Treatment and prognosis of AIDS-related lymphoma in the era of highly active antiretroviral therapy: findings from the Swiss HIV Cohort Study

OBJECTIVE: To assess the characteristics of combination antiretroviral therapy (cART) administered concomitantly with chemotherapy and to establish prognostic determinants of patients with AIDS-related non-Hodgkin's lymphoma. METHODS: The study included 91 patients with AIDS-related non-Hodgkin's lymphoma from the Swiss HIV Cohort Study enrolled between January 1997 and October 2003, excluding lymphomas of the brain. We extracted AIDS-related non-Hodgkin's lymphoma- and HIV-specific variables at the time of lymphoma diagnosis as well as treatment changes over time from charts and from the Swiss HIV Cohort Study database. Cox regression analyses were performed to study predictors of overall and progression-free survival. RESULTS: During a median follow up of 1.6 years, 57 patients died or progressed. Thirty-five patients stopped chemotherapy prematurely (before the sixth cycle) usually due to disease progression; these patients had a shorter median survival than those who completed six or more cycles (14 versus 28 months). Interruptions of cART decreased from 35% before chemotherapy to 5% during chemotherapy. Factors associated with overall survival were CD4+ T-cell count (<100 cells/microl) (hazard ratio [HR] 2.95 [95% confidence interval (CI) 1.53-5.67], hepatitis C seropositivity (HR 2.39 [95% CI 1.01-5.67]), the international prognostic index score (HR 1.98-3.62 across categories) and Burkitt histological subtypes (HR 2.56 [95% CI 1.13-5.78]). CONCLUSIONS: Interruptions of cART were usually not induced by chemotherapy. The effect of cART interruptions on AIDS-related non-Hodgkin's lymphoma prognosis remains unclear, however, hepatitis C seropositivity emerged-as a predictor of death beyond the well-known international prognostic index score and CD4+ T-cell count.     

Draining lymph nodes of corneal transplant hosts exhibit evidence for donor major histocompatibility complex (MHC) class II-positive dendritic cells derived from MHC class II-negative grafts.

To examine the widely accepted dogmas that corneal grafts lack passenger leukocytes or cells capable of migrating directly to lymph nodes (LNs), we tracked the migration of corneal graft-derived transgenic green fluorescent protein (GFP; Ia(b)) cells into the draining LNs of allogeneic (Ia(d)) recipients. GFP(+) cells were identified in cervical LNs several hours after transplantation, and this traffic was significantly enhanced when grafts were placed in inflamed recipient beds. Draining cells were Ia(b+), CD45(+), and CD11c(+), and examination of ungrafted corneas revealed numerous similarly CD45(+)CD11c(+)CD3(-)CD8alpha(-) cells that uniformly lacked major histocompatibility complex (MHC) class II expression; transmission electron microscopy confirmed the presence of morphologically similar cells. After transplantation, or placement in culture, these CD11c(+) cells became class II(+) in a time-dependent manner and were capable of allostimulatory function. However, the stimulatory capacity of these cornea-derived dendritic cells (DCs) was suppressed compared with splenic controls. These results demonstrate for the first time that the cornea is endowed with resident DCs that are universally MHC class II(-) but that are capable of expressing class II antigen after surgery and migrating to draining LNs of allografted hosts. These data refute the tenet that the cornea is immune privileged due to lack of resident lymphoreticular cells or due to antigenic sequestration from systemic immunity.     

Embryonic signaling in melanoma: potential for diagnosis and therapy

As the frequency of melanoma diagnosis increases, current treatment strategies are still struggling to significantly impact patient survival. Some promise has been shown in treating certain melanomas by targeting activated signaling pathways resulting from specific mutations in proteins, such as BRAF and NRAS. Recently, the identification of embryonic signaling pathways in melanoma has helped us better understand certain biological characteristics, such as cellular heterogeneity and phenotypic plasticity, and has provided novel insight pertinent to diagnosis and therapy. For instance, our studies have shown that the TGF-β family member, Nodal, is expressed in melanoma and is responsible, at least in part, for tumor cell plasticity and aggressiveness. Since the majority of normal adult tissues do not express Nodal, we reason that this embryonic morphogen could be used to identify and target aggressive melanoma cells. We have also identified that molecular cross-talk between the Notch and Nodal pathways may represent a mechanism responsible for the overexpression of Nodal in melanoma. Further exploitation of the relationship between embryonic signaling pathways and cancer pathogenesis could lead to novel approaches for diagnosis and therapy in cancers, such as melanoma.     

Kaposi’s sarcoma following living donor kidney transplantation: review of 7,939 recipients

Introduction  Kaposi’s sarcoma (KS) is one of the most common tumors to occur in kidney recipients, especially in the Middle East countries. Limited data with adequate sample size exist about the development of KS in living kidney recipients. Methods  Therefore, we made a plan for a multicenter study, accounting for up to 36% (n = 7,939) of all kidney transplantation in Iran, to determine the incidence of KS after kidney transplantation between 1984 and 2007. Results  Fifty-five (0.69%) recipients who developed KS after kidney transplantation were retrospectively evaluated with a median follow-up of 24 (1–180) months. KS occurred more often in older age when compared to patients without KS (49 ± 12 vs. 38 ± 15 years, P = 0.000). KS was frequently found during the first 2 years after transplantation (72.7%). Skin involvement was universal. Furthermore, overall mortality rate was 18%, and it was higher in patients with visceral involvement compared to those with mucocutaneous lesions (P = 0.01). However, KS had no adverse affect on patient and graft survival rates compared to those without KS. Forty-four patients with limited mucocutaneous disease and four with visceral disease responded to withdrawal or reduction of immunosuppression with or without other treatment modalities. Renal function was preserved when immunosuppression was reduced instead of withdrawn in patients with and without visceral involvement (P = 0.001 and 0.008, respectively). Conclusion  The high incidence of KS in this large population studied, as compared to that reported in other transplant patient groups, suggests that genetic predisposition may play a pathogenetic role.     

A comparative study of Korean with Caucasian breast cancer reveals frequency of methylation in multiple genes correlates with breast cancer in young, ER, PR-negative breast cancer in Korean women

To test whether promoter hypermethylation in breast cancer provides a basis for the interethnic difference in breast cancer incidence and distribution, we compared the methylation profiles of tumors arising in native Korean women with Caucasian women in the United States. Methylation-specific PCR analysis of seven genes frequently methylated in breast cancer (HIN-1, Twist, Cyclin D2, RARbeta, GSTP1, RASSF1A and CDH1) was performed on DNA from 67 Korean and 50 Caucasian invasive ductal breast cancers which were categorized into four subgroups by ER status and age. Methylation frequencies for individual genes were similar between the two races. However, tumors in Korean women of age (< or = 50) at diagnosis had a trend of higher prevalence of promoter hypermethylation for all seven genes compared to those in women at an older age (> 50). Furthermore, methylation of multiple genes (four or more genes per case) was associated with younger age at diagnosis (OR = 3.2; 95% CI = 1.2-8.7; p = 0.03). In contrast, there was no association between promoter hypermethylation and age at diagnosis in Caucasian women. A significantly higher frequency of methylation, for all seven genes and in multiple genes, was observed in ER-/PR breast carcinomas in Korean women of age < or = 50 compared to the same subgroup of tumors in Caucasians. In contrast, compared to Korean breast cancer, the subgroup of ER+/PR+ breast carcinomas arising in Caucasian women age > 50 had a significantly higher frequency of methylation in three of seven genes. Our data suggest that promoter hypermethylation is a prevalent phenomenon in breast cancer of young Korean women. By analyzing the methylation patterns in tumors stratified by race, ER/PR status, and age, dissimilarities in promoter hypermethylation profiles, particularly in the ER-/PR- tumors arising in young women, were revealed that characterize tumors of one ethnicity from the other.     

Successful treatment of a patient with multicolored nevus of Ota using a combination of 1064 and 532 nm Q-switched Nd:YAG lasers

ABSTRACT

Nevus of Ota (NO) is a hamartoma of dermal melanocytes usually presents as unilateral blue, gray or brown macules or patches. It can impose a high burden of cosmetic and psychological disturbances in affected individuals. Q-Switched lasers appear to be an effective treatment for this kind of dermal melanocytosis. Multicolored Ota nevus is a rare variant of this kind of nevus and its treatment may be more challenging compared with unicolor lesions. Herein we report a 21-year-old woman with a multicolored nevus of Ota (blue and brown), which showed a dramatic response to a combination of 1,064 nm and 532 nm Q-Switched Nd:YAG lasers. We also discuss different aspects of the Q-switched laser application of Ota nevus treatment. We also focus on laser combination therapy to treat the nevus of Ota.     

Tamoxifen induces oxidative stress and mitochondrial apoptosis via stimulating mitochondrial nitric oxide synthase

Tamoxifen is an anticancer drug that induces oxidative stress and apoptosis via mitochondria-dependent and nitric oxide (NO)-dependent pathways. The present report shows that tamoxifen increases intramitochondrial ionized Ca(2+) concentration and stimulates mitochondrial NO synthase (mtNOS) activity in the mitochondria from rat liver and human breast cancer MCF-7 cells. By stimulating mtNOS, tamoxifen hampers mitochondrial respiration, releases cytochrome c, elevates mitochondrial lipid peroxidation, increases protein tyrosine nitration of certain mitochondrial proteins, decreases the catalytic activity of succinyl-CoA:3-oxoacid CoA-transferase, and induces aggregation of mitochondria. The present report suggests a critical role for mtNOS in apoptosis induced by tamoxifen.