Primary aldosteronism and hypertensive disease

Recent studies in hypertensive populations that have used the serum aldosterone (SA) to plasma renin activity (PRA) ratio as a screening test have demonstrated a high prevalence of primary aldosteronism (PA). This frequency is higher than that previously described when hypokalemia was used as a screening tool. However, other factors, such as the characteristics of hypertensive disease, could also influence the prevalence of PA. We studied 609 essential hypertensive patients, classified according to the Joint National Committee VI (JNC VI), in 3 different stages depending on the severity of their hypertensive disease. We measured SA and PRA and calculated the SA-PRA ratio for all patients. An SA-PRA ratio >25 was detected in 63 of 609 patients, and the fludrocortisone test confirmed the PA diagnoses in 37 of 609 (6.1%) cases. PA prevalence according to hypertension stage was as follows: stage 1, 6 of 301 cases (1.99%); stage 2, 15 of 187 cases (8.02%); and stage 3, 16 of 121 cases (13.2%). PA patients were slightly younger than the other hypertensive patients (48.4+/-10.5 vs 53.6+/-10.2 years; P<0.05). Serum potassium levels were normal in 36 of 37 PA patients; only 1 patient had minor hypokalemia. Computed tomography scans showed bilateral adrenal enlargement in 7 and an adrenal nodule in 2 cases. In summary, we found a high frequency of PA in essential hypertensives classified in stages 2 and 3 according to the JNC VI. The low frequency of computed tomography scan abnormalities and hypokalemia suggests that the diagnosis for most PA patients corresponds to attenuated forms of the disease.     

Bendamustine: new perspective for an old drug in lymphoproliferative disorders

Bendamustine is an old bifunctional alkylating agent that also has potential antimetabolite properties, and only partial cross-resistance with other alkylators. Although it was synthesized in 1963 only few validated study results exist from this early period. More recently, its peculiar mechanism of action has reawakened interest in this drug that has been extensively studied in indolent non-Hodgkin lymphoma (NHL) and in chronic lymphocytic leukemia (CLL). Experience has also been reported in high-grade NHL and Hodgkin disease. Based on its unique structure, various strategies can be used for mechanism-based combination chemotherapeutic regimens with bendamustine. Moreover, data indicates that bendamustine when combined with rituximab is a valid therapeutic choice for patients with CLL or low-grade NHL demonstrating refractoriness to standard chemotherapy regimens. Furthermore, its documented favorable toxicity profile makes it a particularly useful treatment option for elderly patients.     

Intestinal epithelial cells in inflammatory bowel diseases

The pathogenesis of inflammatory bowel diseases (IBDs) seems to involve a primary defect in one or more of the elements responsible for the maintenance of intestinal homeostasis and oral tolerance. The most important element is represented by the intestinal barrier, a complex system formed mostly by intestinal epithelial cells (IECs). IECs have an active role in producing mucus and regulating its composition; they provide a physical barrier capable of controlling antigen traff ic through the intestinal muco...     

Polarization dictates iron handling by inflammatory and alternatively activated macrophages

Background

Macrophages play a key role in iron homeostasis. In peripheral tissues, they are known to polarize into classically activated (or M1) macrophages and alternatively activated (or M2) macrophages. Little is known on whether the polarization program influences the ability of macrophages to store or recycle iron and the molecular machinery involved in the processes.

Design and Methods

Inflammatory/M1 and alternatively activated/M2 macrophages were propagated in vitro from mouse bone-marrow precursors and polarized in the presence of recombinant interferon-γ or interleukin-4. We characterized and compared their ability to handle radioactive iron, the characteristics of the intracellular iron pools and the expression of molecules involved in internalization, storage and export of the metal. Moreover we verified the influence of iron on the relative ability of polarized macrophages to activate antigen-specific T cells.

Results

M1 macrophages have low iron regulatory protein 1 and 2 binding activity, express high levels of ferritin H, low levels of transferrin receptor 1 and internalize – albeit with low efficiency -iron only when its extracellular concentration is high. In contrast, M2 macrophages have high iron regulatory protein binding activity, express low levels of ferritin H and high levels of transferrin receptor 1. M2 macrophages have a larger intracellular labile iron pool, effectively take up and spontaneously release iron at low concentrations and have limited storage ability. Iron export correlates with the expression of ferroportin, which is higher in M2 macrophages. M1 and M2 cells activate antigen-specific, MHC class II-restricted T cells. In the absence of the metal, only M1 macrophages are effective.

Conclusions

Cytokines that drive macrophage polarization ultimately control iron handling, leading to the differentiation of macrophages into a subset which has a relatively sealed intracellular iron content (M1) or into a subset endowed with the ability to recycle the metal (M2).     

Five year time course of celiac disease serology during gluten free diet: results of a community based “CD-Watch” program

Background

Little information is available on the effect of a follow-up strategy in celiac disease patients during gluten-free diet.

Aims

To assess 5 year time course of t-transglutaminase antibodies (t-TG) in celiac disease patients enrolled in a community based follow-up program.

Methods

Annual t-TG testing and periodical clinic visit in 2245 patients.

Results

Proportion of patients with negative t-TG progressively increased from 83% to 93% during the 5-year follow-up: poor adherence to gluten-free diet (HR 4.764), long duration of gluten-free diet (HR 0.929) and female gender (HR 1.472) were independently associated with serological outcome. In individual patients, 69% tested t-TG “persistently negative”, 1% “persistently positive” and 30% “intermittently negative or positive”. By applying mathematical modelling to t-TG conversion rates observed in this latter group at beginning and end of the follow-up program, the predicted proportion of t-TG negative population increased from 90% to 95% over 5 years.

Conclusions

Time-course of t-TG serology in the community fluctuates in 1/3 of celiac disease patients suggesting inconstant adherence to gluten-free diet and need of follow-up strategy. Periodical serological and clinical follow-up is a viable and efficacious strategy to promote adherence to gluten-free diet as inferred from time-course of t-TG serology.     

Endonasal transsphenoidal surgery and multimodality treatment for giant pituitary adenomas

Objective Giant pituitary adenomas (≥40 mm) pose a major management challenge. We describe the experience of a single surgeon and a dedicated neuro‐endocrine team with multimodality treatment of these tumours in three specialized institutions. Design Retrospective data set analyses. Patients Fifty‐one consecutive patients with a giant adenoma (39 endocrine‐inactive, 12 endocrine‐active; mean tumour diameter 45 mm) treated over 10 years by an endonasal transsphenoidal approach were included. All patients had surgical resection followed by radiotherapy and/or medical therapy as judged necessary. Measurements Hormonal and visual status, extent of resection, tumour control rates, complications and use of medical and radiotherapy were evaluated. Results Surgery resulted in gross total, near total and subtotal removal in21 (41%), 10 (20%) and 20 (39%) patients respectively. Complete tumour removal was associated with absence of cavernous sinus invasion (P < 0·001). Long‐term endocrine function improved in 49% of patients and new endocrinopathy occurred in 14·6%; 76% required long‐term hormone replacement therapy. Vision improved in 81·5% of the patients and there was no visual worsening. At the last follow up (median 30 months), tumour control was achieved in 96% of patients: 59% with surgery alone, 20% with surgery plus focussed radiotherapy, 18% with surgery and medical therapy and two with all three modalities. Conclusions Endonasal surgery provides effective initial treatment for patients with giant adenomas. Multimodality therapy was needed in almost 50% of patients and this rate will likely increase with longer follow up. Close collaboration of neurosurgeons with endocrinologists and radiation oncologists is essential for optimal treatment of patients with these challenging tumours.     

Early-Age-at-Onset Colorectal Cancer and Microsatellite Instability as Markers of Hereditary Nonpolyposis Colorectal Cancer

PURPOSE: Early-age-at-onset colorectal cancer and microsatellite instability are characteristic features of hereditary nonpolyposis colorectal cancer. Our aim was therefore to investigate whether these features might be useful markers in screening for hereditary nonpolyposis colorectal cancer and mismatch repair gene mutations. METHODS: From 1,132 consecutive patients who underwent surgery for colorectal cancer at our department between 1980 and 1999, we selected all patients 40 years of age or younger (study group, n = 59) and a subset of patients 40 years of age or older (control group, n = 60) who were matched for gender and pathologic TNM stage. Patients for whom a complete family cancer history or microsatellite status was unavailable were excluded from the study. Family cancer histories, retrieved from archival charts, were reassessed. Microsatellite status was investigated with the five microsatellites from the Bethesda recommended panel (BAT-26, BAT-25, D2S123, D5S346, and D17S250). On the basis of the number of altered microsatellites ( 2, 1, or 0), tumors were considered as having high or low instability or microsatellite stability, respectively. Mutation analysis for MLH1 and MSH2 genes was performed only in cases of high instability. DNA was investigated for mutations by single-strand conformational polymorphism and sequencing analysis. RESULTS: Data from 95 patients (study group: n = 37, 18 males, mean age 35 years; control group: n = 58, 29 males, mean age 62 years) were available for analysis. Four patients (study group, n = 3; control group, n = 1) fulfilled the Amsterdam II criteria for hereditary nonpolyposis colorectal cancer. Of the 37 study group tumors, 12 (32.4 percent) showed high-frequency microsatellite instability, and 25 had microsatellite stability, whereas among the 58 control group tumors, 4 (7 percent) showed high-frequency microsatellite instability, and 54 had microsatellite stability (P < 0.002). Mismatch repair gene mutation analysis was performed in 12 cases (study group, n = 7; control group, n = 5). We found four mutations (MSH2 119delG, MLH1 ex9 684insT, MSH2 Gln239Stop, and MLH1 del0.8 Kb) in the study group patients and none in the control group. Of four hereditary nonpolyposis colorectal cancer patients who underwent mismatch repair gene mutation analysis, one had a mutation. CONCLUSIONS: Early-age-at-onset colorectal cancer is significantly correlated with high-frequency microsatellite instability tumor status and is a useful criterion to identify hereditary nonpolyposis colorectal cancer patients. Moreover, when used in association with high-frequency microsatellite instability status, it is effective in selecting patients for mismatch repair gene mutation analysis.     

Immunophenotyping and T-cell proliferative capacity in a healthy aged population

The age-related decline of immunological functions is well established but it remains largely unknown which specific changes are related to disease. We analyzed peripheral blood lymphocytes of 42 healthy elderly as well as 24 healthy young subjects from southern Brazil. No differences in phytohemagglutinin-induced proliferation and CD4:CD8 ratio were found between the subjects. However, CD4 expression (considering mean fluorescence intensity) was found up regulated in elderly subjects. No changes in activation molecules CD25, CD28, CD69 and CD95 were observed. A reduced proportion of naive (CD45RA+) T cells was found in the elderly compared to young subjects. No changes in adhesion molecule expression (CD11c and CD31) were observed. However, the frequencies of CD49d-positive cells, as well as expression of CD62L, were increased in the eldery subjects. We further described two subgroups of eldery subjects with an immunological risk profile defined by lower CD4:CD8 ratio and reduced proliferative response to mitogens. These data suggest that healthy aging is associated with intact T-cell proliferation and some compensatory immunophenotypical changes. This revised version was published online in July 2006 with corrections to the Cover Date.     

Experience with alemtuzumab plus rituximab in patients with relapsed and refractory lymphoid malignancies

We explored the safety and efficacy of rituximab plus alemtuzumab in patients with relapsed or refractory lymphoid malignancies. Forty-eight patients were treated and were assessable for response (32 with chronic lymphocytic leukemia [CLL], 9 with CLL/prolymphocytic leukemia [PLL], 1 with PLL, 4 with mantle cell leukemia/lymphoma, 2 with Richter transformation). The overall response rate was 52% (complete remission, 8%; nodular partial response, 4%; partial response, 40%). With a median follow-up of 6.5 months (range, 1-20 months), the median time to progression was 6 months (range, 1-20 months); median survival, 11 months (11+ months for responders vs 6 months for nonresponders). Most toxicities were grade 2 or lower and infusion-related. Infections occurred in 52% of the patients. Cytomegalovirus (CMV) antigenemia assays were positive in 27% of the patients, but only 15% were symptomatic and required therapy. The combination of rituximab and alemtuzumab is feasible, has an acceptable safety profile, and has clinical activity with a short course in a group of patients with poor prognoses.     

Submicroscopic deletions at 7q region are associated with recurrent chromosome abnormalities in acute leukemia

BACKGROUND AND OBJECTIVES: Loss of heterozygosity (LOH) on the long arm of chromosome 7 (7q) has been frequently reported in several types of human cancer including hematologic malignancies. Moreover, monosomy of chromosome 7 and 7q deletions have been associated in acute myeloid leukemia (AML) with aggressive disease and poor prognosis. DESIGN AND METHODS: Using a panel of 11 polymorphic microsatellite markers at bands 7q21-q36, we investigated fifty patients (acute myeloid leukemia [AML], n=33 and acute lymphoid leukemia [ALL], n=17) for LOH, a hallmark of possible involvement of tumor suppressor genes. In parallel, the same acute leukemia (AL) cases were studied by conventional cytogenetics. RESULTS: A total of 48 spots of allelic loss were observed in 16 (32%) out of 50 patients (AML, n=11 and ALL, n=5). Among LOH+ve cases 3 showed chromosome 7 monosomies, whereas no cytogenetically detectable abnormalities were observed in chromosome 7 in the remaining 13. INTERPRETATION AND CONCLUSIONS: Comparison with karyotypic results indicated that presence of LOH at 7q21-q36 was significantly associated with other chromosomal aberrations. In fact, an altered karyotype was detectable in 87% of LOH+ve and in 52% of LOH(-ve) AL cases (p=0.024). In addition, LOH at 7q was prevalently associated with unfavorable cytogenetic lesions (p=0.013). Our study represents the first report of a significant association between LOH and recurrent chromosomal abnormalities in AL patients suggesting that the 7q21-q36, region may be an unstable area prone to chromosome breakage in patients with an abnormal karyotype.