IFN-γ from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer.

BACKGROUND: PD-L1 (programmed cell death 1 ligand 1) on tumour cells suppresses host immunity through binding to its receptor PD-1 on lymphocytes, and promotes peritoneal dissemination in mouse models of ovarian cancer. However, how PD-L1 expression is regulated in ovarian cancer microenvironment remains unclear. METHODS: The number of CD8-positive lymphocytes and PD-L1 expression in tumour cells was assessed in ovarian cancer clinical samples. PD-L1 expression and tumour progression in mouse models under conditions of altering IFN-γ signals was assessed. RESULTS: The number of CD8-positive cells in cancer stroma was very high in peritoneally disseminated tumours, and was strongly correlated to PD-L1 expression on the tumour cells (P<0.001). In mouse models, depleting IFNGR1 (interferon-γ receptor 1) resulted in lower level of PD-L1 expression in tumour cells, increased the number of tumour-infiltrating CD8-positive lymphocytes, inhibition of peritoneal disseminated tumour growth and longer survival (P=0.02). The injection of IFN-γ into subcutaneous tumours induced PD-L1 expression and promoted tumour growth, and PD-L1 depletion completely abrogated tumour growth caused by IFN-γ injection (P=0.01). CONCLUSIONS: Interferon-γ secreted by CD8-positive lymphocytes upregulates PD-L1 on ovarian cancer cells and promotes tumour growth. The lymphocyte infiltration and the IFN-γ status may be the key to effective anti-PD-1 or anti-PD-L1 therapy in ovarian cancer.

Relationships of C-reactive protein, uric acid, and glomerular filtration rate to arterial stiffness in Japanese subjects.

The relationships between C-reactive protein (CRP), uric acid (UA), glomerular filtration rate (GFR), and arterial stiffness have not been fully investigated. The aim of this study was to clarify whether CRP, UA, and estimated GFR are related to arterial stiffness estimated using brachial-ankle pulse wave velocity (baPWV). The subjects were local government employees (3412 men and 854 women). baPWV, CRP, UA, GFR, and conventional risk factors were evaluated. Multiple linear regression analyses revealed that CRP and UA were significantly related to an elevation of PWV in male and female subjects, and that the estimated GFR was significantly related to an elevation of PWV in male subjects. Significant progressive increases in baPWV were observed across the quartiles of CRP in male subjects and for UA in male and female subjects. In female subjects, the relationship of quartile CRP to baPWV had marginal significance (P = 0.055). But, in male and female subjects, quartile of estimated GFR had no significant association with PWV. These results suggest that CRP and UA are associated with an increase of arterial stiffness in male and female subjects, and that estimated GFR is possibly related to arterial stiffness in male subjects.

Effect of topical application of a stable prostacyclin analogue, SM-10902 on wound healing in diabetic mice.

The mechanism of wound healing induced by topical application of an ointment containing a new stable prostacyclin analogue, SM-10902 ((+)-methyl[2-[(2R,3aS,4R,5R, 6aS)-octahydro-5-hydroxy-4-[(E)-(3S,5S)-3-hydroxy-5-methyl-1- nonenyl]-2-pentalenyl] ethoxy] acetate), was investigated in the full-thickness wounds of genetically diabetic mice (db/db mice). The db/db mice treated with SM-10902 ointment (1, 10 and 100 micrograms/g) showed greater decrease in wound lesion area not covered with epidermis and fewer complete healing days than those treated with ointment base, and the effects of this prostacyclin analogue were greater than those of lysozyme chloride ointment (50 mg/g, Reflap ointment). SM-10902 ointment increased skin blood flow in the central site of the wound with development of wound healing. Histological evaluation of wounds revealed that SM-10902 ointment increased the capillary number during the early stage of the wound-healing process. These results suggest that SM-10902 ointment promotes wound healing through the stimulation of angiogenesis and the improvement of blood flow in neovascularization of repairing wound and may be useful in the treatment of skin ulcers caused by peripheral circulatory insufficiency.

Withdrawal-emergent rabbit syndrome during dose reduction of risperidone.

Rabbit syndrome (RS) is a rare extrapyramidal side effect caused by prolonged neuroleptic medication. Here we present a case of withdrawal-emergent RS, which is the first of its kind to be reported. The patient developed RS during dose reduction of risperidone. The symptom was treated successfully with trihexyphenidyl anticholinergic therapy. The underlying mechanism of withdrawal-emergent RS in the present case may have been related to the pharmacological profile of risperidone, a serotonin-dopamine antagonist, suggesting the pathophysiologic influence of the serotonin system in the development of RS.

Inhibitory effect of SM-20550, an Na+/H+ exchange inhibitor, on accumulation of leukocytes in ischemia and reperfusion.

The effect of an Na+/H+ exchange inhibitor, SM-20550, on the adhesion, emigration and accumulation of leukocytes was studied in ischemia and reperfusion injury models using rat mesenteric venules or rabbit heart. Anesthetized rats underwent occlusion of the superior mesenteric artery (20 min) followed by reperfusion (60 min). After ischemia and reperfusion, the numbers of adherent and emigrated leukocytes increased significantly. Bolus intravenous administration of SM-20550 reduced the numbers of adherent and emigrated leukocytes in a dose-dependent manner, with statistical significance at dosages >0.1 mg/kg. Anesthetized rabbits underwent occlusion of the coronary artery (30 min) followed by reperfusion (5 h). Intravenous administration of SM-20550 before ischemia significantly reduced the neutrophil accumulation in the area-at-risk by 46% and reduced the infarct size by 38%. These results suggest that the inhibitory effect of SM-20550 on the neutrophil accumulation could be one of the mechanisms by which this drug limits the severity of infarctions.

Perception and utilization of social support in diabetic control.

This study examined the influence of social support (perception and utilization) on diabetic control. Subjects were 178 patients with diabetes mellitus [insulin dependent diabetes mellitus (IDDM) = 26, non-insulin dependent diabetes mellitus (NIDDM)= 152]. HbA1c values was used as an indicator of diabetic control. Assessment of social support was performed using the Stress and Coping Inventory. HbA1c values were significantly related to the presence or absence of participation in a diabetic education program as well as scores on perception and utilization of social supports. The participation in the diabetic education program was not significantly associated with the two social supports, however, the two social support factors interacted significantly with one another. As for type of DM, these findings were stronger in IDDM patients. These results suggest that, in particular patients with NIDDM, although diabetes education is effective for decreasing HbA1c, a combination of the two social supports also decrease the HbA1c value, independent of diabetic education.

The disclosure of information to cancer patients and its relationship to their mental state in a consultation-liaison psychiatry setting in Japan.

In Japan, as in some other countries, not all cancer patients are informed of their diagnosis and expected prognosis. However, we do not know enough about the relationship between the kind of information given to cancer patients and their mental state. The following is a study that examines this relationship. The subjects were 81 adult cancer inpatients referred to psychiatrists. Those with mental disorders before admission or with delirium were excluded. The subjects were classified into three groups according to the kind of information given to them: 28 were not informed of a diagnosis of cancer, 36 were informed of a diagnosis of cancer, and 17 were informed of both a diagnosis of cancer and a poor prognosis. The distributions of DSM-IV Axis I diagnoses were nearly equal among the three groups of patients. In each group, more than 90% of patients were diagnosed as having either major depressive disorder or adjustment disorders. In the results of HAM-D, HAM-A, and a question about irritability, the mean total HAM-A scores and mean scores for the factors of Suicide, Behavior at Interview, and Irritability, differed significantly among the three groups. They were highest in patients who were not informed of a diagnosis of cancer. The authors discuss the nature of relationship between the disclosure of information and the mental state in cancer patients.

Changes in disclosure of information to cancer patients in a general hospital in Japan.

The disclosure of information to cancer patients is one of the most important issues in oncological practice. In Japan, as in some other countries, few cancer patients were ever given a truthful statement of their diagnosis. However, today more and more patients are being informed of their diagnosis and prognosis. This study investigates the nature of these changes in disclosure policy and suggests possible explanations. We reviewed the medical and nursing charts of 122 adult cancer patients admitted to our hospital in 1993 and 137 admitted in 1998. We examined the information they had been given, and their sociodemographic and medical characteristics. The diagnosis of cancer was shared with 27% of patients in 1993. In 1998, however, 71% were informed of their cancer, and 10% were also told they had a poor prognosis. The rate of disclosure was lower for older patients and those with advanced cancer in both 1993 and 1998. In 1998 the rate was higher in patients undergoing chemotherapy and/or surgery. The higher level of disclosure in 1998 was due basically to the growing importance of informed consent. Psychiatric referrals increased from 2% in 1993 to 10% in 1998. Psychiatrists may have contributed to these changes in the disclosure of information.

Stress coping and social support in glucose tolerance abnormality.

We examined coping with stress, including social support, dealing with illness, and mood states, in a sample of 600 persons who underwent primary health-care screening. Subjects were not yet diagnosed as having glucose tolerance abnormality and considered themselves healthy before the examination. Although no significant differences on the existence and perception of social support were found, the utilization of social support was significantly and negatively correlated with the level of glucose tolerance abnormality. The results suggest that poor utilization of social support is associated with the onset of glucose tolerance abnormality.

SM-20220, a potent Na+/H+ exchange inhibitor, improves consciousness recovery and neurological outcome following transient cerebral ischaemia in gerbils.

We studied the cerebroprotective effect of SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulphonate), a newly synthesized Na+/H+ exchanger (NHE) inhibitor, in Mongolian gerbil global ischaemia. Transient cerebral ischaemia was induced by clipping both common carotid arteries for 30 min followed by 24h reperfusion. Intravenous administration of SM-20220 (0.3 or 1.0 mg kg(-1)) immediately after reperfusion significantly shortened the consciousness recovery time (P < 0.01). SM-20220 also improved the neurological outcome (McGraw's scale) after reperfusion. At the dose of 1.0 mg kg(-1), the mortality rate was significantly reduced at 24 h after reperfusion (P < 0.01). This study shows that NHE is involved in the aggravation of cerebral function, represented by consciousness recovery, and neurological outcome following transient forebrain ischaemia, and that its inhibitor may exert protective effects on post-ischaemic brain damage.

Delayed treatment of Na+/H+ exchange inhibitor SM-20220 reduces infarct size in both transient and permanent middle cerebral artery occlusion in rats.

SM-20220 (N-(aminoiminomethyl)-1-methyl-1H-indole-2-carboxamide methanesulfonate) is a Na+/H+ exchanger (NHE) inhibitor which has been shown to attenuate cerebral edema in the rat transient focal ischemia model. However, to date, the effect of SM-20220 on cerebral infarction has not been examined. The present experiments were designed to investigate these effects, using both transient and permanent middle cerebral artery (MCA) occlusion models in rats. A dose of 1 mg/kg given intravenously 30 min after the onset of transient MCA occlusion reduced the infarcted area. In the permanent MCA occlusion model, SM-20220 reduced the infarcted area when treatment was delayed for 5, 30 or 60 min after the onset of ischemia. The present results show that NHE has a crucial role in the pathogenesis of ischemic brain damage. This NHE inhibitor may be useful for treating stroke because of its effectiveness with both forms of ischemia and because of its postischemic administration.

Content analysis of group work sessions in the context of an educational program for inpatient diabetes patients.

This study investigated the changes in emotions and attitudes of diabetic patients as observed in group work sessions linked to an inpatient diabetic educational program. Using content analysis of transcripts from Sessions 1 and 3 of 8 selected groups (40 patients), in Session 1 negative emotions or attitudes such as anxiety, remorse, or self-blame, a lack of understanding of diabetes, along with a willingness to undertake self-care were frequently expressed. In Session 3, more positive emotions and attitudes towards self-care (willingness, specific plans, and resolutions), satisfaction, and relief or hope were frequently expressed. These results suggest that the patients participating in the group work sessions moved toward adaptation to diabetes, although the effects of the group work were not separated from those of the inpatient educational program.

[AFP producing gastric cancer manifested by metastasis to the tentorium cerebelli; case report and review of the literature].

We report a case of AFP producing gastric cancer manifested by metastasis to the tentorium cerebelli. A 66-year-old male patient was admitted with dysarthria, occipital headache and nausea on May 1, 1990. Neurological examination revealed signs of increased intracranial pressure and the right-sided cerebellar hemispheric signs. CT and MRI showed a round tumor shadow 3cm in diameter, which originated in the right-side tentorium cerebelli and grew in the posterior fossa. Tumor stains fed by the right tentorial artery were recognized by angiography. Serum AFP level was 503.5ng/ml. The patient underwent an operation under general anesthesia in the prone position. The tumor was totally removed via the suboccipital transtentorial approach. Histological examination revealed AFP producing adenocarcinoma. The patient was found to have a gastric cancer after neurosurgical operation, and underwent subtotal gastrectomy by surgeons. Serum AFP level was 254.5ng/ml after removal of metastatic brain tumor, and 5.0ng/ml after subtotal gastrectomy.

[Pick's disease in senescence].

We report two patients with Pick's disease in senescence. Patient 1 is a 78-year-old woman. She developed abnormal behavior at the age of 76 years. Neurological examination at age 76 revealed poor rapport, easy angriness, "Denkfaulheit", oral tendency, and slight dementia [WAIS (Wechsler Adult intelligence Scale) total IQ 62]. Cranial CT scan and MRI showed bilateral atrophy of the frontal and temporal lobe, especially of the temporal lobe. Patient 2 is a 73-year-old man. He developped sexual abnormal behavior and "triebhafte Hemmungslossigkeit" at the age of 71 years. Neurological examination at age 72 revealed poor rapport, lack of spontaneity, easy angriness, "Denkfaulheit", and slight dementia [WAIS total IQ 91]. Transient "stehende Redensarten" was noticed. Cranial CT scan and MRI showed bilateral atrophy of the frontal and temporal lobe, especially of the frontal lobe. To our knowledge, Pick's disease with an onset in the senescence is very rare. Pick's disease should be included in the differential diagnosis of abnormal behavior in the senescence.

[Two cases of renal cell carcinoma that underwent radical nephrectomy subsequent to complete tumor enucleation].

We have reported the favorable therapeutic results of non-ischemic complete enucleation using a microwave tissue coagulator as a method of nephron-sparing surgery for small renal cell carcinoma (RCC). We experienced two elective cases that underwent translumbar nephrectomy subsequent to the tumor enucleation. The first case showed another RCC in a cyst, concomitant with the enucleated RCC. The second case was a pT3a spindle cell carcinoma with high-grade malignancy. We decided to nephrectomize these enucleated kidney after obtaining well-informed consent. Here we report these controversial cases and discuss about the indication and outcomes of complete tumor enucleation for small RCC.