Microfluidic vascular formation model for assessing angiogenic capacities of single islets.

Pancreatic islet transplantation presents a promising therapy for individuals suffering from type 1 diabetes. To maintain the function of transplanted islets in vivo, it is imperative to induce angiogenesis. However, the mechanisms underlying angiogenesis triggered by islets remain unclear. In this study, we introduced a microphysiological system to study the angiogenic capacity and dynamics of individual islets. The system, which features an open-top structure, uniquely facilitates the inoculation of islets and the longitudinal observation of vascular formation in in vivo like microenvironment with islet-endothelial cell communication. By leveraging our system, we discovered notable islet-islet heterogeneity in the angiogenic capacity. Transcriptomic analysis of the vascularized islets revealed that islets with high angiogenic capacity exhibited upregulation of genes related to insulin secretion and downregulation of genes related to angiogenesis and fibroblasts. In conclusion, our microfluidic approach is effective in characterizing the vascular formation of individual islets and holds great promise for elucidating the angiogenic mechanisms that enhance islet transplantation therapy.

Molecularly Imprinted Polymer-Based Sensors for the Detection of Skeletal- and Cardiac-Muscle-Related Analytes.

Molecularly imprinted polymers (MIPs) are synthetic polymers with specific binding sites that present high affinity and spatial and chemical complementarities to a targeted analyte. They mimic the molecular recognition seen naturally in the antibody/antigen complementarity. Because of their specificity, MIPs can be included in sensors as a recognition element coupled to a transducer part that converts the interaction of MIP/analyte into a quantifiable signal. Such sensors have important applications in the biomedical field in diagnosis and drug discovery, and are a necessary complement of tissue engineering for analyzing the functionalities of the engineered tissues. Therefore, in this review, we provide an overview of MIP sensors that have been used for the detection of skeletal- and cardiac-muscle-related analytes. We organized this review by targeted analytes in alphabetical order. Thus, after an introduction to the fabrication of MIPs, we highlight different types of MIP sensors with an emphasis on recent works and show their great diversity, their fabrication, their linear range for a given analyte, their limit of detection (LOD), specificity, and reproducibility. We conclude the review with future developments and perspectives.

[A Case of Multicentric HER2-Positive Breast Cancer with Alterations of the Intrinsic Subtype].

In cases where there are 2 or more tumors, it is crucial to conduct core needle biopsies on each of them. A 39-year-old woman presented at our hospital with pain in her left breast. Ultrasonography(US)revealed the presence of 2 contiguous tumors: a 35 mm tumor(tumor 1)and a 20 mm tumor(tumor 2)in the AC area of the left breast. US-guided core needle biopsies(CNB)were performed. The histological findings confirmed an invasive ductal carcinoma, characterized by ER(-)/ PR(-)/HER2(3+). Neoadjuvant chemotherapy indicated tumor 1 as PD and tumor 2 as PR, and surgery was subsequently performed(Bt plus SLN). Upon histopathological examination, the findings demonstrated a non-pCR invasive ductal carcinoma, featuring an ER(+)/PR(-)/HER2(-)profile. Depending on the specific subtype identified, post-operative treatment included HER2-targeted therapy or ER/PR-targeting hormone therapy in conjunction with chemotherapy.

[MSI-high ascending colon cancer treated with second-line ipilimumab plus nivolumab for conversion surgery:a case report].

A 68-year-old woman with ascending colon cancer was the patient (cT4bN2M1a [LYM] cStage IVA, BRAF V600E mutation-positive, and MSI-high). She was given modified FOLFOXIRI as first-line therapy but did not respond. The infiltration of the primary lesion in the abdominal wall was alleviated, allowing conversion surgery to be performed.

[A Case of Splenectomy for Isolated Splenic Metastasis after Surgery for Gastric Cancer].

Splenic metastasis of gastric cancer is rare. Cases of long-term survival after the resection of metachronous solitary splenic metastasis have been reported, and proactive resection should be performed. A 77-year-old man was presented to our hospital with anorexia. Further investigation showed type 2 gastric cancer in the greater curvature of the stomach in the lower body. Subsequently distal gastrectomy was performed on October 2018. The pathological stage was T3N2M0, Stage ⅢA, and the patient was treated with S-1 as adjuvant chemotherapy for 1 year. Two years after surgery, enhanced computed tomography(CT)showed a solitary splenic tumor with a diameter of 10 mm. Six months later, the tumor had grown to 25 mm, and PET-CT revealed no other tumors. Thus we diagnosed the patient as metachronous solitary splenic metastasis of gastric cancer, and splenectomy was performed on June 2021. Histopathological diagnosis was a metastasis of gastric cancer. The patient was treated with S-1 and remains recurrence-free for 1 year after the second operation.

3D Printing Techniques and Their Applications to Organ-on-a-Chip Platforms: A Systematic Review.

Three-dimensional (3D) in vitro models, such as organ-on-a-chip platforms, are an emerging and effective technology that allows the replication of the function of tissues and organs, bridging the gap amid the conventional models based on planar cell cultures or animals and the complex human system. Hence, they have been increasingly used for biomedical research, such as drug discovery and personalized healthcare. A promising strategy for their fabrication is 3D printing, a layer-by-layer fabrication process that allows the construction of complex 3D structures. In contrast, 3D bioprinting, an evolving biofabrication method, focuses on the accurate deposition of hydrogel bioinks loaded with cells to construct tissue-engineered structures. The purpose of the present work is to conduct a systematic review (SR) of the published literature, according to the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, providing a source of information on the evolution of organ-on-a-chip platforms obtained resorting to 3D printing and bioprinting techniques. In the literature search, PubMed, Scopus, and ScienceDirect databases were used, and two authors independently performed the search, study selection, and data extraction. The goal of this SR is to highlight the importance and advantages of using 3D printing techniques in obtaining organ-on-a-chip platforms, and also to identify potential gaps and future perspectives in this research field. Additionally, challenges in integrating sensors in organs-on-chip platforms are briefly investigated and discussed.

[A Case of Long-Term Survival of Anaplastic Transformation of Thyroid Cancer in Lymph Node Metastasis Due to Radiation Therapy and Lenvatinib].

An 82-year-old woman who underwent total thyroidectomy and left cervical lymph node dissection 21 years ago admitted our hospital because of left cervical pain. Neck CT scan showed a 6 cm tumor on the left clavicle. Pathological diagnosis by needle biopsy revealed poorly differentiated to undifferentiated carcinoma, positive for TTF-1, and diagnosed as thyroid cancer lymph node metastasis anaplastic transformation. Administration of lenvatinib was started after radiation therapy. Since thrombocytopenia was observed, lenvatinib was gradually reduced from 14 mg and the dose was continued at 4 mg. The tumor shrinked and the effect of chemotherapy was partial response. She survived for 3 years while continuing lenvatinib. We reported long-term survival due to radiation therapy and lenvatinib of anaplastic transformation of thyroid cancer in lymph node metastasis due to radiation therapy and lenvatinib.

[Pulse steroid therapy to treat liver injury with risk of liver failure due to immune-related adverse events:a case report].

A 75-year-old woman was diagnosed with clinical stage III lung cancer. The patient was treated with chemoradiotherapy and subsequent durvalumab, an anti-PD-L1 antibody immune checkpoint inhibitor (ICI). Liver dysfunction was observed 14 days after the start of durvalumab therapy (aspartate transaminase, 218U/l;alanine aminotransferase, 169U/l). This corresponded to a grade 3 adverse event according to the Common Terminology Criteria for Adverse Events. The second course of durvalumab was withheld. The patient was hospitalized 31 days after durvalumab therapy because of worsening liver dysfunction. Laboratory findings and imaging examinations suggested liver injury due to an immune-related adverse event (irAE). Liver biopsy performed 38 days after durvalumab therapy showed severe lymphocyte and plasma cell infiltration into the portal tract, focal necrosis in the hepatic lobules, and necrotic changes around the hepatic lobules. These findings were similar to those of autoimmune hepatitis (AIH). Immunohistochemical results revealed infiltration of CD3- and CD8-positive lymphocytes and mild infiltration of CD4-positive lymphocytes. Pathological findings in the liver tissue were consistent with an irAE. Jaundice worsened and the prothrombin time was prolonged, leading to a risk of progression to liver failure. Thus, pulse steroid therapy was performed with methylprednisolone (mPSL) starting at 0.8mg/kg. Liver dysfunction lessened and the mPSL dose was gradually reduced. Moreover, ICIs exert antitumor effects by inhibiting the immune checkpoint system but can cause irAEs in various organs. Liver injury is also relatively common. Liver tissue findings are similar to those in AIH, but immunostaining reveals the presence of numerous CD8-positive lymphocytes. Fewer CD4-positive lymphocytes exist in irAE-associated liver injury than in AIH. Medical departments must cooperate and effectively manage irAEs because ICIs are increasingly being used and can occur in organs throughout the body. In principle, irAEs are treated with steroids. Thus, high-dose steroids diminishing the therapeutic effect of ICIs is a concern, and it is important to control irAEs with low-dose steroids that are started earlier.

Viral and host factors are associated with retreatment failure in hepatitis C patients receiving all-oral direct antiviral therapy.

AIM: Direct-acting antiviral (DAA) therapy for hepatitis C virus is associated with high sustained virologic response rates. However, patients for whom DAA therapy fails acquire resistance-associated substitutions (RASs). We therefore evaluated the efficacy of DAA retreatment and factors associated with retreatment failure. METHODS: Non-structural 5A RASs were investigated at the start of DAA therapy and at treatment failure in 64 patients with hepatitis C virus genotype 1b for whom DAA combination therapy had failed. A total of 59 patients were introduced to DAA retreatment. The factors associated with retreatment failure were investigated. RESULTS: A total of 20 of 43 (46.5%) daclatasvir + asunaprevir-treated patients with virologic failure had no RASs at baseline, and three (15%) acquired P32 deletion RASs. Four of seven sofosbuvir/ledipasvir-treated patients with virologic failure had more than two RASs of NS5A at baseline. The sustained virologic response rates on retreatment were as follows: sofosbuvir/ledipasvir, 81.8%; with elbasvir + grazoprevir, 0%; and glecaprevir/pibrentasvir, 87.5%. Patients for whom sofosbuvir/ledipasvir or elbasvir + grazoprevir failed achieved sustained virologic response with glecaprevir/pibrentasvir. Two of three patients for whom glecaprevir/pibrentasvir retreatment failed had Q24/L28/R30 and A92K RASs; the other had P32 deletion RAS at baseline. Interestingly, 10 of 11 patients with retreatment failure had the interleukin (IL)-28B single-nucleotide polymorphism (SNP) minor allele. A multivariate analysis showed that the IL28B SNP minor allele (P = 0.005, odds ratio 28.291) was an independent risk factor for retreatment failure. CONCLUSIONS: In addition to viral factors (e.g. Q24, L28, R30, and A92 or P32 deletion RASs), host factors (e.g. IL28B SNP) are associated with DAA retreatment failure.

[A Case of Hepatectomy for Primary Hepatic Neuroendocrine Tumor, Preoperatively Diagnosed with Hepatocellular Carcinoma].

A 65-year-old man has pointed out a hepatic tumor when he was rushed to the hospital because of disturbance of consciousness associated with hypoglycemia. Abdominal dynamic CT images showed a tumor, 2.5 cm in diameter, in S2/3 close to the umbilical portion of the portal vein, and it had enhancement in the arterial phase and became washout in the portal phase. We performed left lateral segmentectomy with a diagnosis of hepatocellular carcinoma. The tumor was histopathologically diagnosed as a Grade 1 neuroendocrine tumor(NET). As additional examinations could not detect a primary lesion in any other site, the tumor was considered as a primary hepatic NET(PHNET). PHNETs are rare and because of the possibility that an unknown primary lesion exists, we have to observe for years carefully.

[A Case of Retroperitoneal Primary Well-Differentiated Liposarcoma Treated by Laparoscopic Surgery].

A 76-year-old woman visited the hospital due to occult blood in her urine. An abdominal CT scan showed a low-density tumor inside the left iliopsoas muscle in the retroperitoneum, and a well-differentiated liposarcoma was suspected. Therefore, laparoscopic tumor resection was performed. The tumor was on the inside of the left iliopsoas muscle, without any invasion around it. The macroscopic appearance of the resected tumor showed a yellow, fat-like, solid mass and it was histopathologically diagnosed as a well-differentiated liposarcoma. We conclude that a retroperitoneal primary well-differentiated liposarcoma can be treated by laparoscopic surgery, as in our case.

Compact fluidic system for functional assessment of pancreatic islets.

Transplantation of pancreatic islets is becoming a promising therapy for people with type I diabetes. In this study, we present a compact fluidic system that enables assessment of islet functionality ex vivo for efficient islet transplantation. The fluidic system includes a micromesh sheet-embedded chip. Islets can be loaded easily on the micromesh sheet and observed clearly by microscopy. Islets on the mesh sheet mainly remained in place during perfusion and did not get damaged by hydraulic pressure because of high porosity of the micromesh sheet. The fluidic system was assembled with a sample fraction chip of polydimethylsiloxane. The chip includes a channel and columns, both having surfaces that were super-hydrophilized so that solutions could flow smoothly within the chip by gravity. Using mouse pancreatic islets, a dynamic glucose-stimulated insulin secretion test was performed to examine the performance of the fluidic system. The system successfully analyzed levels and patterns of insulin secretion upon exposure of the islets to low- and high-glucose solutions in turns, thus demonstrating its capacity to assess islet functions more easily and cost-effectively.

[A Case of Curative Resection of Locally Advanced Gastric Cancer after Nutrition Therapy and Chemotherapy with S-1 and Oxaliplatin Using Elemental Diet Tube].

We report a case of advanced gastric cancer with stenosis under severe malnutrition, in which nutritional treatment along with chemotherapy using an elemental diet(ED)tube led to complete resection of the tumor. A 66-year-old man who presented with difficulty in dietary intake came to our hospital. He was emaciated with a body mass index(BMI)score of 13.5 and a prognostic nutritional index(PNI)score of 33.8 and was admitted to the hospital for an emergency. He was diagnosed with advanced gastric cardia cancer invading the distal pancreas, spleen, and left diaphragm(U, type 3, tub2, cT4bN3M0, cStage ⅢC, HER2 score 0). There was obstruction of the passage of food due to the tumor, we performed nutrition therapy and chemotherapy consisting of 3 courses of S-1 and oxaliplatin using an ED tube. After chemotherapy, the primary tumor and lymph nodes were reduced, and we performed total gastrectomy with D2 lymph node, distal pancreas, spleen, and left partial diaphragm dissection. Histopathological diagnosis was ypT4aN1M0, ypStage ⅢA, indicating a pathological partial response(Grade 1). Adjuvant chemotherapy was performed for 6 months, and there has been no relapse for 3 years since the operation.

[A Case Report of Lung Resection for Lung Metastasis from Pancreatic Cancer].

A 66-year-old man had an elevated CEA level. Further examinations showed a pancreatic head tumor. A pancreaticoduodenectomy was then performed. The histopathological examination showed a mixed tumor of papillary adenocarcinoma and neuroendocrine cancer. In addition, a tumor in the upper lobe of the right lung was found 18 months after the initial pancreatic resection, and the bronchoscope indicated lung metastasis. The patient underwent partial pneumonectomy. After the pneumonectomy, he received S-1 chemotherapy. Thirty -nine months after the pneumonectomy, CEA was slightly elevated. We changed the chemotherapy to gemcitabine and nab-paclitaxel without further examinations to confirm the recurrence. The patient discontinued chemotherapy after CEA fell within the normal range. He has been alive without tumor relapse for 64 months since the second operation for the lung metastasis. We report a successful case of lung resection for lung metasta- sis from pancreatic cancer.

Clinical and imaging characteristics in patients undergoing surgery for lumbar epidural lipomatosis.

BACKGROUND: Lumbar epidural lipomatosis (LEL) is characterized by abnormal accumulation of unencapsulated adipose tissue in the spinal epidural space. Such accumulation compresses the dural sac and nerve roots, and results in various neurological findings. However, the pathophysiology of LEL remains unclear. This study examined the associations between imaging and clinical findings in detail, and investigated the mechanisms underlying symptom onset by measuring intraoperative epidural pressures in LEL. METHODS: Sixteen patients (all men; mean age, 68.8 years) were enrolled between 2011 and 2015. Mean body mass index was 26.5 kg/m2. Four cases were steroid-induced, and the remaining 12 cases were idiopathic. All patients presented with neurological deficits in the lower extremities. Cauda equina syndrome (CES) alone was seen in 8 patients, radiculopathy alone in 4, and both radiculopathy and CES (mixed CES) in 4. All patients subsequently underwent laminectomy with epidural lipomatosis resection and were followed-up for more than 1 year. We investigated the clinical course and imaging and measured epidural pressures during surgery. RESULTS: Subjective symptoms improved within 1 week after surgery. Mean Japanese Orthopaedic Association (JOA) score was 15.2 ± 2.8 before surgery, improving to 25.4 ± 2.5 at 1 year after surgery. On magnetic resonance imaging, all lipomatosis lesions included the L4-5 level. On preoperative computed tomography, saucerization of the laminae was not observed in radiculopathy cases, whereas saucerization of the posterior vertebral body was observed in all radiculopathy or mixed CES cases. Intraoperative epidural pressures were significantly higher than preoperative subarachnoid pressures. The results suggest that high epidural pressure resulting from the proliferation of adipose tissue leads to saucerization of the lumbar spine and subsequent symptoms. CONCLUSIONS: Clinical courses were satisfactory after laminectomy. In LEL, epidural pressure increases and symptoms develop through the abnormal proliferation of adipose tissue. Higher epidural pressures induce saucerization of the laminae and/or posterior vertebral body. Furthermore, the direction of proliferative adipose tissue (i.e., site of saucerization) might be related to the types of neurological symptoms.

[A Case of Treated with Laparoscopic Surgery for Intussusception Up to the Splenic Flexion Region Due to Cecum Cancer].

A 93-year-old woman was admitted to the hospital because of respiratorydiscomfort. A chest CT scan indicated aspiration pneumonitis and, simultaneously, intussusception was observed in the splenic flexure region. Abdominal enhance CT scan revealed a tumor in the advanced region of intussusception. Laparoscopy-assisted ileocecal resection was performed. Since the intussusception was difficult to reduce laparoscopically, the ileocecum was mobilized and the intussusception was reduced manually. In the resected specimen, a type 1 tumor was observed in the cecum and histopathologic ally diagnosed as cercal cancer. We report a case with intussusception due to colorectal cancer treated bylaparoscopic surgery.

[A Case of Rectal Gastrointestinal Stromal Tumor(GIST)with Long-Term Survival Treated with Multidisciplinary Therapy].

We report a case of gastrointestinal stromal tumor(GIST)with long-term survival treated by multidisciplinary therapy, including surgery and imatinib to prevent repeated recurrence. A 76-year-old woman visited our hospital with difficulty in defecation and bloody bowel discharge. She was diagnosed with rectal GIST and underwent transanal partial resection of the rectum. Local recurrence occurred 1 year after the operation, and the tumor was resected transanally. Hepatic metastasis occurred 8 months after the second operation. The patient was administered imatinib for 2 months, which caused the tumor to shrink, and extended left lobectomy was performed. Imatinib was administered for 2 years after hepatectomy. After another 2 years, metastasis to the liver and thoracic and lumbar vertebrae occurred. The recurrent tumors reverted to cystic lesions after 6 months of imatinib treatment. She has been alive without tumor progression during re-treatment with imatinib for 7 years(13 years after the first surgery).

[A Case of Paget-Type Recurrence 20 Years after Breast Conserving Surgery for Invasive Ductal Carcinoma].

We report an 85-year-old female suffered Paget-type recurrence at right remnant breast. The patient had undergone breast conserving surgery(BCS)20 years ago in another hospital for invasive ductal carcinoma of the right breast(pT1N0M0, Stage I ). Her chief complain was a skin ulcer of the right nipple. The pathological diagnosis for biopsy specimen from the areola was Paget's disease. She underwent total mastectomy. Paget cells were detected pathologically in the epidermis of the nipple and nearby mammary duct connected with fibrous tissue after BCS, suggesting Paget-type recurrence of invasive breast carcinoma.

p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38.

Nuclear receptor constitutive androstane receptor (CAR, NR1I3), which regulates hepatic drug and energy metabolisms as well as cell growth and death, is sequestered in the cytoplasm as its inactive form phosphorylated at threonine 38. CAR activators elicit dephosphorylation, and nonphosphorylated CAR translocates into the nucleus to activate its target genes. CAR was previously found to require p38 mitogen-activated protein kinase (MAPK) to transactivate the cytochrome P450 2B (CYP2B) genes. Here we have demonstrated that p38 MAPK forms a complex with CAR, enables it to bind to the response sequence, phenobarbital-responsive enhancer module (PBREM), within the CYP2B promoter, and thus recruits RNA polymerase II to activate transcription. Subsequently, p38 MAPK elicited rephosphorylation of threonine 38 to inactivate CAR and exclude it from the nucleus. Thus, nuclear p38 MAPK exerted dual regulation by sequentially activating and inactivating CAR-mediated transcription through phosphorylation of threonine 38.

Characteristics of ossification of the spinal ligament; incidence of ossification of the ligamentum flavum in patients with cervical ossification of the posterior longitudinal ligament - Analysis of the whole spine using multidetector CT.

BACKGROUND: Ossification of the posterior longitudinal ligament (OPLL) and ossification of the ligamentum flavum (OLF) are characterized by replacement of ligamentous tissue by ectopic new bone formation. Although the background of both diseases might be similar, there are some differences between two diseases. Some patients have both OPLL and OLF. However, the incidence of both OPLL and OLF is still unclear and the precise lesions have not been investigated, yet. This study was conducted to evaluate OLF of the whole spine in patients with cervical OPLL and to analyze the relationship of the ossified lesions between OLF and OPLL. METHODS: One hundred seventy eight patients who were diagnosed as cervical OPLL by plain radiographs were included. CT images of the whole spine were taken. Ossified lesions were checked at each level of vertebral body and intervertebral disc. The ossification index of OPLL (OPLL OS index) was determined by the sum of the levels of vertebral bodies and intervertebral discs where OPLL existed. The same index was applied for detecting the level of OLF (OLF OS index). Age, gender and OPLL characteristics were compared between the OLF(+) group, OLF was seen at any levels of the spinal canal, and the OLF(-) group, OLF was not seen. RESULTS: The most frequent level of OPLL was at C5 vertebral level and OLF was predominant at upper and lower thoracic levels. Seventeen patients (9.6%) had OPLL and OLF at the same spinal level. The averaged OPLL OS index of the total spine in these patients was 8.7 ± 6.1, ranged from 1 to 36. The averaged OLF OS index of the total spine was 3.1 ± 2.2 (ranged from 1 to 13) in the patients who had OLF at any levels of the whole spine. One hundred fifteen patients (64.6%) with cervical OPLL had OLF at any levels of the whole spine. No relationship was found between the OPLL OS index and the OLF OS index. There was no significant difference among the data between the OLF(+) group and the OLF(-) group. CONCLUSIONS: This study demonstrated 64.6% of the patients with cervical OPLL had OLF, mainly in the thoracic spine. However, there was no relationship regarding the severity of the ossified lesions between OPLL and OLF. CT analysis of the whole spine should be carried out for the early detection of OPLL and OLF in patients with cervical OPLL.