Skeletal Muscle-Derived Irisin Enhances Gemcitabine Sensitivity and Suppresses Migration Ability in Pancreatic Ductal Adenocarcinoma.

BACKGROUND: High skeletal muscle mass might be a prognostic factor for patients with pancreatic ductal adenocarcinoma (PDAC); however, the underlying reason is unclear. We hypothesized that myokines, which are cytokines secreted by the skeletal muscle, function as suppressors of PDAC. We specifically examined irisin, a myokine, which plays a critical role in the modulation of metabolism, to clarify the anticancer mechanisms. METHODS: First, the effect of the conditioned medium (CM) from skeletal muscle cells and from irisin-knockdown skeletal muscle cells on PDAC cell lines was evaluated. We then investigated the effects and anticancer mechanism of irisin in PDAC cells, and evaluated the anticancer effect of recombinant irisin in a PDAC xenograft mouse model. Finally, patients undergoing pancreatic resection for PDAC were divided into two groups based on their serum irisin level, and the long-term outcomes were evaluated. RESULTS: The CM enhanced gemcitabine sensitivity by inducing apoptosis and decreasing cell migration by inhibiting epithelial-mesenchymal transition (EMT) in PDAC cell lines. The CM derived from irisin-knockdown skeletal muscle cells did not affect the PDAC cell lines. The addition of recombinant irisin to PDAC cell lines facilitated sensitivity to gemcitabine by inhibiting the mitogen-activated protein kinase (MAPK) pathway, and decreased migration by inhibiting EMT via the transforming growth factor-ß/SMAD pathway. Xenografts injected with gemcitabine and recombinant irisin grew slower than the xenografts injected with gemcitabine alone. The overall survival was prolonged in the high-irisin group compared with that in the low-irisin group. CONCLUSIONS: Skeletal muscle-derived irisin may affect PDAC by enhancing its sensitivity to gemcitabine and suppressing EMT.

Intraocular pressure elevation after subtenon triamcinolone acetonide injection; Multicentre retrospective cohort study in Japan.

PURPOSE: To evaluate real-world evidence for intraocular pressure (IOP) elevation after subtenon triamcinolone acetonide injection (STTA) in 1252 Japanese patients (1406 eyes) in the Japan Clinical REtina STudy group (J-CREST). METHODS: This was a multicentre retrospective study of the medical records of 1252 patients (676 men (758 eyes); mean age: 63.8 ± 12.9 years) who received STTA in participating centres between April 2013 and July 2017. RESULTS: IOP elevation was observed in 206 eyes (14.7%) and IOP increase ≥ 6 mmHg was found in 328 eyes (23.3%). In total, 106 eyes (7.5%) needed medication and two eyes (0.14%) needed surgical procedures. Younger age, higher baseline IOP, and steroid dose were risk factors associated with IOP elevation. Risk factors associated with IOP increase ≥ 6 mmHg were younger age, lower baseline IOP, steroid dose, and higher incidences of diabetic macular oedema (DME) and uveitis. In contrast, with steroid dose fixed at 20 mg, a lower incidence of DME was a risk factor for increased IOP, suggesting that STTA had dose-dependent effects on IOP increase, especially in patients with DME. CONCLUSION: Our real-world evidence from a large sample of Japanese patients who received STTA showed that the incidence of IOP elevation after STTA was 14.7%, and was associated with younger age, higher baseline IOP, and steroid dose. Thus, IOP should be monitored, especially in patients with younger age, higher baseline IOP, and higher incidences of DME and uveitis.

Giant cell arteritis without cranial manifestations caused mesenteric involvement: a case report.

BACKGROUND: Giant cell arteritis (GCA) is a granulomatous vasculitis and targets large vessels with predominance for the aortic arch and the cranial branches. GCA with cranial symptoms shows headache, jaw claudication, and ophthalmologic symptoms and thus was previously called temporal arteritis. Recently, cases of GCA without cranial manifestations and extracranial GCA have been reported. CASE PRESENTATION: A 76-year-old woman was referred to our hospital complaining of sudden abdominal pain and high fever. Her present history of illness did not show any cranial symptoms such as headache, visual disturbance, or stroke. CT images showed severe thickening of the small intestinal mesentery and massive ascites. She was diagnosed to have acute abdomen probably with gastrointestinal perforation and underwent the emergent laparotomy. Excisions of a 60-cm length of the jejunum including the thickening mesenteric lesion were carried out. Marked hypertrophy of the vascular intima and mild stenosis of the arterial lumen were displayed with infiltration of lymphocytes, neutrophils, and eosinophils. Scattered multinucleated giant cells on the endothelium, in the intima, media, and adventitia were demonstrated. Elastica van Gieson stain showed focal loss and fragmentation of the internal elastic lamina. Histopathological examinations showed typical GCA. Her postoperative process was uneventful without any symptoms, and she was followed as an out-patient prescribed with daily doses of 40 mg of prednisolone. CONCLUSIONS: We hereby report a rare case of mesenteric involvement in GCA without cranial manifestations and elucidate the histopathological features of extracranial GCA in arteries as well as veins and jejunum.

Macular retinoschisis in eyes with glaucomatous optic neuropathy: Vitrectomy and natural course.

PURPOSE: Our purpose was to determine the effectiveness of vitrectomy in resolving the macular retinoschisis in an eye with glaucomatous optic neuropathy and also to determine the natural course of macular retinoschisis. METHODS: This was a retrospective case series of patients who were diagnosed with macular retinoschisis and glaucomatous optic neuropathy. Fourteen eyes of 13 patients were studied. Patients with high myopia, vitreomacular traction syndrome, and the pit macular syndrome were excluded. RESULTS: There were three men and ten women, and 12 had unilateral and one had bilateral macular retinoschisis. Vitrectomy was performed for a serous retinal detachment, macular hole, or severe visual loss in five eyes. The mean follow-up time was 68.8 months in these five eyes, and the macular retinoschisis was resolved and the best-corrected visual acuity (BCVA) at the final visit was significantly improved in all eyes (P = 0.007). However, two of these fiv e eyes developed a macular hole and required a second vitrectomy. Of the nine eyes without treatment with a mean follow-up time of 29.0 months, the BCVA at the final visit remained unchanged from the baseline BCVA in all eyes. The macular retinoschisis was resolved or reduced in three eyes without treatment. CONCLUSIONS: Vitrectomy was effective for the resolution of macular retinoschisis in eyes with glaucomatous optic neuropathy and serous retinal detachment or macular hole or severe reduction of the BCVA. Macular retinoschisis can be resolved without a reduction of the BCVA in some cases without treatment.

Clinical significance of CD13 and epithelial mesenchymal transition (EMT) markers in hepatocellular carcinoma.

BACKGROUND & AIMS: To improve prognosis in patients with hepatocellular carcinoma (HCC), the molecular mechanisms of tumor thrombus formation and metastasis must be clarified. The epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) play crucial roles in tumor invasion and metastasis. This study aimed to reveal the clinical significance of the expression of the functional CSC marker, CD13, and investigate the correlation between CD13 expression and two EMT markers, E-cadherin and vimentin. METHODS: We acquired clinical samples from 86 patients with HCC that underwent radical liver resections. We performed immunohistochemistry to evaluate CD13, E-cadherin and vimentin expression. We investigated the relationships among protein expression levels, clinicopathological factors and prognosis. RESULTS: Based on CD13 expression, patients were categorized into CD13high (n = 30, 34.9%) and CD13low (n = 56, 65.1%) groups. The mean tumor size was significantly larger in the CD13high group than in the CD13low group (P = 0.049). Compared with the CD13low group, the CD13high group showed significantly earlier recurrences and shorter survival times. In the multivariate analysis, CD13high was an independent prognostic factor for overall survival (hazard ratio, 1.98; P = 0.044). The disease-free survival time was shorter in the vimentin-positive group than that in the vimentin-negative group (P = 0.014). In an analysis of the relationship between CD13 and EMT, there was no significant correlation between CD13 and EMT markers. CONCLUSIONS: Our findings suggested that CD13 enrichment was correlated with early recurrences, and poor prognosis in patients with HCC and that vimentin was associated with early recurrences. CD13 represents a potential therapeutic target for HCC, because CSC regulation and EMT suppression are essential in cancer therapy.

Changes of choroidal structure after intravitreal aflibercept therapy for polypoidal choroidal vasculopathy.

AIMS: To quantify the changes of the choroidal structure in the enhanced depth imaging optical coherence tomographic (EDI-OCT) images after intravitreal aflibercept (IVA) injections for polypoidal choroidal vasculopathy (PCV). METHODS: Retrospective, observational case series. Forty eyes of 40 treatment-naive patients who underwent IVA for PCV were examined by EDI-OCT before, and 3 months and 12 months after IVA. The EDI-OCT images were binarised by ImageJ software. The cross-sectional luminal and stromal areas of the inner and outer subfoveal choroid of 1500 µm width were quantified. RESULTS: The stromal but not the luminal area of the inner choroid was significantly decreased at 3 months and 12 months after the IVA (stromal area, both p<0.001; luminal area, both p>0.050). On the other hand, the luminal but not the stromal area of the outer choroid was significantly decreased at 3 months and 12 months (luminal area, both p<0.001; stromal area, both p>0.050). The Pachychoroid Index, ratio of luminal/stromal area (L/S ratio) of the outer choroid divided by the L/S ratio of the inner choroid, was significantly decreased at 3 months and 12 months (both p<0.050). The Pachychoroid Index was increased and returned almost to the baseline level after recurrences and decreased again after successful re-treatment. The baseline Pachychoroid Index was significantly correlated with the presence of a dry macula, thinner fovea and better visual acuity at 12 months (all p<0.050). CONCLUSION: The binarisation of the EDI-OCT images can be used to quantify the activity of PCV and to predict the prognosis after IVA.

[A case of advanced hepatocellular carcinoma with inferior vena cava tumor thrombus and multiple intrahepatic metastases treated successfully by transcatheter arterial chemoembolization and radical hepatectomy].

A 76-year-old man, who had been treated with interferon-α(IFN-α) for hepatitis C, was diagnosed with multiple hepatocellular carcinomas (HCC; S7/8, S8, S5, S2) with right hepatic vein tumor thrombus (Vv2). He initially underwent transcatheter arterial chemoembolization(TACE). One month after TACE, the hepatic vein tumor thrombi extended into the inferior vena cava(Vv3). No distant metastasis was observed, and his liver function was well-preserved. Therefore, we performed a posterior segmentectomy, partial hepatectomy(S8, S5, S2), inferior vena cava tumor thrombus excision, and cholecystectomy. Four months after the operation, intrahepatic recurrences were detected, and these lesions were controlled via TACE. Four years and 2 months after the initial treatment, the patient survived and presently, is in a good condition. This case suggested that long-term survival is possible by surgery and repeated TACE in case of good liver function by a sustained virologic response (SVR) via treatment with IFN-α for hepatitis C virus.

[A case report of long-term survival of endocrine cell carcinoma of the esophagus with chemo-radiation therapy].

The patient was an 84-year-old man, who was diagnosed with cT3N2 (101L, 109L) M0, stage III esophageal cancer. The tumor, immunohistochemically, was stained positive for CD56 and NSE yielding a definitive diagnosis of endocrine cell carcinoma of the esophagus. We selected chemo-radiation therapy (5-FU/CDDP and 2 Gy/day total 60 Gy) for this patient. As adjuvant chemotherapy, 7 courses of chemotherapy with 5-FU/CDDP, was performed. At 8 months from the chemo-radiation therapy, the disease was diagnosed as cCR. But two years later, lung metastasis appeared, so we started chemotherapy with docetaxel/CDDP/5-FU. After 2 courses, lung metastasis was almost disappeared. He has been survived for four years and five months after chemo-radiation. This case suggests that chemo( FP) -radiation therapy and adjuvant chemotherapy could be an effective treatment for endocrine cell carcinoma of the esophagus.

[Schwannoma in the brachial plexus resected by thoracoscopic approach].

A 50-year-old male was detected an abnormal shadow in the right apical region by chest X-ray examination. Computed tomography (CT) scan and magnetic resonance imaging (MRI) findings suggested the mass to be a neurogenic tumor. The tumor was originated from lower brachial plexus and enuclated by thoracoscopic approach with no major nerve damage. The pathological finding was benign schwannoma.

[A case of super advanced gastric cancer responding to S-1+CDDP and S-1 single regimen which led to a clinical complete response].

A patient is a 62-year-old man who was presented by epigastralgia. He was pointed out super advanced gastric cancer with paraaortic lymph node metastasis and pancreatic invasion by gastrointestinal endoscopy (GIS) and computed tomography (CT). We diagnosed as cT4N3M0, and started with chemotherapy as follows. S-1 (120 mg/day) was orally administered for 3 weeks followed by 2-week rest as one course, and CDDP (90 mg/body)was administered by intravenous drip on day 8. Partial response was indicated after 6 courses of this procedure. We changed the procedure to S-1 single treatment for 2 weeks followed by 2-week rest. After 12-course of this procedure, he was attacked by brain infarction, the procedure was interrupted for about 8 months. After rehabilitation, an S-1 single treatment was restarted. The main tumor and metastatic lymph node appeared no change before the interruption of S-1 single treatment. So, we considered that complete response was continued. S-1+CDDP and S-1 single regimen appears to be effective for super advanced gastric cancer.

[A case of bilateral pulmonary metastasis from gastric cancer performed radical thoracoscopic lobectomy after neoadjuvant chemotherapy].

A 40s male was performed proximal gastrectomy with D1+alpha dissection and interposition reconstruction for type 1 esophago-gastric junctional cancer in January 2002. Pathological findings were as follows: pap, se, ly0, v0, n1 (#3, 1/9) stage IIIA, curability B. Adjuvant chemotherapy by 5'-DFUR (800 mg/day) was done for 1 year. Bilateral pulmonary metastasis was detected in left S6 (3.8 cm) and right S10 (3 cm) in February 2006. After S-1 (120 mg/day) was administered for 4 courses, right pulmonary metastasis had become scar, and the other was remained and growing. S-1 (100 mg/ day 1-21)+CPT-11 (120 mg div day 1, 15) was done for 6 courses. However, the tumor was growing. As no other lesions but left pulmonary metastasis in S10, radical thoracoscopic left lower lobectomy with ND1 lymph node dissection was performed. Pathological finding was pulmonary metastasis from gastric cancer with no lymph node metastasis. There were no recurrences observed in May 2009 since gastrectomy was done 7 years ago, and 3 years since pulmonary metastasis was detected.

[A long-term survival case of liver metastasis of gastric cancer under interdisciplinary therapy].

We report herein a long-term survival case of liver metastasis after distal gastrectomy for gastric cancer. A 72-year-old woman, whom we performed distal gastrectomy with D2 lymph node dissection for type 2 gastric cancer at age 66, was diagnosed as pT2N1M0, stage II. No adjuvant therapy was performed. Liver metastasis was found 1 year and 7 months after surgery. PTX plus CPT-11 was performed. Six courses of therapy were done, and found cCR in the liver metastasis. A total of 23 courses of therapy were done. A recurrence of liver metastasis was found, transcatheter arterial chemoembolization (TACE), radiofrequency ablation( RFA)and operation were performed. She received S-1 plus CDDP, and cCR has been maintained for 6 years and 11 months after gastrectomy (5 years and 4 months after liver metastasis) suggesting that the interdisciplinary therapy was effective.

[A case of advanced gastric cancer with liver metastases resected successfully after S-1 monotherapy and S-1/CDDP combination chemotherapy].

The patient was a 75-year-old man, who was diagnosed with type 3 gastric cancer with solitary liver metastasis whose diameter was 12 mm. Distal gastrectomy with D2 lymph node dissection was performed in June 2008. S-1 monotherapy (120 mg/day, day 1-28/42 days) for liver metastasis started as the first-line chemotherapy. After 3 courses, the diameter of liver metastasis enlarged to 22 mm. Moreover, S-1 and CDDP combined chemotherapy (S-1: 120 mg/day, day 1-21/ 35 days, CDDP: 60 mg/m2, day 8/35 days) was performed as the second-line chemotherapy, nevertheless the diameter of liver metastasis enlarged to 26 mm. No distant metastasis without solitary liver tumor was observed for 6 months after gastric resection, so a partial hepatic resection was performed in February 2009. Five months after the operation, the patient is doing well and shows no signs of recurrence of the cancer. A combination gastrectomy with D2 lymphadenectomy and postoperative chemotherapy was considered to be a radical treatment for H1, Stage IV gastric cancer.

[A case of left inguinal malignant lymphoma occurred after radical operation for gastric cancer and gastrointestinal stromal tumor].

In March 2005, a 70-year-old male patient underwent distal gastrectomy with D2 lymph node dissection for type 3 gastric cancer located in the lower-third of the stomach, and partial gastrectomy for submucosal tumor located in the upper- third of the stomach. A post operative pathological finding of cancer was T2N0P0H0M0 (f-Stage II) and that of submucosal tumor was gastrointestinal stromal tumor. Although the adjuvant chemotherapy of S-1 was administered, it was discontinued because of cerebral infarction. Forty months after the operation, CT scan revealed a left inguinal lymph node swelling and recurrence of gastric cancer was doubted. FDG-PET scan confirmed increased uptake only in one lymph node of left inguinal region. In September 2008, left inguinal lymph node dissection was performed and its pathological finding was follicular lymphoma (grade 1). At present, the patient was doing well and showed no signs of recurrence. However, it is important to follow-up the patient carefully because the relapse rate of follicular lymphoma is comparatively high.

Multiple hepatocellular carcinomas developed 15 months after commencement of chemotherapy for elderly acute myelogenous leukemia.

In May 2006, a 72-year-old man with acute myelogenous leukemia (M4Eo) was admitted to our hospital. He had been receiving antiandrogen treatment for prostate cancer (after an operation in 1998) and treatment for diabetes mellitus. He received chemotherapy according to the JALSG GML200 protocol, which led to complete remission; however, in January 2007, his leukemia recurred. CAG combination chemotherapy also resulted in complete remission by May 2007. In August 2007, he developed multiple liver tumors, abdominal pain, and fever. Contrast-enhanced computed tomography revealed hypovascular tumors in both early and delayed phases. Angiography showed ring-like tumor staining and a massive tumor, similar to those seen in metastatic hepatocellular carcinomas (HCCs). He eventually died because of aggressive enlargement of liver tumors during the following month accompanied by the simultaneous recurrence of leukemia and unsuccessful embolization of the hepatic artery. Autopsy specimens showed fibrosis and considerable iron deposition in the liver, suggested secondary hemochromatosis due to transfusion. We also detected multiple moderately differentiated primary HCCs. Secondary hemochromatosis, androgen imbalance, and humoral factors from leukemic cells were believed to be the causes of the rapid onset and development of HCCs.

Construction of imaging system for wide-field-range ESR spectra using localized microwave field and its case study of crystal orientation in suspension of copper sulfate pentahydrate (CuSO4 . 5H2O).

A scanning electron spin resonance (ESR) microscope using a localized microwave field was redesigned to measure ESR spectra from 0 to 400 mT using electromagnets. Divalent copper ion (Cu2+) in copper sulfate pentahydrate (CuSO4 . 5H2O) was imaged, after the powdered samples were cemented in silicone rubber under a magnetic field. The ratio of the two signal intensities at g=2.27 and 2.08 clearly indicates the orientation of the particles. This method can be used for mapping the local magnetic field and its direction.

ESR study of Gd3+ and Mn2+ ions sorbed on hydroxyapatite.

Adsorption of Gd3+ and Mn2+ into hydroxyapatite (HAP (Ca5(PO4)3(OH)2) was studied by ESR, ion chromatography and ICP-AES to investigate the U-uptake model. HAP absorbed Gd3+ via a cation exchange reaction and resulted in a signal width of 240 mT. The growth of the thermally stable Gd3+ signal in HAP was also fitted by saturation and diffusion equations. The ESR signals of Gd3+ and Mn2+ were observed overlapping the CO2- signals, however, the dose-response curves of the CO2- signal were similar to that of control HAP.