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.

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.

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.

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.

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.

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.

Poorly differentiated ("insular") carcinoma of the thyroid gland--two cases report.

Poorly differentiated ("insular") carcinoma of the thyroid shares insular, trabecular, and solid histological patterns that are different from those of papillary, follicular, medullary, and anaplastic varieties. This tumor is situated morphologically and biologically in the intermediate position between the well differentiated (papillary and follicular) and the totally undifferentiated (anaplastic) thyroid tumors. We report two cases of insular carcinoma of the thyroid, occurring in 39-year-old and 52-year-old women. Grossly, these cases showed a lobulated mass with fibrous septa. The histologic finding showed characteristic "insular" growth pattern with focal follicular or papillary areas. Thyroglobulin was demonstrated within cytoplasmic paranuclear vacuoles of the neoplastic cells. Calcitonin and amyloid were not demonstrated. The aspiration cytology showed high cellularity, low grade of atypia, presence of clusters, nests, and trabeculae of cells with poorly outlined cytoplasm. The ultrastructural finding showed primordial cells having cytoplasmic organelles such as rough endoplasmic reticulum, mitochondria, and free ribosomes. We believe that its separation from other types of thyroid carcinoma will lead to a more accurate estimate of its biologic behavior and a more appropriate therapeutic approach.

Microcystic meningioma. A case report.

Microcystic meningioma is a distinct morphological variant of meningioma, characterized by loose texture and microcysts with formation of large extracellular spaces containing edematous fluid. The tumor cells have stellate and vacuolated cytoplasm with long cytoplasmic processes. We experienced a case of typical microcystic meningioma occurring in the falx cerebri adjacent to the left superior parasagittal sinus in a 41-year-old man. The tumor showed the typical histologic features with a few nests of meningothelial whorls. The tumor cells showed diffuse immunoreactivity for vimentin, epithelial membrane antigen (EMA), and S-100 protein. Ultrastructural study confirmed the meningiomatous nature of the tumor.

Atretic encephalocele/myelocele--case reports with emphasis on pathogenesis.

Atretic encephaloceles or myelomeningoceles are frequently solid due to hamartomatous proliferation of fibrous tissue and blood vessels. Because of the fibrous nature of the tumor with no cystic cavity and unusual location with no connection to CNS, they are frequently regarded as insignificant hamartomas. Apart from this terminology, they are also described as cutaneous meningiomas or hamartomas with ectopic meningothelial elements by the presence of meningothelial cells. We report a case of atretic encephalocele in the parietal scalp of an 8 year-old boy and a case of myelomeningocele in the posterior mediastinum of a 31 year-old woman. The terms atretic encephalocele and myelomeningocele are more appropriate for these cases because they include their pathogenesis and the non-neoplastic nature of the lesion.

Fibrous hamartoma of infancy manifested as multiple nodules--a case report.

Fibrous hamartoma of infancy is an uncommon benign fibrous proliferation, usually presenting as a solitary nodule. A rare example of multiple fibrous hamartoma of infancy is described. Two masses which developed in the upper arm of a 10-month-old boy were successfully excised, and one month later three small nodules 2 cm below the previous operation field appeared. It will be further elucidated whether multiple forms and early recurrence are related or not as cases accumulate.

A national study on biopsy-confirmed thyroid diseases among Koreans: an analysis of 7758 cases.

In order to determine the incidence and to understand recent trend of thyroid neoplasm and other thyroid diseases among Korean, a nation-wide collection of biopsy-confirmed and surgically removed thyroid lesions from 30 pathology laboratories of university and general hospitals was made over a 3-year-period from 1986 to 1988. These tumors and tumor-like lesions of the thyroid were classified according to the WHO classification. Results of this study were compared with those of the previous in Korea and other countries. Among the 7758 collected cases from 7449 patients, adenomatous goiter was the most common, comprising 2681 cases (34.6%), followed by follicular adenoma, 1868 cases (24.1%) and papillary carcinoma, 1474 cases (19%). Neoplastic condition comprised 48.8% (3786 cases). Of malignant tumors, papillary carcinoma was the most frequent accounting for 79.8%. The female to male ratio was 7.5:1 with female predominance. This female predominance was noted in all but two thyroid diseases. Medullary carcinoma showed equal distribution in both sexes, and two cases of malignant lymphoma developed in males. Thyroid diseases were common at the 3rd to 6th decades with peak incidence at the 4th decade. The right lobe of the thyroid was more frequently involved than the left lobe (1.6:1). The diagnoses were made largely on the surgically excised specimen (85.3%). Multiplicity of the lesions revealed single lesion in 64%, multiple and diffuse lesion in 36% of cases investigated. Average size of the lesion was in the range of 1-5 cm in diameter (62%).