Carving axon arbors to fit: master directs one kinase at a time.

Pyramidal neurons in the cortex require the master kinase LKB1 for early axon specification. Courchet et al. now uncover a later role for LKB1 and its tango with the downstream effector kinase NUAK1 in controlling terminal axonal branching through influencing mitochondrial motility in axons.

Ultrafast time-resolved single-shot birefringence microscopy for laser-induced anisotropy.

The interaction between ultrashort laser pulses and materials in the ultrafast time domain, especially regarding the effect of laser polarization, has attracted much attention. In this study, ultrafast time-resolved single-shot birefringence microscopy is performed to observe laser-induced anisotropy. The birefringences of the optical Kerr effect and laser-induced anisotropic nanostructures by femtosecond laser pulses in silica glass are measured, and their slow axis is confirmed to correspond to the linear polarization angle of the pump light. We discuss the time variations of these birefringences in the picosecond time domain.

Humanized UGT2 and CYP3A transchromosomic rats for improved prediction of human drug metabolism.

Although "genomically" humanized animals are invaluable tools for generating human disease models as well as for biomedical research, their development has been mainly restricted to mice via established transgenic-based and embryonic stem cell-based technologies. Since rats are widely used for studying human disease and for drug efficacy and toxicity testing, humanized rat models would be preferred over mice for several applications. However, the development of sophisticated humanized rat models has been hampered by the difficulty of complex genetic manipulations in rats. Additionally, several genes and gene clusters, which are megabase range in size, were difficult to introduce into rats with conventional technologies. As a proof of concept, we herein report the generation of genomically humanized rats expressing key human drug-metabolizing enzymes in the absence of their orthologous rat counterparts via the combination of chromosome transfer using mouse artificial chromosome (MAC) and genome editing technologies. About 1.5 Mb and 700 kb of the entire UDP glucuronosyltransferase family 2 and cytochrome P450 family 3 subfamily A genomic regions, respectively, were successfully introduced via the MACs into rats. The transchromosomic rats were combined with rats carrying deletions of the endogenous orthologous genes, achieved by genome editing. In the "transchromosomic humanized" rat strains, the gene expression, pharmacokinetics, and metabolism observed in humans were well reproduced. Thus, the combination of chromosome transfer and genome editing technologies can be used to generate fully humanized rats for improved prediction of the pharmacokinetics and drug-drug interactions in humans, and for basic research, drug discovery, and development.

[Clinical Outcome of Robot-Assisted Distal Pancreatectomy in Our Institutional Introduction].

We evaluated the clinical outcome and assessed the safety of robot-assisted distal pancreatectomy(RADP)of early 5 cases in our institutional introduction. We followed the guidelines for introduction of robot-assisted pancreatectomy proposed by Japanese Society of Endoscopic Surgery. Patients' characteristics were 2 men and 3 women, 45-79(median 52) years old, and 3 patients with neuroendocrine neoplasm, 1 with intraductal papillary neoplasm and 1 with mucinous cystic neoplasm. Spleen-preserving RADP was performed in 2 cases. Clinical outcomes of 5 cases underwent RADP were, operation time was 308-437(median 330)minutes, blood loss was 5-270(median 100)mL and none received transfusion. Postoperative pancreatic fistula and postoperative complication more than Grade Ⅲa(Clavien-Dindo classification)were none. Postoperative hospital stay was 7-11(median 8)days. RADP in our institution was safely introduced by following the proposal of guidelines.

Independent contribution of optical attenuation length in ultrafast laser-induced structural change.

Although laser irradiation with femtosecond pulses is known to generate crystallization and morphological changes, the contribution of optical parameters to material changes is still in discussion. Here, we compare two structures irradiated near Si-L2,3 edges by an extreme ultraviolet femtosecond pulse. Our result implies that, despite the femtosecond irradiation regime, these values of the optical attenuation length between the wavelengths of 10.3-nm and 13.5-nm differ by one order of magnitude. From the structural comparison, the original crystalline state was maintained upon irradiation at 13.5-nm, on the other hand, transition to an amorphous state occurred at 10.3-nm. The difference in optical attenuation length directly influence to the decision of material crystallization or morphological changes, even if the irradiation condition is under the femtosecond regime and same pulse duration. Our result reveals the contribution of optical attenuation length in ultrafast laser-induced structural change.

[Outcome of Repeated Surgical Resections of Hepatic and Pulmonary Metastases from Colorectal Cancer].

Previous reports have demonstrated that repeated surgical resections of resectable hepatic and pulmonary metastases from colorectal cancer contribute to a better prognosis. We retrospectively assessed the outcomes of 19 patients with colorectal cancer who underwent repeated resections of hepatic and pulmonary metastases between February 2007 and February 2017. The median observation period was 69.9 months, and 26 liver and 27 lung resections were performed. The cumulative 5-year survival rates after resection of the last metastasis was 75.1% and the median disease-free survival after resection of the last metastasis was 34.7 months. Although 7 patients showed recurrence and 4 patients died, 7 patients exhibited long-term survival. Univariate analysis revealed that simultaneous liver and lung metastases were significantly predictor of poor prognosis(p=0.039). Progress of the patients in the present study were comparable to those in previous reports. Therefore, we propose that repeated surgical resection of hepatic and pulmonary metastasis from colorectal cancer could improve patient prognosis. Further studies should examine to identify more accurate prognostic factor with large series.

[Simultaneous Distal Gastrectomy, Distal Pancreatectomy, and Splenectomy Based on Remnant Gastric Blood-Flow Evaluation with Intraoperative ICG Fluorescence].

The splenic artery and vein are important to the remnant stomach after distal gastrectomy(DG). Hence, total gastrectomy is recommended when performing gastrectomy and distal pancreatectomy(DP)with splenectomy(S). In the present case, a man in his 70s was diagnosed with early gastric cancer. Abdominal CT detected a dilated main pancreatic duct. Chronic pancreatitis was suspected, but malignancy could not be completely ruled out. Thus, DG with Roux-en-Y reconstruction and DP with S were performed simultaneously. The remnant gastric blood flow was evaluated with intraoperative indocyanine green(ICG)fluorography and the blood flow was confirmed. Finally, the remnant stomach was preserved. The postoperative course was uneventful, except for the occurrence of anastomosis edema. This result suggests that ICG fluorescence is useful to evaluate remnant gastric blood flow and that it may be possible to perform DG and DP with S simultaneously depending on the case.

A Multicenter, Randomized, Controlled Trial Comparing Reinforced Staplers with Bare Staplers During Distal Pancreatectomy (HiSCO-07 Trial).

BACKGROUND: Although distal pancreatectomy (DP) using a reinforced stapler is expected to reduce PF, no multicenter RCT has been performed. To investigate whether reinforced staplers reduce the incidence of clinically relevant pancreatic fistula (PF) after DP compared with staplers without reinforcement. METHODS: Between July 2016 and December 2017, patients scheduled for DP were enrolled in a multicenter, randomized, controlled trial (RCT) at nine hospitals in Hiroshima Japan. Patients were randomized either to reinforced stapler or bare stapler. The primary endpoint was incidence of clinically relevant PF. This RCT was registered with UMIN Clinical Trial Registry (UMIN000022341). RESULTS: A total of 122 patients were assigned to reinforced stapler (n = 61) or bare stapler (n = 61), and 119 patients (61 reinforced stapler and 59 bare stapler) were analyzed. There was no significant difference in the incidence of clinically relevant PF between the reinforced stapler and bare stapler groups (16.3% vs. 27.1%, p = 0.15). Furthermore, the rates of major complication (16.3% vs. 18.6%, p = 0.74), postpancreatectomy hemorrhage (0% vs. 3.4%, p = 0.08), and median postoperative in-hospital days (19 days vs. 20 days, p = 0.78) did not differ between the two groups. Within a subset of 82 patients in whom the thickness of pancreatic transection line was less than 14 mm, a significant difference was found in the incidence of clinically relevant PF (4.5% vs. 21.0% in the reinforced stapler vs. bare stapler groups, respectively, p = 0.01). CONCLUSIONS: Reinforced stapler for pancreatic transection during DP does not reduce the incidence of clinically relevant PF compared to stapler without reinforcement.

[Analysis of Hepatectomy for Liver Metastasis from Gastric Cancer].

INTRODUCTION: The indication of hepatectomy for liver metastasis from gastric cancer has not been definitely established. PATIENTS AND METHODS: Among 12 cases that were performed hepatectomy for liver metastasis from gastric cancer in our institute from 2008 to 2016, we analysed prognosis and the benefit of surgical resection. RESULTS: The overall 5-year survival rates of all cases were 42.3%, and median survival time was 2 years. The overall survival rates of synchronous metastasis was 59.3%and of metachronous metastasis was 0%. Recurrence rate of all cases within 1 year was 75%. There was no long-term survivor for metachronous metastasis because of its early recurrence though it was solitary liver tumor. CONCLUSION: We should carefully indicate surgical resection for liver metastasis from gastric cancer.

[Clinical Outcome of Hepatectomy of Liver Metastasis of Duodenal Ampullary Cancer].

We evaluated the clinical outcome and assessed the indication of hepatectomy for liver metastasis of duodenal ampullary cancer. We analyzed 42 cases of duodenal ampullary cancer and 4 patients who underwent hepatectomy for liver metastasis. Eleven(50%)of 22 cases with recurrence of duodenal ampullary cancer had liver metastasis. Four cases were solitary and 7 cases were multiple. Four patients underwent hepatectomy didn't had other organ metastasis. Three of 4 cases with solitary liver metastases and one of 7 cases with multiple metastasis underwent hepatectomy. One of 3 cases of solitary liver metastasis died of lung and bone metastases without liver recurrence 2 years and 8 months after hepatectomy. Other 2 cases are long surviving without recurrence 8 years and 8 months and 4 years and 9 months after hepatectomy respectively. One case of multiple liver metastases died of early liver recurrence 10 months after hepatectomy. The indication of hepatectomy for liver metastasis was restrictive. However the prognosis of patients with solitary liver metastasis was relatively favorable. Therefore hepatectomy could be indicated for solitary liver metastasis of duodenal ampullary cancer.

[A Case of Anaplastic Carcinoma Spindle Cell Type of the Pancreas].

Anaplastic carcinoma spindle cell type is an extremely rare disease and its prognosis is very poor. We herein report a case of anaplastic carcinoma spindle cell type of the pancreas. A 50-year-old man complaining of epigastralgia was found to have a pancreatic body-tail tumor by abdominal US and CT studies. Abdominal CT showed an irregular poorly-enhanced 33mm tumor containing a cystic component. ERCP revealed the main pancreatic duct was cut off at the tumor. Cytology of the pancreatic fluids did not indicate malignancy. A pancreatic tumor with a cystic component similar to pancreatic neoplasms containing cystic degeneration or a mass-forming pancreatitis concomitant with pancreatic pseudocyst was suspected. Therefore, we performed distal pancreatectomy. Histological findings showed the center of the tumor was severely necrotized and oval or spindle dysplastic cells proliferated around the peripheral area. According to the immunohistological staining pattern, the patient was diagnosed as having anaplastic carcinoma spindle cell type. He was administered oral S-1 for 6 months and is now recurrence-free, surviving for 15 months after pancreatectomy. Reports of long-term survival cases that also demonstrated R0 resection should be indicated in the treatment of anaplastic carcinoma spindle cell type despite the poor prognosis.

[A Case of Mixed Hepatocellular and Primary Hepatic Neuroendocrine Carcinomas with Remnant Liver Recurrence and Rapid Exacerbation].

The patient was a 77-year-old man with a 4.0 cm hepatictumor in hepaticsegment 4. Plain computed tomography(CT) showed the tumor with low density. On dynamicexamination, the tumor showed heterogeneous enhancement during the arterial phase. Magneticresonanc e imaging showed the tumor as a low intensity area in the hepatobiliary phase in hepatic segments 4, 6, and 8. A month later, CT showed an enlarged tumor in segment 4 measuring 7.0 cm. We diagnosed the tumor as primary liver cancer and suspected it to be hepatocellular carcinoma(HCC)preoperatively. We performed extended medial segmentectomy and partial hepatectomy of segment 6. The histopathological diagnosis was mixed HCC and primary hepatic neuroendocrine carcinoma(PHNEC). Three months after hepatectomy, the patient died of multiple intrahepatic recurrences. In most of the reported cases of mixed HCC and PHNEC, only the PHNEC component has been detected in the biopsy of the metastatic lesions. This fact might suggest that PHNEC has a higher proliferative activity and malignant potential than HCC. Standard treatment for mixed HCC and PHNEC is unclear; therefore, development of multidisciplinary treatment strategies combining surgical treatment and systemic chemotherapy is required.

Total Synthesis of the Proposed Structure for Aromin and Its Structural Revision.

This paper describes the first total synthesis of the proposed structure for aromin, an annonaceous acetogenin possessing an unusual bis-THF ring system, and its 4S,7R-isomer. The key steps involve an oxidative cyclization of a couple of terminal-diene alcohols and an intermolecular metathesis of an alkenyl tetrahydrofuran with an enone carrying a tetrahydrofuranyl lactone. The spectral data of both samples did not match those of aromin. Re-examination of the NMR data using the CAST/CNMR Structure Elucidator and chemical derivations suggested that the real structure of aromin should be revised to be a tetrahydropyran acetogenin, montanacin D. Cytotoxicities in human solid tumor cell lines for synthetic samples were also evaluated.

[A Case of Malignant Obstruction of the Colon Due to Peritoneal Dissemination of Gastric Carcinoma Treated with Colon Stenting and Colectomy after Chemotherapy].

A man in his 60s underwent gastrectomy to treat gastric carcinoma. Approximately 2.5 years after the surgery, he was admitted to the hospital because of abdominal pain. He was diagnosed with obstruction of the transverse colon due to a colon tumor. A stent was placed to treat the obstruction and avoid oncologic emergency. Biopsy results and imaging showed that the patient did not have colon cancer, but his previous gastric cancer had disseminated peritoneally. Chemotherapy was selected as treatment for recurrent gastric cancer. After chemotherapy, the patient underwent colectomy with removal of the stent. His postoperative course was good, and he was discharged from hospital without complications. The patient received additional chemotherapy. We encountered a case of colon obstruction due to peritoneal dissemination of gastric cancer that was successfully treated using a metallic colorectal stent. Colon stenting for malignant bowel obstruction is useful to avoid oncologic emergencies. However, there is no evidence at this time that long-term placement of a stent is safe. The decision to remove or retain the stent should be made upon carefully considering the condition of the patient and progression of the disease.

[A Case of Locally Advanced Pancreatic Cancer Showing R0 Resection after Resection of the Portal Vein Following Preoperative Chemoradiotherapy].

We report a case of pancreatic cancer showing R0 resection after resection of the portal vein(PV)following preoperative chemoradiotherapy. A 71-year-old woman was admitted to our hospital with back pain. We diagnosed the patient with pancreatic cancer using computed tomography scan and fine-needle aspiration biopsy. Because the tumor directly invaded the PV, we diagnosed it as a borderline resectable locally advanced pancreatic cancer. Radiation therapy(40 Gy/20 Fr)was administered with S-1 monotherapy(120 mg/body/day on days 1-5 and days 8-12). After the treatment, the main tumor was stable without distant metastasis. Therefore, we performed pancreaticoduodenectomy with resection of the PV. Pathological examination confirmed negative margin status. The patient was healthy and showed no sign of recurrence eight months after surgery.

[Assessment of Endoscopic Resection and Partial Duodenectomy for Duodenal Mucosal Tumor].

INTRODUCTION: The risk of perforation following endoscopic resection is high. We analyzed the outcome of partial duodenectomy and discussed the therapeutic strategy for duodenal mucosal tumor(DMT). PATIENTS AND METHODS: We analyzed 19 cases who have undergone endoscopic resection, and 11 cases who have undergone partial duodenectomy for DMT in our institute since 2007. We divided them into the first period(ESD actively indicated)and late period(ESD carefully indicated according to the alteration of indication of ESD for DMT in 2013)groups. RESULTS: In the first period, all 17 cases initially underwent endoscopic resection and 4 cases were complicated by perforation. On the other hand, in the late period, 6 of 12 cases initially underwent endoscopic resection and 1 case was complicated by perforation. Emergent partial duodenectomy was performed with additional resection in the perforation cases. There were no complications associated with surgery, and all 29 cases achieved curative resection, based on the histology results. CONCLUSION: We can safely indicate endoscopic resection for DMT with surgical back-up and cooperation with the endoscopic internal department.

[Two Cases of Locally Recurrent Rectal Cancer after Intersphincteric Resection That Were Controlled with a Combination of Chemoradiotherapy and Abdominoperineal Resection].

We report 2 cases of locally recurrent rectal cancer after intersphincteric resection(ISR)that were controlled with a combination of chemoradiotherapy and abdominoperineal resection(APR). In Case 1, we performed preoperative chemoradiotherapy( TS-1 plus RT 45 Gy)and APR for the local recurrence of ISR. On pathology, viable neoplastic cells were noted. In Case 2, we performed preoperative chemotherapy(Bmab plus mFOLFOX6)and APR for the local recurrence of ISR. On pathology, no viable neoplastic cells were noted. However, a local recurrence developed again 3 months later. Therefore, we performed chemoradiotherapy(TS-1 plus RT 53 Gy). The 2 patients survived without recurrence until now. Their pathology tissues and clinical courses showed that control of local recurrence with only chemoradiotherapy or surgical resection was likely to be difficult. We might be able to improve the prognosis of patients with a combination of chemoradiotherapy and surgical resection.

[A Long-Surviving Case of Unresectable Gall Bladder Carcinoma Treated with Gemcitabine-Based Chemotherapy].

We report a 5-year surviving patient with unresectable gall bladder carcinoma treated with gemcitabine(GEM)-based chemotherapy. A 64-year-old man was diagnosed with unresectable gall bladder carcinoma with peritoneal dissemination based on laparotomy findings. Two months later, he started to receive GEM chemotherapy. Twelve months after surgery, the patient chose to suspend GEM treatment. One year and 10 months later, multiple lung metastases appeared and GEM was restarted in combination with UFT. Although the primary lesion and lung metastases gradually progressed, the patient maintained a good quality of life. After 3 years and 2 months, chemotherapy was changed to GEM plus S-1 because of progressive disease. Five years and 2 months after surgery, his condition was complicated by a secondary pneumothorax, and the patient received home oxygen therapy. Five years and 8 months after surgery he died of respiratory distress caused by the progression of lung metastases. Even in the case of unresectable advanced gall bladder carcinoma, effective chemotherapy could improve quality of life and prolong survival.

[Report of a Case of Long-Term Survival with Mulitidisciplinary Therapy for a Patient with Multiple Liver Metastases from Rectal Cancer].

Multidisciplinary therapy is necessary to prevent recurrence of advanced rectal cancer and advanced cancer with metastases. Here we report a case of long-term survival of a patient with advanced rectal cancer with multiple liver metastases. An 80's woman had previously undergone both Hartmann's operation and a partial hepatectomy for advanced rectal cancer with multiple liver metastases. A year after chemotherapy, a CT scan revealed multiple liver metastases. Thus, we performed partial liver resection. After another round of chemotherapy, a CT scan revealed lung metastases and local recurrence of the rectal cancer; therefore, we performed partial lung resection and a Miles operation. These procedures were conducted 4 years after her first operation. The following year, PET-CT revealed a mediastinum lymph node metastasis; consequently, we performed radiation therapy. New lung metastases and local recurrences of rectal cancer were identified after the radiation therapy; thus, we resumed the therapy, including a molecular targeting drug. Although the patient is in a tumor-bearing state, she is still alive 10 years after her first operation.

Enlarging lymphoepithelial cyst of the pancreas during 12 months of observation: report of a case.

Pancreatic lymphoepithelial cysts (LECs) are rare benign pancreatic cystic lesions, the etiology of which is unknown. We report a case of a pancreatic LEC, discovered incidentally in a 63-year-old man during a follow-up clinic visit for an abdominal aneurysm. Computed tomography showed a multilocular cyst, 60-mm diameter in the body of the pancreas. This cyst increased from 6.0 to 6.5 cm during 12 months of observation. Part of the cyst was also visualized on positron emission tomography imaging. Since a pancreatic cystic neoplasm could not be ruled out, we performed distal pancreatectomy and postoperative pathological examination confirmed that the lesion was an LEC of the pancreas. Despite the conclusive postoperative findings, resection is unavoidable when a true pancreatic neoplasm cannot be excluded.