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The expression of programmed death 1 (PD-1) and programmed death-ligand 1 (PD-L1) indicate the efficacy of anti-PD-1/PD-L1 therapy in colorectal cancer (CRC), but are less useful for monitoring the efficacy of therapy of CRC liver metastasis (CRLM). This study investigated the effects of immune molecules on the prognosis of CRLM. We enrolled 71 patients with CRLM who underwent curative resection for CRC. We used immunohistochemistry to analyze the expression of PD-1, PD-L1, indoleamine-pyrrole 2,3-dioxygenase (IDO), and CD163 (a marker of tumor-associated macrophages [TAMs]) in metastatic tumors. The immune molecules PD-1, PD-L1, IDO, and TAMs were expressed in 32.3%, 47.8%, 45.0%, and 47.9% of metastatic CRC samples, respectively. The 5-year overall survival rates associated with immune molecule-positive groups were significantly better than in the negative groups (PD-1: 87.7% vs 53.2%, p = 0.023; PD-L1: 82.4% vs 42.3%, p = 0.007; IDO: 80.7% vs 43.5%, p = 0.007; TAMs: 82.6% vs 48.0%, p = 0.005). Multivariate analysis revealed PD-1 expression (p = 0.032, hazard ratio: 0.19), IDO expression (p = 0.049, hazard ratio: 0.37), and tumor differentiation (p<0.001, hazard ratio: 0.02) as independent prognostic indicators. PD-1 and TAMs in metastases were associated with less aggressive features such as smaller tumors. Furthermore, TAMs positively and significantly correlated with PD-1 expression (p = 0.011), PD-L1 expression (p = 0.024), and tended to correlate with IDO expression (p = 0.078). PD-1, PD-L1, IDO, and TAMs in CRLM were associated with less aggressive features and better prognosis of patients with CRC, indicating adaptive antitumor immunity vs immune tolerance. These molecules may therefore serve as prognostic markers for CRLM. [ABSTRACT FROM AUTHOR]

Purpose: Venous thromboembolism (VTE) is a major complication after abdominal surgery; however, the best strategy for preventing VTE after surgery is not yet established. We performed this study to investigate the incidence of perioperative VTE and evaluate the efficacy of a VTE preventive strategy for patients undergoing surgery for colorectal cancer (CRC). Methods: The subjects of this retrospective analysis were 228 patients who underwent curative surgical resection for CRC between 2012 and 2016. The patients were treated with thromboprophylaxis including enoxaparin. We assessed the perioperative VTE occurrence rate and investigated the risk factors for postoperative VTE. Results: Among the 228 patients, 77 had a preoperative D-dimer level of > 1.0 μg/mL and 12 had deep vein thrombosis (DVT) diagnosed by ultrasonography preoperatively. Of the remaining 216 patients, short-term VTE (< 30 days) developed in two patients (0.9%) and long-term VTE (30 days–3 years) developed in seven (3.2%). The mortality rate of patients with VTE was 0%. The univariate analysis indicated that pulmonary disease was the risk factor for short-term VTE, whereas obesity, hyperlipidemia, and a preoperative history of pulmonary embolism were the risk factors for long-term VTE (p < 0.05). Conclusion: The findings of this analysis show that our preventive protocol including enoxaparin is an effective strategy for preventing postoperative VTE. [ABSTRACT FROM AUTHOR]

Background: No universal classification method for intrahepatic cholangiocarcinoma (IHCC) has been reported based on the embryological origin of biliary epithelial cells. The aim of this study was to classify IHCC according to protein expression levels of somatostatin receptor 2 (SSTR2) and b-cell leukemia/lymphoma 2 (Bcl2) and to elucidate the clinicopathological features of each group. Methods: Fifty-two IHCC patients who underwent hepatic resection were enrolled in this study. Protein expression levels of SSTR2 and Bcl2 were examined using immunohistochemistry. Clinicopathological factors were compared between the three groups and prognostic factors were investigated. Results: The patients were divided into three groups: SSTR2 positive and Bcl2 negative (p-Group H, n = 21), SSTR2 negative and Bcl2 positive (p-Group P, n = 14), and the indeterminate group (p-Group U, n = 17) for cases where SSTR2 and Bcl2 were both positive or both negative. All p-Group P cases displayed curability A or B. The 5-year survival rates of p-Group H and U patients were worse than those in p-Group P. p-Group H had higher T-factor, clinical stage, and incidence of periductal infiltration than p-Group P. Conclusions: This method could be used to classify IHCC into peripheral and perihilar type by embryological expression patterns of SSTR2 and Bcl2. [ABSTRACT FROM AUTHOR]

Cerebrotendinous xanthomatosis (CTX), a treatable autosomal recessive lipid‐storage disease, is caused by mutations in the CYP27A1 gene. Clinical manifestations include progressive neurologic dysfunction, tendon xanthoma, cataracts, and diarrhea. Patients with CTX generally have several non‐neurologic signs and symptoms, and thus, patients with only neurologic findings have been rarely reported. We here report a patient who solely had neurologic findings with compound heterozygous mutations in the CYP27A1 gene. [ABSTRACT FROM AUTHOR]

Background and purpose: Takotsubo cardiomyopathy (TCM) is a serious autonomic complication of Guillain–Barré syndrome (GBS). However, the association between TCM and GBS has not been investigated in detail. We investigated the characteristics of GBS patients with TCM (GBS-TCM). Methods: Clinical features and anti-ganglioside antibody between the GBS-TCM patients and 62 classical GBS patients without TCM as control patients were compared. Results: Eight GBS-TCM patients were identified, in whom TCM was diagnosed at a mean of 6.5 [range 3–42] days after the onset of GBS. The age at onset of GBS was elder in the GBS-TCM patients than in the control GBS patients (76.5 [56–87] vs. 52 [20–88] years, p < 0.01). Notably, cranial nerve deficits, particularly in the lower cranial nerves, were observed in all GBS-TCM patients (100% vs. 41.9%, p < 0.01). Additionally, the GBS-TCM patients showed a higher GBS disability score at nadir (5 [4–5] vs. 4 [1–5], p < 0.01), and lower Medical Research Council sum scores at admission and nadir (37 [30–44] vs. 48 [12–60] at admission, p < 0.05, and 20 [12–44] vs. 40 [0–60] at nadir, p < 0.05, respectively). Mechanical ventilation was more frequently required in the GBS-TCM patients (62.5% vs. 11.3%, p < 0.01). Three GBS-TCM patients were positive for anti-ganglioside antibodies. Conclusions: TCM occurred at a relatively early phase of GBS. The characteristics of GBS-TCM were the elder, lower cranial nerve involvements, severe limb weakness, and respiratory failure. [ABSTRACT FROM AUTHOR]

Insulin-producing cells (IPCs) generated by our established protocol have reached the non-clinical 'proof of concept' stage. Our strategy for their clinical application is the autotransplantation of IPCs into patients with type 1 diabetes mellitus (T1DM). In this context, the autoimmunity that characterized T1DM is important, rather than allorejection. We aimed to determine how these IPCs respond to T1DM autoimmunity. IPCs were generated from the subcutaneous fat tissue of non-obese diabetic (NOD) mice using our protocol. IPCs derived from NOD mice were transplanted under the kidney capsules of NOD mice at the onset of diabetes and the subsequent changes in blood glucose concentration were characterized. Blood glucose decreased within 30 days of transplantation, but increased again after 40–60 days in three of four recipient NOD mice. In tissue samples, the numbers of CD4+ and CD8+ T cells were significantly higher 60 days after transplantation than 30 days after transplantation. In conclusion, IPCs significantly ameliorate the diabetes of mice in the short term, but are damaged by autoimmunity in the longer term, as evidenced by local T cells accumulation. This study provides new insights into potential stem cell therapies for T1DM. [ABSTRACT FROM AUTHOR]

The post-synthetic modification of an oligonucleotide is a powerful strategy for the synthesis of various analogs of the oligonucleotide, aiming to achieve the desired functions. In this study, we synthesized the thymidine phosphoramidite of 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA, which was introduced into oligonucleotides. Oligonucleotides containing a 2′-N-pentafluorophenoxycarbonyl-2′-amino-LNA unit could be isolated under ultra-mild deprotection conditions (50 mM K2CO3 in MeOH at room temperature for 4 h). Moreover, by treatment with various amines as a post-synthetic modification, the oligonucleotides were successfully converted into the corresponding 2′-N-alkylaminocarbonyl-2′-amino-LNA (2′-urea-LNA) derivatives. The duplex- and triplex-forming abilities of the synthesized oligonucleotides were evaluated by UV-melting experiments, which showed that 2′-urea-LNAs could stabilize the nucleic acid complexes, similar to the proto-type, 2′-amino-LNA. Thus, 2′-urea-LNAs could be promising units for the modification of oligonucleotides; the design of a substituent on urea may aid the formation of useful oligonucleotides. In addition, pentafluorophenoxycarbonyl, an amino moiety, acted as a precursor of the substituted urea, which may be applicable to the synthesis of oligonucleotide conjugates. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) has recently been attributed to biallelic repeat expansions in RFC1. More recently, the disease entity has expanded to atypical phenotypes, including chronic neuropathy without cerebellar ataxia or vestibular areflexia. Very recently, RFC1 expansions were found in patients with Sjögren syndrome who had neuropathy that did not respond to immunotherapy. In this study RFC1 was examined in 240 patients with acute or chronic neuropathies, including 105 with Guillain-Barré syndrome or Miller Fisher syndrome, 76 with chronic inflammatory demyelinating polyneuropathy, and 59 with other types of chronic neuropathy. Biallelic RFC1 mutations were found in three patients with immune-mediated neuropathies, including Guillain-Barré syndrome, idiopathic sensory ataxic neuropathy, or anti-myelin-associated glycoprotein (MAG) neuropathy, who responded to immunotherapies. In addition, a patient with chronic sensory autonomic neuropathy had biallelic mutations, and subclinical changes in Schwann cells on nerve biopsy. In summary, we found CANVAS-related RFC1 mutations in patients with treatable immune-mediated neuropathy or demyelinating neuropathy. [ABSTRACT FROM AUTHOR]

Background: The role of the immune system in locally advanced rectal cancer (LARC) following preoperative chemoradiotherapy (CRT) has been widely investigated in recent years. This study examined the prognostic significance of indoleamine-pyrrole 2,3-dioxygenase (IDO) expression in patients with LARC who received preoperative CRT.Methods: Ninety patients with LARC who underwent preoperative CRT and curative resection were enrolled. IDO and programmed death-ligand 1 (PD-L1) expression was evaluated by immunohistochemistry.Results: Clinicopathological factors did not significantly differ between patients with positive or negative IDO expression, excluding the correlation of positive IDO expression with better tumor differentiation (p = 0.02). IDO expression was not associated with pathological response (p = 0.44), but it was associated with PD-L1 expression. The 5-year overall survival (OS) rate was significantly worse in the IDO-positive group than in the IDO-negative group (64.8% vs. 85.4%, p = 0.02). Univariate analysis identified IDO and PD-L1 expression (p = 0.02), surgical procedure (p = 0.01), final pathological stage (p = 0.003), lymph node metastasis (p < 0.001), and lymphatic invasion (p = 0.002) as significant prognostic factors for OS. Multivariate analysis revealed that IDO expression (HR: 7.10, p = 0.0006), surgical procedure (HR: 5.03, p = 0.01), lymph node metastasis (HR: 2.37, p = 0.04) and lymphatic invasion (HR: 4.97, p = 0.01) were independent prognostic indicators. Disease-free survival was not correlated with IDO or PD-L1 expression.Conclusions: IDO expression in patients with LARC who received preoperative CRT could be a potential prognostic indicator. IDO expression could be a useful marker for specifying individual treatment strategies in LARC. [ABSTRACT FROM AUTHOR]

Purpose: Urethral injury is one of the most important complications in transanal total mesorectal excision (TaTME) in male patients with rectal cancer. The purpose of this study was to investigate holographic image-guided surgery in TaTME. Methods: Polygon (stereolithography) files were created and exported from SYNAPSE VINCENT, and then uploaded into the Holoeyes MD system (Holoeyes Inc., Tokyo, Japan). After uploading the data, the three-dimensional image was automatically converted into a case-specific hologram. The hologram was then installed into the head mount display, HoloLens (Microsoft Corporation, Redmond, WA). The surgeons and assistants wore the HoloLens when they performed TaTME. Results: In a Wi-Fi-enabled operating room, each surgeon, wearing a HoloLens, shared the same hologram and succeeded in adjusting the hologram by making simple hand gestures from their respective angles. The hologram contributed to better comprehension of the positional relationships between the urethra and the surrounding pelvic organs during surgery. All surgeons were able to properly determine the dissection line. Conclusions: This first experience suggests that intraoperative holograms contributed to reducing the risk of urethral injury and understanding transanal anatomy. Intraoperative holograms have the potential to become a new next-generation surgical support tool for use in spatial awareness and the sharing of information between surgeons. [ABSTRACT FROM AUTHOR]

Purpose: The concept of 'diversity and inclusion' is being adopted worldwide, but it is not yet understood well in Japan. We conducted this study to evaluate the impact of a lecture aimed at increasing awareness of academic careers and the benefits of having diversity and inclusion. Methods: Two female surgeons delivered a 120-min lecture on "diversity and inclusion" to third-year medical students at Tokushima University. To assess the impact of the lecture, a questionnaire was distributed, for participants to complete anonymously before and after the lecture. Results: Eighty-two students participated in the study (39 men, 38 women, and 5 unknown). Based on the questionnaire responses, 57.1% of the students had already perceived inequality in conduct because of gender. A comparison of pre- and post-lecture responses revealed a significant increase in confidence to succeed in their medical career (56.5% vs. 77.5%, p < 0.01). Learners were more likely to believe that gender would not become a barrier to career development (42.4% vs. 66.7%, p < 0.01). Moreover, 90.4% of the students felt positively about a career in surgery following the lecture. Conclusion: The lecture promoted awareness about diversity, self-awareness, and career development and motivated students to consider specializing in surgery later in their career. [ABSTRACT FROM AUTHOR]

Background: Tumor-infiltrating lymphocytes (TILs) are a prognostic factor or an indicator of chemotherapy response for various malignancies. The aim of this study was to investigate the prognostic impact of TILs in resected intrahepatic cholangiocarcinoma (IHCC). We also investigated the usefulness of the apparent diffusion coefficient (ADC) in diffusion-weighted magnetic resonance imaging (DW-MRI) to predict TILs. Methods: We enrolled 23 patients with IHCC who underwent initial hepatic resection in Tokushima University Hospital from 2006 to 2017. We evaluated stromal TILs in the tumor marginal area and central area in surgical specimens. Patients were divided into low vs high stromal TILs groups. We analyzed the patients' clinicopathological factors, including prognosis, according to the degree of stromal TILs. We also analyzed the correlation between stromal TILs and the minimum ADC value. Results: Stromal TILs in the marginal area reflected overall survival more accurately than that in the central area. Additionally, marginal low TILs was significantly associated with lymph node metastasis and portal vein invasion. Both overall- and disease-free survival rates in the marginal low TILs group were significantly worse than those in the marginal high TILs group (P < 0.05). In the multivariate analysis, marginal low TILs were an independent prognostic factor for both overall- and disease-free survival (P < 0.05), and marginal low TILs were significantly associated with lower minimum ADC values (P < 0.02). Conclusions: Stromal TILs, especially in the marginal area, might demonstrate prognostic impact in patients with IHCC. Moreover, the ADC values from MRI may predict TILs in IHCC tumor tissue. [ABSTRACT FROM AUTHOR]

Purpose: To clarify whether the preoperative lymphocyte/C-reactive protein (CRP) ratio (LCR) is a prognostic factor for patients with intrahepatic cholangiocarcinoma (IHCC), and investigate its mechanism via tumor-infiltrating lymphocytes. Methods: The subjects of this retrospective study were 42 patients who had undergone hepatectomy for IHCC. We divided the patients into low LCR and high LCR groups (cutoff value: 8780) and analyzed their overall survival (OS) and disease-free survival (DFS) with respect to LCR and other clinicopathological factors. We also investigated the levels of stromal tumor-infiltrating lymphocytes (TILs) and CD8+ TILs in surgical specimens, and the relationship between LCR and TILs. Results: A low LCR was identified in 21 patients and was significantly correlated with older age, a high CRP-albumin ratio, and advanced disease stage, and was a prognostic factor for OS and DFS. Multivariate analysis revealed that a low LCR was an independent prognostic factor for worse OS (HR 10.40, P = 0.0077). Although the LCR and levels of stromal TILs were not significantly related, LCR and levels of CD8+ TILs were significantly related (P = 0.0297). Conclusion: The preoperative LCR may predict the postsurgical prognosis of patients with IHCC and reflect the CD8+ TILs. [ABSTRACT FROM AUTHOR]

Background: Intrahepatic cholangiocarcinoma (IHCC) has a poor prognosis, and surgery remains the only effective treatment. However, tumor recurrence after primary hepatectomy is common. We examined the significance of repeat surgery for IHCC. Methods: We collected data for all patients with IHCC between 1992 and 2018 (n = 67) in our database. Fifty-three (79.1%) of all 67 patients experienced recurrence after primary hepatectomy and we analyzed data for those 53 recurrent patients. We divided recurrent patients into a repeat surgery group (n = 9), chemotherapy group (n = 19), and best supportive care group (n = 25). We analyzed differences in patients' clinicopathological factors, including prognosis, between the three groups. Results: The IHCC recurrence rate after hepatectomy in our institution was 79.1%. Of the 53 patients with recurrence, nine underwent repeat surgery (17.0%). The characteristics of the patients undergoing repeat surgery was lower stage at primary hepatectomy. Recurrence sites in the repeat surgery group were liver (n = 6), lung (n = 2), and adrenal gland (n = 1), as a single nodule. The period between primary hepatectomy and recurrence was comparatively longer in the repeat surgery group, at 1.8 years. The prognosis in patients undergoing repeat surgery was significantly better compared with the other groups. Not undergoing repeat surgery (hazard ratio: 5.506; p = 0.0077) and positive lymph node metastasis (hazard ratio: 2.207; p = 0.0242) were independent poor prognostic factors. Conclusions: Repeat surgery should be considered in patients with IHCC with a single recurrence site and negative lymph node metastasis at primary surgery and at least more than 6 months of disease-free period after primary surgery. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that mast cells play critical roles in disruption and maintenance of intestinal homeostasis, although it remains unknown how they affect the local microenvironment. Interleukin-9 (IL-9) was found to play critical roles in intestinal mast cell accumulation induced in various pathological conditions, such as parasite infection and oral allergen-induced anaphylaxis. Newly recruited intestinal mast cells trigger inflammatory responses and damage epithelial integrity through release of a wide variety of mediators including mast cell proteases. We established a novel culture model (IL-9-modified mast cells, MCs/IL-9), in which murine IL-3-dependent bone-marrow-derived cultured mast cells (BMMCs) were further cultured in the presence of stem cell factor and IL-9. In MCs/IL-9, drastic upregulation of Mcpt1 and Mcpt2 was found. Although histamine storage and tryptase activity were significantly downregulated in the presence of SCF and IL-9, this was entirely reversed when mast cells were cocultured with a murine fibroblastic cell line, Swiss 3T3. MCs/IL-9 underwent degranulation upon IgE-mediated antigen stimulation, which was found to less sensitive to lower concentrations of IgE in comparison with BMMCs. This model might be useful for investigation of the spatiotemporal changes of newly recruited intestinal mast cells. [ABSTRACT FROM AUTHOR]

We examined the effect of different embryo developmental stages, culture periods, and media on the cryotolerance of in vitro –produced porcine blastocysts. All media used for in vitro production, vitrification, and warming were chemically defined. When in vitro –produced embryos at the blastocyst and expanded blastocyst stages were vitrified using the Cryotop method on Day 5 or 6 (Day 0 = the day of IVF), the survival rate and hatching rate of expanded blastocysts after warming were higher than those of blastocysts. The viability after vitrification and warming of Day-6 embryos cultured in porcine blastocyst medium from Day 5 were higher than that of embryos cultured in porcine zygote medium 5. On the other hand, there were no significant differences on the cryotolerance between Day-5 embryos cultured in porcine zygote medium 5 and those replaced with porcine blastocyst medium on Day 4. There were no significant differences in viability between the embryonic ages of 5 and 6 days after vitrification and warming. When expanded blastocysts vitrified on Day 5 or 6 were surgically transferred to recipient gilts, all three recipients became pregnant in the Day-5 group, whereas only one out of three recipients became pregnant in the Day-6 group. These results indicate that the cryotolerance of porcine in vitro –produced blastocysts after vitrification appears to depend on the embryonic stage, culture period, and medium. [ABSTRACT FROM AUTHOR]

In the present study, the effects of glucose and/or glycine on the in vitro development of Day 5 (Day 0 = IVF) porcine blastocysts were determined. The addition of 2.5–10 mM glucose to the chemically defined culture medium porcine zygote medium (PZM)-5 significantly increased blastocyst survival rates compared with those of blastocysts cultured in the absence of glucose. The addition of 5 and 10 mM glycine to PZM-5 containing 5 mM glucose significantly enhanced the development to hatching and the number of hatched blastocysts compared with no addition of glycine. However, the addition of glycine to PZM-5 with no glucose did not improve blastocyst development. The ATP content of Day 6 blastocysts cultured with glucose was significantly higher than that of blastocysts cultured in the absence of glucose, regardless of glycine supplementation. The diameter and total cell numbers were significantly greater, and the apoptotic index was significantly lower, in Day 6 blastocysts cultured with both glucose and glycine. These results indicate that glucose is an important energy source for the porcine blastocyst and that glucose and glycine act synergistically to enhance development to the hatching and hatched blastocyst stage in vitro. Blastocyst hatching is an important developmental process for successful implantation. The present study reveals that supplementation of a chemically defined protein-free medium with glucose and glycine synergistically improves the viability and hatching of in vitro-produced porcine blastocysts. The increase in quality of later-stage preimplantation embryos may enhance development to full term after embryo transfer. [ABSTRACT FROM AUTHOR]