GLUT1 expression patterns in different Hodgkin lymphoma subtypes and progressively transformed germinal centers.

BACKGROUND: Increased glycolytic activity is a hallmark of cancer, allowing staging and restaging with 18F-fluorodeoxyglucose-positron-emission-tomography (PET). Since interim-PET is an important prognostic tool in Hodgkin lymphoma (HL), the aim of this study was to investigate the expression of proteins involved in the regulation of glucose metabolism in the different HL subtypes and their impact on clinical outcome. METHODS: Lymph node biopsies from 54 HL cases and reactive lymphoid tissue were stained for glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA) and lactate exporter proteins MCT1 and MCT4. In a second series, samples from additional 153 HL cases with available clinical data were stained for GLUT1 and LDHA. RESULTS: Membrane bound GLUT1 expression was frequently observed in the tumor cells of HL (49% of all cases) but showed a broad variety between the different Hodgkin lymphoma subtypes: Nodular sclerosing HL subtype displayed a membrane bound GLUT1 expression in the Hodgkin-and Reed-Sternberg cells in 56% of the cases. However, membrane bound GLUT1 expression was more rarely observed in tumor cells of lymphocyte rich classical HL subtype (30%) or nodular lymphocyte predominant HL subtype (15%). Interestingly, in both of these lymphocyte rich HL subtypes as well as in progressively transformed germinal centers, reactive B cells displayed strong expression of GLUT1. LDHA, acting downstream of glycolysis, was also expressed in 44% of all cases. We evaluated the prognostic value of different GLUT1 and LDHA expression patterns; however, no significant differences in progression free or overall survival were found between patients exhibiting different GLUT1 or LDHA expression patterns. There was no correlation between GLUT1 expression in HRS cells and PET standard uptake values. CONCLUSIONS: In a large number of cases, HRS cells in classical HL express high levels of GLUT1 and LDHA indicating glycolytic activity in the tumor cells. Although interim-PET is an important prognostic tool, a predictive value of GLUT1 or LDHA staining of the primary diagnostic biopsy could not be demonstrated. However, we observed GLUT1 expression in progressively transformed germinal centers and hyperplastic follicles, explaining false positive results in PET. Therefore, PET findings suggestive of HL relapse should always be confirmed by histology.

Pilot trial on determinants of progenitor cell recruitment to the infarcted human myocardium.

BACKGROUND: Clinical trials indicate a beneficial effect of intracoronary infusion of progenitor cells on myocardial function in patients with ischemic heart disease. The extent and potential determinants of proangiogenic progenitor cell homing into the damaged myocardium after intracoronary infusion and the underlying mechanisms are still unknown. METHOD AND RESULTS: Circulating proangiogenic progenitor cells isolated from peripheral blood and cultivated for 3 days were labeled with radioactive indium oxine ((111)In-oxine). Radiolabeled proangiogenic progenitor cells (7.6+/-3.0 MBq, mean+/-SD) were administered to patients with previous myocardial infarction and a revascularized infarct vessel at various stages after infarction (5 days to 17 years). Viability of the infarcted myocardium was determined by (18)F-fluorodeoxyglucose-positron emission tomography and microcirculatory function by intracoronary Doppler measurements. One hour after application of progenitor cells, a mean of 6.9+/-4.7% (range, 1% to 19%; n=17) of total radioactivity was detected in the heart, which declined to 2+/-1% after 3 to 4 days. Average activity within the first 24 hours was highest among patients with acute myocardial infarction (14 days to 1 year; 4.5+/-3.2%; n=4) or a chronic stage (infarct age >1 year; 2.5+/-1.6%; n=5). Low viability of the infarcted myocardium and reduced coronary flow reserve were significant (P<0.05) predictors of proangiogenic progenitor cell homing. CONCLUSIONS: In patients after myocardial infarction undergoing intracoronary infusion of (111)In-oxine-labeled proangiogenic progenitor cells, a substantial amount of radioactivity is detected for several days in the heart, indicating homing of progenitor cells to the myocardium. The amount of proangiogenic progenitor cells retained in the heart decreased progressively with time after the acute myocardial infarction. Proangiogenic progenitor cells preferentially home to extensive acute myocardial infarcts characterized by low viability and reduced coronary flow reserve.

Positive sentinel lymph nodes are a negative prognostic factor for survival in T1-2 oral/oropharyngeal cancer-a long-term study on 103 patients.

BACKGROUND: To evaluate prognostic value of sentinel node biopsy (SNB) in oral/oropharyngeal squamous cell cancer (OOSCC) concerning overall/disease-free survival. METHODS: One hundred three consecutive patients with T1-2N0 OOSCC were consecutively recruited for SNB as single invasive staging method for the neck. Two hundred seventy-three sentinel nodes (SNs) were removed (mean, 2.65 per patient). Nine patients had 10 positive SNs (upstaging rate, 8.7%) found in levels I to III, leading to a therapeutic neck dissection. RESULTS: Mean observation time of all patients was 6.7 years; mean survival time of patients with negative or positive SNs was 6.9 and 3.7 years, respectively. There has been no false-negative result of SNB to date becoming manifest in ipsilateral node metastasis during follow-up. Five-year overall/disease-free survival of all patients was 82%/72%, respectively. The same parameters for the patients with negative SNs were 85%/74%, for those with positive SNs 38%/47%, respectively (statistically significant). There has been a higher statistical risk for locoregional recurrence for patients with positive SNs. Rates of metachronous second primary tumors developing during follow-up were 10.6% (negative SNs) and 44.4% (positive SNs). CONCLUSION: SNB was a valuable diagnostic method in patients with T1-2N0 OOSCC avoiding elective neck dissections. Patients with positive SNs had statistically significantly higher rates of locoregional recurrences, second primary tumors, tumor-related deaths, and a worse overall/disease-free survival. To date, no therapeutic consequences in case of a positive SN beyond execution of modified radical neck dissection (to remove other positive nodes) and closer attention during follow-up can be concluded from this study.

Calculation and validation of a plasma calcitonin limit for early detection of medullary thyroid carcinoma in nodular thyroid disease.

BACKGROUND: The early diagnosis of medullary thyroid carcinoma (MTC) is crucial for effective therapy. Elevated plasma calcitonin concentrations (pCT-Cs) are generally a specific and sensitive indicator for C-cell hyperplasia or MTC. The presence of thyroid nodules raises the possibility of MTC. Hence, in endemic goiter regions, there is a need for information regarding the pCT-C values that are indicative of C-cell hyperplasia or MTC. The aim of this study, therefore, was to determine an upper pCT-C to distinguish patients with and without MTC in a collective with nodular thyroid disease, and to give an estimation of the prevalence of MTC in an endemic goiter area. METHODS: Basal pCT-C was measured in 21,928 patients with thyroid nodules living in central Germany, an area with endemic goiter due to previous iodine deficiency. In 218 subjects with pCT-Cs exceeding 10 ng/L, stimulated pCT-C was additionally determined, as suggested by the German consensus recommendation. A nominal normal range for basal pCT-C was calculated with data from 21,900 subjects without known MTC. The predicted upper limit was then validated using the known diagnoses of 376 patients with pCT-Cs exceeding 10 ng/L, 28 of whom presented with MTC. RESULTS: For basal pCT-C, calculation of the three-sigma borders after logarithmic transformation revealed upper limits of the nominal normal range of 14.6 ng/L in females and 32.8 ng/L in males, respectively. However, three male patients with small MTCs had basal pCT-Cs between 15 and 33 ng/L. None of the patients with MTC had a basal pCT-C below 15 ng/L or an increase in pCT-C after pentagastrin stimulation that was less than 80 ng/L. In the basal pCT-C range between 15 and 50 ng/L (n = 192; eight with MTC), the positive predictive value for the detection of MTC was 4% in our group. Applying an upper limit for basal pCT-C of 15 ng/L in both sexes, 329 of the total of 21,928 patients exceeded this range. Among these, the final outcome is known in 231 subjects, including all 28 MTCs. CONCLUSIONS: An upper limit of 15 ng/L instead of 10 ng/L for basal pCT-C is able to detect all MTC and reduce false-positive cases. The prevalence of MTC in nodular thyroid disease in our group was approximately 1.8 per thousand.