Diabetes can increase the prevalence of EBV infection and worsen the prognosis of nasopharyngeal carcinoma.

Epstein‒Barr virus (EBV) infection is a primary oncogenic factor of nasopharyngeal carcinoma (NPC) that elicits epithelial-mesenchymal transition (EMT). Although diabetic patients are more susceptible to various infectious diseases, the pathological association with virus-related NPC has not yet been clarified. Herein, we evaluated the influence of diabetes on the clinicopathological changes of 70 patients with NPC. Disease-specific survival (DSS) modified by viral infection was also analysed. The proportion of NPC patients with diabetes was 32.9% (23/70 cases), and 91.3% (21/23 cases) were infected with EBV detected by EBER-I in situ hybridisation. NPC with diabetes showed an effect on EMT evaluated by immunostaining for E-cadherin and vimentin, which was correlated with HbA1c levels. Receiver operating characteristic (ROC) curve analysis determined a HbA1c level of 6.5% as the cut-off value for primary disease death at 2 years [area under the curve (AUC) 0.76; sensitivity 0.64; and specificity 0.81]. High HbA1c levels (≥6.5%) significantly increased the number of lymph node metastases in NPC compared to low HbA1c levels (<6.5%, p<0.01). Diabetic NPC patients had a significantly poorer prognosis than all non-diabetic patients (DSS, 72 months vs not reached, p<0.05). Diabetic EBV-positive NPC patients had a significantly poorer prognosis than non-diabetic EBV-positive patients (DSS, 35 months vs not reached, p<0.01). Multivariate analysis using the Cox proportional hazards model also suggested that HbA1c ≥6.5% was a significant factor in poor prognosis, with a hazard ratio of 6.84 (p<0.05). Collectively, our results revealed for the first time a high prevalence of EBV infection, poor prognosis and the importance of proper glycaemic control in diabetic NPC patients.

Dual epigenetic changes in diabetes mellitus-associated pancreatic ductal adenocarcinoma correlate with downregulation of E-cadherin and worsened prognosis.

Diabetes mellitus (DM) is a risk factor for pancreatic ductal adenocarcinoma (PDAC) that promotes the promoter methylation of CDH1. It is still unclear whether DM can exert other epigenetic effects, such as altering microRNA (miR) expression, in PDAC. The expression of miR-100-5p is known to be changed in DM patients and can suppress the expression of E-cadherin. In this study, the correlation between DM status and dual epigenetic changes was evaluated in PDAC specimens from patients who underwent radical surgical resection. A total of 132 consecutive patients with PDAC were clinicopathologically evaluated. E-cadherin and nuclear ß-catenin expression was measured using immunohistochemistry. DNA and miRs were extracted from the main tumor site on formalin-fixed paraffin-embedded tissue sections. TaqMan miR assays were applied to assess miR-100-5p expression. Bisulfite modification was conducted on the extracted DNA, which was then subjected to methylation-specific polymerase chain reaction. Immunohistochemistry revealed that decreased E-cadherin expression and increased nuclear ß-catenin expression were significantly associated with DM and poor tumor cell differentiation. The presence of long-duration DM (≥3 years) was a significant factor contributing to CDH1 promoter methylation (p < 0.01), while miR-100-5p expression was proportionally correlated with the preoperative HbA1c level (R = 0.34, p < 0.01), but not the duration of DM. The subjects with high miR-100-5p expression and CDH1 promoter methylation showed the highest level of vessel invasion and prevalence of tumor size ≥30 mm. PDAC subjects with dual epigenetic changes showed poorer overall survival (OS) than those with a single epigenetic change. miR-100-5p expression ≥4.13 and CDH1 promoter methylation independently predicted poor OS and disease-free survival (DFS) in the multivariate analysis. OS and DFS worsened in DM subjects with both HbA1c ≥ 6.5% and DM duration ≥3 years. Thus, DM is associated with two modes of epigenetic change by independent mechanisms and worsens prognosis.

Diabetes mellitus impacts on expression of DNA mismatch repair protein PMS2 and tumor microenvironment in pancreatic ductal adenocarcinoma.

AIMS/INTRODUCTION: The mismatch repair (MMR) protein recognizes DNA replication errors and plays an important role in tumorigenesis, including pancreatic ductal adenocarcinoma (PDAC). Although PMS2, a MMR protein, is degraded under oxidative stress, the effects of diabetes are still unclear. Herein, we focused on whether diabetes affected MMR protein expression in PDAC. MATERIALS AND METHODS: Tissues from 61 surgically resected PDAC subjects were clinicopathologically analyzed. Immunohistochemical analysis was performed for MMR protein expression, oxidative stress, and immune cell infiltration. The change of MMR protein expression was assessed in PDAC cell lines under stimulation with 25 mM glucose and 500 µM palmitic acid. Survival curves were analyzed by the Kaplan-Meier method with the log-rank test. RESULTS: Diabetes complicated with dyslipidemia significantly decreased the expression of PMS2 in PDAC tissues with an inverse correlation with the degree of oxidative stress. Palmitic acid combined with high glucose induced degradation of PMS2 protein, enhancing oxidative stress in vitro. CD8+ T-cell infiltration was associated with a short duration of type 2 diabetes (≤4 years) and a low expression of PMS2 in PDAC tissues, while CD163+ tumor-associated macrophage infiltration was increased with a long duration of diabetes (>4 years). A short duration of diabetes exhibited a better prognosis than nondiabetic subjects with PDAC (P < 0.05), while a long duration of diabetes had a worse prognosis (P < 0.05). CONCLUSIONS: The different phases of diabetes have a major impact on PDAC by altering PMS2 expression and the tumor immune microenvironment, which can be targeted by an immune checkpoint inhibitor.

RAGE activation in macrophages and development of experimental diabetic polyneuropathy.

It is suggested that activation of receptor for advanced glycation end products (RAGE) induces proinflammatory response in diabetic nerve tissues. Macrophage infiltration is invoked in the pathogenesis of diabetic polyneuropathy (DPN), while the association between macrophage and RAGE activation and the downstream effects of macrophages remain to be fully clarified in DPN. This study explored the role of RAGE in the pathogenesis of DPN through the modified macrophages. Infiltrating proinflammatory macrophages impaired insulin sensitivity, atrophied the neurons in dorsal root ganglion, and slowed retrograde axonal transport (RAT) in the sciatic nerve of type 1 diabetic mice. RAGE-null mice showed an increase in the population of antiinflammatory macrophages, accompanied by intact insulin sensitivity, normalized ganglion cells, and RAT. BM transplantation from RAGE-null mice to diabetic mice protected the peripheral nerve deficits, suggesting that RAGE is a major determinant for the polarity of macrophages in DPN. In vitro coculture analyses revealed proinflammatory macrophage-elicited insulin resistance in the primary neuronal cells isolated from dorsal root ganglia. Applying time-lapse recording disclosed a direct impact of proinflammatory macrophage and insulin resistance on the RAT deficits in primary neuronal cultures. These results provide a potentially novel insight into the development of RAGE-related DPN.

Perivascular infiltration reflects subclinical lymph node metastasis in invasive lobular carcinoma.

Invasive lobular carcinoma (ILC) is characterized by discohesive cells due to irreversible loss of E-cadherin expression and multiple satellites, where individual cell migration is evident without disturbance of the stroma. Neoplastic cells sometimes infiltrate the surrounding vessel in satellites. Here, we aimed to clarify the specific role of perivascular infiltration (PVI) and ameboid migration, characterized by nondisturbance of the background stromal structure, in ILCs. A total of 139 cases with ILC and 122 cases with invasive breast carcinoma of no special type (IBC-NST) were evaluated retrospectively. PVI was significantly more common in ILC than in IBC-NST (50% [70 of 139 cases] vs. 9% [11 of 122 cases], p < 0.001). ILC cases with PVI showed a larger pathological tumour size than clinical tumour size (p < 0.01), a higher frequency of pathological node status pN2-pN3 when limited to clinically node-negative cases (p < 0.01) and lower circularity of tumour morphology on imaging (p < 0.01) than ILC cases without PVI. In the pathological evaluation, the intensity and occupancy of tumour cells expressing phospho-myosin light chain 2, which is a hallmark of ameboid migration, were significantly higher in ILC cases with PVI than in those without PVI at the tumour margins (p < 0.05). ILC with PVI is associated with irregular, poorly defined tumour margins and lymph node metastasis without adenopathy, which is difficult to assess using imaging. PVI may be caused by ameboid migration, as shown by the positive expression of phospho-myosin light chain 2. The presence of PVI may be a predictor for clinically node-negative pN2-pN3 in ILC patients.

A case of intussusception caused by cecal duplication after COVID-19.

Coronavirus disease 2019 (COVID-19) was thought to have respiratory symptoms as the main manifestation, but it has become clear that extrapulmonary symptoms such as gastrointestinal disorders also occur. There are several reports of intussusception associated with COVID-19 in children, but these are rare in adults. In this report, we present a case of cystic intestinal duplication that enlarged during the course of COVID-19 treatment and resulted in intussusception. Right hemicolectomy was performed for intussusception due to the cystic lesion. To the best of our knowledge, this is the first resected case of intussusception due to alimentary tract duplication after COVID-19 infection.

A case of dermatofibrosarcoma protuberans with neurofibromatous change.

A 31-year-old man with posterior neck mass visited a hospital. The mass recurred four times on the same location during the past 6 years. Needle biopsy diagnosis was suspicious for benign stromal tumor. Tumor excision was performed 3 months after the biopsy. The tumor size was 8.3 × 4.5 cm and was located at subcutaneous tissue. Histologically, main tumor cells showed comma-shaped nuclei, which are same as neurofibroma. Immunohistochemically, tumor cells were positive for vimentin, CD34, but were negative for S-100. Fluorescence in situ hybridization analysis disclosed a split signal of PDGFB gene. Reverse transcriptase-polymerase chain reaction clarified COL1A1 exon 47/PDGFB exon 2 chimeric gene. Final diagnosis was dermatofibrosarcoma protuberans (DFSP) with neurofibromatous change. DFSP with neurofibromatous change is rare and could be misdiagnosed as benign tumor, especially in a biopsy specimen. Molecular diagnosis is a promising aid in a challenging case and in biopsy specimens.

Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma.

Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with ≦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF-ß and IL-6, but not from RAGE-deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease-free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.

A case of gastric cancer with delayed onset of tumor reduction effect by nivolumab therapy.

Immune checkpoint inhibitors may have different clinical effects compared with conventional anticancer drugs. An 85-year-old male received chemotherapy for recurrent gastric cancer. As liver metastasis progressed, nivolumab was introduced as a fourth line treatment. Progression of liver metastasis in size was observed in CT after 3 courses of nivolumab therapy. Nivolumab treatment was discontinued, because the general condition of the patient also worsened. However, his general condition improved as hepatobiliary enzyme levels, inflammatory response, and tumor markers improved. Liver metastasis was shrinking on the image, so we resumed nivolumab therapy. To the authors' knowledge, this is the first case of pseudoprogression undergoing immunotherapy for gastric cancer. In this case, the antitumor effect was exhibited in a delayed manner and the tumor shrinkage was obtained.

Successful Treatment with 5-fluorouracil and Levofolinate Calcium in Advanced Gastric Cancer Patient with Disseminated Intravascular Coagulation.

A 32-year-old woman was found to have a gastric adenocarcinoma with multiple bone metastases. Chemotherapy in the first, second and third-line was not effective. Blood examinations showed disseminated intravascular coagulation(DIC)at the end of the second-line chemotherapy. The fourth-line chemotherapy, infusional 5-fluorouracil and levofolinate calcium was performed. This resulted in a good response for DIC. This palliative therapy was effective and safety.

Usefulness of Oblique Multiplanar Images on Multi-Detector Computed Tomography for Diagnosing Intersigmoid Hernia.

BACKGROUND: Intersigmoid hernia is a hernia of the small intestine into the intersigmoid fossa. Because the cavity of the intersigmoid fossa is so small, the preoperative detection of incarcerated intestine and/or mesenteric convergence is very difficult. We report a case of intersigmoid hernia in which the incarcerated bowel and mesenteric convergence could be visualized by oblique multiplanar reconstruction (MPR) images on multi-detector computed tomography (MDCT). CASE REPORT: An 82-year-old man with small bowel obstruction was treated conservatively with a long intestinal tube. Axial plane images of MDCT detected only a thickening of the small bowel wall and a narrowing of the lumen in the pelvis. Since a fourteen-day waiting period did not improve the condition at all, he underwent surgery. The small bowel was herniated into the intersigmoid fossa. After surgery, we studied the preoperative images of MDCT once again. However, neither converged mesentery nor hernia orifice had been depicted. We attempted to make oblique coronal/sagittal MPR images using SYNAPSE VINCENT® and succeeded in visualizing not only the incarcerated bowels but also the hernia orifice and mesenteric convergence. CONCLUSION: Creating oblique MPR images from the MDCT volume data would help in making a preoperative diagnosis of sigmoid mesocolon hernias such as intersigmoid hernia with increasing confidence.

Hepatic angiomyolipoma: differential diagnosis from other liver tumors in a special reference to vascular imaging - importance of early drainage vein.

A 51-year-old female had been diagnosed with a hemangioma in the hepatic segment 6 (S6). After a 6-year follow-up, enlargement of the tumor was detected. The tumor was clearly enhanced in the arterial phase, and the enhancement remained in the portal phase on computed tomography (CT). Although the primary differential diagnosis on CT was hepatocellular carcinoma (HCC), we worried about the possibility of other vessel system tumors because the tumor remained to be enhanced at the portal phase for HCC and all tumor markers of HCC were negative. We performed angiography to determine the tumor nature and to seek other tumors. Angiography showed tumor stain at the hepatic S6 with an early obvious drainage vein from the tumor flowing through the right hepatic vein into the inferior vena cava. In addition to tumor stain and the drainage vein, there were many small poolings of contrast medium in the whole liver, which were suspected as dilatation of the hepatic peripheral artery. We suspected the tumor as a benign tumor such as hepatocellular adenoma or focal nodular hyperplasia, but the possibility of HCC could not be ruled out. Hepatic posterior sectionectomy was done to completely remove the drainage vein with the tumor. Intraoperative histological examination revealed the tumor as not malignant and not HCC. Later, immunohistochemical analysis uncovered that the tumor had high expression of HMB-45 and, therefore, the final diagnosis was angiomyolipoma. We think that detecting an early drainage vein from the tumor would be a key point for diagnosing hepatic angiomyolipoma.

High-dose corticosteroid therapy for erlotinib-induced interstitial lung disease in Japanese patient with advanced pancreatic cancer.

CONTEXT: Erlotinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor used as a target therapy against non-small lung cancer and advanced pancreatic cancer. A regimen of erlotinib plus gemcitabine has been proven to prolong overall survival in the patient with advanced pancreatic cancer. In addition to common adverse effects, such as diarrhea, mucositis and skin rash (acne form eruptions), acute interstitial lung disease (ILD) has been reported as an infrequent but potentially fatal complication. We here report a case of a Japanese patient with erlotinib-induced ILD in whom high-dose corticosteroid therapy was successful. CASE REPORT: A fifty-five-year-old male with cancer of the head of the pancreas with multiple liver metastases started treatment with gemcitabine plus erlotinib. On the 13th day of erlotinib treatment, he had high fever. Chest computed tomography (CT) scan showed a diffuse ground-glass like infiltration of both lungs. He was diagnosed with ILD, and high-dose corticosteroid therapy was started. Two weeks after the introduction of steroid therapy, the reticular shadow faded away on CT. He was successfully treated with corticosteroid for erlotinib-induced acute ILD although he died 6 months after the initiation of chemotherapy owing to disease progression. CONCLUSION: we showed a case of a successfully treated Japanese patient of erlotinib-induced ILD. Because erlotinib-induced ILD would frequently occur in Japanese patients, closer attention to ILD should be paid for Japanese patients than in Western populations. If erlotinib-induced ILD occurs, a high-dose corticosteroid therapy would be a useful option of treatment.

Nrf2 activation protects the liver from ischemia/reperfusion injury in mice.

OBJECTIVE: To investigate the role of Nrf2 in the pathogenesis of hepatic ischemia-reperfusion (I/R) injury. BACKGROUND: Hepatic I/R injury is a serious complication that leads to liver failure after liver surgery. NF-E2-related factor 2 (Nrf2) is a transcription factor that plays a critical role in protecting cells against oxidative stress. Therefore, it is suggested that Nrf2 activation protects the liver from I/R injury. METHODS: Wild-type and Nrf2-deficient mice were treated with 15-deoxy-Δ(12,14)-prostaglandin J2 (15d-PGJ2), or a vehicle. Subsequently, these mice were subjected to 60-minute hepatic 70% ischemia, followed by reperfusion. Liver and blood samples were collected to evaluate liver injury and mRNA expressions. RESULTS: After hepatic I/R, Nrf2-deficient livers exhibited enhanced tissue damage; impaired GSTm1, NQO1, and GCLc inductions; disturbed redox state; and aggravated tumor necrosis factor α mRNA expression in comparison with wild-type livers. 15d-PGJ2 treatment protected the livers of wild-type mice from I/R injury via increased expressions of GSTm1, NQO1, and GCLc; maintained redox status; and decreased tumor necrosis factor α induction. These effects induced by 15d-PGJ2 were not seen in the livers of Nrf2(-/-) mice and were not annulled by peroxisome proliferator-activated receptor γ antagonist in Nrf2(+/+) mice, suggesting that the protective effect of 15d-PGJ2 is mediated by Nrf2-dependent antioxidant response. CONCLUSIONS: Nrf2 plays a critical role in the mechanism of hepatic I/R injury and would be a new therapeutic target for preventing hepatic I/R injury during liver surgery.

Liver epithelial cells proliferate under hypoxia and protect the liver from ischemic injury via expression of HIF-1 alpha target genes.

BACKGROUND: The remnant liver after extended liver resection is susceptible to ischemic injury, resulting in the failure of liver regeneration and liver dysfunction. The present study is aimed to investigate the protective role of the liver epithelial cells (LEC), a liver progenitor cell, on hepatocytes with ischemia in vitro and in vivo. METHODS: LECs were isolated from rats and cultured under hypoxic conditions (2% O(2)). The cell viability and intracellular ATP levels were measured. The activation of hypoxia-inducible factor-1α (HIF-1α) was assessed by immunofluorescence. The expression of pyruvate dehydrogenase kinase-1 (PDK-1), stromal cell-derived factor-1 (SDF-1), and chemokine receptor 4 (CXCR4) were measured. Hepatocytes were treated with SDF-1 or LEC-conditioned medium under hypoxia, and cell viability was assessed. Finally, hemorrhagic shock was induced in rats with in vivo induction of endogenous LECs, and liver damage was assessed. RESULTS: In LECs, but not in hepatocytes, cellular viability and intracellular ATP levels were maintained, and nuclear translocation of HIF-1α and expression of pyruvate dehydrogenase kinase-1 mRNA were increased under hypoxic culture conditions. LECs express SDF-1, and CXCR4 expression was increased in hepatocytes under hypoxia. The survival of hepatocytes under hypoxic condition was significantly increased after treatment with SDF-1 or LEC-conditioned medium. The protective effect of conditioned medium was impaired by CXCR4 antagonists. In vivo induction of endogenous LECs suppressed elevation of serum AST and ALT levels after hemorrhage shock and ischemia-reperfusion. CONCLUSION: LECs are resistant to hypoxia and have a protective role for hepatocytes against hypoxia. Our results suggest that induction of endogenous LECs protected the liver from lethal insults by paracrine signaling of SDF-1 and differentiation into parenchymal cells.

Pyoderma gangrenosum first presenting as a recalcitrant ulcer of the ear lobe.

A 59-year-old Japanese man with pyoderma gangrenosum occurring at the unusual location of the ear lobe is herein reported. The patient was not associated with any other systemic diseases and had suffered from chilblains at the same site for ten years before the ulcer appeared. The ulcer followed the development of a purpuric exudative lesion and had neither an undermined nor a surpiginous border in the early lesion. It gradually increased in size after various conservative treatments, recurred within a month after being excised and became aggravated after the administration of potassium iodide. Repeated histopathology of the ulcer revealed a mixed inflammatory cell infiltrate with abscesses and an extravasation of red blood cells in the whole dermis, without showing leukocytoclastic vasculitis. A culture of the excised tissue yielded no growth. Laboratory tests were not specific and c-ANCA was also negative. The ulcer of the ear did dramatically respond to systemic predonisolone of 40 mg/day. The auricular and periauricular area are quite rare anatomical sites of this disease and the difference between pyoderma gangrenosum and cutaneous Wegener's granulomatosis is also discussed.

Malignant melanoma arising from cutaneous bronchogenic cyst of the scapular area.

Bronchogenic cyst, an uncommon developmental anomaly that originates from the primitive tracheobronchial tree, is rare in the skin. The shoulder region is a particularly rare location. We report a 46-year-old Japanese man with recurrent malignant melanoma that arose from such a cutaneous bronchogenic cyst in the left scapular area. Despite wide local excision and subsequent chemotherapy, he died 18 months after surgery of the melanoma because of its lung metastasis. This is the first case of bronchogenic cyst in which malignant melanoma occurred.