Development of Magnetocardiograph without Magnetically Shielded Room Using High-Detectivity TMR Sensors.

A magnetocardiograph that enables the clear observation of heart magnetic field mappings without magnetically shielded rooms at room temperatures has been successfully manufactured. Compared to widespread electrocardiographs, magnetocardiographs commonly have a higher spatial resolution, which is expected to lead to early diagnoses of ischemic heart disease and high diagnostic accuracy of ventricular arrhythmia, which involves the risk of sudden death. However, as the conventional superconducting quantum interference device (SQUID) magnetocardiographs require large magnetically shielded rooms and huge running costs to cool the SQUID sensors, magnetocardiography is still unfamiliar technology. Here, in order to achieve the heart field detectivity of 1.0 pT without magnetically shielded rooms and enough magnetocardiography accuracy, we aimed to improve the detectivity of tunneling magnetoresistance (TMR) sensors and to decrease the environmental and sensor noises with a mathematical algorithm. The magnetic detectivity of the TMR sensors was confirmed to be 14.1 pTrms on average in the frequency band between 0.2 and 100 Hz in uncooled states, thanks to the original multilayer structure and the innovative pattern of free layers. By constructing a sensor array using 288 TMR sensors and applying the mathematical magnetic shield technology of signal space separation (SSS), we confirmed that SSS reduces the environmental magnetic noise by -73 dB, which overtakes the general triple magnetically shielded rooms. Moreover, applying digital processing that combined the signal average of heart magnetic fields for one minute and the projection operation, we succeeded in reducing the sensor noise by about -23 dB. The heart magnetic field resolution measured on a subject in a laboratory in an office building was 0.99 pTrms and obtained magnetocardiograms and current arrow maps as clear as the SQUID magnetocardiograph does in the QRS and ST segments. Upon utilizing its superior spatial resolution, this magnetocardiograph has the potential to be an important tool for the early diagnosis of ischemic heart disease and the risk management of sudden death triggered by ventricular arrhythmia.

Peritoneal adenomatoid (microcystic) mesothelioma.

There are several reports of pleural adenomatoid (microcystic) mesothelioma, but peritoneal adenomatoid mesothelioma is extremely rare. A 64-year-old Japanese woman presented with no symptoms and no asbestos exposure history. An abdominal computed tomography scan revealed multiple hypervascular masses on the liver surface, pelvic cavity and anterior peritoneum. Over 10 pieces of the multiple resected tumors showed numerous microcysts composed of a bland mesothelial cell background with rich capillary vessels. Focally, atypical cells with bizarre nuclei with prominent nucleoli were observed. Adenomatoid mesothelioma was suspected based on histochemical, immunohistochemical and fluorescence in situ hybridization findings. The tumors relapsed 4 years later and metastasized to the lung, but the patient remains alive 7 years after the first tumor resection surgery. Although the prognosis of adenomatoid mesothelioma of pleural origin is poor, the progression of this peritoneal case is slow.

[Combination Therapy of Bevacizumab plus Paclitaxel Was Effective for a Metastatic Choroidal Tumor Secondary to Breast Cancer in a Patient with Ocular Symptoms].

A 44-year-old woman experienced loss of vision and distorted vision in the right eye. After she visited our hospital, she was diagnosed with a right metastatic choroidal tumor. At the age of 35 years, she had undergone surgery for left breast cancer; as recurrence of the breast cancer was suspected, the patient was referred to our department. A CT scan revealed left axillary lymph node swelling, liver metastasis, and lung metastasis. Lymph node needle biopsy was performed under ultrasound guidance, and the pathological findings revealed recurrence of breast cancer. Combination chemotherapy of bevacizumab( BV)plus paclitaxel(PTX)was administered. After chemotherapy, the metastatic lesion had remarkably shrunk, as observed on a CT scan. Optical coherence tomography(OCT)revealed that the tumor was flattened in her right eye. Choroidal metastasis of breast cancer is rare. BV plus PTX therapy was effective for treating choroidal metastasis of breast cancer, and it should be followed by ophthalmological examination over time.

Congenital hyperinsulinism associated with Hirschsprung's disease-a report of an extremely rare case.

BACKGROUND: Congenital hyperinsulinism (CH) is a rare disease, characterized by severe hypoglycemia induced by inappropriate insulin secretion from pancreatic beta-cells in neonate and infant. Hirschsprung's disease (HD) is also a rare disease in which infants show severe bowel movement disorder. We herein report an extremely rare case of combined CH and HD. CASE PRESENTATION: The patient was a full-term male infant who showed poor feeding, vomiting, and hypotonia with lethargy on the day of birth. He was transferred to tertiary hospital after a laboratory analysis revealed hyperinsulinemic hypoglycemia. The patient showed remarkable abdominal distension without meconium defecation. An abdominal X-ray showed marked dilatation of the large bowel. He was diagnosed with CH (nesidioblastosis) associated with suspected HD. He was initially treated with an intravenous infusion of high-dose glucose with the intermittent injection of glucagon. This was successfully followed by treatment with diazoxide and octreotide (a somatostatin analog). At 8 months of age, HD was confirmed by the acetylcholinesterase staining of a rectal mucosal biopsy specimen, and a transanal pull-through operation was performed to treat HD. At 14 months of age, subtotal pancreatectomy was performed for the treatment of focal CH located in the pancreatic body. His postoperative course over the past 12 years has been uneventful without any neurologic or bowel movement disorders. CONCLUSIONS: Although it is extremely rare for CH to be associated with HD, associated HD should be considered when a patient with CH presents severe constipation.

Decreased cytokeratin 7 expression correlates with the progression of cervical squamous cell carcinoma and poor patient outcomes.

AIM: To identify potential biomarkers for tumor progression and patient outcomes in cervical squamous cell carcinoma. METHODS: We examined the expressions of CK7 and CK17 as potential markers of the squamo-columnar junction, and podoplanin as a basal cell marker using surgical and biopsy samples of patients in grade 3 cervical intraepithelial neoplasia (n = 30), operable invasive carcinoma (OP group, n = 53) and inoperable invasive carcinoma before radiotherapy and/or chemotherapy (RC group, n = 76). RESULTS: The positive rates of CK7 and podoplanin in invasive carcinoma were significantly lower than those in grade 3 cervical intraepithelial neoplasia (P = 0.001, P < 0.0001). The positive rates of CK7 and podoplanin in the RC group were significantly lower than those in the OP group (P < 0.0001, P = 0.04), while CK17 expression showed significantly higher positivity in the RC group than in the OP group (P < 0.0001). Negative CK7 expression showed a potential impact on overall survival in early-stage patients. In the RC group, the prevalence of cases with post-therapeutic residual carcinoma cells was higher in the CK7-negative group than in the positive group (P = 0.003). We found that decreased expression of CK7 could be a prognostic factor in early-stage cervical cancer patients. CONCLUSION: This result may provide strategies and suggestions for new treatment options and follow-up practices in managing patients with cervical cancer.

Focal segmental glomerulosclerosis in which urinary protein improved after surgical treatment for acromegaly: a case report.

BACKGROUND: Focal segmental glomerulosclerosis is characterized by partial (segmental) sclerotic lesions in some glomeruli (focal). Primary focal segmental glomerulosclerosis is generally considered resistant to steroid therapy. However, acromegaly is a disease that causes peculiar facial features, body types, and metabolic abnormalities due to the excessive secretion of growth hormone by a pituitary adenoma. Growth hormone has been reported to be involved in glomerular cell growth, mesangial proliferation, and glomerulosclerosis in the kidney. CASE PRESENTATION: We report a case of a Japanese patient with focal segmental glomerulosclerosis in whom decreased urinary protein was observed after surgical treatment for acromegaly. CONCLUSION: The patient's urinary protein improved as the concentration of growth hormone/insulin-like growth factor 1 decreased.

Development of Lobular Panniculitis Long After Completing the Personalized Peptide Vaccine Therapy.

BACKGROUND Personalized peptide vaccine therapy is regarded as a well-tolerated, safe and effective immunotherapy for patients with advanced cancers. Herein we report an exceptional case of a patient with advanced pancreatic cancer who developed delayed lobular panniculitis at sites corresponding to vaccine injections. CASE REPORT A 64-year-old Japanese female visited our clinic due to thirst and polydipsia; she was diagnosed as having type 2 diabetes. Simultaneously, she was diagnosed as having advanced pancreatic cancer; and a distal pancreatectomy and splenectomy were performed. Afterwards, she received adjuvant chemotherapy with titanium silicate-1 and personalized peptide vaccination using Montanide® ISA-51 by a subcutaneous injection to her abdomen over a total of 30 times. Thirteen months after the vaccine therapy had come to an end, lobular panniculitis appeared at the vaccination sites. At this point, corticosteroid was administered, resulting in significant improvement in the condition of the subcutaneous nodules. CONCLUSIONS This case report highlights the importance of careful patient explanation before initiation of cancer vaccine therapy about the possibilities of lobular panniculitis as an adverse event. It also highlights that it is important that physicians have a greater awareness of the possibility of panniculitis in patients with concerns regarding subcutaneous indurations even long after the end of peptide vaccine therapy.

A high-density collagen xerogel thread prevents the progression of peritoneal fibrosis.

Peritoneal fibrosis is often provoked by peritoneal dialysis and is an essential precursor condition to the development of encapsulating peritoneal sclerosis. This study aimed to determine the efficacy of a high-density collagen xerogel thread (CXT) for the prevention of peritoneal fibrosis. Female ICR mice received intraperitoneal injections of chlorhexidine gluconate (CG) every other day to induce peritoneal fibrosis. For evaluation, the insertion of CXT or infusion of atelocollagen gel into the peritoneal cavity was conducted on the day before CG injection. For comparison, no collagen treatment after CG injection, and abdominal puncture without CG injection were also performed. Peritoneal fibrosis and inflammation were significantly suppressed by CXT for a long period. CXT prevented mesothelial epithelial-mesenchymal transition, myofibroblast emergence, and inflammatory cell invasion in the peritonitis tissue. In the early phase, atelocollagen gel modulated the expression of the fibrosis-associated protein transforming growth factor (TGF)-ß, connective tissue growth factor (CTGF), and CD105 in the peritoneum under CG-induced inflammation, while CXT did not. In contrast, CXT regulated the expression of CTGF and CD105 in the late phase and maintained antimicrobial protein REG3G at the same level as the Sham group in the early and late phases. Although the precise mechanism remains to be clarified, these findings suggest that CXT may have the potential to be developed as a simple therapeutic device to prevent peritoneal fibrosis, a severe complication in patients undergoing long-term peritoneal dialysis.

Inverse correlation between CD8+ inflammatory cells and E-cadherin expression in gallbladder cancer: Tissue microarray and imaging analysis.

AIM: To investigated the association between the tumor cells' expression of E-cadherin and the numbers of several types of inflammatory cells infiltrating into the invasive portion of gallbladder cancer (GBC). METHODS: We analyzed 50 GBC cases for which a sufficient amount of tumor tissues for tissue microarray (TMA) had been saved. Three tissue cores (3.0 mm) of invasive lesion from each case were used for the TMA. The 4-µm cut sections on slides were immunostained using primary antibodies including E-cadherin for cancer cells, leukocyte common antigen for leukocyte, myeloperoxidase for neutrophils, CD3 for T cells, CD4 for helper T cells, CD8 for killer T cells, CD20 for B cells and CD68 for macrophages. The immunostained slides were digitally analyzed by imaging analysis software. RESULTS: A significant inverse correlation between the number of infiltrating CD8+ cells at invasive areas and the expression of E-cadherin by cancer cells was observed (P = 0.0001), although the degree of this correlation was relatively weak (R = 0.32). The number of CD8+ cells and the cancer cells' E-cadherin expression were also significantly correlated with tumor differentiation (well-differentiated vs poorly differentiated) (P = 0.0467 and P = 0.0294, respectively). Inverse correlation of T-stage and the number of CD8+ cell infiltration was observed with statistical significance in comparison of T2 and T3 cases (P = 0.0324). CONCLUSION: Our findings indicate an inverse correlation of CD8+ T cell infiltration and cancer cells' E-cadherin expression at invasive areas of GBC. Further analyses are essential to test these findings.

Chemotherapy for primary mediastinal yolk sac tumor in a patient undergoing chronic hemodialysis: a case report.

BACKGROUND: The safety and efficacy of chemotherapy for patients undergoing concomitant hemodialysis have not been fully established and optimal doses of anti-cancer drugs and best timing of hemodialysis remains unclear. Although chemosensitive cancers, such as germ cell tumors, treated with chemotherapy should have sufficient dose intensity maintained to achieve the desired effect, many patients with cancer undergoing hemodialysis might be under-treated because the pharmacokinetics of anti-cancer drugs in such patients remains unknown. CASE PRESENTATION: We describe a 31-year-old Japanese man with a mediastinal yolk sac tumor treated with surgery followed by five cycles of chemotherapy containing cisplatin and etoposide while concomitantly undergoing hemodialysis. The doses of these agents used in the first cycle were 50% of the standard dose of cisplatin (10 mg/m2) and 60% of the standard dose of etoposide (60 mg/m2) on days 1 through to 5; the doses were subsequently escalated to 75% with both agents. Hemodialysis was started 1 hour after infusions of these agents. Severe hematological toxicities were observed despite successful treatment. During treatment with concurrent hemodialysis, pharmacokinetic analysis of cisplatin was performed and its relationship with adverse effects was assessed. Compared with patients with normal renal function, the maximum drug concentration was higher, and concentration increased in the interval between hemodialysis and the subsequent cisplatin infusion, resulting in a higher area under the curve despite a reduction in the dose to 75% of the standard regimen. CONCLUSIONS: Because of the altered pharmacokinetics pharmacodynamics status of patients with renal dysfunction undergoing hemodialysis, pharmacokinetics pharmacodynamics analysis is deemed to be helpful for effective and safe management of chemotherapy in patients undergoing hemodialysis.

Cytokeratin immunohistochemistry improves interobserver variability between unskilled pathologists in the evaluation of tumor budding in T1 colorectal cancer.

Tumor budding is a major risk factor for T1 colorectal cancer. Quality control of the pathological diagnosis of budding is crucial, irrespective of the pathologist's experience. This study examines the interobserver variability according to pathologists' experience and evaluates the influence of cytokeratin (CK) immunostaining in the assessment of budding. Hematoxylin-eosin (HE) and CK-immunostained slides of 40 cases with T1 primary colorectal cancer were examined. Budding grades were individually evaluated by 12 pathologists who we categorized into three groups by their experience (expert, with >10 years of experience (n = 4), senior, with 5-10 years (n = 4), and junior, < 5 years (n = 4)). The results revealed a tendency for the more experienced pathologists to assign higher budding grades compared to the less-experienced pathologists. In the junior group, the interobserver variability obtained with HE slides was poor, but it was markedly improved in the evaluation using CK-immunostained slides. The benefit of CK immunostaining was only slight in the expert group. CK immunostaining would be useful when a pathologist is not experienced enough or does not have enough confidence in the assessment of budding.

Immunopathological significance of ovarian teratoma in patients with anti-N-methyl-d-aspartate receptor encephalitis.

BACKGROUND: The clinical importance of ovarian teratoma in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been established, however investigations of ovarian teratoma in patients with anti-NMDAR encephalitis remain limited. OBJECTIVE: To clarify differences in NMDAR distribution and lymphocyte infiltration in ovarian teratoma between patients with and without anti-NMDAR encephalitis. METHODS: Participants initially comprised 26 patients with ovarian teratomas. NMDAR distribution and lymphocyte infiltration in ovarian teratomas were examined using immunopathological techniques. Clinical, laboratory, and radiological data were compared between patients showing the features of encephalitis. Anti-NMDAR antibodies in the serum and cerebrospinal fluid were also measured in encephalitis patients. RESULTS: Neuronal tissues were obtained from ovarian teratomas in 22 patients (after excluding 4 patients who did not satisfy the inclusion criteria), and the presence of NMDA receptor subunits was revealed in all patients. Lymphocyte infiltration was more frequent in the encephalitis group (n = 3) than in the non-encephalitis group. In particular, dense B-lymphocyte infiltration near neural tissues was observed in the encephalitis group. CONCLUSIONS: Differences in lymphocyte infiltration in ovarian teratomas between anti-NMDAR encephalitis and non-encephalitis patients suggest the immunological importance of the ovarian teratoma as the site of antigen presentation in anti-NMDAR encephalitis.

A case of mucosa-associated lymphoid tissue lymphoma of the gastrointestinal tract showing extensive plasma cell differentiation with prominent Russell bodies.

A 73-year-old Japanese woman was hospitalized for detailed examination of nausea, diarrhea and loss of appetite. Atypical erosion in the ileum was found on endoscopy. Biopsy of this erosion showed proliferation of cells containing numerous Russell bodies. Differential diagnoses considered were Russell body enteritis, crystal-storing histiocytosis, Mott cell tumor, immunoproliferative small intestinal disease (IPSID) and mucosa-associated lymphoid tissue (MALT) lymphoma. The cells containing prominent Russell bodies showed diffuse positivity for CD79a and CD138, but negative results for CD20, CD3, UCHL-1, CD38 and CD68. Russell bodies were diffusely positive for lambda light chain, but negative for kappa light chain, and immunoglobulin (Ig) G, IgA and IgM. Based on these findings, Russell body enteritis, crystal-storing histiocytosis and IPSID were ruled out. As the tumor formed no mass lesions and was restricted to the gastrointestinal tract, MALT lymphoma with extensive plasma cell differentiation was finally diagnosed. The patient showed an unexpectedly aggressive clinical course. The number of atypical lymphocytes in peripheral blood gradually increased and T-prolymphocytic leukemia (T-PLL) emerged. The patient died of T-PLL 7 mo after admission. Autopsy was not permitted.

Actual status of clinical diagnosis in patients with primary gallbladder cancer associated with adenomyomatosis.

AIM: The purpose of this study was to reveal differences in clinical diagnosis of gallbladder cancer among patients with or without adenomyomatosis (ADM) by analyzing demonstrated tumor patterns on imaging and diagnostic opportunities. METHODS: Ninety-seven patients with gallbladder cancer were enrolled. Demonstrated imaging patterns were classified into mass lesion (ML), wall thickening (WT), and papillary lesion (PL). Clinical status during periodic follow up and other diagnostic opportunities were determined from medical records. RESULTS: All adenomyomatosis-associated cases were diagnosed at the T2 or higher stage. The distribution of demonstrated imaging patterns was significantly different between the adenomyomatosis-associated and non-adenomyomatosis-associated groups (p = 0.0002). No adenomyomatosis-associated gallbladder cancer had the PL pattern, which was readily identifiable and characteristic of early-stage cancer. The WT pattern presented difficulties for diagnosis, and the ML pattern was relatively specific, although most of these cases were at advanced stages. Approximately 40% of ADM patients were found to be in advanced stages of gallbladder cancer, in spite of undergoing periodic follow up. CONCLUSIONS: This study revealed the difficulty of early diagnosis of primary gallbladder cancer in the setting of concurrent ADM. Current results suggest the possible utility of preventive cholecystectomy for management of asymptomatic ADM patients.

Pathological features of classical polyarteritis nodosa: analysis of 19 autopsy cases.

Classical polyarteritis nodosa (cPN) is a rare autoimmune disease featuring systemic inflammation of middle- and small-sized arteries. Because most of autopsy cases underwent clinical treatment, arterial fibrinoid necrosis, which is the most specific finding of cPN, is often obscure. The aim of this study was to seek morphological characteristics of the middle-sized arteries in autopsy cases of cPN, and to identify immunohistochemical markers for the diagnosis of cPN. Nineteen patients who had undergone autopsy with a diagnosis of cPN were enrolled. Twenty-one autopsy cases without cPN were examined as control group. Arterial fibrinoid necrosis in medium-sized arteries was observed in 8/19 autopsy cases. Elastica van Gieson staining showed an increased number of elastic fiber layers (P<0.0001) and greater distances between elastic fiber layers (P<0.0001) in the renal middle-sized arteries of the cPN group. These findings probably reflected the post-inflammatory remodeling process after necrotizing vasculitis. On immunohistochemical examination, the cPN group showed high matrix metalloproteinase-1 and tumor necrosis factor-α expressions and decreased smoothelin expression in the vascular wall compared to the control group. When uncertain or atypical autopsy cases of cPN are examined, these findings can help to make the pathological diagnosis of cPN.

Mitotic count reflects prognosis of gallbladder cancer particularly among patients with T3 tumor.

The surgical strategy for gallbladder cancer (GBC) depends on the extent of the disease. Thus, the identification of useful prognostic markers exerting strong prognostic impact for each T stage would be beneficial in the development of rational therapeutic strategies. The purpose of this study was to identify useful prognostic markers of GBC for each T stage. CD8+ tumor-infiltrating lymphocytes (TIL), Ki-67 labeling index (LI), p53 nuclear expression and mitotic count (MC) were investigated as candidate prognostic markers. In total, 86 patients with invasive GBC were included. Of the prognostic markers examined, only MC showed a correlation with reduced survival (P=0.0383) in the univariate analysis of overall T stage. In the univariate analysis of T2 stage (n=31), only high p53 expression correlated with survival showing a positive correlation (P=0.0154). In the univariate analysis of T3 stage (n=40), the only factor showing a significant correlation with survival was MC (P=0.0113). Multivariate analysis, including N and M as factors, identified only MC as an independent prognostic factor in T3 stage GBC (P=0.0419). In conclusion, this study demonstrated the strong prognostic impact of MC in GBC, particularly in patients with T3 tumor.

Analysis of Extrahepatic Multiple Primary Malignancies in Patients with Hepatocellular Carcinoma according to Viral Infection Status.

Previous studies have investigated extrahepatic multiple primary malignancy (EHPM) associated with hepatocellular carcinoma (HCC). However, its correlation with viral infection, such as hepatitis B virus (HBV) or hepatitis C virus (HCV), has not been examined. The aim of this study is to investigate the association between EHPM and hepatitis infection in HCC patients. A total of 412 patients who underwent surgical resection for primary HCC were enrolled. Viral infection was evaluated by serum HBV surface antigen (HBs Ag) and HCV antibody (HCV Ab). Sixty-eight (16.5%) patients had one or more EHPM. The most frequent EHPM was gastric cancer (n = 32) in this cohort. No statistical significance was observed in the distribution of viral infection and incidence of entire EHPM. However, HCV Ab, HBs Ag, and negative status for both were correlated with the frequency of gastric (P = 0.0194), urinary tract (P = 0.0067), and breast cancer (P = 0.0036), respectively. Infection of Helicobacter pylori was investigated by immunohistochemistry in gastric EHPM and resulted that 20 out of 21 analyzed cases were negative for Helicobacter pylori. Although it should be verified by well-designed large cohort studies, the current results suggested correlation between HCV infection and gastric cancer, HBV infection and urinary tract cancer and viral hepatitis-free status and breast cancer in HCC patients.