Toxicity of cytotoxic agents to granulocyte-macrophage progenitors is increased in obese Zucker and non-obese but insulin resistant Goto-Kakizaki rats.

Increased risk of anticancer chemotherapy in seriously obese patients is known. Obesity may be among factors that predict treatment-related toxicity during chemotherapy. We investigated whether functional changes in granulopoiesis may also contribute to increased myelotoxicity in addition to the known alterations of pharmacokinetic parameters in obesity. Hemopoiesis - as measured by cellularity, frequency of granulocyte-macrophage progenitors (CFU-GM) and total CFU-GM content of the femoral bone marrow - did not differ in obese, insulin resistant Zucker rats compared with Wistar rats. Nevertheless increased sensitivity of their CFU-GM progenitor cells to cytotoxic drugs was found by culturing them in vitro in the presence of carboplatin, doxorubicin and 5-fluorouracil. All drugs were more toxic on CFU-GM progenitor cells of insulin resistant Zucker rats than on CFU-GM cells of the control strain. This might be based on metabolic disorders, at least in part, because we could demonstrate a similar increase in toxicity of the studied anticancer drugs to the CFU-GM progenitors originated from the non-obese but insulin resistant Goto-Kakizaki rats in the same dose ranges. After in vivo administration of rosiglitazone, an insulin sensitizer, the anticancer drug sensitivity of CFU-GM progenitors of Goto-Kakizaki rats was decreased concurrently with improvement of insulin resistance. Although the increased treatment-related myelotoxicity and mortality are well-known among obese patients with malignant diseases, only the altered half lives, volumes of distribution and clearances of cytotoxic drugs are thought to be the underlying reasons. According to our knowledge the results presented here, are the first observations about an impaired granulopoiesis in obese animals.

Effect of rosiglitazone, an insulin sensitizer, on myelotoxicity caused by repeated doses of 5-fluorouracil.

Haematopoietic colony-stimulating factors are used frequently to moderate myelotoxicity, but administration of granulocyte-colony-stimulating factor (G-CSF) prior to chemotherapy actually may worsen the toxic effects on bone marrow. This is important in the design of clinical cancer treatment protocols. Previously, we found that rosiglitazone may protect granulocyte-macrophage progenitor cells (CFU-GM) against damage caused by a single dose of 5-fluorouracil (5-FU). Our new studies are designed to evaluate whether rosiglitazone has similar beneficial effects on bone marrow preservation when administered concurrently with repeated, daily doses of 5-FU while restricting regeneration time. Myelotoxicity characterized by the decrease in cellularity, frequency of granulocyte-macrophage progenitor cells and CFU-GM content of femoral bone marrow in mice. Five-day oral rosiglitazone pre-treatment decreased the susceptibility of granulocyte-macrophage progenitors to 5-FU damage. Significantly, more CFU-GM cells survived after the single intraperitoneal dose of 5-FU (100 mg kg(-1)). The increased frequency of CFU-GM cells with their intensive proliferation allowed faster restoration of the damaged CFU-GM compartment than was seen in the case of repeated daily administration of the cytostatic drug (25 or 50 mg kg(-1)) together with rosiglitazone for 7 consecutive days. The expansion of the CFU-GM compartment was 3 times and 50 times greater in the combined-treated mice than in their counterparts treated with repeated doses of 5-FU alone, although differences in absolute neutrophil counts were not significant. In conclusion, our results indicated that rosiglitazone has protective effects on bone marrow progenitor cells even after daily 5-FU treatment but further studies are warranted to evaluate the optimal treatment schedules.

[The effect of mammographic screening on tumor size, axillary node status and the degree of histologic anaplasia]. / A mammográfiás emlorákszurés hatása a tumorméretre, a hónalji nyirokcsomó státuszra és a szövettani anaplázia fokára.

UNLABELLED: Breast cancer is the most frequent malignant tumor in women in Hungary. Significant reduction of mortality has been brought about not only by the increasing efficiency of complex therapy but also by regular mammographic screening. Of the histopathological data of 633 patients operated with primary breast tumor at the 1st Surgical Clinic of the Debrecen Medical University between January 1st 2000 and December 31st 2004, the authors analyzed tumor diameter, axillary node status and the degree of histologic anaplasia and compared them with the data of mammographic screening. RESULTS: Of the "screened"patients, 70.7% were diagnosed with T1 size tumors, 28.5% with T2 size, and 0.8% with tumors bigger than that. In the "unscreened" patients, our findings were 44.3%, 45.9% and 9.8% respectively. Within T1 tumors, Tla tumors were found in 11%, TIb in 37.6% and T1c in 51.4% in the "screened" group of patients, while the "unscreened" group's results were 2.3%, 12.6% and 85% respectively. 72.7% of the "screened" patients and 56.2% of the "unscreened" patients were found to be axillary node-negative. A study of the degree of histologic anaplasia showed G-I tumors in 15.6%, G-IIs in 62.1% and G-IIIs in 22.3% of the "screened" patients. The corresponding values for the "unscreened" patients were 6.1%, 53.8% and 40.1%, respectively. The differences were highly significant (p < 0.001) in all the parameters investigated. The authors have found a significant increase in the proportion of node-negative patients and patients with smaller tumors even after the first round of mammographic screening and at less than 50% participation. It is to be hoped that a 20% reduction in mortality can be achieved by further increasing the rate of participation.

[Enzyme replacement therapy in Gaucher disease: monitoring visceral and bone changes with MRI]. / Enzimszubsztitúciós terápia gaucher-kórban: az MRI-vizsgálat szerepe a visceralis és a csontelváltozások monitorozásában.

INTRODUCTION: Gaucher disease (GD) is the most common lysosomal storage disorder. It can be successfully treated with infusion of the modified deficient enzyme. AIM: Visceral and skeletal changes during enzyme replacement therapy (ERT) in patients with type 1 Gaucher disease (GD) were studied by radiological methods. METHODS: Eight patient with GD (8-39 years) were examined, who underwent ERT for 1-8 years (30-80 IU/bwkg/months Ceredase or Cerezyme). MRI from the upper abdomen were made before ERT was started and once a year during ERT, that allowed measurement of hepatic and splenic volume. The bone changes were depicted by MRI and conventional X-ray images. Bone marrow infiltration was estimated by MRI scans of femora with semiquantitative method. RESULTS: Hepato- and splenomegaly were detected before ERT, which decreased in each patient during therapy. Decrease of liver volume was more expressed in patients with splenectomy. The infiltration of the bone marrow with Gaucher cells has reduced during treatment in six cases. Decreases of hepatosplenomegaly occured earlier and faster, than the improvement of bone disorders. Two splenectomised patients exhibited 4 episodes of bone crisis diagnosed by MRI. Their symptoms regrediated on increased enzyme doses. The grade of bone marrow infiltration and concurrent bone complications could not be detected by conventional X-ray films. CONCLUSIONS: We conclude that the use of ERT in all patients leads to marked improvements in visceral and skeletal pathology of patients with Gaucher disease. The volume of the liver and the spleen, and the extension of bone marrow infiltration can be measured precisely by MRI, so it can be the method of choice in the diagnosis and in the monitoring of response to ERT. MRI helps to determine the appropriate enzyme dosage and to establish the necessity of elevation the enzyme dose. MRI can be practicable in the differential diagnosis of bone crisis and osteomyelitis.

[Results of mammographic screening at the Mammary Center of Debrecen in 1999 and 2000]. / A mammográfiás emlórákszúrés eredménye a debreceni Emlócentrumban 1999-ben és 2000-ben.

INTRODUCTION: The screening mammography decreases the mortality of female breast cancer. METHODS: A complex, independent centre of screening mammography has been operating in Debrecen since 1999. RESULTS: The number of the examinations were 10,399 in 1999 and 13,800 in 2000. The number of explored breast cancer cases were 43 (0.41%) in 1999 and 62 (0.45%) in 2000. CONCLUSION: Although the mortality reduction can be exactly measured after several years, we are convinced that the chances for a better life of these 107 women operated on with breast cancer in early state increased thanks to our project. The results of the breast cancer screening program in Debrecen fulfilled the professional requirements of mammographic service-screening.