Evaluation of the antiparasitic and antifibrotic effects of gallic acid on experimental hepatic schistosomiasis mansoni.

Schistosomiasis afflicts approximately 120 million individuals globally. The hepatic pathology that occurs due to egg-induced granuloma and fibrosis is commonly attributed to this condition. However, there is currently no efficacious treatment available for either of these conditions.Our study aimed to investigate the potential antifibrotic and antiparasitic properties of different doses of gallic acid (GA) in experimental schistosomiasis mansoni. In addition, we investigated the outcomes of co-administering it with the standard anti-schistosomiasis treatment, praziquantel (PZQ).In experiment I, Schistosoma mansoni-infected mice were administered GA at doses of 10, 20, or 40 mg/kg. Their effectiveness was evaluated through parasitological (worm and egg loads, granuloma number and diameter), pathological (fibrosis percentage and H-score of hepatic stellate cells (HSCs)), and functional (liver enzymes) tests. In experiment II, we investigated the optimal dosage that yielded the best outcomes. This dosage was administered in conjunction with PZQ and was evaluated regarding the parasitological, pathological, functional, and immunological (fibrosis-regulating cytokines) activities.Our findings indicate that the administration of 40 mg/kg GA exhibited the highest level of effectiveness in experiment I. In experiment II, it exhibited lower antiparasitic efficacy in comparison to PZQ. However, it surpassed PZQ in other tests. It showed enhanced outcomes when combined with PZQ.In conclusion, our findings reveal that GA only slightly increased the antischistosomal activity of PZQ. However, it was linked to decreased fibrosis, particularly when administrated with PZQ. Our pilot study identifies GA as a natural antifibrotic agent, which could be administered with PZQ to mitigate the development of fibrosis.

111In-pentetreotide scintigraphy and 18F FDG PET-CT in differentiated thyroid carcinoma metastases with negative whole body radioiodine scan.

Metastases of differentiated thyroid cancer (DTC) can lose affinity to radioiodine with the passage of time, with resultant difficulty in management. Thyroid tumors are known to express somatostatin receptors and therefore 111In-pentetreotide, somatostatin analogue, can visualize tumors with high concentration of somatostatin receptors. We report a case of I-131 whole body scan (WBS) negative recurrent metastatic papillary thyroid carcinoma with positive 18F FDG PET-CT and 111In-pentetreotide scan. Somatostatin receptor scintigraphy (SRS) with 111In-pentetreotide may be useful both in the staging and monitoring of patients with non-iodine avid carcinoma of the thyroid. 111In-pentetreotide scan positive patients are potential candidates for somatostatin receptor-targeted therapy.

The appearance of cartilage used in deep inferior epigastric perforator breast reconstruction surgery as a calcified mass on CT scan.

This paper describes an unusual radiological appearance of implanted cartilage on CT scan in a patient who had recently undergone deep inferior epigastric perforator (DIEP) breast reconstruction surgery following a mastectomy for ductal carcinoma in situ. The purpose of this paper is to alert medical practitioners involved with DIEP breast reconstruction surgery, as well as general radiologists, to the possibility of surgically implanted costal cartilage undergoing calcification and then appearing on imaging studies as a malignant process. Information on the patient was gathered from clinical records, imaging reports and pathological samples. A literature search was performed to identify similar cases and the results showed that this occurrence has never before been described and therefore represents an advancement of knowledge about the imaging characteristics of reconstructed breast tissue.

Evidence for a time-dependent association between FOLR1 expression and survival from ovarian carcinoma: implications for clinical testing. An Ovarian Tumour Tissue Analysis consortium study.

BACKGROUND: Folate receptor 1 (FOLR1) is expressed in the majority of ovarian carcinomas (OvCa), making it an attractive target for therapy. However, clinical trials testing anti-FOLR1 therapies in OvCa show mixed results and require better understanding of the prognostic relevance of FOLR1 expression. We conducted a large study evaluating FOLR1 expression with survival in different histological types of OvCa. METHODS: Tissue microarrays composed of tumour samples from 2801 patients in the Ovarian Tumour Tissue Analysis (OTTA) consortium were assessed for FOLR1 expression by centralised immunohistochemistry. We estimated associations for overall (OS) and progression-free (PFS) survival using adjusted Cox regression models. High-grade serous ovarian carcinomas (HGSC) from The Cancer Genome Atlas (TCGA) were evaluated independently for association between FOLR1 mRNA upregulation and survival. RESULTS: FOLR1 expression ranged from 76% in HGSC to 11% in mucinous carcinomas in OTTA. For HGSC, the association between FOLR1 expression and OS changed significantly during the years following diagnosis in OTTA (Pinteraction=0.01, N=1422) and TCGA (Pinteraction=0.01, N=485). In OTTA, particularly for FIGO stage I/II tumours, patients with FOLR1-positive HGSC showed increased OS during the first 2 years only (hazard ratio=0.44, 95% confidence interval=0.20-0.96) and patients with FOLR1-positive clear cell carcinomas (CCC) showed decreased PFS independent of follow-up time (HR=1.89, 95% CI=1.10-3.25, N=259). In TCGA, FOLR1 mRNA upregulation in HGSC was also associated with increased OS during the first 2 years following diagnosis irrespective of tumour stage (HR: 0.48, 95% CI: 0.25-0.94). CONCLUSIONS: FOLR1-positive HGSC tumours were associated with an increased OS in the first 2 years following diagnosis. Patients with FOLR1-negative, poor prognosis HGSC would be unlikely to benefit from anti-FOLR1 therapies. In contrast, a decreased PFS interval was observed for FOLR1-positive CCC. The clinical efficacy of FOLR1-targeted interventions should therefore be evaluated according to histology, stage and time following diagnosis.

Ectopic prolactin secretion secondary to an ovarian tumour.

UNLABELLED: Ectopic hormone secretion is a well-recognised phenomenon; however, ectopic prolactin secretion is exceptionally rare. Hoffman and colleagues reported the first ever well-documented case of ectopic prolactin secretion secondary to a gonadoblastoma. We report a lady who presented with galactorrhoea and a large ovarian tumour that was found to secrete high levels of prolactin. LEARNING POINTS: Aim of this case report is to highlight the occurrence of this condition.Lack of awareness can often lead to a diagnostic conundrum.

Fibroepithelial polyps of the vagina in bitches: a histological and immunohistochemical study.

The histological and immunohistochemical features of 13 cases of suspected vaginal fibroepithelial polyps are reported. The characteristic microscopical features of these lesions were an abundant oedematous or fibrous stroma containing spindle-shaped and stellate cells and the presence of variable inflammation and haemorrhage. There was often a superficial layer of compressed tissue, but the stroma in the peripheral areas of the masses was generally more loosely arranged than in central areas. The connective tissue cells expressed vimentin and desmin, but did not express smooth muscle actin or calponin. Individual cases had additional changes including granulomatous inflammation, epithelial dysplasia suggestive of papillomavirus infection and a lesion resembling phyllodes tumour in women.

The chemokine, CXCL12, is an independent predictor of poor survival in ovarian cancer.

BACKGROUND: The chemokine CXCL12 and its cognate receptor, CXCR4, have been implicated in numerous tumour types where expression promotes tumour growth, angiogenesis, metastasis and suppresses tumour immunity. METHODS: Using a tissue microarray of 289 primary ovarian cancers coupled to a comprehensive database of clinicopathological variables, the expression of CXCL12 and CXCR4 was assessed by immunohistochemistry and its impact in terms of survival and clinicopathological variables was determined. RESULTS: Patients whose tumours expressed high levels of CXCL12 had significantly poorer survival (P=0.026) than patients whose tumours failed to produce this chemokine. Lack of CXCL12 expression within tumours was associated with a 51-month survival advantage for patients when compared with patients whose tumours expressed high levels of CXCL12. FIGO stage, adjuvant chemotherapy and the absence of macroscopic disease after surgery were all shown to predict prognosis independently of each other in this cohort of patients. CXCL12 was independently predictive of prognosis on multivariate analysis (P=0.016). There was no correlation between CXCL12 and any clinicopathological variable. CONCLUSION: The chemokine CXCL12 is an independent predictor of poor survival in ovarian cancer. High expression of CXCL12 was seen in only 20% of the tumours, suggesting a role for anti-CXCL12/CXCR4 therapy in the management of these patients.

Sequential genetic change at the TP53 and chemokine receptor CXCR4 locus during transformation of human ovarian surface epithelium.

Early genetic events in the development of high-grade serous ovarian cancer (HGSOC) may define the molecular basis of the profound structural and numerical instability of chromosomes in this disease. To discover candidate genetic changes we sequentially passaged cells from a karyotypically normal hTERT immortalised human ovarian surface epithelial line (IOSE25) resulting in the spontaneous formation of colonies in soft agar. Cell lines transformed ovarian surface epithelium 1 and 4 (TOSE 1 and 4) established from these colonies had an abnormal karyotype and altered morphology, but were not tumourigenic in immunodeficient mice. TOSE cells showed loss of heterozygosity (LOH) at TP53, increased nuclear p53 immunoreactivity and altered expression profile of p53 target genes. The parental IOSE25 cells contained a missense, heterozygous R175H mutation in TP53, whereas TOSE cells had LOH at the TP53 locus with a new R273H mutation at the previous wild-type TP53 allele. Cytogenetic and array CGH analysis of TOSE cells also revealed a focal genomic amplification of CXCR4, a chemokine receptor commonly expressed by HGSOC cells. TOSE cells had increased functional CXCR4 protein and its abrogation reduced epidermal growth factor receptor (EGFR) expression, as well as colony size and number. The CXCR4 ligand, CXCL12, was epigenetically silenced in TOSE cells and its forced expression increased TOSE colony size. TOSE cells had other cytogenetic changes typical of those seen in HGSOC ovarian cancer cell lines and biopsies. In addition, enrichment of CXCR4 pathway in expression profiles from HGSOC correlated with enrichment of a mutated TP53 gene expression signature and of EGFR pathway genes. Our data suggest that mutations in TP53 and amplification of the CXCR4 gene locus may be early events in the development of HGSOC, and associated with chromosomal instability.

Human leukocyte antigen class I expression is an independent prognostic factor in advanced ovarian cancer resistant to first-line platinum chemotherapy.

BACKGROUND: Loss of HLA class I is important in ovarian cancer prognosis but its role as a prognostic indicator in relation to therapy remains unproven. We studied the prognostic potential of this antigen and its significance in relation to platinum therapy. METHODS: A total of 157 primary ovarian cancers were assessed for HLA class I immunohistochemically and linked to a comprehensive database of clinicopathological variables, treatment details, and platinum sensitivity. RESULTS: Tumours expressing high levels of HLA class I had significantly improved survival (P=0.044). There was a 19-month difference in the median overall survival between tumours with high and low antigen expression. HLA class I antigen expression, stage, and platinum sensitivity were independently predictive of prognosis on multivariate analysis. HLA class I antigen was shown to be expressed at higher levels in patients with good overall survival in platinum-resistant patients (P=0.042). HLA class I significantly correlated with overall survival on multivariate analyses (P=0.034). CONCLUSION: Low-level HLA class I expression is an independent prognostic indicator of poor clinical outcome in ovarian cancer. The survival advantage of patients with platinum-resistant tumours expressing high levels of HLA class I suggests that immunotherapy may be of use in these ovarian cancers resistant to standard chemotherapy.

Demyelinating events in early multiple sclerosis have inherent severity and recovery.

BACKGROUND: It is unclear whether the severity of and recovery from the initial demyelinating event (IDE) are recapitulated in subsequent multiple sclerosis (MS) relapses. We sought to identify the factors associated with relapse severity and recovery and to evaluate whether events have inherent severity or recovery. METHODS: Patients seen at the UCSF MS Clinic within 1 year of disease onset were identified from a prospective database. Ordinal logistic regression was used to analyze predictors of three-level categorizations of event severity and recovery. RESULTS: We identified 330 patients with MS or clinically isolated syndrome; 152 had a second event and 63 had a third event. Nonwhite and younger patients were at an increased risk of more severe demyelinating events. A severe prior event predicted a substantial increase in the odds of being above any given severity cutoff for a severe subsequent event (for second event severity, odds ratio [OR] = 5.62, 95% confidence interval [CI] [2.39, 13.26], p < 0.0001; for third event severity, OR = 6.74, 95% CI [1.67, 27.18], p = 0.007). Similarly, poor recovery of the IDE predicted poor second event recovery (OR = 5.28, 95% CI [1.95, 14.25], p = 0.001), while fair or poor second event recovery predicted about a 5- or 13-fold increase in the odds of poor third event recovery. A more severe event also predicted a substantial increase in the odds of poor recovery. CONCLUSIONS: Patients with severe presentation and poor recovery at disease onset continue on a similar trajectory with subsequent demyelinating events. Whether genetic or other biologic factors are responsible for this pattern remains to be determined.

The onset location of multiple sclerosis predicts the location of subsequent relapses.

BACKGROUND: Demyelinating events in relapsing-remitting multiple sclerosis (RRMS) can involve several locations in the central nervous system. We sought to determine if initial clinical demyelinating event (IDE) location predicts subsequent clinical relapse locations in early RRMS. METHODS: We identified all RRMS patients from two large MS clinics who were seen within 1 year of disease onset. Logistic regression was performed with the outcome defined as the second or third exacerbation location and the predictor defined as IDE+/-second event location. RESULTS: 195 patients with at least two clinical exacerbations were identified. There was an increased odds of a patient's second relapse occurring in the spinal cord if the IDE was in the spinal cord (odds ratio (OR) = 3.79, 95% CI 2.06 to 7.00, p<0.001). There was more than a sixfold increase in the odds of a patient's second relapse occurring in the optic nerve if the IDE was in the optic nerve (OR = 6.18, 95% CI 2.90 to 13.18, p<0.001). These associations remained similar after adjusting for treatment and patient characteristics. If the IDE and second event were both in the same location (spinal cord, optic nerve or brainstem/cerebellum), the third event was likely to remain in that location. CONCLUSION: Patients with RRMS have relatively localised clinical relapses. It remains to be determined if genetic or biological processes are responsible for this pattern.

Predictors of the location of multiple sclerosis relapse.

BACKGROUND: While clinical relapses are the defining feature of relapsing-remitting multiple sclerosis (RRMS), their characteristics vary widely from patient to patient. This study sought to identify predictors of MS relapse location. Based on the current literature, two potential predictors were identified: treatment with interferon beta (IFNB) and location of previous relapse. METHODS: Patients with RRMS were identified from the UCSF MS Center database who underwent at least 3 months of treatment with IFNB or glatiramer acetate (GA). The relapse immediately preceding the initiation of treatment (pretreatment relapse) and the first relapse occurring after the initiation of treatment (on-treatment relapse) were coded as affecting the spinal cord (SC), optic nerve (ON), brainstem/cerebellum (BC) or cerebrum. Logistic regression was performed to identify independent predictors of on-treatment relapse location. RESULTS: The 134 IFNB and 56 GA patients did not differ in gender, race, age at symptom onset (30.3 years) or disease duration at the start of treatment (5.7 years). Patients with pretreatment SC relapses had increased odds of having on-treatment SC compared with non-SC relapses (OR 2.31, p = 0.013); the same tendency for localisation occurred with BC (OR 3.05, p = 0.013) and ON (OR 3.63, p = 0.011) relapses. Additionally, patients who relapsed on treatment had a higher SC (but not ON or BC) relapse risk when they were receiving IFNB compared with GA (OR 2.05, p = 0.041), independent of pretreatment relapse location. CONCLUSION: These results show a tendency for patients to have localised exacerbations, which could be mediated by genetic or immunological factors. In addition, and to be confirmed in subsequent studies, IFNB treatment may influence SC relapse risk.

Comparison of examination of the entire uterine cervix with routine cervical sampling in hysterectomy specimens from women with endometrial cancer.

BACKGROUND: Cervical involvement by endometrial cancer alters the FIGO stage and determines clinical management, but there are no accepted guidelines for cervical sampling of these cases. AIM: To assess whether sampling more than two "routine" blocks of the cervix (anterior and posterior) alters the pathological staging of hysterectomy specimens for endometrial cancer. METHODS: Histological involvement of the cervix was prospectively compared in hysterectomies performed for proven endometrial cancer (n = 61). Specimens had two "routine" blocks taken from anterior and posterior cervix; all of the remaining cervix was also processed for histological assessment. RESULTS: 61 cases of endometrial cancer had the entire uterine cervix processed. There were 54 cases of endometrioid adenocarcinoma and 7 special types. Twelve cases had cervical involvement (stage 2A or 2B), and seven cases were stage 3A or above, of which three also had cervical involvement. In none of the 61 cases did the additional cervical blocks (n = 544) taken alter the staging made on the "routine" blocks. CONCLUSION: Sampling of two blocks from the cervix appears sufficient for histological staging of endometrial cancer in hysterectomy specimens.

A grading scale for epistaxis in hereditary haemorrhagic teleangectasia.

BACKGROUND: Epistaxis is the most common symptom in patients with Hereditary Haemorrhagic Telangiectasia (HHT). Different institutions are using different treatment modalities and different grading systems. The treatment options depend on the grade of epistaxis. It is important to have a common grading system to compare and evaluate the effectiveness of different treatment options. Furthermore, it is important to correlate quality of life with an epistaxis grading system. The aim of this work was to propose a new grading system for epistaxis in HHT. METHODS: A medical literature search was performed for grading systems of epistaxis in HHT. A questionnaire on five criteria's for a new grading system was sent to 22 internationally renowned medical experts, who have published results on epistaxis in HHT. RESULTS: Four different grading systems are currently in use for the grading of epistaxis in HHT. The response rate of the questionnaire was 43%. All the experts who answered the questionnaire agreed that the aimed grading system should be easy to understand for the patients. 90% of them wanted the system to focus on a definite time period. 70% answered that blood transfusion should be included in the grading system as an important factor. There was no clear consensus on whether the system should be a single multi-item scale or a composite scale consisting of more than one single scales, and similarly there was no clear consensus on whether is should be an absolute or a relative scale. CONCLUSION: The proposed system should be easy to understand for the patients, focus on a definite time period of observation, and include blood transfusion as one of its parameters. For statistical reasons, an epistaxis grading scale with at least one absolute end point would be preferable.

Probucol and liver efficiency during chemically-induced hepatocarcinogenesis.

Probucol is a clinically used cholesterol-lowering drug, with pronounced antioxidant properties. The chemoprotective effect of probucol during the early steps of DENA and CCl4-induced hepatocarcinogenesis was studied. Treatment of animals with a single lethal dose of CCl4 (2ml/Kg, i.g.) after two weeks of DENA initiation, induced a significant increase in hepatic gamma-glutamyl transferase and liver content of glutathione and lipid peroxides five weeks later. On the other hand, a significant decrease in hepatic glutathione peroxidase activity was also observed after five weeks of CCl4 injection. Moreover, there was a significant decrease in hepatic blood flow manifested by decrease in indocyanine green elimination rate constant and increase in its half-life and area under the curve. The pharmacokinetic of antipyrine (a marker for hepatic metabolizing capacity) was altered due to decrease in the metabolizing capacity of damaged liver. In addition, haemorrhagic centrilobular necrosis and multifocal neoplastic lesions were microscopically detected. Treatment of animals with probucol (10 mg/Kg) three times/week for six weeks during DENA and CCl4-induced hepatocarcinogenesis counteracted significantly the alteration in hepatic blood flow and the hepatic metabolizing capacity. Moreover, probucol treatment restored the hepatic gamma-glutamyl transferase and liver content of glutathione and lipid peroxides. In addition, histopathological examination of liver specimens showed minimal centrilobular necrosis without any evidence of neoplastic lesions. The result of this study suggest that probucol may be useful as a chemopreventive agent, in addition to being a cholesterol-lowering drug with low toxicity.

Twinning rates in Ghana.

The incidence of twin births in Accra and Kumasi, the two major cities in Ghana, was investigated. In Accra, data were collected from the Korle-Bu Teaching Hospital while data were collected and analyzed from the Komfo Anokye Teaching Hospital in Kumasi. Both hospitals are the leading teaching hospitals in Ghana. The data consisted mainly of single and twin births recorded in the hospitals over a period of 12 years in Accra (1988-1999) and 15 years in Kumasi (1985-1999). The study revealed an incidence of 33.4 twin births per thousand live births for Accra and 26.6 twin births per thousand live births for Kumasi. Though these values are not as high as those reported among the Yoruba tribe of southwest Nigeria, who are reported to have the highest twin birth rates in the world, the present values still rank among the highest recorded twin birth rates.

Radical prostatectomy for high grade prostatic intraepithelial neoplasia.

High Grade Prostatic Intraepithelial Neoplasia (HGPIN) has been recognized as the most likely precursor of invasive carcinoma of the prostate. Close surveillance and follow-up are indicated if subsequent procedures fail to identify carcinoma. There is still considerable controversy about the natural history of high grade PIN and most authors agree that its identification should not influence or dictate therapeutic decisions. We performed a prophylactic radical prostatectomy in such a case which has not been reported in the world literature.

Endometrial histomorphometry of trimegestone-based sequential hormone replacement therapy: a weighted comparison with the endometrium of the natural cycle.

Histomorphometric changes in the endometrium were evaluated under the effect of a trimegestone-based sequential hormone replacement therapy (HRT) regimen, and the findings were compared to those in endometrium of the natural cycle. Endometrial samples were taken from postmenopausal women who completed a randomized, double blind, dose-ranging study of oral trimegestone (0.05, 0.1, 0.25 and 0.5 mg per day) from day 15 to day 28 with continuous micronized oestradiol 2 mg daily for six treatment cycles. The HRT-treated endometrium, irrespective of the dose, had a smaller mean total glandular area, smaller average glandular diameter, smaller mean total vascular space area and diameter than the luteal phase. Stromal cellularity was similar in the four dose groups. There were reduced glandular secretions in the endometrium from the high dose group. The relative weighting of these histological parameters was evaluated by linear discriminant analysis. The weighted values were dose independent, and may therefore represent either a specific effect of trimegestone, number of days administered, or both. We have constructed an equation to assign a value for a histological parameter which determines the position on linear discriminant functions. These assigned values can be used in other sequential HRT regimens to determine the relative influence of a given progestogen on endometrial morphology in relation to different phases of the natural cycle.

Differential cytologic features of fibroepithelial lesions of the breast.

The surgical treatment of phyllodes tumors differs from that for fibroadenomas, with the former necessitating complete excision with no remaining neoplastic tissue to produce local recurrence. To determine whether we could predict the type of breast lesion on cytology we reviewed the cytological features of 39 fibroepithelial lesions, including ordinary fibroadenomas, fibroadenoma variants (intermediate group), benign phyllodes tumors, and malignant phyllodes tumors, which had a biopsy diagnosis and adequate cytology. We found no differences in the glandular elements, the myoepithelial and single stromal cells, and the type of stromal fragments seen in the three benign groups. The stromal nuclei, the number of leaf-shaped fragments, and the numbers of spindle-cell groups present showed a spectrum of changes varying from those of fibroadenomas at one end to those of benign phyllodes tumors at the other. Malignant phyllodes tumors had characteristic features which were quite different from those of the benign lesions.