Older age is an adverse prognostic factor in stage I, favorable histology Wilms' tumor treated with vincristine monochemotherapy: a study by the United Kingdom Children's Cancer Study Group, Wilm's Tumor Working Group.

PURPOSE: To identify clinical prognostic factors in children with stage I, favorable histology (FH) Wilms' tumor treated with vincristine monochemotherapy after immediate nephrectomy to define subgroups for consideration of further reduction in treatment intensity. PATIENTS AND METHODS: During two consecutive trials of the United Kingdom Children's Cancer Study Group (UKW2 and UKW3, 1986 to 2001), 242 children with stage I FH Wilms' tumor were treated with immediate nephrectomy followed by 10 weekly injections of vincristine 1.5 mg/m2. Event-free survival (EFS) and overall survival (OS) were compared by age group. RESULTS: The 4-year EFS rate was 93.2%, 87.2%, and 71.3% for children less than 2 years old, 2 to 4 years old, and 4 years old or older at diagnosis, respectively (log-rank, P =.001); the corresponding 4-year OS rate was 98.1%, 95.0%, and 87.2% (log-rank, P =.01). There were no toxicity- or procedure-related deaths. In multivariate analysis, specimen weight was not of independent prognostic value (P =.66). Among the 186 children younger than 4 years at diagnosis, there were 17 relapses and five deaths, compared with 16 relapses and eight deaths among the 56 children at least 4 years old at diagnosis. OS after relapse was surprisingly poor (61.6% at 4 years). CONCLUSION: Treatment for stage I FH Wilms' tumor is generally successful using vincristine monotherapy after immediate nephrectomy, and therefore, the risks of dactinomycin hepatopathy can be avoided. However, age at least 4 years is a significant adverse prognostic factor. This treatment schedule should be considered in any trial of treatment reduction in very young children with stage I FH Wilms' tumor, regardless of tumor size, and we suggest that the upper age limit for the reduced therapy be set at 4 years.     

Interdisciplinary approach to abdominal Burkitt’s lymphoma

Burkitt’s lymphoma is a high-grade, rapidly growing B-cell neoplasm. It is recognized by its aggressive course, brief median survival, and low rates of long-term survival. The authors discuss the case of a patient who acutely presented with intraabdominal complications from a new onset of Burkitt’s lymphoma. The clinical and pathological features, staging, treatment options, and survival data are reviewed. In addition, the role of surgical intervention is carefully analyzed.     

Polymorphisms in glutathione-S-transferase genes (GST-M1, GST-T1 and GST-P1) and susceptibility to prostate cancer among male smokers of the ATBC cancer prevention study.

Glutathione-S-transferase (GST) genes encode a family of detoxification enzymes that offer protection against endogenous and exogenous sources of reactive oxygen species (ROS). Germline variations in GST genes may alter the catalytic efficiency of GST isoenzymes leading to a potential increase in susceptibility to the genotoxic effects of ROS and electrophilic substances. A nested case-control study design was used to examine the association between the polymorphic GST genes and prostate cancer risk among Finnish male smokers of the ATBC Cancer Prevention Study. A case-case analysis was used to determine the association between these genetic polymorphisms and prostate cancer progression. Germline DNA was obtained from 206 prostate cancer cases and 194 controls frequency matched on age, intervention group and study clinic. Cases and controls were genotyped for three GST genes using MALDI-TOF mass spectrometry or multiplex polymerase chain reaction (PCR). Relative to the wild-type genotype, we observed a 36% reduction in prostate cancer risk associated with the GST-M1-null genotype (odds ratio (OR) 0.64, 95% confidence interval (CI) 0.43, 0.95). Unlike GST-M1, GST-T1-null (OR 0.74, 95% CI 0.42, 1.33) and GST-P1*B (OR 1.10, 95% CI 0.72, 1.69) were not strongly associated with prostate cancer risk. We did not observe any significant associations between the selected polymorphic GST genes and tumour grade or stage. In conclusion, we did not observe a direct association between polymorphic GST-T1 or GST-P1 and prostate cancer risk. Our observation of a relatively strong inverse association between the GST-M1-null genotype and prostate cancer risk needs to be confirmed in larger association studies.     

EQUAL FREQUENCY OF TEL/AML1 ACUTE LYMPHOBLASTIC LEUKEMIA IN CHILDREN WITH AND WITHOUT DOWN SYNDROME

Constitutional trisomy 21 is the most prominent predisposing factor to childhood leukemia, whereas the t(12;21)(p13;q22) with its molecular genetic counterpart, the TEL/AML1 fusion gene, is the most common acquired chromosomal rearrangement in childhood B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). Thus, it was somewhat surprising that according to the currently available literature the incidence of TEL/AML1+ BCP ALL is extremely low in patients with Down syndrome (DS). To further investigate this issue in a population-based fashion, the authors retrospectively assessed the number of DS patients with a TEL/AML1+ ALL in two consecutive Austrian ALL multicenter trials. Accordingly, they were able to analyze 8 of 10 individuals with DS and a BCP ALL, including 2 who suffered from a TEL/AML1+ leukemia. Based on this observation we concluded that individuals with a constitutional trisomy 21 may have the similar likelihood to develop a TEL/AML1+ leukemia as BCP ALL patients without this specific predisposing factor.     

Double germline mutations in the RET Proto-oncogene in MEN 2A and MEN 2B kindreds.

Medullary thyroid carcinoma (MTC) is a rare form of thyroid cancer representing about 10% of all thyroid malignancies. It occurs mostly as a sporadic tumor or in association with autosomal dominant inherited cancer syndromes--multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC. Germline mutations in exons 8, 10, 11, 13, 14, 15 and 16 of the RET proto-oncogene are found in most of the familial cases. There are only a few published data reporting multiple germline mutations in the RET proto-oncogene. We have detected double germline mutations in 2 different exons on the same RET allele in two MEN 2 families. In the MEN 2A family, double germline mutation in exons 10 (Cys620Phe) and 13 (Tyr791Phe) was detected. In the MEN 2B family, beside the classical germline mutation in exon 16 (Met918Thr) a second germline mutation in exon 13 (Tyr791Phe) was found. This study revealed that MEN 2 syndromes can also be caused by double germline mutations in the RET proto-oncogene and these families can be added to small worldwide cohort of families with multiple germline mutations.     

Relationship between peripheral diabetic neuropathy and microvascular reactivity in patients with type 1 and type 2 diabetes mellitus -- neuropathy and microcirculation in diabetes.

The aim of the study was to evaluate differences in the relationship between peripheral diabetic neuropathy and microvascular reactivity in type 1 and type 2 diabetic patients. Twenty-eight type 1 and 37 type 2 diabetic patients were included in the study. Control groups consisted of 18 and 25, age and body mass index matched healthy persons. The presence of peripheral neuropathy was estimated by vibration perception threshold higher than 20 V evaluated by biothesiometry. Microvascular reactivity was examined by laser doppler fluxmetry using postocclusive reactive hyperemia and thermal hyperemia. The following variables of vascular reactivity were examined: peak flow after occlusion as a difference between maximal and basal perfusion (PORH (max)), mean velocity increase during postocclusive hyperemia (PORH (max)/t (1)), peak flow during thermal hyperemia (TH (max)) and the mean velocity increase in the perfusion during thermal hyperemia (TH (max)/t (2)). These parameters are expressed in perfusion units (PU) or in perfusion units per second (PU . s (-1)). The microvascular reactivity in type 1 diabetic patients without evidence of peripheral neuropathy was comparable with that in healthy persons and it was significantly higher than in type 1 diabetic patients with peripheral neuropathy in all tested parameters (PORH (max): 64 [40; 81] PU vs. 24 [17; 40] PU, p < 0.001, PORH (max)/t (1): 5.41 [2.69; 8.18] PU/s vs. 1.21 [0.69; 2.5] PU/s, p < 0.001, TH (max): 105 [77; 156] PU vs. 56 [46; 85] PU, p < 0.001 and TH (max)/t (2): 2.48 [1.67; 3.33] PU/s vs. 0.87 [0.73; 1.06] PU/s, p < 0.001). On the contrary, no difference in the microvascular reactivity parameters was found between type 2 diabetic patients with and without neuropathy (PORH (max): 48 [30; 60] PU vs. 49 [36; 57] PU, NS, PORH (max)/t (1): 3.46 [2.15; 5.19] PU/s vs. 3.29 [2.45; 4.8] PU/s, NS, TH (max): 95 [78; 156] PU vs. 97 [73; 127] PU, NS and TH (max)/t (2): 1.45 [0.95; 2.84] PU/s vs. 1.37 [1.12; 1.95] PU/s, NS). In both these groups microvascular reactivity was comparable with that estimated in the age and BMI matched healthy persons. An inverse relationship was observed between microvascular reactivity and vibratory perception threshold in type 1 diabetic patients, but it was not true in type 2 diabetic patients. We suppose that the pathogenesis of neuropathy and impaired microvascular reactivity may be differently influenced by metabolic factors in type 1 and type 2 diabetic patients.     

Did the gradual loss of GLUT2 cause a shift to diabetic disorders in the New Zealand obese mouse (NZO/Hl)?

The New Zealand obese mouse (NZO/Hl) is characterised by hereditary obesity and type-2 diabetes, including insulin resistance, hyperinsulinaemia, and glucose intolerance. In other diabetic models, it has been revealed that the proper functioning of the glucose transporter isoform 2 (GLUT2) is essential for adequate secretion of insulin. The aim of this study was to compare the distribution of islet cells and GLUT2, as well as the expression of GLUT2-mRNA, in the pancreas of NZO mice and metabolically unimpaired NMRI (Naval Medical Research Institute) mice. Pancreas tissue was obtained from different stages of development. For molecular determination of the expression level of GLUT2-mRNA, total-RNA was extracted from the pancreas and analysed by quantitative real-time RT-PCR. All investigated NZO mice displayed increased weight, elevated hyperinsulinaemia, and slightly enhanced blood glucose levels compared with the NMRI control mice. By means of immunofluorescence microscopy drastically reduced insulin levels were detected, which might be compensated by the observed islet cell hyperplasia and hypertrophy. Furthermore, the normally peripheral localisation of the alpha-cells within islets was disturbed. By contrast, there were no changes in somatostatin cell distribution. However, considerable differences appeared with regard to GLUT2: whereas the beta-cells of NMRI mice showed dense immunostaining of the GLUT2 transporter on the cell surface, in all age groups of NZO mice, GLUT2 on the plasma membranes was reduced and dispersed in the cytoplasm. These findings agree with the molecular biological results, which displayed decreased mRNA-expression of GLUT2. In summary, the observed alteration of islet morphology and of GLUT2 expression in diabetic mice complements our previous results from a superfusion protocol and further clarifies the mechanisms of diabetogenesis in NZO mice.     

Sniff nasal inspiratory pressure: what is the optimal number of sniffs?

Sniff nasal inspiratory pressure (SNIP) measurement is a volitional noninvasive assessment of inspiratory muscle strength. A maximum of 10 sniffs is generally used. The purpose of the present study was to investigate whether the maximum SNIP improved after the tenth sniff. In total, 20 healthy volunteers and 305 patients with various neuromuscular and lung diseases were encouraged to perform 40 and 20 sniffs, respectively. The best SNIP among the first 10 sniffs was lower than the best SNIP among the next 10 sniffs in the healthy volunteers and patients. The SNIP improvement after the twentieth sniff was marginal. In conclusion, a learning effect persists after the tenth sniff. The current authors suggest using 10 additional sniffs when the best result of the first 10 sniffs is slightly below normal, or when sniff nasal inspiratory pressure is used to monitor a progressive decline in inspiratory muscle strength.