Matricellular TSP-1 as a target of interest for impeding melanoma spreading: towards a therapeutic use for TAX2 peptide

Thrombospondin-1 (TSP-1) is a matricellular glycoprotein known for being highly expressed within a tumor microenvironment, where it promotes an aggressive phenotype particularly by interacting with the CD47 cell-surface receptor. While it originates from the stromal compartment in many malignancies, melanoma is an exception as invasive and metastatic melanoma cells overexpress TSP-1. We recently demonstrated that a new molecular agent that selectively prevents TSP-1 binding to CD47, called TAX2, exhibits anti-cancer properties when administered systemically by decreasing viable tumor tissue within subcutaneous B16 melanoma allografts. At the same time, emerging evidence was published suggesting a contribution of TSP-1 in melanoma metastatic dissemination and resistance to treatment. Through a comprehensive systems biology approach based on multiple genomics and proteomics databases analyses, we first identified a TSP-1-centered interaction network that is overexpressed in metastatic melanoma. Then, we investigated the effects of disrupting TSP-1:CD47 interaction in A375 human malignant melanoma xenografts. In this model, TAX2 systemic administrations induce tumor necrosis by decreasing intra-tumoral blood flow, while concomitantly making tumors less infiltrative. Besides, TAX2 treatment also drastically inhibits B16F10 murine melanoma cells metastatic dissemination and growth in a syngeneic experimental model of lung metastasis, as demonstrated by histopathological analyses as well as longitudinal and quantitative µCT follow-up of metastatic progression. Altogether, the results obtained by combining bioinformatics and preclinical studies strongly suggest that targeting TSP-1/CD47 axis may represent a valuable therapeutic alternative for hampering melanoma spreading.     

O(6) -methylguanine-DNA methyltransferase (MGMT) promoter methylation and low MGMT-encoded protein expression as prognostic markers in glioblastoma patients treated with biodegradable carmustine wafer implants after initial surgery followed by radiotherapy with concomitant and adjuvant temozolomide

BACKGROUND:

O⁶‐methylguanine‐DNA methyltransferase (MGMT) promoter methylation status was proposed as a prognostic biomarker for patients with glioblastoma. However, the prognostic impact of MGMT in patients with newly diagnosed glioblastoma who receive carmustine‐releasing wafers (Gliadel) along with temozolomide (TMZ) is still unknown.

METHODS:

MGMT promoter methylation status and protein expression were analyzed in formalin‐fixed, paraffin‐embedded tumor specimens obtained from 111 French patients with newly diagnosed glioblastoma. Patients received the Gliadel wafers followed by radiotherapy plus concomitant and adjuvant TMZ chemotherapy while they were enrolled in a French multicenter prospective study.

RESULTS:

For the whole cohort, the median overall survival (OS) was 17.5 months, and the progression‐free survival was 10.3 months. Patients with tumors that harbored MGMT methylation had a significantly longer OS compared with patients who had wild‐type MGMT (21.7 months vs 15.1 months; P = .025). Similarly, patients who had low MGMT protein expression (≤15%) had a significantly improved OS compared with patients who had high MGMT expression (27.0 months vs 15.1 months; P = .021). The extent of resection was the strongest clinical predictor of outcome. In multivariate Cox models that were adjusted for sex, performance status, and extent of surgery, both MGMT methylation and protein expression were identified as independent prognosticators, and the finding was validated internally using a bootstrap resampling technique. Discrepancies were identified between protein expression and MGMT methylation status, thus suggesting that the 2 assays probably assess different biologic features.

CONCLUSIONS:

MGMT promoter methylation status and low MGMT expression both were identified as positive prognosticators in patients with newly diagnosed glioblastoma who underwent surgical resection and received Gliadel wafer implants followed by adjuvant radiotherapy and concomitant oral TMZ chemotherapy (the Stupp protocol). Cancer 2012. © 2012 American Cancer Society.     

Prospective evaluation of magnetic resonance enterography for the detection of mesenteric small bowel tumours

Purpose

To prospectively evaluate magnetic resonance (MR) enterography for detecting mesenteric small-bowel tumours (MSBTs) and assess the added value of gadolinium-chelate injection.

Material and methods

Over a 2-year period MR enterography examinations of 75 patients (33 men, 42 women; mean age, 53.8 years; range, 19–85) with suspected MSBT were blindly analysed by two readers for the presence of MSBT. Sensitivities, specificities, predictive positive values (PPVs), negative predictive values (NPVs) and accuracies of MR enterography for the detection of MSBT were calculated on per-patient and per-lesion bases. The McNemar test was used to compare sensitivities and specificities of the unenhanced and gadolinium-enhanced sets of MR enterographies.

Results

Thirty-seven MSBTs were pathologically confirmed in 26 patients. The mean tolerance score of the examinations was 0.7. On a per-patient basis, sensitivity, specificity, PPV, NPV and accuracy for detection of MSBT were 96 % [95 % CI, 89–100 %], 96 % [90–100 %], 93 % [83–100 %], 98 % [94–100 %] and 96 % [92–100 %], respectively. On a per-lesion basis, sensitivity and PPV were 70 % [56–85 %] and 93 % [83–100 %], respectively. Gadolinium injection yielded higher sensitivities on both bases (P?=?0.008).

Conclusion

MR enterography is an accurate and well-tolerated imaging modality for detecting MSBT. Intravenous administration of gadolinium-chelate improves sensitivity for MSBT detection.

Key Points

? MR enterography accurately detects mesenteric small bowel tumours. ? MR enterography is a well-tolerated imaging technique. ? Intravenous administration of gadolinium chelate improves sensitivity for detecting small-bowel tumours.     

Risk factors and long-term course of thyroid dysfunction during antiviral treatments in 221 patients with chronic hepatitis C

AIM: To identify the predictive factors of dysthyroidism during treatment for chronic viral hepatitis C and to evaluate the long-term outcome of these patients. METHODS: Patients treated for chronic viral hepatitis C between 1990 and 2001 were analyzed retrospectively. Patients with dysthyroidism before treatment and patients positive for hepatitis B surface antigen or human immunodeficiency virus antibodies were excluded. Dysthyroidism was defined by an abnormal serum TSH level on two separate occasions. RESULTS: 221 consecutive patients were included. Among them, a hundred were treated twice by interferon alpha, 21 had 3 treatments and 3 had 4 treatments. Fifteen of these patients (7%) had dysthyroidism during antiviral therapy. There was no significant difference in the frequency of dysthyroidism during the first and the second treatment [respectively 4,1% (N = 9) and 6% (N = 6)]. Female gender and the presence of antimicrosome or antithyroperoxydase (anti-TPO) antibodies before antiviral treatment were predictive factors of dysthyroidism. Treatment by interferon and ribavirin did not increase the risk of dysthyroidism compared to monotherapy with interferon. Pegylated interferon (N = 49) was not a risk factor compared to standard interferon. Thirteen patients had hypothyroidism (2 of them as a result of biphasic thyroiditis) and 2 had hyperthyroidism. The antiviral treatment was continued in 11 patients. Seven out of 13 patients with hypothyroidism required an indefinite treatment (follow-up: 15 to 90 months). CONCLUSIONS: In our series, 7% of patients with chronic viral hepatitis C had a dysthyroidism during antiviral therapy. Predictive factors were female gender and positive antimicrosome or anti-TPO antibodies before treatment. Absence of dysthyroidism during a first antiviral treatment did not preclude from the risk of dysthyroidism during a second treatment.     

Is there any relationship between pernicious anemia and iron deficiency ?

INTRODUCTION: Previous studies have suggested that iron deficiency could be due to atrophic gastritis of the body/fundus. The aim of this study was to determine the prevalence of iron deficiency among patients with pernicious anemia and associated factors. PATIENTS AND METHODS: All patients with pernicious anemia diagnosed at our institution between January 1990 and February 2005 were included. Inclusion criteria were: 1- histological diagnosis of atrophic fundic gastritis and 2- criteria of gastric autoimmune involvement. Histology of gastric biopsies was performed in a blinded manner. Iron deficiency was defined as serum ferritin level<15 microg/L in women and<40 microg/L in men. RESULTS: Ninety-five patients (69 women), mean age 60 years (range: 23-90) were included. Twenty patients (21.1%) had normal blood cell counts; 12 patients (12.6%) had microcytosis with or without anemia and 53 patients (55.8%) macrocytosis with or without anemia. Serum ferritin levels were measured in 58 patients, 16 (27.6%) of whom, all women, had iron deficiency. They were significantly younger (39.2 years) than patients without iron deficiency (61.6 years, P<0.0001). Serum gastrin levels did not differ between the groups with and without iron deficiency. A significantly more severe inflammatory infiltrate of the fundus and endocrine cell hyperplasia was observed in iron deficiency patients. Multivariate analysis showed that iron deficiency was linked to female gender and age<50 years. CONCLUSION: Iron deficiency and microcytic anemia are not rare in patients with pernicious anemia and should not rule out the diagnosis. Iron deficiency does not appear to be related to the degree of atrophic fundic gastritis but is linked to female gender and young age, suggesting menstrual blood loss could play a role. Whether decreased iron absorption due to reduced acid secretion favors the expression of gynecological iron loss cannot be ascertained.