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Background Although postoperative pancreatic fistula (POPF) is a common and critical complication of pancreatoduodenectomy (PD), effective strategies to prevent POPF have not yet been completely developed. Because appropriate management of POPF is important to reduce the mortality rate after PD, in this study we aimed to evaluate our approach for the management of POPF after PD, including the postoperative course. Methods This retrospective study included 605 consecutive patients who underwent PD at our hospital between 2010 and 2020. All patients who developed POPF were first managed conservatively, with drainage tubes placed during surgery retained to manage POPF. In cases wherein conservative treatment was unsuccessful, open drainage, followed by continuous negative pressure and continuous irrigation, was used. For open drainage, the surgical wound was opened bluntly (approximate length, 5 cm) under local anesthesia, and the fluid was directly and completely drained. Results The prevalence of POPF of grades B and C was 15.4% (n = 93) and 0.33% (n = 2), respectively. Of these patients, 1 required reoperation, 43 recovered with conservative management only, 47 required open drainage, and 4 required image-guided percutaneous drainage. Postoperative hemorrhage with a pseudoaneurysm was identified in 3 (0.66%) patients. The postoperative in-hospital mortality rate was low (n = 1, 0.16%). The rate of successful POPF management was 98.9%. Conclusion Based on our high success rate in POPF management, we consider open drainage to be a safe primary management method for POPF.

Background Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions. Method We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone’s combination therapy on subcutaneous tumor formation and splenic xenografted mouse models. Results In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone’s combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level. Conclusion NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.

Background The incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. The present study aimed to clarify the efficacy of our modified DuVal (mDuVal) pancreatojejunostomy following DP in patients with a high risk of POPF. Methods The medical records of 346 consecutive patients who underwent DP between 2006 and 2016 were retrospectively reviewed. Perioperative features were compared between 24 patients undergoing mDuVal (mDuVal group) and 322 patients undergoing standard DP (standard DP group). Results Preoperative American Society of Anesthesiologists physical status 1 was more frequent in the standard group than in the mDuVal group ( P = .02). The start of a solid diet after operation was significantly earlier in the mDuVal group than in the standard DP group ( P = .01), while there were no significant differences between the groups for clinically relevant POPF, amylase concentration in the drainage fluid on postoperative day 1 and days 3-5, time to drain removal, additional intervention for POPF, overall complications, or postoperative hospital stay. Discussion The mDuVal procedure could be an option for patients with a high risk of POPF to improve the outcomes after DP. Further investigation involving large study populations is necessary to clarify the efficacy of this procedure.

The aim of this study was to investigate the genetic mutation profiles of Japanese pancreatic ductal adenocarcinoma (PDAC) patients. Next-generation sequencing was performed using FoundationOne® CDx on 17 PDAC patients who were treated by surgical resection at Kyushu University Hospital between February 2016 and January 2019. The tumor mutational burden and microsatellite instability status were also assessed. There were 16 patients (94%) with KRAS mutations, 13 (76%) with TP53 mutations, three (18%) with SMAD4 mutations, and one (6%) with a CDKN2A mutation. All patients had at least one pathogenic variant or a likely pathogenic variant. No patient had targeted therapies that matched with any clinical benefit according to FoundationOne® CDx. An unresectable PDAC patient with BRCA2-mutant disease was successfully treated by conversion surgery using platinum-based neoadjuvant chemotherapy. Currently, FoundationOne® CDx might be difficult to use on PDAC patients, although further investigations with larger study populations are called for.

A 17-year-old mongrel dog and 12-year-old Shiba Inu dog presented with ataxia and paresis of the pelvic limbs, respectively. Gas accumulation within the spinal canal adjacent to the herniated disc was suspected in both cases. Since the gas remained accumulated for a prolonged period, hemilaminectomy was performed to decompress the spinal cord. The bulged external lamina of the dura matter was removed and histopathologically examined. Granulomatous inflammation and hyperplasia of fibrous connective tissues was noted, suggesting that the gas was encapsulated and the fibrous nodules made reabsorption difficult. Clinical signs resolved post-surgery. This is the first report describing histopathological features of pneumorrhachis in dogs. The accumulated gas was successfully removed by surgery. Postoperative course remained uneventful in both cases.

Aim As the prognosis of patients who undergo resection for pancreatic cancer has improved, reports of remnant pancreatic cancer after pancreatic cancer resection have been increasing. Previous studies regarding early‐stage pancreatic cancer showed a high incidence of remnant pancreatic cancer in these patients. The aim of this study was to investigate the incidence of remnant pancreatic cancer according to the degree of progression of the initial pancreatic cancer. Methods Patients who underwent partial pancreatic resection for primary pancreatic cancer were retrospectively reviewed and divided into an early‐stage group and an advanced‐stage group according to the stage of the initial cancer. Patient characteristics and long‐term outcomes, including development of remnant pancreatic cancer, were compared between the two groups. Results This study included 321 patients who underwent partial pancreatectomy for pancreatic cancer; 32 patients in the early‐stage group and 289 patients in the advanced‐stage group. Remnant pancreatic cancer developed in 19 patients (5.9%); seven patients (21.9%) in the early‐stage group and 12 patients (4.5%) in the advanced‐stage group. The cumulative incidence of remnant pancreatic cancer according to the Kaplan–Meier method was comparable between the two groups (5‐year cumulative incidence: 20.6% vs 9.9%, early‐stage group vs advanced‐stage group; P = .1827). Conclusion Our results suggested that the potential for developing remnant pancreatic cancer was comparable between the early‐stage and the advanced‐stage groups. Therefore, the incidence of remnant pancreatic cancer may increase along with improved pancreatic cancer treatment., Remnant pancreatic cancer occasionally develops after pancreatic resection for pancreatic cancer. Although the proportion of patients who develop remnant pancreatic cancer was larger in early‐stage pancreatic cancer than advanced‐stage cancer, the potential for developing remnant pancreatic cancer was comparable between early‐stage cancer and advanced‐stage cancer.

OBJECTIVE To measure expression of microRNAs (miRNAs) in plasma and in extracellular vesicles (EVs) derived from plasma for dogs with glioma and dogs with other brain diseases. SAMPLE Plasma samples from 11 dogs with glioma and 19 control dogs with various other brain diseases. PROCEDURES EVs were isolated from plasma samples by means of ultracentrifugation. Expression of 4 candidate reference miRNAs (let-7a, miR-16, miR-26a, and miR-103) and 4 candidate target miRNAs (miR-15b, miR-21, miR-155, and miR-342-3p) was quantified with reverse transcription PCR assays. Three software programs were used to select the most suitable reference miRNAs from among the 4 candidate reference miRNAs. Expression of the 4 target miRNAs was then calculated relative to expression of the reference genes in plasma and EVs, and relative expression was compared between dogs with glioma and control dogs with other brain diseases. RESULTS The most suitable reference miRNAs were miR-16 for plasma and let-7a for EVs. Relative expression of miR-15b in plasma and in EVs was significantly higher in dogs with glioma than in control dogs. Relative expression of miR-342-3p in EVs was significantly higher in dogs with glioma than in control dogs. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that miR-15b and miR-342-3p have potential as noninvasive biomarkers for differentiating glioma from other intracranial diseases in dogs. However, more extensive analysis of expression in specific glioma subtypes and grades, compared with expression in more defined control populations, will be necessary to assess their clinical relevance.

A 2-year-old Maltese was presented with wobbly gait of the pelvic limbs. Based on imaging examinations, a diagnosis of congenital malformation at T5–T8 and severe kyphosis causing spinal cord compression at T6–T7 was made. Dorsal laminectomy and stabilization of T6 and T7 vertebrae were performed. As the size of the vertebrae was small and they were severely deformed, novel custom-made titanium implants were used for spinal stabilization. Clinical signs were resolved 2 weeks after surgery. Although radiographic examination 373 days after surgery showed slight loosening of implants, post-operative course remained uneventful. This report describes the use of novel custom-made titanium implants for spinal fixation surgery in a dog.

A 9-year-old neutered male Wire Fox Terrier presented with an 1-month history of hindlimb paresis. Magnetic resonance imaging revealed a contrast-enhanced mass at the level of the L2 vertebral canal. The dog became paraplegic with no deep perception of the hindlimbs, and the mass was surgically removed. The histopathological diagnosis was of a malignant peripheral nerve sheath tumor (MPNST). The dog suffered a relapse of right hindlimb ataxia at 225 days after the surgery. The dog died 434 days after the surgery. Necropsy found a large mass in the abdominal cavity invading from the L2-nerve. This is the first report of MPNST invading the abdominal cavity through the nerve root.

Thoracolumbar intervertebral disk herniation (TL-IVDH) with caudal articular process anomalies has been reported in Pugs. It currently remains unclear whether congenital caudal articular process aplasia/hypoplasia predisposes to the development of TL-IVDH. However, there are difficulties in proving the causal relationship between caudal articular process anomalies and TL-IVDH. The aim of this study was to describe the prevalence of TL-IVDH at the vertebral space containing anomalous and normal caudal articular processes in Pugs. Fifty-seven pugs were eligible to be included in this study. Caudal articular process aplasia/hypoplasia affected 52/57 (91.2%) dogs. The caudal articular process anomalies were most frequently located between T10 and T13. Colocalization of caudal articular process aplasia/hypoplasia and TL-IVDH was detected in 11 dogs (19.3%). The prevalence of TL-IVDH at vertebral spaces containing abnormal caudal articular processes was 12.3%, whereas the prevalence of TL-IVDH at vertebral spaces containing normal articular processes was 2.4%. With the increase in the number of vertebrae with caudal articular process anomalies, the prevalence of TL-IVDH also increased. The results of this study suggested the prevalence of caudal articular process anomalies was high in Pugs. The caudal articular process anomalies could be associated with TL-IVDH. A large cohort is needed to prove the causal relationship between caudal articular process anomalies and TL-IVDH.

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is characterized by cystic dilation of the pancreatic duct, caused by mucin hypersecretion, with slow progression via the adenoma-carcinoma sequence mechanism. Mutation of GNAS at codon 201 is found exclusively in IPMNs, occurring at a rate of 41-75%. Recent advances in molecular biological techniques have demonstrated that GNAS mutation might play a role in the transformation of IPMNs after the appearance of neoplastic cells, rather than in the tumorigenesis of IPMNs. GNAS mutation is observed frequently in the intestinal subtype of IPMNs with MUC2 expression, and less frequently in IPMNs with concomitant pancreatic ductal adenocarcinoma (PDAC). Research has focused on assessing GNAS mutation status in clinical practice using various samples. In this review, we discuss the clinical application of GNAS mutation assessment to differentiate invasive IPMNs from concomitant PDAC, examine the clonality of recurrent IPMNs in the remnant pancreas using resected specimens, and differentiate pancreatic cystic lesions using cystic fluid collected by endoscopic ultrasound-guided fine needle aspiration (EUS-FNA), duodenal fluid, and serum liquid biopsy samples.

Accumulation of evidence suggests that neoadjuvant chemotherapy improves the outcomes of borderline resectable pancreatic cancer (BRPC). Gemcitabine plus nab-paclitaxel (GnP) has been widely accepted as systemic chemotherapy for unresectable pancreatic cancer and reportedly results in remarkable tumor shrinkage. This study was performed to evaluate the safety and efficacy of neoadjuvant chemotherapy using neoadjuvant GnP for BRPC. The medical records of 57 patients who underwent treatment of BRPC from 2010 to 2017 were retrospectively reviewed. The patient characteristics and short- and intermediate-term outcomes were compared between the GnP and upfront surgery (UFS) groups. The GnP group comprised 31 patients and the UFS group comprised 26 patients. The patient characteristics were comparable with the exception of a higher prevalence of arterial involvement in the GnP group. Twenty-seven of the 31 patients (87%) in the GnP group and all 26 patients in the UFS group underwent resection. The GnP group showed a significantly shorter operation time (429 vs. 509.5 min, p = 0.0068), less blood loss (760 vs. 1324 ml, p = 0.0115), and a higher R0 resection rate (100% vs. 77%, p = 0.0100) than the UFS group. Postoperative complications and hospital stay were comparable between the two groups, and no treatment-related mortality occurred in either group. Both the disease-free survival and overall survival times were significantly longer in the GnP group (p = 0.0018 and p = 0.0024, respectively). Neoadjuvant GnP is a safe and effective treatment strategy for BRPC. It potentially improves patients’ prognosis and facilitates surgical procedures.

Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the 'neuroactive ligand-receptor interaction' pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.

Background/objectives Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation. Methods We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models. Results In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown. Conclusions Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

Introduction Laparoscopic pancreaticoduodenectomy has recently been covered under Japan's insurance system for patients not requiring lymph node dissection. Only high-volume hospitals that meet specific criteria are permitted to perform laparoscopic pancreaticoduodenectomy. Although open and laparoscopic pancreaticoduodenectomy outcomes with lymph node dissection have been described previously, procedures performed without lymph node dissection have not been compared using a nationwide database. This study aimed to review the results of laparoscopic pancreaticoduodenectomy and compare them to those of open pancreaticoduodenectomy (OPD) using records from a nationwide database. Methods We collected patient demographic and medical data of 2900 patients who underwent pancreaticoduodenectomy (laparoscopic, n = 162; open, n = 2738) without lymph node dissection between 2016 and 2018 from the National Clinical Database in Japan. Coarsened exact matching was used to match patients in the laparoscopic and open pancreaticoduodenectomy groups. Results In-hospital mortality was not observed in the laparoscopic pancreaticoduodenectomy group. The rate of conversion to an open procedure was 6.8% (11 cases). After 1:1 matching, we obtained 141 pairs of patients for comparison. The mortality rate was comparable in the laparoscopic and open pancreaticoduodenectomy groups (0.0% vs 0.7%, respectively; P = 1.00). The laparoscopic approach showed more favorable results in terms of median blood loss. Postoperative pancreatic fistula formation and complications were comparable between the two groups. Conclusions Our results indicate that laparoscopic pancreaticoduodenectomy could be introduced successfully, and the outcomes achieved by the institutions included in our study were comparable to those of open pancreaticoduodenectomy.

T1 gastric cancer (GC) with seven or more metastatic lymph nodes is extremely rare, and very few clinical studies have been conducted to evaluate the clinicopathological features of their recurrence. We retrospectively analyzed the outcomes of T1 GC and T2–4 GC patients who had multiple nodal metastases after radical surgery from 2006 to 2020. Propensity score matching was performed to compare the two groups of patients. After propensity score matching, 18 of 22 patients in the T1 group and 36 of 144 patients in the T2–4 group were selected. Recurrence occurred in six patients (33.3%) in the T1 group. In the T1 group, the most common site of initial recurrence was bone (15.0%). The prevalence of bone recurrence was significantly higher in the T1 group than in the T2–4 group (P = 0.02). The median interval time between radical surgery and bone recurrence was 24 months, and the median survival time after bone recurrence was 14 months. Bone recurrence was more frequently identified as an initial recurrence site in T1 GC cases with multiple metastases after radical surgery compared with that in T2–4 GC cases. Careful attention should be paid to postoperative bone recurrence in the long-term postoperative course of these patients.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.

Background/objectives Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer. Methods Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo. Results Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased α-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine. Conclusions A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation.

Background: Peripheral intravenous injection of gemcitabine often causes vascular pain; however, preventive measures have not yet been established. Objectives: This study focused on identifying predictive factors for gemcitabine-induced vascular pain. Methods: We retrospectively analyzed risk factors for developing vascular pain in patients with pancreatic cancer receiving gemcitabine infusions at our institution. Infusions were divided into groups according to presence or absence of vascular pain symptoms, and variables were compared. Odds ratios for risk factors were calculated using logistic regression analyses. Results: Overall, 272 patients with pancreatic cancer were subjected to 725 gemcitabine infusions, and of these, 18.4% (n = 50) experienced vascular pain. There were significant differences in the gemcitabine dose ( P = 0.025), dose of gemcitabine/body surface area (BSA; P = 0.004), concentration of gemcitabine ( P = 0.025), and hot pack use ( P = 0.011) between the vascular pain and no vascular pain groups. Multivariable analyses indicated that gemcitabine dose/BSA and lack of hot pack use were risk factors for developing vascular pain. Moreover, on administration of a higher dosage (>930 mg/m2), the incidence of vascular pain in patients using a hot pack (6.7%) was significantly lower than that in patients not provided a hot pack (16.2%). Conclusions and Relevance: High gemcitabine dosages and lack of hot pack use were predictive factors for gemcitabine-induced vascular pain in patients with pancreatic cancer. Patients receiving gemcitabine treatment should apply a hot pack to the injection site. Scrupulous clinical attention is required for patients presenting with these risk factors to improve pain management.

A 4-month-old cat with epileptic seizures and nasal discharge was presented, and diagnosed with intranasal meningoencephalocele based on the clinical symptoms and findings of CT and MRI. As liquorrhea was suspected, the meningoencephalocele was surgically excised and the postoperative course was favorable. For cribriform plate reconstruction, the autologous tunica vaginalis was used. Rhinorrhea of the cerebrospinal fluid and seizures disappeared after surgery. On CT and MRI at 7 months after surgery, septum formation between the cranial and nasal cavities was confirmed. Currently, no seizures have occurred even though no oral antiepileptic agent was administered. There are few reports of surgical treatment for meningoencephalitis, and there are no reports of reconstruction of the cribriform plate using tunica vaginalis, so we reported the details.

This study aimed at investigating the function and significance of CD110 expression in pancreatic cancer. We performed immunohistochemical staining for CD110 expression in tumor samples from 86 patients with pancreatic cancer. We evaluated clinical outcomes and other clinicopathological factors to determine the significance of CD110 on survival and liver metastasis. We examine thrombopoietin–CD110 signaling in cancer cell extravasation in vitro and in vivo. We investigated the effects of CD110 knockdown on liver metastasis in a splenic xenograft mouse model. CD110 expression in cancer cells was associated with low-histological-grade invasive ductal carcinoma, and patients with high CD110 expression had poorer prognosis (P = 0.0003). High CD110 expression was an independent predictor of liver metastasis (P = 0.0422). Knockdown of CD110 expression significantly attenuated cell migration and invasion. Treatment with thrombopoietin promoted pancreatic cancer cell extravasation. In the presence of thrombopoietin, CD110 increased cell viability through the activation of the ERK–MYC signaling pathway. Knockdown of CD110 expression inhibited liver metastases in the mouse model. CD110 promotes pancreatic cancer progression and it may serve as a predictive factor for liver metastasis.

Background The definition of postoperative acute pancreatitis as a specific complication of pancreatic surgery was proposed in 2016. Its presence and relevance have not been established, especially after a distal pancreatectomy. Methods Medical records of 319 patients who underwent pancreatoduodenectomy or distal pancreatectomy were analyzed. Postoperative acute pancreatitis was defined as an increase in serum amylase activity greater than the upper normal limit on postoperative day 1, according to Connor’s definition of postoperative acute pancreatitis. Results Postoperative acute pancreatitis occurred in 63.4% of 153 of the patients undergoing pancreatoduodenectomy and 65.7% of the 166 undergoing distal pancreatectomies. Patients who developed postoperative acute pancreatitis after pancreatoduodenectomy experienced an increase in the rate of morbidity (22.7% vs 7.1%; P = .0137), including postoperative pancreatic fistula (18.6% vs 1.8%; P = .024), resulting in greater postoperative stays (21 days vs 17 days; P = .0008). Postoperative acute pancreatitis in association with an increased serum C-reactive protein ≥18.0 mg/dL (which we defined as a clinically relevant postoperative acute pancreatitis) more strongly indicated the occurrence of severe complications (P = .0032) and was an independent predictor of postoperative pancreatic fistula after pancreatoduodenectomy (odds ratio, 3.03; P = .0448). Patients who developed postoperative acute pancreatitis after distal pancreatectomy experienced similar postoperative courses regarding morbidity and the duration of postoperative stay. Conclusion The clinical relevance of postoperative acute pancreatitis differs after a pancreatoduodenectomy versus a distal pancreatectomy. The development of effective strategies for preventing postoperative acute pancreatitis might improve surgical outcomes after pancreatoduodenectomy.

Although recent studies revealed that adipose tissue accelerates pancreatic tumor progression with excessive extracellular matrix, key players for desmoplasia in the adipose microenvironment remains unknown. Here, we investigated the roles of adipose tissue-derived stromal cells (ASCs) in desmoplastic lesions and tumor progression by in vitro and in vivo experiments. In a three-dimensional (3-D) organotypic fat invasion model using visceral fat from CAG-EGFP mice, GFP-positive fibroblastic cells infiltrated toward cancer cells. When tumor cells were inoculated into transplanted visceral fat pads in vivo, tumor weights and stromal components were enhanced compared to subcutaneous and orthotopic tumor cells inoculated without fat pads. Expression of αSMA in established human ASCs was lower compared to cancer associated fibroblasts, and the 3-D collagen matrices produced by ASCs cultured in cancer cell-conditioned medium changed from loose to dense structures that affected the motility of cancer cells. Microarray analyses revealed upregulation of S100A4 in ASCs, while S100A4-positive stromal cells were observed at extrapancreatic invasion sites of human pancreatic cancer. The present findings indicate that ASCs are recruited to extrapancreatic invasion sites and produce dense collagen matrices that lead to enhanced tumor progression. Both inhibition of ASCs recruitment and activation could lead to a novel antistromal therapy.

Preoperative nutritional and immunological patient factors have been found to be associated with prognostic outcomes of malignant tumors; however, the clinical significance of these factors in pancreatic ductal adenocarcinoma (PDAC) remains controversial.The aim of this study was to evaluate the prognostic value of nutritional and immunological factors in predicting survival of patients with PDAC.Retrospective studies of 329 patients who underwent surgical resection for PDAC and 95 patients who underwent palliative surgery were separately conducted to investigate the prognostic impact of tumor-related factors and patient-related factors, including Glasgow Prognostic Score (GPS), modified GPS, Prognostic Nutritional Index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio, and lymphocyte/monocyte ratio.In multivariate analysis for patients with surgical resection for PDAC, PNI was an independent factor for overall survival (OS) and disease-free survival. The median OS of patients with PNI ≤ 45 was significantly shorter than that of patients with PNI 45 (17.5 and 36.2 months, respectively; p 0.001). In multivariate analysis for patients undergoing palliative surgery for PDAC, only NLR was an independent prognosis factor. The median OS of patients with NLR 5 was significantly shorter than that of patients with NLR ≤ 5 (2.7 and 8.9 months, respectively; p 0.001).PNI in patients with surgical resection and NLR in patients with palliative surgery for PDAC may be useful prognostic factors.

Endoscopic management is presently the recommended first-line of treatment for biliary strictures. However, surgery still has an important role especially for biliary obstruction (BO) with duodenal obstruction. Even though endoscopic treatment for concurrent BO and gastric-outlet obstruction has been proposed, it is still not widespread. Duodenal obstruction is often associated with malignant BO which makes endoscopic treatment more challenging. Biliary and gastrointestinal double bypass with Roux-en-Y hepaticojejunostomy and gastrojejunostomy is the most common surgical intervention for malignant biliary and gastric-outlet obstruction. A variety of procedures of biliary bypass and gastrointestinal bypass have been reported. According to several studies, mortality rates range from 0% to 7%, while morbidity rates range from 3% to 50%. Higher morbidity was observed in symptomatic patients caused by the disease. Most common morbidity after double bypass was delayed gastric emptying. Recurrence of BO and gastric-outlet obstruction was less frequently seen after surgical bypass compared to after endoscopic treatment. Minimally invasive approach has been applied to double bypass. Studies showed that laparoscopic double bypass has a shorter hospital stay and reduced postoperative pain; however, due to its technical demand, it is still presently an uncommon procedure. Robotic bypass surgery may resolve this issue in the future. Further analyses of outcomes of both surgical and endoscopic treatments are necessary to establish better and suitable palliation options for concurrent biliary and duodenal obstruction caused by unresectable malignant tumors.

Background/Objectives It is often difficult to determine an adequate resection line during pancreatectomy for intraductal papillary mucinous neoplasm involving the main pancreatic duct during partial pancreatectomy. The aim of this study was to evaluate the usefulness of improved peroral pancreatoscopy using SpyGlass-DStm in the preoperative assessment of intraductal papillary mucinous neoplasm involving the main pancreatic duct. Methods We collected and retrospectively analyzed clinicopathological data from seven consecutive patients who underwent preoperative assessment of intraductal papillary mucinous neoplasm involving the main duct using SpyGlass-DStm. Results Good imaging quality of the intraductal protruding lesion was obtained in all seven patients, and only one adverse event was noted wherein a patient had mild pancreatitis. Six patients underwent pancreatectomy. In one patient, masked-type concomitant pancreatic ductal adenocarcinoma and low-length dysplastic lesion was found near the surgical margin, which was not detected by preoperative imaging modalities including SpyGlass-DStm. The sensitivity of targeting biopsy during SpyGlass-DStm to diagnose high-grade dysplasia was 0%. Conclusions SpyGlass-DStm can be safely performed in patients with intraductal papillary mucinous neoplasm involving the main duct, and has excellent visualization of the target lesion. However, challenges include poor diagnostic ability of targeting biopsy, and, therefore, intraoperative frozen section is still needed to obtain negative surgical margins.

Specific cell populations leading the local invasion of cancer are called "leading cells". However, the underlying mechanisms are unclear. Here, we identified leading cells in pancreatic cancer and determined how these cells lead and promote cancer cell invasion in the extracellular matrix (ECM). Using three-dimensional matrix remodeling assay, we found that pancreatic stellate cells (PSCs) frequently invaded the collagen matrix with pancreatic cancer cells (PCCs), which invaded behind the invading PSCs. In addition, invading PSCs changed the alignment of collagen fibers, resulting in ECM remodeling and an increase in the parallel fibers along the direction of invading PSCs. Endo180 expression was higher in PSCs than in PCCs, Endo180 knockdown in PSCs attenuated the invasive abilities of PSCs and co-cultured PCCs, and decreased the expression level of phosphorylated myosin light chain 2 (MLC2). In mouse models, Endo180-knockdown PSCs suppressed tumor growth and changes in collagen fiber orientation in co-transplantation with PCCs. Our findings suggest that PSCs lead the local invasion of PCCs by physically remodeling the ECM, possibly via the function of Endo180, which reconstructs the actin cell skeleton by phosphorylation of MLC2.

The aim of this study was to assess the feasibility of prophylactic pancreatojejunostomy after enucleation or limited pancreatic resection regarding the risk of postoperative pancreatic fistula (PF). We retrospectively reviewed the medical records of 32 patients who underwent enucleation or limited pancreatic resection and compared the clinical parameters between patients with ( n = 10) and without ( n = 22) prophylactic pancreatojejunostomy. Prophylactic pancreatojejunostomy was performed in patients with a possible high risk ofPF. No operation-related mortality occurred. Operation time was significantly longer ( P < 0.01) and blood loss significantly greater ( P < 0.01) in patients with pancreatojejunostomy. Overall complications were more frequent ( P = 0.02) and postoperative hospital stay was significantly longer ( P = 0.02) in patients with pancreatojejunostomy. However, other assessed factors including the prevalence of postoperative PF did not differ between groups. In conclusion, prophylactic pancreatojejunostomy is feasible, and its efficacy in preventing PF after enucleation or limited pancreatic resection in high-risk patients will require further study.

Canine degenerative myelopathy (DM), recognized as a spontaneous model of amyotrophic lateral sclerosis, is known as a late-onset progressive degenerative disease of the spinal cord. Because of the progressive nature of DM, many dogs are elected to be euthanized, resulting in limited information on the end-stage clinical presentation. We investigated the long-term clinical course from diagnosis to natural death to further deepen our understanding of the entire clinical picture of this disease. Because curcumin was administered in some cases, the therapeutic effect of curcumin on DM was also examined. Forty dogs included in this study were client-owned Pembroke Welsh Corgis with a definitive diagnosis of DM by necropsy and histopathology. Dogs were excluded from this study if they died from another disease or were elected to be euthanized. Information on the long-term clinical symptoms of DM was investigated based on a questionnaire, which was collected from the dog owners. Urinary incontinence and respiratory disorder were observed in most dogs, as was respiratory impairment-correlated death. In contrast, signs consistent with brainstem dysfunction were noticed at the terminal stage in a small portion of dogs. Although further studies with more cases are needed, the results of this study suggest that administration of curcumin is effective in slowing the progression of DM.

We studied the prevalence of the transpancreatic common hepatic artery (tp-CHA) and coexisting variant anatomy. The study group comprised 788 consecutive liver transplant donor candidates who had undergone thin-section multidetector-row computed tomography (MDCT) studies to investigate vascular anatomy. Multiplanar reformatted (MPR) images obtained from the arterial phase were retrospectively reviewed to assess the presence/absence of the tp-CHA. Five cases of tp-CHA with pancreaticobiliary tumors were also included in an investigation of the presence/absence of variant hepatic arteries, celiac stenosis, and circumportal pancreas. Three of the 788 (0.38%) donor candidates had a tp-CHA. Overall, eight tp-CHA cases were assessed for coexisting variant anatomy. Seven of these eight cases had a hepatomesenteric trunk, six had celiac stenosis, and two had a circumportal pancreas. The prevalence of the tp-CHA was 0.38% (approx. one in 260 in normal populations). A tp-CHA can commonly be associated with a hepatomesenteric trunk and celiac stenosis. A circumportal pancreas can also coexist with a tp-CHA. Clin. Anat. 31:598-604, 2018. © 2017 Wiley Periodicals, Inc.

Background Circumportal pancreas is a rare congenital pancreatic anomaly. The aim of this study was to clarify the clinical characteristics of patients with circumportal pancreases undergoing pancreatectomy. Methods The medical records of 508 patients who underwent pancreatectomy were retrospectively reviewed. The prevalence of circumportal pancreas and related anatomical variations were assessed. Surgical procedures and postoperative outcomes were compared in patients with and without circumportal pancreas. Results Circumportal pancreas was observed in 9 of the 508 patients (1.7%). In all nine patients, the portal vein was completely encircled by the pancreatic parenchyma above the level of the splenoportal junction, and the main pancreatic duct ran dorsal to the portal vein. The rate of variant hepatic artery did not differ significantly in patients with and without circumportal pancreas. Pancreatic fistula developed more frequently in patients with than without circumportal pancreas (44% vs. 14%, p = 0.03), but other clinical parameters did not differ significantly in these two groups. Conclusions Despite being rare, circumportal pancreas may increase the risk of postoperative pancreatic fistula in patients undergoing pancreatectomy. However, a prospective, large-cohort study is necessary to determine the real incidence of relevant anatomical variations and the definitive clinical significance of this rare anomaly.

Pancreatic cancer is characterized by increased hyperplasia of fibrotic tissue, termed desmoplasia, and lymph node metastasis is an independent prognostic factor in this disease. However, there are no reports focused on desmoplasia in pancreatic cancer lymph node metastases. The present study evaluated a range of factors and investigated their association with poor prognosis in pancreatic cancer cases with lymph node metastasis, including the degree of desmoplasia in lesions. To identify the poor prognostic factors associated with lymph node metastasis, the present study retrospectively reviewed the clinical data of 65 patients with lymph node metastases that underwent surgical pancreatic cancer resection between 2007 and 2012 at a single institution. The investigation focused on the degree of fibrosis in metastatic lesions in 216 lymph nodes, and investigated associations with prognosis or clinicopathological findings. The ratios of the fibrotic area in metastatic lymph node lesions were evaluated and classified into three categories, high (≥70%), moderate (10–70%) and low (

Laparoscopic surgery as a treatment for congenital biliary dilatation is uncommon. We herein present a series of laparoscopic surgeries for congenital biliary dilatation performed in our institution and review our experience with this approach over a long period of time. Medical records of 36 consecutive patients who underwent laparoscopic surgery for congenital biliary dilatation from 1996 to 2015 were retrospectively reviewed. Data on patient demographics, operative time, blood loss, hospital stay, and complications were evaluated. A comparison between the former period (Group A, 1996–2005) and the latter period (Group B, 2006–2015) was performed. The patients comprised 23 females and 13 males with a median age of 34 years. The median operative time, blood loss, and hospital stay was 493 min, 154 g, and 11 days, respectively. Total early and late complications occurred in 7 (19%) and 2 (5%) patients, respectively. A comparison between Groups A and B revealed no significant difference in operative time or complications, but operative blood loss, open conversion, and hospital stay were significantly lower in Group B than in Group A (P

Cancer‑associated fibroblasts (CAFs) promote the progression of pancreatic ductal adenocarcinoma (PDAC) via tumor‑stromal interactions. Neutrophil extracellular traps (NETs) are extracellular DNA meshworks released from neutrophils together with proteolytic enzymes against foreign pathogens. Emerging studies suggest their contribution to liver metastasis in several types of cancer. Herein, in order to investigate the role of NETs in liver metastasis in PDAC, the effects of NET inhibitors on spontaneous PDAC mouse models were evaluated. It was demonstrated that DNase I, a NET inhibitor, suppressed liver metastasis. For further investigation, further attention was paid to liver micrometastasis and an experimental liver metastasis mouse model was used that was generated by intrasplenic tumor injection. Furthermore, DNase I also suppressed liver micrometastasis and notably, CAFs accumulated in metastatic foci were significantly decreased in number. In vitro experiments revealed that pancreatic cancer cells induced NET formation and consequently NETs enhanced the migration of hepatic stellate cells, which was the possible origin of CAFs in liver metastasis. On the whole, these results suggest that NETs promote liver micrometastasis in PDAC via the activation of CAFs.

Background Extracellular signal-regulated kinases (ERKs) have been related to multiple cancers, including breast cancer, hepatocellular cancer, lung cancer and colorectal cancer. ERK1/2 inhibitor can suppress growth of KRAS-mutant pancreatic tumors by targeting cancer cell. However, no studies have shown the expression of ERK1/2 on pancreatic stromal and its effect on pancreatic cancer–stromal interaction. Methods Immunohistochemistry and western blotting were performed to detect the expression of p-ERK1/2 in pancreatic tissues and cells. Cell viability assay was used to study IC50 of ERK inhibitor on pancreatic cancer cells (PCCs) and primary cancer-associated pancreatic stellate cells (PSCs). Transwell migration, invasion, cell viability assay, senescence β-galactosidase staining were performed to determine the effect of ERK inhibitor on PCCs and PSCs in vitro and in vivo. The expression of key factors involved in autophagy and epithelial-to-mesenchymal transition (EMT) process were evaluated by western blotting. The expression of key factors related to cell invasiveness and malignancy were confirmed by qRT-PCR. Co-transplantation of PCC Organoid and PSC using a splenic xenograft mouse model was used to evaluated combined treatment of ERK inhibitor and autophagy inhibitor. Results Immunohistochemical staining in pancreatic tumor samples and transgenetic mice detected p-ERK1/2 expression in both cancer cells and stromal cells. In pancreatic tissues, p-ERK1/2 was strongly expressed in cancer-associated PSCs compared with cancer cells and normal PSCs. PSCs were also significantly more sensitive to ERK1/2 inhibitor treatment. Inhibition of ERK1/2 suppressed EMT transition in HMPCCs, upregulated cellular senescence markers, activated autophagy in cancer-associated PSCs; and suppressed cancer–stromal interaction, which enhanced invasiveness and viability of cancer cells. We also found that chloroquine, an autophagy inhibitor, suppressed ERK inhibition-induced autophagy and promoted PSC cellular senescence, leading to significantly decreased cell proliferation. The combination of an ERK inhibitor and autophagy inhibitor suppressed liver metastasis in a splenic pancreatic cancer organoid xenograft mouse model. Conclusions These data indicate that inhibition of ERK1/2 in cancer-associated pancreatic stellate cells suppresses cancer–stromal interaction and metastasis. Electronic supplementary material The online version of this article (10.1186/s13046-019-1226-8) contains supplementary material, which is available to authorized users.

Progress in diagnostic modalities, surgical procedures, and multidisciplinary treatment for pancreatic diseases has increased the number of long-term survivors after pancreatic resection. Several reports have focused on high-risk lesions (HRLs), including high-grade pancreatic intraepithelial neoplasia (PanIN), pancreatic ductal adenocarcinoma, high-grade intraductal papillary mucinous neoplasm (IPMN), and IPMN with an associated invasive carcinoma, in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The etiology of HRLs in the remnant pancreas is thought to be either isolated local recurrence of the initial lesion in the remnant pancreas or a newly developed primary lesion. Although it is difficult to distinguish between local recurrence and a new primary lesion, comparison of genetic alterations between two lesions may help with this distinction. Early detection of HRLs in the remnant pancreas may improve the prognosis of patients, and several investigators have proposed predictive factors for HRLs in the remnant pancreas after partial pancreatic resection for pancreatic cancer or IPMN. The reported short- and long-term outcomes of surgical resection of HRLs in the remnant pancreas are relatively favorable. Life-long surveillance of the remnant pancreas is recommended after partial pancreatic resection for pancreatic cancer or IPMN.

Backgrounds Laparoscopic distal pancreatectomy (LDP) is gaining acceptance as a standard approach for removal of various benign and malignant pancreatic diseases. There are several methods of LDP which includes classic LDP with splenectomy for benign diseases, laparoscopic spleen and vessel preserving distal pancreatectomy, and laparoscopic radical pancreatectomy for invasive pancreatic cancers for pancreatic cancer. Several conditions may contribute to the difficulty of LDP based on type of operation, characteristics of the disease, patients' body habitus and tumor location. We have previously developed a difficulty scoring (DS) system to quantify the degree of difficulty in LDP to aid surgeons who would like to learn or teach this procedure in a stepwise manner. Aim The aim of this study is to validate the DS system in LDP, proposed by the study group of Japan Society for Hepato-Biliary-Pancreatic Surgery/Asian-Pacific Hepato-Pancreato-Biliary Association in 2018 (J Hepatobiliary Pancreato Sci 2018;25:489-497). Effect of score assessed by DS system on surgical outcomes including conversion rate, operation time and blood loss was validated in both Korean and Japanese cohort. Results We found significant difference of operation time and conversion rates in both Japanese and Korean cohort. However, the DS was not related with blood loss in both cohorts. Conclusions We observed associations between the DS system and operative outcomes, to some extent, and the trend seems to be same in both Korean and Japanese. To make the DS system for more useful one, we would like to modify the system in the future.

Pancreatic cancer progression involves components of the tumor microenvironment, including stellate cells, immune cells, endothelial cells, and the extracellular matrix. Although peripancreatic fat is the main stromal component involved in extra-pancreatic invasion, its roles in local invasion and metastasis of pancreatic cancer remain unclear. This study investigated the role of adipose tissue in pancreatic cancer progression using genetically engineered mice (Pdx1-Cre; LSL-KrasG12D; Trp53R172H/+) and an in vitro model of organotypic fat invasion. Mice fed a high fat diet had significantly larger primary pancreatic tumors and a significantly higher rate of distant organ metastasis than mice fed a standard diet. In the organotypic fat invasion model, pancreatic cancer cell clusters were smaller and more elongated in shape and showed increased fibrosis. Adipose tissue-derived conditioned medium enhanced pancreatic cancer cell invasiveness and gemcitabine resistance, as well as inducing morphologic changes in cancer cells and increasing the numbers of lipid droplets in their cytoplasm. The concentrations of oleic, palmitoleic, and linoleic acids were higher in adipose tissue-derived conditioned medium than in normal medium, with these fatty acids significantly enhancing the migration of cancer cells. Mature adipocytes were smaller and the concentration of fatty acids in the medium higher when these cells were co-cultured with cancer cells. These findings indicate that lipolytic and fibrotic changes in peripancreatic adipose tissue enhance local invasiveness and metastasis via adipocyte-released fatty acids. Inhibition of fatty acid uptake by cancer cells may be a novel therapy targeting interactions between cancer and stromal cells.

Objectives Hepatic steatosis, one of the most frequent long-term complications of pancreatectomy, influences not only hepatic function but also survival rate. However, its risk factors and pathogenesis have not been established. The purpose of this study was to clarify the risk factors for hepatic steatosis after pancreatectomy. Methods In this retrospective study of 21 patients who had undergone pancreatectomy (19 cases of pancreatoduodenectomy and 2 cases of total pancreatectomy), serum carnitine concentrations, fractions of carnitine, and hepatic attenuation on computed tomography images were analyzed with the aim of identifying risk factors for hepatic steatosis. Results Thirteen (61.9%) of the 21 patients were diagnosed as having hypocarnitinemia after pancreatectomy. Average hepatic attenuation was as low as 42.2HU (±21.3 SD). A high ratio of acyl/free carnitine was associated with less pronounced hepatic attenuation according to both univariate (P Conclusions The serum carnitine concentrations were low after pancreatectomy in some patients. The statistical analyses suggest that a high ratio of acyl/free carnitine is an independent risk factor for hepatic steatosis after pancreatectomy.

The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.

Canine degenerative myelopathy (DM) is a progressive and fatal neurodegenerative disorder that has been linked to mutations in the superoxide dismutase 1 (SOD1) gene. The accumulation of misfolded protein aggregates in spinal neurons and astrocytes is implicated as an important pathological process in DM; however, the mechanism of protein aggregate formation is largely unknown. In human neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), cell-to-cell propagation of disease-relevant proteins has been demonstrated. Therefore, in this study, propagation of aggregation-forming property of mutant SOD1 protein in DM in vitro was investigated. This study demonstrated that aggregates composed of canine wild type SOD1 protein were increased by co-transfection with canine mutant SOD1 (E40K SOD1), indicating intracellular propagation of SOD1 aggregates. Further, aggregated recombinant SOD1 proteins were released from the cells, taken up by other cells, and induced further aggregate formation of normally folded SOD1 proteins. These results suggest intercellular propagation of SOD1 aggregates. The hypothesis of cell-to-cell propagation of SOD1 aggregates proposed in this study may underly the progressive nature of DM pathology.

Atlantoaxial instability (AAI)/subluxation commonly occurs in small breed dogs. Ventral stabilization techniques using screws and/or pins and a plate or, more commonly, polymethylmethacrylate are considered to provide the most favorable outcome. However, the implantation of screws of sufficient sizes for long-term stability becomes challenging in toy breed dogs (e.g.

Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.

The pancreas is an organ prone to inflammation, fibrosis, and atrophy because of an abundance of acinar cells that produce digestive enzymes. A characteristic of pancreatic cancer is the presence of desmoplasia, inflammatory cell infiltration, and cancer-associated acinar atrophy (CAA) within the invasive front. CAA is characterized by a high frequency of small ducts and resembles acinar-to-ductal metaplasia (ADM). However, the clinical significance of changes in acinar morphology, such as ADM with acinar atrophy, within the tumor microenvironment remains unclear. Here, we find that ADM within the invasive front of tumors is associated with cell invasion and desmoplasia in an orthotopic mouse model of pancreatic cancer. An analysis of resected human tumors revealed that regions of cancer-associated ADM were positive for TGFα, and that this TGFα expression was associated with primary tumor size and shorter survival times. Gene expression analysis identified distinct phenotypic profiles for cancer-associated ADM, sporadic ADM and chronic pancreatitis ADM. These findings suggest that the mechanisms driving ADM differ according to the specific tissue microenvironment and that cancer-associated ADM and acinar atrophy contribute to tumor cell invasion of the local pancreatic parenchyma.