Current status of integrating oncology and palliative care in Japan: a nationwide survey.

BACKGROUND: Palliative care (PC) is increasingly recognized as essential for oncology care, and several academic societies strongly recommend integrating oncology and palliative care (IOP) in daily practice. Similarly, the Japanese government encouraged the implementation of IOP through the Cancer Control Act of 2007; however, its detailed progress remains unclear. Therefore, this cross-sectional nationwide survey was conducted to investigate the current status and hospital executive physicians' perception of IOP. METHODS: The questionnaire was developed based on IOP indicators with international consensus. It was distributed to executive physicians at all government-designated cancer hospitals (DCHs, n = 399) and matched non-DCHs (n = 478) in November 2017 and the results were compared. RESULTS: In total, 269 (67.4%) DCHs and 259 (54.2%) non-DCHs responded. The number of PC resources in DCHs was significantly higher than those in non-DCHs (e.g., full-time PC physicians and nurses, 52.8% vs. 14.0%, p < 0.001; availability of outpatient PC service ≥3 days per week, 47.6% vs. 20.7%, p < 0.001). Routine symptom screening was more frequently performed in DCHs than in non-DCHs (65.1% vs. 34.7%, p < 0.001). Automatic trigger for PC referral availability was limited (e.g., referral using time trigger, 14.9% vs. 15.3%, p = 0.700). Education and research opportunities were seriously limited in both types of hospitals. Most executive physicians regarded IOP as beneficial for their patients (95.9% vs. 94.7%, p = 0.163) and were willing to facilitate an early referral to PC services (54.7% vs. 60.0%, p < 0.569); however, the majority faced challenges to increase the number of full-time PC staff, and < 30% were planning to increase the staff members. CONCLUSIONS: This survey highlighted a considerable number of IOP indicators met, particularly in DCHs probably due to the government policy. Further efforts are needed to address the serious research/educational gaps.

Interleukin-25 is involved in cutaneous T-cell lymphoma progression by establishing a T helper 2-dominant microenvironment.

BACKGROUND: Interleukin (IL)-25 is a member of the IL-17 family, which can promote and augment T-helper (Th) type 2 responses. The expression of IL-25 and its cognate receptor, IL-25 receptor (IL-25R), is upregulated and correlated with disease activity in Th2-associated diseases. OBJECTIVES: To examine the expression and function of IL-25 in cutaneous T-cell lymphoma (CTCL). METHODS: Expression and location of IL-25 in lesional skin was investigated with immunohistochemistry. The effect of various cytokines on IL-25 production from normal human epidermal keratinocytes was assessed by quantitative reverse-transcription real-time polymerase chain reaction. Serum IL-25 levels were measured by enzyme-linked immunosorbent assay. The direct effect of IL-25 on tumour cells was also examined using CTCL cell lines and peripheral blood mononuclear cells in patients with Sézary syndrome. RESULTS: IL-25 expression was increased in epidermal keratinocytes in lesional skin of CTCL. Th2 cytokines, IL-4 and IL-13, and periostin induced IL-25 expression by normal human epidermal keratinocytes. Serum IL-25 levels were increased in patients with advanced CTCL and correlated with serum lactate dehydrogenase levels. MyLa cells expressed IL-25R and its expression was augmented by stimulation with IL-25. IL-25 enhanced IL-13 production from MyLa cells via phosphorylation of signal transducer and activator of transcription 6. Peripheral blood mononuclear cells from one patient with Sézary syndrome expressed IL-25R and showed increase of IL-13 production by IL-25. CONCLUSIONS: Th2 cytokines highly expressed in CTCL lesional skin induce IL-25 production by epidermal keratinocytes, which may, in turn, lead to formation of a Th2-dominant microenvironment through the direct induction of IL-13 by tumour cells.

Fucosylated TGF-ß receptors transduces a signal for epithelial-mesenchymal transition in colorectal cancer cells.

BACKGROUND: Transforming growth factor-ß (TGF-ß) is a major inducer of epithelial-mesenchymal transition (EMT) in different cell types. TGF-ß-mediated EMT is thought to contribute to tumour cell spread and metastasis. Sialyl Lewis antigens synthesised by fucosyltransferase (FUT) 3 and FUT6 are highly expressed in patients with metastatic colorectal cancer (CRC) and are utilised as tumour markers for cancer detection and evaluation of treatment efficacy. However, the role of FUT3 and FUT6 in augmenting the malignant potential of CRC induced by TGF-ß is unclear. METHODS: Colorectal cancer cell lines were transfected with siRNAs for FUT3/6 and were examined by cell proliferation, invasion and migration assays. The expression and phosphorylation status of TGF-ß downstream molecules were analysed by western blot. Fucosylation of TGF-ß receptor (TßR) was examined by lectin blot analysis. RESULTS: Inhibition of FUT3/6 expression by siRNAs suppressed the fucosylation of type I TßR and phosphorylation of the downstream molecules, thereby inhibiting the invasion and migration of CRC cells by EMT. CONCLUSION: Fucosyltransferase 3/6 has an essential role in cancer cell adhesion to endothelial cells by upregulation of sialyl Lewis antigens and also by enhancement of cancer cell migration through TGF-ß-mediated EMT.

Can a belly board reduce respiratory-induced prostate motion in the prone position?--assessed by cine-magnetic resonance imaging.

The purpose of this study is to evaluate the real-time respiratory motion of the prostate and surrounding tissues/organs in the supine and prone positions and to investigate, using cine-MRI, whether a belly board can reduce respiratory-induced motion in the prone position. Cine-MRI scans were made of 13 volunteers in the supine and prone positions on a flat board and in two different prone positions using a belly board. Images in cine mode were recorded for 20 seconds. For each session, the points of interest (POIs) were located at the apex, base, mid-anterior surface and mid-posterior surface of the prostate; the tip of the seminal vesicle; the pubic symphysis; and the sacrum. The maximum range and standard deviation (SD) of the displacement from the mean value were calculated. The SDs for each of the four different positions were compared using a paired t-test. Respiratory-induced prostate motion was significantly larger in the prone position than in the supine position. However, when a belly board was used in the prone position, motion in the prostate and surrounding tissues/organs was significantly reduced. There were no significant differences between the two different positions using a belly board in any of the POIs.

The endoscopic diagnosis of nonerosive reflux disease using flexible spectral imaging color enhancement image: a feasibility trial.

Nonerosive reflux disease (NERD) is classified into grade M (minimal change, endoscopically; erythema without sharp demarcation, whitish turbidity, and/or invisibility of vessels due to these findings) and grade N (normal) in the modified Los Angeles classification system in Japan. However, the classification of grades M and N NERD is not included in the original Los Angeles system because interobserver agreement for the conventional endoscopic diagnosis of grades M or N NERD is poor. Flexible spectral imaging color enhancement (FICE) is a virtual chromoendoscopy technique that enhances mucosal and vascular visibility. The aim of this study is to evaluate whether the endoscopic diagnosis of grades M or N NERD using FICE images is feasible. Between April 2006 and May 2008, 26 NERD patients and 31 controls were enrolled in the present study. First, an experienced endoscopist assessed the color pattern of minimal change in FICE images using conventional endoscopic images and FICE images side-by-side and comparing the proportion of minimal change between the two groups. Second, three blinded endoscopists assessed the presence or absence of minimal change in both groups using conventional endoscopic images and FICE images separately. Intraobserver variability was compared using McNemar's test, and interobserver agreement was described using the kappa value. Minimal changes, such as erythema and whitish turbidity, which were detected using conventional endoscopic images, showed up as navy blue and pink-white, respectively, in color using FICE images in the present FICE mode. The NERD group had a higher proportion of minimal change, compared with the control group (77% and 48%, respectively) (P= 0.033). In all three readers, the detection rates of minimal change using FICE images were greater than those using conventional endoscopic images (P= 0.025, <0.0001, and 0.034 for readers A, B, and C, respectively). The kappa values for all pairs of three readers using FICE images were between 0.683 and 0.812, while those using conventional endoscopic images were between 0.364 and 0.624. Thus, the endoscopic diagnosis of grades M or N NERD using FICE images is feasible and may improve interobserver agreement.

Hepatic falciform ligament artery in patients with chronic liver diseases: detection on computed tomography hepatic arteriography.

BACKGROUND: The detection rate of hepatic falciform ligament artery (FLA) has been reported as ranging from 2-25%. The rate of FLA on laparotomy, however, is reported to be higher, at 68%. PURPOSE: To compare the detection rate of FLA on computed tomography hepatic arteriography (CTHA) with that on angiography and dynamic CT, and to clarify the clinical significance of FLA in patients with chronic liver disease. MATERIAL AND METHODS: 126 consecutive patients underwent CTHA angiography and dynamic CT to evaluate suspected liver tumors. Liver function was classified as follows: normal, n=5; Child-Pugh class A, n=94; B, n=21; and C, n=6. All CT images were obtained using multidetector (MDCT) scanners (Aquilion; Toshiba, Tokyo, Japan). For CTHA, CT images were obtained during contrast material injection through the left hepatic, proper, or common hepatic artery. On CT, FLAs were retrospectively identified within the hepatic falciform ligament and the hepatic round ligament by the paging method on a workstation (TWS-5000; Toshiba, Tokyo, Japan). The detection rates were compared among the three modalities (hepatic arterial phase of dynamic CT, CTHA, and angiography). The calibers of FLA were also correlated with the hepatic function of the patients. RESULTS: The detection rates of FLA by angiography, dynamic CT, and CTHA were 37% (47/126), 10% (13/126), and 77% (97/126), respectively. The calibers of FLA increased as the hepatic function deteriorated (P=0.001). CONCLUSION: The detection rates of FLA with CTHA are far higher than those with angiography and dynamic CT. Careful interpretation with recognition of FLA on CTHA images is important, as inadvertent embolization or chemotherapeutic infusion of the FLA may result in supraumbilical skin rash.

Heparanase expression in endometrial cancer: analysis of immunohistochemistry.

The human enzyme heparanase has been shown to function in tumour progression, metastatic spread and tumour angiogenesis. The aim of the present study was to assess heparanase expression assessed by immunohistochemical staining (IHC) in endometrial cancer in correlation with clinicopathological factors. A total of 52 endometrial cancers were obtained from previously untreated patients (median age, 56 years, range, 35-80 years). The expression of heparanase was evaluated by using IHC with anti-heparanase polyclonal antibody. This antibody was raised by immunising a rabbit with a peptide containing the amino acid residues from 238 to 250 of the heparanase. The IHC data were used to determine the relationship between heparanase expression, and clinicopathological parameters. IHC showed that the heparanase was expressed in 23 of 52 (44.2%) endometrial cancers. Heparanase was abundantly and equally expressed in both the cytoplasm and the cell membrane of the cells in endometrial cancer. Strong heparanase-positive staining was also seen at the invasive front of the tumour into myometrium. The expression was significantly related to lymph-vascular space involvement (p = 0.0028), depth of myometrial invasion (p = 0.0026), and histological tumour grade (p = 0.0135). In six tumours with positive lymph nodes, the heparanase expression was observed as being higher compared with tumours with negative lymph nodes, which was not significant (p = 0.2349). In terms of peritoneal cytology, ovarian metastasis, and cervical invasion, we observed no significant difference in the heparanase expression assessed by IHC. These results suggest that the expression of heparanase may promote tumour invasion into myometrium and lymph vascular space in endometrial cancer.

Neoadjuvant chemotherapy followed by extended-field concurrent chemoradiotherapy in squamous cell carcinoma of the cervix with positive paraaortic lymph nodes: two cases.

PURPOSE: To report the feasibility of neoadjuvant chemotherapy (NAC) followed by extended-field concurrent chemoradiotherapy (EF-CCRT) for squamous cell carcinoma of the cervix (CC) with paraaortic lymph node (PAN) metastasis. METHODS: Two patients were diagnosed with CC with positive PAN, and received two courses of cisplatin (120 mg/m2) in a neoadjuvant setting. They then received extended-field, external-beam radiotherapy (50.4 Gy) followed by intracavitary brachytherapy concurrently with cisplatin (20 mg/m2 x 5 days) at 21-day intervals. RESULTS: EF-CCRT was interrupted in one patient for five days because of grade 4 neutropenia. No severe late toxicities were observed. The two patients are alive with no evidence of recurrence at present. CONCLUSIONS: NAC followed by EF-CCRT is feasible and may improve the survival outcome of patients with CC with positive PAN.

Age-related maculopathy and sunlight exposure evaluated by objective measurement.

AIM: To study the relationship between age-related maculopathy (ARM) and exposure to sunlight using an objective method. METHODS: In a case-control study of Japanese men aged > or = 50 years (67 controls without ophthalmic disease and 148 with ARM), those with ARM were separated into groups of early (n = 75) and late (n = 73) ARM. Facial wrinkle length and area of hyperpigmentation, which are considered to be associated with exposure to sun, were measured using imaging with computer-based image analysis. Skin tone was also measured on the upper inner arm, which is not exposed to sun. Early and late ARM association with skin measurements was then evaluated. RESULTS: Significantly more facial wrinkling (p = 0.047, odds ratio 3.8; 95% CI 1.01 to 13.97) and less facial hyperpigmentation (p = 0.035, odds ratio 0.3; 95% CI 0.08 to 0.92) was present in late ARM cases. The relationship between skin tone and ARM risk was not statistically significant. CONCLUSIONS: This objective method showed that lifetime exposure to sunlight is an important factor in the progression of late ARM. An individual's reaction to sunlight exposure may have a role in ARM progression in addition to total lifetime exposure to sunlight.

Recurrent juvenile granulosa cell tumor of the ovary managed by palliative radiotherapy.

Prognosis in the few patients with advanced-stage juvenile granulosa cell tumor (JGCT) of the ovary has traditionally been unfavorable. We report a recurrent JGCT patient managed by palliative radiotherapy. A 37-year-old woman with recurrent JGCT received a combination of paclitaxel-carboplatin chemotherapy and then single-agent docetaxel, but her disease progressed with multiple abdominal masses and ascites. We chose palliative radiation therapy to relieve her complaints. Whole-abdominal external beam radiotherapy with pelvic boost was delivered. She tolerated the treatment well. After the completion of radiotherapy, ultrasonography showed shrinkage of the tumor, and the ascites disappeared. We should consider using radiation therapy in a palliative setting for such patients with recurrent JGCT suffering from abdominal complaints.

Increased cytotoxicity of carbon tetrachloride in a human hepatoma cell line overexpressing cytochrome P450 2E1.

Cytotoxic free radicals generated during the metabolism of carbon tetrachloride by cytochrome P450 2E1 (CYP2E1) are thought to cause hepatotoxicity. Here, the cytotoxic effects of carbon tetrachloride in a liver cell line expressing CYP2E1 (HLE/2E1) are compared with those in the mother cell line (HLE). The effects of carbon tetrachloride on the gene expression of HSP70, a potential marker of oxidative stress, were also examined. The viability of HLE/2E1 cells after exposure to carbon tetrachloride was significantly decreased compared with that of HLE cells. Northern blot analysis revealed that the HSP70 mRNA level was significantly increased after carbon tetrachloride treatment in both cell lines, while the magnitude of its increase was much greater in HLE/2E1 cells than in HLE cells. These results suggest that the oxidative stress induced by CYP2E1 plays an important role in the increase in cytotoxicity of carbon tetrachloride in CYP2E1-overexpressing cells.

Histological findings after placement of a self-expanding stent in rectal carcinoma with complete obstruction--case report.

Patients with acute obstruction due to colorectal carcinomas frequently require emergency surgery. However, such emergency procedures are associated with various complications, a high mortality rate and a poor prognosis. If the obstruction could be immediately relieved, the patient could later undergo an elective operation with a much better prognosis. Recently, expanding metallic stents have been used to treat obstruction due to colorectal carcinoma. In the case reported here, we initially inserted a colonoscopic retrograde bowel drainage tube per anus to achieve decompression. We then placed a self-expanding metallic stent, since we anticipated a prolonged preoperative period due to high fever, congestive heart failure, cerebral infarction, and persistent high blood sugar concentrations. The patient had no complications for 57 days after placement of the stent, and eventually underwent an elective operation. Histologically, the side of the cancerous lesion compressed by the stent was thin and consisted solely of a serosal layer. Implantation of a metallic stent is safe for the treatment of acute malignant obstruction. Stent placement is indicated not only as a palliative treatment for inoperable or recurrent cases, but also as a preoperative procedure before elective surgical resection.

Osteoporosis, bone turnover and hypogonadism in elderly men with treated leprosy.

In male hypogonadism associated with bone loss, it is important to determine whether bone loss continues with ageing and an increased risk of fracture. We studied bone metabolism in 86 male leprosy patients, who were classified according to the presence or absence of osteoporosis. Osteoporosis was present when men had lumbar compression fractures or a mean BMD-2SD that of normal Japanese men in each age decade. Four men had fractures. Serum concentrations of 1,25-dihydroxyvitamin D and high-sensitivity parathyroid hormone were almost normal in both groups, whereas free testosterone and oestradiol were significantly lower in the osteoporosis group than in the non-osteoporosis group (free testosterone: P < 0.01, oestradiol: P < 0.05). The urinary concentrations of pyridinoline and deoxypyridinoline, as a marker of bone absorption, were significantly higher in the osteoporosis group than in the non-osteoporosis group (pyridinoline: P < 0.01, deoxypyridinoline: P < 0.01). The serum concentration of osteocalcin, a marker of bone formation, was significantly higher in the osteoporosis group than in the non-osteoporosis group (P < 0.01). Elevated concentration means that bone repair is increased possibly because of compensation mechanisms for increased bone loss. In the osteoporosis group, hypogonadism occurred, and high bone turnover continued even in older men. We recommend clinical studies of treatment such as replacement therapy to prevent bone loss and increasing risk of fractures in older men with leprosy.

[A case of central retinal artery occlusion after anterior posterior fusion of the lumbar spine].

We report a case of central retinal artery occlusion after anterior-posterior fusion of the lumbar spine. The patient suddenly lost his vision of the right eye in the ICU just after the end of long procedure for anterior-posterior fusion of the lumbar spine. The patient was diagnosed as having central retinal artery occlusion, and treated successfully with treatments including immediate administration of urokinase and PGE1, stellate ganglion block, and hyperbaric oxygen therapy. The patient was discharged from the hospital on the 54th postoperative day with adequate vision to drive a car. Central retinal artery occlusion is a rare but very serious complication during and after supine surgery with prone position. It is very important for us to be aware of its possible occurrence. We have to diagnose and treat, as soon as possible, the vision loss after the spine surgery.

Significance of adrenomedullin under cardiopulmonary bypass in children during surgery for congenital heart disease.

To elucidate the effect of adrenomedullin (AM) on fluid homeostasis under cardiopulmonary bypass (CPB), we investigated the serial changes in plasma AM and other parameters related to fluid homeostasis in 13 children (average age, 28.2 months) with congenital heart disease during cardiac surgery under CPB. Arterial blood and urine samples were collected just after initiation of anesthesia, just before commencement of CPB, 10 min before the end of CPB, 60 min after CPB, and 24 h after operation. Plasma AM levels increased significantly 10 min before the end of CPB and decreased 24 h after operation. Urine volume increased transiently during CPB, which paralleled changes in AM. Simple regression analysis showed that plasma AM level correlated significantly with urinary vasopressin, urine volume, urinary sodium excretion, and plasma osmolarity. Stepwise regression analysis indicated that urine volume was the most significant determinant of plasma AM levels. Percent rise in AM during CPB relative to control period correlated with that of plasma brain natriuretic peptide (r = 0.57, P < 0.01). Our results suggest that AM plays an important role in fluid homeostasis under CPB in cooperation with other hormones involved in fluid homeostasis.

Temporal profiles of the levels of endogenous antioxidants after four-vessel occlusion in rats.

Although it is known that development of lipid peroxidation after ischemia occurs predominantly in vulnerable regions, temporal profiles of antioxidants after ischemia have not been regionally elucidated. After reperfusion periods of 0, 3, 24, and 72 hours following 20 minutes of four-vessel occlusion (n = 6 in each group), the concentration of total glutathione (GSH) and the activities of superoxide dismutase (SOD), catalase, and glutathione peroxidase (GSH-Px) were assayed in the hippocampus, parietal cortex, striatum, thalamus, and brain stem. The levels of all antioxidants were unchanged in all regions without reperfusion; however, the concentration of total GSH significantly decreased in the hippocampus at 3 hours after the onset of reperfusion, and showed a maximum decrease in the hippocampus (68% of the sham-control level), parietal cortex (78% of the sham-control level), and striatum (76% of the sham-control level) after 24 hours of reperfusion. After 72 hours of reperfusion, these regions and the thalamus showed restoration and an increase in the total GSH concentration, respectively. The activities of SOD, GSH-Px, and catalase were stable during the reperfusion period, but the hippocampus showed significant increases in these enzyme activities and the parietal cortex and striatum showed significant increases in SOD activities at 72 hours after the onset of reperfusion. These results indicate that endogenous antioxidants take 72 hours for restoration in vulnerable regions after 20 minutes of four-vessel occlusion in rats.