Treatment of early-stage mycosis fungoides: results from the PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is a prospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) in patients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB) staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centres in 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smaller percentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariate analysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA, 20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs. T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%, while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improved significantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices, and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, future treatment guidelines for early-stage MF need to address these issues.

[Extraction and Separation of Sinapine from Rapeseed Cake and the Mode of Action of Melanin Production Inhibition].

Brassica campestris L. is the important oil-bearing crop in China. Rapeseed cake is the main byproduct of rapeseed oil extraction. As the main active ingredient in rapeseed cake, sinapine has several important biological activities. Therefore, the inhibitory activity of sinapine on tyrosinase in vitro and its free radical-scavenging rate were determined. Tyrosinase activity in A-375 human melanocytes was also investigated and the effects of sinapine on the melanin content and its antioxidant effects on melanin biosynthesis were studied. The results showed that sinapine had significant antioxidant activity. Sinapine significantly inhibited A-375 human melanocytes in a dose-dependent manner. Sinapine inhibited melanin synthesis in A-375 cells by downregulating the mRNA and protein expression of TRP-1, TRP-2, and MITF factors. The results showed that rapeseed cake sinapine inhibited melanin production and could be used as a potential active ingredient in the development of whitening agents.

T-category reflects the histopathologic characteristics of gallbladder cancer.

AIMS: Gallbladder (GB) cancer is a relatively uncommon gastrointestinal malignancy and is known to often result in unfavorable outcomes. Recent advances in aggressive surgical resection have improved the overall survival rate of patients with GB cancer. We aimed to evaluate the outcomes and prognostic factors of GB cancer following a surgical resection with curative intent. METHODS: Between March 2001 and March 2009, 89 patients with GB cancer underwent surgical resection with curative intent at the National Cancer Center of Korea. We then conducted a retrospective analysis of clinicopathologic data. RESULTS: Nineteen patients underwent simple cholecystectomy and 70 patients underwent extended cholecystectomy. Tumor-free resection margins were obtained in 84 cases. The 1-, 3- and 5-year disease-specific survival rates in the 89 patients were 85.8%, 68.0% and 64.1%, respectively. By multivariate analysis, only the T-category was significant (p < 0.001). The T-category showed a close correlation with all of the other histopathologic factors which were significant in univariate analysis. CONCLUSION: The T-category of GB cancer represents not only the depth of the primary tumor but also the aggressiveness of its histopathologic nature.

Downregulation of Spry2 by miR-21 triggers malignancy in human gliomas.

Gliomas are associated with high mortality because of their exceedingly invasive character. As these tumors acquire their invasiveness from low-grade tumors, it is very important to understand the detailed molecular mechanisms of invasion onset. Recent evidences suggest the significant role of microRNAs in tumor invasion. Thus, we hypothesized that deregulation of microRNAs may be important for the malignant progression of gliomas. We found that the aberrant expression of miR-21 is responsible for glioma invasion by disrupting the negative feedback circuit of Ras/MAPK signaling, which is mediated by Spry2. Upregulation of miR-21 was triggered by tumor microenvironmental factors such as hyaluronan and growth factors in glioma cells lacking functional phosphatase and tensin homolog (PTEN), but not harboring wild-type PTEN. Consistently with these in vitro results, Spry2 protein levels were significantly decreased in 79.7% of invasive WHO grade II-IV human glioma tissues, but not in non-invasive grade I and normal tissues. The Spry2 protein levels were not correlated with their mRNA levels, but inversely correlated with miR-21 levels. Taken together, these results suggest that the post-transcriptional regulation of Spry2 by miR-21 has an essential role on the malignant progression of human gliomas. Thus, Spry2 may be a novel therapeutic target for treating gliomas.

Effects of heparin-binding epidermal growth factor-like growth factor on cell repopulation and signal transduction in periodontal ligament cells after scratch wounding in vitro.

BACKGROUND AND OBJECTIVE: A growing amount of attention has been placed on periodontal regeneration and wound healing for periodontal therapy. This study was conducted in an effort to determine the effects of heparin-binding epidermal growth factor-like growth factor on cell repopulation and signal transduction in periodontal ligament cells after scratch wounding in vitro. MATERIAL AND METHODS: Human periodontal ligament cells were acquired from explant tissue of human healthy periodontal ligament. After the wounding of periodontal ligament cells, the change in expression of heparin-binding epidermal growth factor-like growth factor and epidermal growth factor receptors 1-4 mRNA was assessed. The effects of heparin-binding epidermal growth factor-like growth factor on periodontal ligament cell proliferation and repopulation were assessed in vitro via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and by photographing the injuries, respectively. Extracellular signal-regulated kinase (Erk)1/2, p38 and Akt phosphorylation was characterized via western blotting. RESULTS: Scratch wounding resulted in a significant up-regulation of heparin-binding epidermal growth factor-like growth factor mRNA expression, whereas wounding had no effect on the expression levels of epidermal growth factor receptors 1-4. Interestingly, no expression of epidermal growth factor receptors 2 and 4 was detectable prior to or after wounding. Heparin-binding epidermal growth factor-like growth factor treatment promoted the proliferation and repopulation of periodontal ligament cells. The scratch wounding also stimulated the phosphorylation of Erk1/2 and p38, but not of Akt, in periodontal ligament cells, and heparin-binding epidermal growth factor-like growth factor treatment applied after wounding amplified and extended the activations of Erk1/2 and p38, but not of Akt. Furthermore, Erk1/2 inhibition blocked the process of cell repopulation induced by heparin-binding epidermal growth factor-like growth factor, whereas the inhibition of p38 delayed the process. CONCLUSION: These results indicate that heparin-binding epidermal growth factor-like growth factor may constitute a critical factor in the wound healing of human periodontal ligament cells by a mechanism that requires the activation of Erk1/2 via specific interaction with epidermal growth factor receptor 1.

Thymidine phosphorylase expression in tumour cells and tumour response to capecitabine plus docetaxel chemotherapy in non-small cell lung cancer.

BACKGROUND: Thymidine phosphorylase (TP) is the key enzyme for capecitabine activation in tumour cells. AIMS: To examine whether TP expression in tumour cells and stroma is predictive of the tumour response to capecitabine plus docetaxel chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Tumour samples were available from 30 of 39 patients enrolled in a previous phase II study of capecitabine/docetaxel chemotherapy in patients with advanced NSCLC. Stromal and tumour cell TP expression was evaluated by immunohistochemistry using monoclonal antibody PD-ECGF. RESULTS: High tumour cell TP expression was found in 13 of 30 cases and was negatively associated with stromal TP expression (p = 0.000). High stromal TP expression was found in 16 of 28 cases and was strongly associated with intense macrophage infiltration (p = 0.002), suggesting that macrophages are the major component of TP expression in the stroma. Tumour response to capecitabine/docetaxel was significantly associated with high tumour cell TP expression (p = 0.004) and low stromal TP expression (p = 0.009). Moreover, high tumour cell TP expression was significantly associated with severe hand-foot syndrome, a toxic side effect of capecitabine (p = 0.01). Improved survival was seen for high tumour cell and low stromal TP expression, although results were not significant (p = 0.6 and 0.3, respectively). CONCLUSIONS: In advanced NSCLC, TP expression in tumour cells and stroma is associated with tumour response to capecitabine/docetaxel chemotherapy, and might be a useful predictor of tumour response to capecitabine based chemotherapy. A large scale prospective study is needed to confirm the prognostic significance of TP expression in NSCLC.

Comparative study of the subserosal versus submucosal dye injection method for sentinel node biopsy in gastric cancer.

AIMS: To determine the most efficient injection method for a sentinel node (SN) biopsy in gastric cancer. METHODS: Gastric adenocarcinoma patients without serosal invasion and distant metastasis were prospectively enrolled in this study. Isosulfan blue was injected into the subserosa (SS) of the first set of 71 consecutive patients and an intraoperative endoscopic submucosal (SM) injection of the same dye was injected into the second set of 50 consecutive patients. After the biopsy of blue-stained SNs, a gastrectomy with a D2 lymphadenectomy was performed. All dissected lymph nodes were evaluated for metastasis. The results of the SN biopsies were compared between the SS and SM dye injection methods. RESULTS: Detection rate (0.92 vs 0.94), mean number of SNs (2.5 vs 2.9) and sensitivity (0.61 vs 0.46) of the SN biopsies were not significantly different between the SS and SM injection methods (P>0.05). The operation time was significantly shorter in the SS than the SM injection method (159.7 vs 172.7 min, P=0.030). CONCLUSIONS: Both injection methods were equally efficient in their roles for a SN biopsy in gastric cancer. However, the SS injection method was more preferable due to its easy technique and short operation time.

Ion-channel currents of smooth muscle cells isolated from the prostate of guinea-pig.

OBJECTIVE: To characterize the voltage-activated ion-channel currents in guinea-pig prostate smooth muscle cells (GPSMCs). MATERIALS AND METHODS: GPSMCs were isolated using collagenase, and used in a whole-cell patch clamp study. RESULTS: When GPSMCs were dialysed with a CsCl solution all the outward K+ currents were blocked and the step-like depolarization (holding voltage -70 mV) of the cell membrane evoked inward currents that were completely blocked by nifedipine (1 micromol/L). With KCl solution, step depolarizations showed outward K+ currents composed of fast, transient outward current (Ito) and outward currents that did not inactivate. Ito was resistant to a high concentration of tetraethylammonium (TEA, 5 mmol/L) but was blocked by 4-aminopyridine (5 mmol/L). The half-activation and half-inactivation voltages of Ito were 6 mV and -58 mV, respectively. With low Ca2+ buffer (0.1 mmol/L EGTA) in the solution, there were spontaneous transient outward currents (STOCs) at depolarized membrane voltages (0 mV). STOCs were blocked by TEA (1 mmol/L) or iberiotoxin (10 nmol/L) but were insensitive to apamin (100 nmol/L). CONCLUSION: This voltage-clamp study showed that GPSMCs have l-type Ca2+ channels and more than two types of K+ channels. The voltage- and time-dependent changes of these ion channels and their interactions might be important in forming action potentials and regulating contractility.

Idiopathic multilocular thymic cyst: CT features with clinical and histopathologic correlation.

OBJECTIVE: We performed this study to describe the CT features of idiopathic multilocular thymic cysts with clinical and histopathologic correlation. CONCLUSION: Multilocular thymic cysts typically manifest on CT as unilocular or multilocular cystic thymic masses, often with soft-tissue attenuation components. CT cannot be used to distinguish neoplastic from nonneoplastic soft-tissue components.

Two imported cases of cutaneous larva migrans.

Cutaneous larva migrans (CLM) is a rare serpiginous cutaneous eruption caused by accidental penetration and migration in the skin with infective larvae of nematode that normally do not have the human as their host. Although CLM has a worldwide distribution, the infection is most frequent in warmer climates. More recently, they have been increasingly imported from the tropics or subtropics by travelers. We experienced two patients who had pruritic serpiginous linear eruption in their skin for a few weeks after traveling to the endemic areas (Brazil and Thailand, respectively). After the treatment with albendazole, the skin lesions resolved with post-inflammatory hyperpigmentation. We report herein two cases of cutaneous larva migrans successfully treated with albendazole.

Aberrant Crypt Foci in the Background Mucosa of Colorectal Adenocarcinoma.

PURPOSE: This study was performed in order to determine the histologic features, incidence & frequency of the Aberrant Crypt Foci (ACFs) including mucosal abnormalities arising in the sporadic colonic cancer. MATERIALS AND METHODS: We investigated the proximal and distal colonic mucosa surrounding the tumor in 22 cases (right colon 7 cases and left colon 15 cases) of resected colonic adenocarcinoma specimen. The methylene blue- stained colonic mucosa was examined in en face preparations and rolled totally. The rolled colonic mucosa was embedded in paraffin and examined by using 4micrometer thick serial sections. RESULTS: We found one hundred twenty two ACFs. The 97 foci (78.7%) were simple hypertrophic foci (SH), composed of more elongated and larger crypts than normal with apical branching associated with goblet cell hyperplasia. The 17 foci (13.9%) were hyperplastic foci (HP) resembling hyperplastic polyp, and 7 (5.7%) were adeno matous foci (AD) while 2 (1.6%) were adenomatous foci with dysplasia (Dys). The mean number of ACFs/cm of the examined mucosa were 0.18+/-0.21 and were higher in the left colon than in the right colon (0.22+/-0.24 vs. 0.10+/-0.10). Immunohistochemical stains for p53 and Ki-67 in these foci revealed strong and upper cryptal staining patterns in AD and Dys of ACFs, like that of neoplasia or preneoplastic condition. However, the staining intensities in SH and HP of ACFs were equal to or lower than that of normal crypts. CONCLUSION: These results suggest that grossly defined ACFs include reactive process and the majority of ACFs are induced by simple reactive alteration without preneoplastic potential; and two types of ACFs (AD and Dys) are more likely to be direct precursors of colon tumors than SH or HP.

Expression of tenascin-C in astrocytic tumors: its relevance to proliferation and angiogenesis.

BACKGROUND: The expression and distribution of the extracellular matrix protein tenascin-C (TN-C) may be enhanced in human astrocytomas. The purpose of this study is to evaluate the expression of TN-C according to histological malignancy of tumor cells and its relevance to neoplastic angiogenesis in human astrocytic tumors. METHODS: Between 1994 and 1998, 52 astrocytic tumor specimens including 4 pilocytic astrocytomas, 13 astrocytomas, 3 anaplastic astrocytomas, and 32 glioblastomas were used in this study. A retrospective analysis was performed to evaluate a statistical correlation between TN-C expression and proliferative indices. We characterized the expression of TN-C in neoplastic vessels, around individual tumor cells as a tumor network, and in tumor cells by immunohistochemistry using antibodies against human TN-C. The proliferative indices were also investigated by immunostaining with the MIB-1 antibody against the Ki-67 proliferation antigen. RESULTS: TN-C immunoreactivity was found to be enhanced in tumor vessels and tumor networks of high-grade astrocytic tumors. The vascular TN-C deposition was greater in high-grade than in low-grade astrocytic tumors (p < 0.05). Its expression was the most intense in glioblastomas. Proliferation indices increased with tumor grade and MIB-1 labeling index (LI) was highest in glioblastomas. Moreover, expression of TN-C in tumor vessels was correlated with proliferative indices. CONCLUSIONS: Our data show that TN-C in human astrocytic tumors may be identified as a factor contributing to malignant progression. And also, enhanced expression of TN-C in tumor vessels having a high proliferative index indicates that TN-C could be involved in neoplastic angiogenesis.

Water extract of 1:1 mixture of Phellodendron cortex and Aralia cortex has inhibitory effects on oxidative stress in kidney of diabetic rats.

Enhanced activity of the lipid peroxidation and oxidative damages have been implicated in the pathogenesis of diabetic kidney complications. We explored to determine whether these changes in diabetic kidney could be prevented by water extract of mixture of Phellodendron cortex and Aralia cortex (P55A). Greatly elevated content of thiobarbituric acid reactive substances (TBARS) and carbonylated protein in kidneys of diabetic rats were significantly reduced by P55A treatment. In addition, abnormally low ratio of GSH/GSSG in diabetic kidneys was elevated to almost normal levels by the treatment with P55A. These results suggest that P55A extracts exert antioxidant effect by reducing lipid peroxidation and protein carbonylation as well as by elevating the ratio of GSF/GSSG in diabetic kidney.

Posterior tibial neuropathy by a Baker's cyst: case report.

Baker's cysts are rare cause of peripheral nerve entrapment and only a few cases of tibial nerve entrapment resulting from the popliteal cyst in the calf muscle have been reported in the literature. We present a case of rheumatoid arthritis complicated by a Baker's cyst with a tibial nerve entrapment. It is important to diagnose a Baker's cyst early and to differentiate it from thrombophlebitis, a popliteal aneurysm, tumor or muscle tear to effect optimal therapy and to obviate a potential neuropathy. Prompt recognition of these cases may save the patients unnecessary procedures and delay in treatment.

Time dependent patient satisfaction with sildenafil for erectile dysfunction (ED) after nerve-sparing radical retropubic prostatectomy (RRP).

PURPOSE: The response to sildenafil after radical retropubic prostatectomy (RRP) has been reported to be approximately 40% by the Sildenafil Study Group. We undertook a study in a large cohort of post-RRP erectile dysfunction (ED) patients in order to examine the relationship between satisfaction with sildenafil and time from surgery to start of sildenafil treatment. METHODS: Pre- and post-operative erectile function was assessed by the O'Leary Brief Sexual Function Inventory questionnaire. Patient satisfaction with sildenafil before and after sildenafil treatment was assessed by the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaire. Between April and October 1998, EDITS questionnaires were given to 579 patients who had undergone RRP between 1994 and 1998. 316 (55%) patients returned questionnaires. Of these, 198 (63%) had sildenafil treatment and completed post-treatment questionnaires and were included in the study group. RESULTS: In the study group, mean age was 61y. Pre-operatively, 92% had erections sufficient for vaginal penetration, 95% had bilateral nerve-sparing (NS) RRP. There was a significant increase in the treatment satisfaction rate with increasing time from surgery. Between zero and six months after surgery, the treatment satisfaction rate was 26%, which improved with time, peaking at 60% between 18 months and 2y. Self-perceived erectile function as determined by post-RRP pre-sildenafil treatment O'Leary questionnaires was not as predictive of response to sildenafil as time from surgery. CONCLUSIONS: The response to sildenafil appears to be dependent upon the interval between RRP and the start of sildenafil. The treatment satisfaction rate was found to peak at 60% between 18 months and 2y. Early nonresponders to sildenafil should not be disheartened, as they will more likely later respond.

Expression of cyclin D1 and cyclin E in human gastric carcinoma and its clinicopathologic significance.

Cyclin D1 and cyclin E are the mammalian G1 cydins that are both required and rate limiting for entry into S phase. Alterations in cell cycle regulators and subsequent deregulation of the cell cycle are frequently involved in tumorigenesis and/or tumor progression. We investigated the expression of cyclin D1 and cyclin E protein in 84 gastric carcinoma by immunohistochemical staining and also the relevance of each cyclin expression to the clinical outcomes. Overexpression of cyclin D1 and cyclin E was noted in 21 of 84 (25.0%) and 34 of 84 (40.5%) gastric cancer tissues, respectively. There was a significant correlation between overexpression of cyclin E and lymph node metastasis (p=0.003), recurrence (p=0.043), disease free survival (p=0.0378) and overall survival (p=0.0319), but no correlation was noted between overexpression of cyclin D1 and other clinicopathologic variables. These findings suggest that overexpression of cyclin E and cyclin D1 is a frequent finding in gastric cancer and immunohistochemical analysis for cell cycle regulators, especially cyclin E might be a useful prognostic indicator in gastric cancer.

Eosinophil-induced chronic hepatitis.

Chronic hepatitis associated with hypereosinophilia has been very rarely reported worldwide. A 7-month-old male infant presented with a high fever, cough, non-projectile vomiting and hepatomegaly. The eosinophil count of the peripheral blood increased up to 21,500/mm3 (49% of WBC). The infant had a history of frequent contact with a neighbor keeping a pigsty. The pathologic examinations of the liver showed severe porto-periportal necroinflammation with marked eosinophilic infiltration, giant cell transformation and ballooning degeneration of hepatocytes, and degranulation of the eosinophils. Bone marrow showed increased eosinophils and decreased myeloid series. Pericardial effusion and bilateral pulmonary consolidation were noted. Corticosteroid aggravated the clinical symptoms of the infant. Anthelmintic treatment significantly normalized the eosinophil count and liver function tests, but cardiopulmonary manifestations continued.

Enhanced anti-tumour effects of acriflavine in combination with guanosine in mice.

The anti-tumour activity of acriflavine in combination with guanosine has been evaluated in solid or ascitic tumour-implanted animal models. Guanosine is known to potentiate the anti-tumour effects of some chemotherapeutic agents. Administration of acriflavine (15 mg kg-1 day-1, i.m., 14 days) to ICR mice subcutaneously implanted with Ehrlich carcinoma resulted in approximately 30% inhibition in tumour growth. In contrast, minor tumour growth inhibition was observed in animals treated with guanosine at the same daily dose. Treatment of animals with both acriflavine and guanosine (AG60, 1:1, w/w) at 30 mg kg-1 resulted in approximately 65% inhibition in tumour growth rate. Whereas treatment with acriflavine or guanosine resulted in 70% or 30% decrease in tumour weight, respectively, treatment of tumour-implanted mice with AG60 (30 mg kg-1) resulted in a 96% decrease in tumour weight, relative to control, 14 days after tumour-cell implantation. Dose-related inhibition in tumour growth rate was also observed in animals treated with AG60, with maximum (65%) inhibition noted at a dose of 30 mg kg-1 (ED50 23 mg kg-1). Suppression of body weight increase and elevated plasma glucose levels by acriflavine or AG60 indicated that glucose utilization might be impaired. The anti-tumour effect of AG60 was also determined in CDF1 mice intraperitoneally implanted with Ehrlich ascitic tumour. Ehrlich ascitic tumour proliferation was completely suppressed by AG60 (30 mg kg-1, i.p.). Microscopic analyses of intraperitoneal touch-prints revealed that AG60 was more effective in suppressing tumour proliferation than acriflavine alone. Fluorescent microscopic examinations demonstrated that acriflavine avidly bound with Yac-1 cell plasma membrane, leading to morphological changes in the cells, such as bleb formations, swelling and ballooning. The time-related changes in tumour cell morphology by acriflavine or AG60 might represent energy depletion, followed by osmotic lysis as a result of cationic influx. Enhanced anti-tumour activity of acriflavine in combination with guanosine might be explained by the blocking of nutrient transport through selective acriflavine binding with plasma membrane and by concomitant guanosine perturbation of cellular ATP production. This study demonstrates that guanosine enhances the anti-tumour effects of acriflavine against a variety of cancer cells without serious adverse effects, providing a preclinical basis for potential application of this combination against cancer proliferation.