate logistic regression analysis, HBs-Ag positivity, larger HCC tumor (or = 70 mm), lower ICGR15 (15%), and lower preoperative lymphocyte count (1000/mm3) were predictors of extrahepatic metastasis (P.1). By multivariate analysis, HBs-Ag positivity was an independent predictor of postoperative extrahepatic metastasis (P = .04).In patients positive for HBs-Ag, radiologic examination of extrahepatic organs should be performed as a part of the postoperative surveillance. Hepatitis B virus infection may promote establishment of extrahepatic metastasis.

Splenopneumopexy, which was developed in Japan, has been recognized as an effective surgical procedure in patients with Budd-Chiari syndrome. We report the case of a 72-year-old woman with Budd-Chiari syndrome and prominent hepatic encephalopathy. She was treated by splenopneumopexy 19 years previously at our institute. Recently, during a follow-up visit, she experienced disorientation and unconsciousness. Flapping tremor was also recognized, and electroencephalography demonstrated a triphasic wave. In computed tomography and angiography imagings, the inferior vena cava was obstructed and the portopulmonary shunt placed by splenopneumopexy was remarkably dilated. There were no other major collaterals of the portal venous system. These findings showed that the hepatic encephalopathy was caused by the change in the portopulmonary shunt. Because hepatic encephalopathy can appear after splenopneumopexy, long-term follow-up may be necessary in patients with Budd-Chiari syndrome who are treated by splenopneumopexy.

Proteinase-activated receptor-2 (PAR-2), which is a G protein-coupled receptor, is activated in inflammatory processes and cell proliferation. We previously demonstrated that an anti-PAR-2 antibody suppresses proliferation of human pancreatic cells in vitro. However, there have been no studies of PAR-2 signaling pathways in vivo. The aim of this study was to determine whether blockade of PAR-2 by RNA interference influences pancreatic tumor growth. We originally constructed small interfering RNAs (siRNAs) targeting human PAR-2, and performed cell proliferation assays of Panc1 human pancreatic cancer cell line with these siRNAs. Intratumoral treatment with these PAR-2 siRNAs and atelocollagen was also performed in a xenograft model with nude mice and Panc1 cells. siRNAs against human PAR-2 inhibited proliferation of Panc1 cells, whereas control scramble siRNAs had no effect on proliferation. The PAR-2 siRNAs dramatically suppressed tumor growth in the xenograft model. PAR-2-specific siRNA inhibited growth of human pancreatic cancer cells both in vitro and in vivo. Blockade of PAR-2 signaling by siRNA may be a novel strategy to treat pancreatic cancer.

The life expectancy continues to gradually increase worldwide. Laparoscopic liver resection (LLR) was recently reported to be a relatively safe procedure for treatment of liver disease because of the development of new techniques and instruments. The aim of this study was to evaluate the surgical outcomes of elderly patients who underwent LLR. Of these 61 patients who underwent LLR in our institute from January 2010 through April 2014, 21 were aged 75 years and above (group E), and 40 were aged below 75 years (group NE). Patient characteristics were retrospectively analyzed between the 2 groups. The results showed that patient characteristics were similar between the 2 groups, although the incidence of hypertension was significantly greater among patients in group E. There were no significant differences in the incidence of postoperative complications or length of hospital stay between the 2 groups. In conclusion, LLR for elderly patients was a feasible procedure compared with nonelderly patients.

We report 2 cases of splenic inflammatory pseudotumor treated by laparoscopic splenectomy. The first patient was a 58-year-old woman who complained of constipation. Computed tomography (CT) showed a well-demarcated mass that measured 4 cm in diameter and was not enhanced. She underwent laparoscopic splenectomy under a preoperative diagnosis of hemangioma. The final histopathologic diagnosis was inflammatory pseudotumor. The second patient was a 29-year-old man who complained of abdominal pain. Computed tomography revealed a demarcated splenic tumor that measured 3 cm in diameter and was not enhanced. Laparoscopic splenectomy was performed. The pathologic and operative diagnoses were both inflammatory pseudotumor. In both cases, the postoperative course was uneventful, and the postoperative hospital stays were 10 and 11 days. Preoperative diagnosis of a splenic inflammatory pseudotumor is very difficult. However, laparoscopic splenectomy is safe and beneficial treatment for this tumor and should be performed in cases in which it is diagnosed.

In recent years, ultrasound technology has made remarkable strides, and the application of these latest advances to endoscopic ultrasonography (EUS) and intraductal ultrasonography (IDUS) is crucially important. EUS equipped with electronic scanners (both radial and convex types) has been developed, and now EUS with the function of tissue harmonic imaging (THI) and color/power Doppler is applicable clinically. THI facilitates the acquisition of ultrasound images clearer than those of fundamental imaging, and color/power Doppler sonography demonstrates the precise hemodynamics with the use of a contrast agent. In addition, the progress of image processing technology has realized three-dimensional (3D) images in EUS and IDUS. Reconstruction of 3D images enables us to diagnose more objectively. Here we describe the roles of these new ultrasound technologies in the diagnosis of biliary malignancies.

Background and Aims: Chemokines and their receptors have recently been shown to have major roles in cancer metastasis. The aim of this study was to determine whether the interaction between chemokine receptor 6 (CCR6) and its ligand, macrophage inflammatory protein-3 alpha (MIP-3α), correlates with metastasis of hepatocellular carcinoma (HCC). Methods: To observe the reaction of CCR6 expressed cancer cells to MIP-3α stimulation, chemotactic and actin polymerization assays for both CCR6 high cells (HepG2) and CCR6 low cells (MCF-7) were performed. CCR6 mRNA levels in tumor specimens from 30 HCC patients were quantified by real-time polymerase chain reaction. Patients were classified into two groups, high (≥ 20 copies; n = 10) CCR6 and low (

We report the case of a 53-year-old woman with a gastrointestinal stromal tumor (GIST) of the duodenum that showed only extramural growth, mimicking a pancreatic tumor. Preoperatively, computed tomography (CT) and angiography revealed a hypervascular mass, 3.0 cm in diameter, in the pancreatic head. Hypotonic duodenography showed compression of the second and third portions of the duodenum by the pancreatic lesion. Endoscopic examination showed no specific mucosal abnormalities in the duodenal lumen. The pancreatic head tumor was diagnosed preoperatively as a nonfunctioning islet cell tumor of the pancreas, and the patient underwent pylorus-preserving pancreaticoduodenectomy. A hard mass was palpated intraoperatively in the pancreatic head region, and neither peritoneal dissemination nor metastasis was detected. Histologically, the tumor was composed of spindle-shaped cells with a fascicular growth pattern, and only a few mitotic features were seen. Immunohistochemically, most of the tumor cells were positive for c-kit oncoprotein and CD34, but negative for alpha-smooth muscle actin and S-100 protein. Therefore, this neoplasm was finally diagnosed as a duodenal GIST of the uncommitted type. This is a rare case of a duodenal GIST with exclusively extramural growth mimicking a pancreatic head tumor.