Natriuretic peptide receptor A is related to the expression of vascular endothelial growth factors A and C, and is associated with the invasion potential of tongue squamous cell carcinoma.

Natriuretic peptide receptor A (NPRA) is one of the natriuretic peptide receptors. NPRA has been reported to play a role in the carcinogenesis of various tumours, as well as functional roles in renal, cardiovascular, endocrine, and skeletal homeostasis. The clinicopathological significance of NPRA in tongue squamous cell carcinoma (TSCC) was examined in this study. The overexpression of NPRA was more frequent in TSCC (21/58, 36.2%) than in the normal oral epithelium (0/10, 0%) (P<0.05). It was also more frequently observed in cancers with higher grades according to the pattern of invasion (grades 1-2 vs. grades 3-4, P<0.01). Additionally, there was a tendency towards an association between the N classification and NPRA expression (N0 vs. N1-2, P=0.06). Significant correlations were also observed between the expression of NPRA and that of VEGF-A (P<0.001) and VEGF-C (P<0.001). The high-NPRA expression group had a significantly poorer prognosis, with a 5-year disease-specific survival rate of 39.7%, compared to 97.0% in the low-expression group (P<0.001). Multivariate analysis suggested that the overexpression of NPRA may also be an independent prognostic factor (P<0.05). In conclusion, NPRA is associated with VEGF expression levels, invasion, and metastasis, and may be a prognostic factor in TSCC patients.

Drosophila myeloid leukemia factor acts with DREF to activate the JNK signaling pathway.

Drosophila myelodysplasia/myeloid leukemia factor (dMLF), a homolog of human MLF1, oncogene was first identified by yeast two-hybrid screen using the DNA replication-related element-binding factor (DREF) as bait. DREF is a transcription factor that regulates proliferation-related genes in Drosophila. It is known that overexpression of dMLF in the wing imaginal discs through the engrailed-GAL4 driver causes an atrophied wing phenotype associated with the induction of apoptosis. However, the precise mechanisms involved have yet to be clarified. Here, we found the atrophied phenotype to be suppressed by loss-of-function mutation of Drosophila Jun N-terminal kinase (JNK), basket (bsk). Overexpression of dMLF induced ectopic JNK activation in the wing disc monitored with the puckered-lacZ reporter line, resulting in induction of apoptosis. The DREF-binding consensus DRE sequence could be shown to exist in the bsk promoter. Chromatin immunoprecipitation assays in S2 cells with anti-dMLF IgG and quantitative real-time PCR revealed that dMLF binds specifically to the bsk promoter region containing the DRE sequence. Furthermore, using a transient luciferase expression assay, we provide evidence that knockdown of dMLF reduced bsk gene promoter activity in S2 cells. Finally, we show that dMLF interacts with DREF in vivo. Altogether, these data indicate that dMLF acts with DREF to stimulate the bsk promoter and consequently activates the JNK pathway to promote apoptosis.

Minimal deviation endometrioid adenocarcinoma of the endometrium and its MRI findings.

Minimal deviation endometrioid adenocarcinoma (MDA-E) of the endometrium is a rare pathological entity, and its radiological features are rarely documented. A 73-year-old Japanese woman was referred to the authors when an endometrial biopsy revealed moderately differentiated endometrioid adenocarcinoma. Preoperative radiological examinations, including ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) showed no evidence of cancer nests. In the hysterectomy specimen, mildly atypical glands were scattered throughout the entire depth of the myometrium, without stromal desmoplastic reaction, and a tiny focus of typical, ruptured, endometrioid adenocarcinoma glands was found in the atrophic endometrium. MRI had not been able to identify this unusual, scattered, myometrial invasion. It should be kept in mind that in cases showing Stage IA endometrial carcinoma without endometrial thickening on MRI, this rare form of invasion may be present.

Clinicopathological features of narrow-band imaging endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms.

To reveal clinicopathological features of narrow-band imaging (NBI) endoscopy and immunohistochemistry in ultraminute esophageal squamous neoplasms. If a lesion diameter was smaller or same compared with a width of closed biopsy forceps, a lesion was defined to be an ultraminute lesion. Twenty-five consecutive patients with 33 ultraminute esophageal lesions that were removed by endoscopic mucosal resection were included in the present study. We conducted two questionnaire surveys of six endoscopists by their retrospective review of endoscopic still images. The six endoscopists evaluated the endoscopic findings of the ultraminute lesions on still images taken by conventional white-light imaging endoscopy and non-magnified NBI endoscopy in the first questionnaire, and taken by magnified NBI endoscopy in the second questionnaire. An experienced pathologist who was unaware of any endoscopic findings made histological diagnosis and evaluated immunoexpression of p53 and Ki67. The 33 ultraminute lesions were all determined to be either 11 high-grade intraepithelial neoplasias (HGIENs) or 22 low-grade intraepithelial neoplasias (LGIENs). The tumor diameters were histologically confirmed to be <3 mm. All of the ultraminute tumors were visualized as unstained areas and brownish areas by real-time endoscopy with Lugol dye staining and non-magnified NBI endoscopy, respectively. All of the ultraminute IENs were visualized as brownish areas by real-time non-magnified NBI endoscopy. Three of the 25 patients with the ultraminute IENs (12%) had multiple brownish areas (more than several areas) in the esophagus on real-time non-magnified NBI endoscopy. All of the ultraminute IENs were visualized as unstained areas by real-time Lugol chromoendoscopy. Twenty of the 25 patients (80%) had multiple unstained areas (more than several areas) in the esophagus on real-time Lugol chromoendoscopy. The first questionnaire survey revealed that a significantly higher detection rate of the ultraminute IENs on non-magnified NBI endoscopy images compared with conventional white-light imaging endoscopy ones (100% vs. 72%, respectively: P < 0.0001). The second questionnaire survey revealed that presence rates of any magnified NBI endoscopy findings were not significantly different between HGIENs and LGIENs. Proliferation, dilation, and various shapes of intrapapillary capillary loops indicated remarkably high presence rates of more than 90% in both HGIENs and LGIENs. Six of 22 LGIENs (27%) and 3 of 11 HGIENs (27%) show a positive expression for p53. None of peri-IEN epithelia was positive for p53. A mean of Ki67 labeling index of LGIENs was 33% and that of HGIENs 36%. Ki67 labeling index was significantly greater in the LGIENs and HGIENs compared with that in the peri-IEN epithelia. There were no significant differences in p53 expression and Ki67 labeling index between the HGIENs and LGIENs. Non-magnified/magnified NBI endoscopy could facilitate visualization and characterization of ultraminute esophageal squamous IENs. The ultraminute HGIENs and LGIENs might have comparable features of magnified NBI endoscopy and immunohistochemistry.

Risk factors affecting cardiac left-ventricular hypertrophy and systolic and diastolic function in the chronic phase of allogeneic hematopoietic cell transplantation.

Chronic impairment of cardiac function can be an important health risk and impair the quality of life, and may even be life-threatening for long-term survivors of allogeneic hematopoietic cell transplantation (HCT). However, risk factors for and/or the underlying mechanism of cardiac dysfunction in the chronic phase of HCT are still not fully understood. We retrospectively investigated factors affecting cardiac function and left-ventricular hypertrophy (LVH) in the chronic phase of HCT. Sixty-three recipients who survived for >1 year after receiving HCT were evaluated using echocardiography. Based on simple linear regression models, high-dose TBI-based conditioning was significantly associated with a decrease in left-ventricular ejection fraction and the early peak flow velocity/atrial peak flow velocity ratio, following HCT (coefficient=-5.550, P=0.02 and coefficient=-0.268, P=0.02, respectively). These associations remained significant with the use of multiple linear regression models. Additionally, the serum ferritin (s-ferritin) level before HCT was found to be a significant risk factor for LVH on multivariable logistic analysis (P=0.03). In conclusion, our study demonstrated that a myeloablative regimen, especially one that involved high-dose TBI, impaired cardiac function, and that a high s-ferritin level might be associated with the development of LVH in the chronic phase of HCT.

Immunoglobulin prophylaxis against cytomegalovirus infection in patients at high risk of infection following allogeneic hematopoietic cell transplantation.

Reports on the efficacy of intravenous immunoglobulin (IVIG) prophylaxis against cytomegalovirus (CMV) infection after allogeneic hematopoietic cell transplantation (HCT) have often sparked controversy. In addition, we are not aware of any study that has examined whether prophylaxis with IVIG affects the incidence of CMV infection in high-risk patients--those who are elderly or have received human leukocyte antigen (HLA) mismatched HCT. In the present open-label, phase II study, we addressed this question. We enrolled 106 patients in the study. The cumulative incidences of CMV infection at 100 days after HCT were similar in the intervention and the control groups (68% and 64%, P=.89; 89% and 87%, P=.79, respectively, for patients 55 years or older and those who received HLA-mismatched HCT). In those who received HLA-mismatched HCT, 1-year overall survival after HCT was 46% in the intervention group and 40% in the control group (P=.31); for age≥55 years, the corresponding values were 46% and 40% (P=.27). Our data showed that prophylaxis with regular polyvalent IVIG did not affect the incidence of CMV infections or survival among older patients or those who receive HLA-mismatched HCT.

[Graft replacement for surgical repair of coarctation of the aorta in adults].

We report the graft replacement for surgical repair of coarctation of the aorta (CoA) in 2 men, aged 19 and 30 years old, respectively. In both patients, the pressure gradients were higher than 20 mmHg across the coarctaion by cathetherization, and higher than 30 mmHg between the upper and lower limbs. The graft replacement of the coarctated aorta was performed under cardiopulmonary bypass. Postoperatively, the pressure gradients between the upper and lower limbs dropped below 20 mmHg in both cases. Since about 50% of surgically untreated patients with this disease may be expected to die before 30 years of age, repair of CoA in adults should be performed as soon as possible.

Individualized pterional keyhole clipping surgery based on a preoperative three-dimensional virtual osteotomy technique for unruptured middle cerebral artery aneurysm.

OBJECTIVE: Individualized surgical simulation using three-dimensional (3D) imaging to allow safe performance of clipping surgery for unruptured middle cerebral artery (MCA) aneurysm via pterional keyhole mini-craniotomy was performed in 100 consecutive patients. METHODS: 3D images were reconstructed of the skin, skull, cerebral arteries and veins, and aneurysm. The size, shape, and location of the scheduled keyhole and the patient's head position were individually optimized using this preoperative simulation system. The site of opening of the sylvian fissure was also preoperatively determined according to the spatial relationships between the aneurysm and sylvian veins. 110 pterional keyhole clipping surgeries were consecutively performed in 100 patients. RESULTS: The mean diameter of the pterional keyhole was 25±2 mm. Magnetic resonance imaging detected lacunar infarction in 4 cases (3.6%) but no other abnormalities. 1 patient suffered a reversible ischemic neurological deficit and 1 patient (79 years old) showed mild dementia. The modified Rankin scale at 3 months after the operation was grade 0 in all cases except 1 patient with mild dementia (grade 1). Mini-mental state examination, Hamilton rating scale for depression, and Beck depression inventory were all significantly improved (p<0.01) after the operations. CONCLUSION: Pterional keyhole clipping surgery based on careful surgical simulation with 3D images is a safe and less invasive means to treat relatively small unruptured MCA aneurysms.

Lateral supraorbital keyhole approach to clip unruptured anterior communicating artery aneurysms.

OBJECT: Clipping of an anterior communicating artery (A-com A) aneurysm requires various working angles for safe manipulation and observation. The lateral supraorbital keyhole approach provides a more lateral subfrontal corridor to observe and clip an A-com A aneurysm than the standard Perneczky method. METHODS: Preoperative planning was individualized in each patient based on three-dimensional computed tomography (3D-CT) angiography and 3D-CT osteotomy planning images. The procedure consisted of a 40-50 mm periorbital skin incision, partial dissection of the anterior portion of the temporal muscle, a 35 x 25 mm keyhole minicraniotomy from the supraorbital area to the sphenoid ridge, and opening of the carotid cistern and sylvian fissure in an antegrade fashion. Ten keyhole clipping procedures were performed in 10 patients with unruptured A-com A aneurysms. RESULTS: No shaving of scalp hair, drain placement, or anticonvulsant medication were required. No patient suffered neurological deficits or abnormal findings on postoperative magnetic resonance imaging. Most patients were discharged on the 2nd to 3rd postoperative days except for one patient who suffered from meningitis. CONCLUSIONS: The lateral supraorbital keyhole approach is a minimally invasive treatment option for relatively small and unruptured A-com A aneurysms.

Surgical management for glossopharyngeal neuralgia associated with cardiac syncope: two case reports.

Two patients with glossopharyngeal neuralgia associated with cardiac syncope were treated with temporary cardiac pacemakers for cardiac syncope and then microvascular decompression. The offending arteries were the posterior inferior cerebellar artery in one patient and the anterior inferior cerebellar artery in the other. The offending arteries were attached to the glossopharyngeal nerve and the vagal nerve at the root entry zones. After surgery, the patients were free from neuralgia and cardiac syncope did not occur after the pacemakers were extracted. Implantation of a temporary cardiac pacemaker in the perioperative period ensures safe microvascular decompression.

Pterional keyhole approach to middle cerebral artery aneurysms through an outer canthal skin incision.

OBJECT: The supraorbital keyhole approach via an eyebrow skin incision provides a method for the minimally invasive clipping of aneurysms located in the circle of Willis, but has disadvantages for aneurysms located in the lateral Sylvian fissure. The pterional keyhole minicraniotomy via an outer canthal skin incision is proposed for the clipping of unruptured aneurysms of the middle cerebral artery (MCA). METHODS: The procedure consists of a 35-mm outer canthal skin incision, partial temporal muscle dissection restricted in the pterion, a 20-25-mm keyhole minicraniotomy, and a 15-20-mm dural incision to expose the lateral Sylvian fissure. Twenty keyhole clipping procedures were performed in 20 patients with unruptured MCA aneurysms. RESULTS: Only one patient showed a temporary mild hemiparesis (reversible ischemic neurological deficit) due to lacunar infarction. No shaving of scalp hair, drain placement, or anticonvulsant drug administration were required. Most patients were discharged on the 2nd or 3rd postoperative day. One patient showed a weakness of the frontalis muscle, but this complication was eliminated by the definition of a safety zone to avoid damage to the frontal branch of the facial nerve. CONCLUSIONS: The pterional keyhole approach via outer an canthal skin incision is another treatment option for relatively small, unruptured MCA aneurysms.

Endoscopic hematoma evacuation for hypertensive cerebellar hemorrhage.

OBJECT: The management of spontaneous cerebral hemorrhage remains controversial, particularly the surgical indications. Endoscopic surgery was evaluated for the treatment of spontaneous cerebellar hemorrhage. METHODS: The records of 69 patients with hypertensive cerebral hemorrhage were retrospectively reviewed. Patients treated by endoscopic surgery (n = 10) were compared with patients treated by conventional surgical hematoma evacuation (n = 10) under the same surgical indications. RESULTS: The surgical procedure time, duration of ventricular drainage, extent of hematoma evacuation, necessity for cerebrospinal fluid (CSF) shunt, surgical complications, and outcome at discharge and at 3 months after onset were compared. The extent of hematoma evacuation was greater in the endoscopic group (95.2 %) than in the craniectomy group (90.6 %) but without significant difference. The endoscopic technique (64.5 min) took significantly less time than the craniectomy method (230.6 min, p < 0.0001). The period of ventricular drainage was significantly shorter in the endoscopic group (2.6 days) compared to the craniectomy group (12.3 days, p < 0.01). CSF shunt surgery was required in no patient in the endoscopic group compared to three in the craniectomy group. CONCLUSION: Endoscopic hematoma evacuation is a rapid, effective, and safe technique for the removal of hypertensive cerebellar hemorrhage. Reduction of the mass effect can be accomplished with low risk of recurrent hemorrhage. Release of obstructive hydrocephalus in the early stage may improve the patient's outcome and decrease the requirement for permanent shunt emplacement.

The human cathepsin H gene encodes two novel minor histocompatibility antigen epitopes restricted by HLA-A*3101 and -A*3303.

Minor histocompatibility antigens (mHags) play crucial roles in the induction of graft versus host disease (GVHD) and/or graft versus leukaemia (GVL) effects following human leucocyte antigen (HLA)-identical haematopoietic stem cell transplantation (HSCT). Using HLA-A*3101- and -A*3303-restricted cytotoxic T lymphocyte (CTL) clones generated from different post-HSCT recipients, we identified two novel mHag epitopes encoded by the leader sequence of cathepsin H (CTSH) isoform a. The nonameric sequence ATLPLLCAR was defined as an HLA-A*3101-restricted epitope (CTSH(R)/A31), while a decameric peptide featuring a one N-terminal amino acid extension, WATLPLLCAR, was presented by HLA-A*3303 (CTSH(R)/A33). The immunogenicity of both epitopes was totally dependent on the polymorphic C-terminal arginine residue and substitution with glycine completely abolished binding to the corresponding HLA molecules. Thus, the immunogenicity of this mHag is exerted by differential HLA binding capacity. CTSH is relatively ubiquitously expressed at protein levels, thus it may be involved in GVHD and anti-leukaemic/tumour responses. Interestingly, however, CTL clones predominantly lysed targets of haematopoietic cell origin, which could not be explained in terms of the immunoproteasome system. Although the mechanisms involved in the differential susceptibility remain to be determined, these data suggest that CTSH-encoded mHags could be targets for GVL effects.

Metastatic tumor extending through the inferior vena cava into the right atrium: a case report of carcinoma of the uterine cervix with para-aortic lymph node metastases.

Carcinoma of the uterine cervix with cardiac metastasis is not uncommon in autopsy cases. However, an intraatrial tumor extending through the inferior vena cava (IVC) from the site of para-aortic lymph node metastasis has never been reported. A 57-year-old Japanese woman was admitted to an emergency care unit complaining of mild chest pain and shortness of breath. She had progressive multiple lymphatic metastases of stage IIIB squamous cell carcinoma of the uterine cervix that had initially been treated with concurrent chemoradiation. Echocardiogram showed pedunculated tumor in the right atrium (RA), and computed tomography demonstrated multiple pulmonary tumor embolism. Surgical specimen from the RA showed squamous cell carcinoma resembling the primary cervical tumor, and the peduncle appeared to originate from within the IVC. Postoperative ultrasonography showed severe stenosis of the abdominal IVC due to the invasive growth of para-aortic lymph node metastases. The stalk of the tumor originated from this lesion. We present an extremely unusual case of intraatrial metastatic tumor originating from the para-aortic lymph nodes of cervical cancer.

Endometrial extension of adenosquamous carcinoma of the uterine cervix.

Endometrial in situ extension of cervical cancer is extremely uncommon. Previous reports only present the cases of squamous cell carcinoma or related category. This report presented adenosquamous carcinoma of the uterine cervix that showed a paradoxical extension of each component in a 72-year-old patient. Main tumor in the cervix was revealed to be adenosquamous carcinoma. The glandular component extended to the vagina, while the squamous component grew into the entire uterine cavity and replaced the glandular epithelium. We presented the first case of adenosquamous carcinoma of the uterine cervix with vaginal and endometrial extension. Furthermore, the endometrium was replaced with squamous component, while the vagina was invaded by glandular component. The observed paradoxical extension of the present case was extremely rare.

Germinoma in the fourth ventricle.

A 33-year-old male presented with trigeminal, abducens, and facial nerve pareses associated with cerebellar signs. Magnetic resonance imaging showed a homogeneously enhanced mass occupying the lower half of the fourth ventricle and attached to the floor of the fourth ventricle. The mass was subtotally removed. The histological diagnosis was pure germinoma. Neuro-imaging cannot distinguish germinoma in the fourth ventricle from ependymoma. Germinoma in the fourth ventricle is extremely rare and requires histological differentiation from ependymoma to determine the indications for adjuvant irradiation and/or chemotherapy.

Orbital cystic neurinoma.

A 64-year-old woman presented with a 6-month history of exophthalmus of her right eye. She had no neurological deficit except for the exophthalmus and numbness in the right side of her forehead (frontal nerve territory). Neuro-imaging demonstrated a cystic mass in the right orbit. The tumour was totally removed by microsurgical transcranial surgery. The histological diagnosis was neurinoma. The origin of the tumour was considered to be the frontal nerve. Only two other cases of orbital cystic neurinoma have been reported. This rare clinical entity should be included in the differential diagnosis of a cystic mass in the orbit.

Seronegative Lambert-Eaton myasthenic syndrome: study of 110 Japanese patients.

The authors characterized the clinical and immunologic features of 110 patients with Lambert-Eaton myasthenic syndrome (LEMS). Anti-P/Q-type voltage-gated calcium channels (VGCC) antibodies were detected in 85% of the patients (seropositive) but not in the rest (seronegative). Except for the indication that small cell lung carcinoma is less common in seronegative patients, no significant differences were found in the clinical characteristics of patients who had or did not have anti-P/Q-type VGCC antibodies. The results of passive transfer experiments suggest that seronegative LEMS is also an autoantibody-mediated disorder.

A possible role of VEGF in osteolytic bone metastasis of hepatocellular carcinoma.

The incidence of bone metastasis was around 13% in 404 patients with hepatocellular carcinoma (HCC) who underwent treatment at the National Kyushu Cancer Center between 1988-97, which is a high value among various cancers. This is, in part, due to the prolonged survival time of HCC patients in recent years. Serum vascular endothelial growth factor (VEGF) levels were significantly elevated in HCC patients with bone metastases as compared to those in patients with liver cirrhosis/chronic hepatitis and HCC patients without bone metastasis. VEGF was positively stained in both the primary lesion and bone metastasis of HCC by immunohistochemistry. In the process of bone metastasis, an increase in bone resorption is a crucial step prior to invasion of the bone. VEGF, the most important angiogenic factor, has been shown to stimulate bone resorption through its effects on osteoclasts. Thus, HCC cells reach the bone marrow space, and then secrete VEGF which facilitates osteolytic bone metastasis. VEGF may also facilitate tumor growth in the bone by acting as an angiogenic factor once invasion of the bone is complete. This might be another reason for the high incidence of bone metastasis in HCC.