Low hemoglobin is associated with increased serum levels of vascular endothelial growth factor (VEGF) in cancer patients. Does anemia stimulate angiogenesis?

BACKGROUND: Vascular endothelial growth factor (VEGF) is an endothelial cell specific mitogen with strong angiogenic activity. Expression of VEGF may therefore be an indicator for the angiogenic potential and biological aggressiveness of a tumor. Recently, measurement of the VEGF-protein in sera has become available. We report results of serum-VEGF in an unselected group of patients with cancer with special emphasis on a possible role of anemia. PATIENTS AND METHODS: Between August 1997 and January 1998, serum-levels of VEGF were determined in a total number of 54 consecutive patients with previously untreated, non-metastatic carcinomas at the Department of Radiotherapy at the Martin-Luther University Halle-Wittenberg. The age ranged from 35 through 89 years with a median age of 67 years. All patients had locoregional confined disease without evidence of hematogenous metastases. Tumor sites were gynecological cancers in 22, head and neck in 14, gastrointestinal in 13, lung in 4 and prostate in 1 case. Forty-four patients had squamous carcinomas and 10 adenocarcinomas. Prior to treatment, routine laboratory work-up was done including measurement of serum-vascular endothelial growth factor (VEGF). The pretreatment hemoglobin ranged from 8.9 through 15.6 g/dl with a median of 13 g/dl. VEGF was measured with a quantitative sandwich enzyme immunoassay technique. RESULTS: The serum levels of VEGF in 40 patients with benign diseases ranged from 57 through 891 pg/ml with a mean of 267 +/- 170 pg/ml. In the investigated 54 cancer patients, VEGF ranged from 62 through 2,609 pg/ml with a mean of 614 +/- 551 pg/ml. Age, UICC/FIGO-stage, T- or N-category, primary tumor site, grade and histologic type had no significant impact on VEGF-serum levels. There was, however, an association between hemoglobin level and serum-VEGF with an increased mean serum-VEGF in 26 patients with a low hemoglobin (< 13 g/dl) as compared to 28 patients with a hemoglobin > 13 g/dl (805 +/- 656 vs 438 +/- 360, p = 0.016, 2-sided t-test). CONCLUSIONS: With regard to the recently established correlation between anemia and intratumoral hypoxia, the increased serum-VEGF levels in patients with low hemoglobin may be explained via hypoxia-induced VEGF secretion. This would suggest that anemia may stimulate angiogenesis via hypoxia. The hypothesis, however, requires further investigation and might have important therapeutical impact.

[Intratumor pO2, S-phase fraction and p53 status in cervix carcinomas]. / Intratumoraler pO2, S-Phase-Anteil und p53-Status bei Zervixkarzinomen.

PURPOSE: Investigation whether tumor tissue oxygenation is influenced by proliferation or p53-status in cervical cancers. MATERIAL AND METHODS: From April 1995 through December 1996, 28 patients with locally advanced cervical cancers (age 36 to 78 years; FIGO stages: 10 patients IIB, 16 patients IIIB, 2 patients IVA) underwent intratumoral measurement of pO2 prior to definitive radiotherapy. The histological specimens were examined for grading and quantitative immunohistological expression of the MIB-antigen and p53-protein. Proliferation was estimated by measuring the S-phase fraction with flow cytometry. RESULTS: The median pO2-values showed a broad variation from 2.2 through 60.4 mm Hg, median 19.7 mm Hg. The S-phase fraction varied from 4.2 through 34.2% (median 11.6%), MIB-positive cells from 20 through 100% (median 74%), and immunohistologically p53-positive cells from 0 through 95% (median 2%). The patients were divided in 2 groups according to the pretreatment pO2. Tumors with a pO2 above the median had a lower S-phase fraction than tumors with a pO2 below the median, 10.4 +/- 3.8% versus 16.3 +/- 5.5%, p < 0.02. MIB and p53 were not different in both groups (MIB: 68.1 +/- 27.7% versus 75.0 +/- 18.4%, p = 0.1; p53: 26.4 +/- 38.5% versus 18.1 +/- 19.8%, n. s.). Grade of differentiation and FIGO stage had no impact on pO2. CONCLUSION: Locally advanced cervical cancers with a poor oxygenation have a higher proliferative activity. Tumor proliferation may play a causative role for the development of hypoxia as suspected from radiobiological theories.

[Effect of ultraviolet irradiation on renal osteopathy in patients in the chronic hemodialysis program]. / Einfluss der ultravioletten Bestrahlung auf die renale Osteopathie bei Patienten im chronischen Hämodialyseprogramm.

Under influence of the ultraviolet radiation the formerly lowered 25-hydroxycholecalciferol (25-OH-CC) level increases in persons with healthy kidneys. Such investigations were not yet carried out in patients undergoing dialysis. Since the insufficiency of active vitamin-D-metabolites plays an essential role in the development of the renal osteopathy, since 1978 in 13 patients undergoing dialysis a regular ultraviolet radiation has been performed, in order to stimulate the cutaneous vitamin-D-production. The time of observation was 31.7 +/- 14.3 months. Deionized water served for the production of dialysate. The calcium content was about 3.5 +/- 3.8 mval/l. The patients had very rarely bone and joint complaints. Severe clinical complications of renal osteopathy developed only in one female patient in the 3rd year of dialysis with a fracture of the neck of the femur as well as in a 2nd patient after transplantation of a kidney with permanently progressing demineralization and spondylitis. Controls of the courses showed only in 18.2% a progressing loss of the peripheral mineral content of the bones. The alkaline phosphatase was not increased, the alkaline bone phosphatase appeared with low and not provable activities. A suppression of the secondary hyperparathyroidism could not be proved. Parathormone was increased with 2.30 +/- 1.90 micrograms/l. The 25-OH-CC-levels were normal or slightly increased with 39.1 +/- 12.4 micrograms/l, whereas they were essentially lower in a comparative group without ultraviolet radiation. Therefore in connection with the very low rate of complications of the renal osteopathy with normalized 25-OH-CC-levels new therapeutic possibilities were the result in patients undergoing dialysis after ultraviolet radiation. The increasing importance consists also in the fact that 90% of the human vitamin-D-need are supplied via skin and it was proved by animal experiments that also after bilateral nephrectomy the formation of the active vitamin-D-metabolite 1,25-dihydroxycholecalciferol is possible by photosynthesis.

[Determination of isoenzymes of alkaline phosphatase and alpha-amylase in feces]. / Bestimmungen von Isoenzymen der alkalischen Phosphatase und alpha-Amylase im Stuhl.

Investigations for the proof of isoenzymes of the alkaline phosphatase and the alpha-amylase in stool were carried out. The measurements of the faecal enzyme activities were performed in 96 patients with intestinal diseases. The disc electrophoresis in the polyacrylamide gel served for the separation of isoenzymes. The separated enzyme bands of the extracts of stool were compared with those ones of serum duodenal juice and extracts of the mucous membrane of the duodenum, the jujunum, the ileum as well as of the colon. Hereby up to 4 very much anodically wandering bands were present, which might be subunits or fission products of the alkaline phosphatase. In the alpha-amylase up to 5 bands could be proved, which were compared with those ones of the serum, the duodenal juice and the urine. A coordination of these isoenzymes concerning their origin is not possible. The faecal activities of enzymes correlate with the weights of stool. In exocrine pancreatic insufficiency and ulcerous colitis increased faecal activities of enzymes are found, the genesis of which is discussed.

[Early symptoms of hyperparathyroidism in nephropathies]. / Zur Frühsymptomatik des Hyperparathyreoidismus bei Nephropathien.

The development of an autonomous (tertiary) hyperparathyroidism in patients with renal diseases must clinically be taken into consideration, when by therapeutic measures the causes of a compensatory overfunction of the parathyroid glands were excluded, but the symptoms of a hyperparathyroidism continue or even increase. This is of special importance in the control of patients with renal grafts. The increase of the serum calcium on more than the normal value in simultaneously increased serum phosphate level and increased activity of the alkaline bone phosphatase in connection with demineralisation of the skeleton, osteoclastic changes of the bones and estraossary calcifications may be regarded as early symptoms of a hyperparathyroidism. It is to be discussed the hypothesis, whether in every autonomous hyperparathyroidism a regulative reaction precedes. In patients with renal diseases in a limited number a prevention of the regulative overfunction of the parathyroid glands is possible by an early compensation of a calcium deficit (acquired vitamin D resistance), a hyperphosphataemia and a renal acidosis.