Baseline and therapy-induced chromosome damages in peripheral blood lymphocytes of breast cancer patients assessed by the micronucleus assay.

PURPOSE: Radiotherapy (RT) alone or in combination with chemotherapy (CT) leads nearly always to increase of DNA damage in cancer patients. The purpose of this study was to determine the variability rate and individual sensitivity of breast cancer (BC) patients to the applied RT and RT in combination with CT. METHODS: The analysed sample included 30 women with histologically confirmed BC. The frequency of micronuclei (MN) was estimated in peripheral blood lymphocytes (PBL) by using the cytokinesis-block micronucleus (CBMN) assay before the administered therapy and one month later. RESULTS: The mean therapy-induced MN value was significantly higher (p < 0.001) compared with mean baseline MN. Both therapies (RT and combined RT+CT) significantly increased the MN frequency in patients' lymphocytes (p<0.001), but without significant differences in the therapy-induced MN frequency between these two groups (p > 0.05). The administered therapy induced significant difference in cell kinetics (p < 0.05). The results showed a wide range of inter-individual variability in both baseline and the therapy-induced MN frequency. CONCLUSION: The applied therapies increased the MN frequency in PBL in BC patients, and the presented data indicate absence of synergistic effect of these two therapies. None of the variation factors (age, smoking and therapy type) had influence on the noticed variability.

Outcome of childhood brain tumors in Serbia.

PURPOSE: To present the results of treatment for childhood brain tumors in Serbia. METHODS: The medical records of patients with brain tumors diagnosed and operated at the Institute of Neurosurgery, Clinical Center of Serbia and treated with postoperative radiotherapy and chemotherapy at the Institute of Oncology and Radiology of Serbia, Belgrade, between January 1995 and December 2004, were reviewed. Of the 247 patients who were identified, 212 formed the basis of this study. Overall survival (OS) was determined by the Kaplan-Maier method, using log-rank test for comparisons. RESULTS: With a mean follow up of 46.9-33.6 months (range 7-120), the 5-and 8-year OS rates were 70.0% and 61.5%, respectively. At the time of evaluation 119 (60.1%) patients had no evidence of disease. Among 79 patients who failed therapy, most of them (n=61; 77.2%) had local failure only. According to histologic tumor type most of them (n=27; 34.2%) were in the group of malignant medulloblastoma. Girls had better survival than boys, but without statistical significance (p=0.185). Also, no significant difference in survival in relation to age was seen (p=0.291). Patients with supratentorial tumors had significantly better survival than those with infratentorial localizations (p=0.036). Patients with low grade astrocytomas had significantly better survival than malignant gliomas, ependymomas and primitive neuroectodermal tumors (PNETs) (p=0.0001). CONCLUSION: OS rates were concordant with the results of other modern series. Although the survival rates were encouraging, there is still significant room for improvement in the management of childhood brain tumors.

In vitro evaluation of the genotoxicity of ritodrine and verapamil in human lymphocytes.

The aim of this study was to investigate the genotoxic effects of ritodrine and verapamil on human peripheral lymphocytes in vitro using micronucleus (MN) test. Also, fluorescence in situ hybridization (FISH) with a centromeric probe was performed to determine the origin of the induced MN. Cells were treated with 8.4 × 10(-6) M - 25.2 × 10(-4) M concentrations for ritodrine and 0.56 - 11 × 10(-5) M concentrations for verapamil, separately and combined. The MN frequencies showed increase after all treatments, but the difference between treated cells and untreated controls were found to be statistically significant only in the concentration range from 8.4 × 10(-5) M - 4.5 × 10(-4) M for ritodrine, 1.1 - 3.3 × 10(-5) M for verapamil, and in combined treatment with concentrations 8.4 × 10(-5) M + 1.1 × 10(-5) M for ritodrine and verapamil. The highest tested concentrations of both medicaments showed cytotoxic effect. Both medicaments decreased the nuclear division index (NDI) in tested concentrations. The results of FISH analysis suggest that verapamil, separately or combined with ritodrine, shows to a larger extent aneugenic than clastogenic effect.

Neurocysticercosis mimicking brain tumor.

Neurocysticercosis together with brain tumors is one of the leading causes of seizures in the developing world. In Western Europe NCC is rare and a high degree of physician awareness is necessary for diagnosis.

Intraventricular textiloma with granuloma formation following third ventricle colloid cyst resection - a case report.

Despite precautions, cotton and gauze pads used for dissection or to achieve haemostasis during neurosurgical procedures can inadvertently be left behind and result in clinically symptomatic or asymptomatic and radiologically apparent mass lesion, sometimes referred to as "textilomas" or "gossypibomas", often mimicking recurrent tumour or abscess on neuroimaging studies. We report the neuroimaging evaluation, including computed tomography (CT), magnetic resonance imaging (MRI) and spectroscopy (H1-MRS), in a case of textiloma developing after the treatment of a third ventricle colloid cyst.

[Pediatric brain tumors--diagnostic and treatment].

During the period 1995-2004 we treated 212 patients (pts) with brain tumors. There were 133 boys and 79 girls, aged from 2,5 yrs up to 18 yrs (Me = 9, 7 yrs). The majority of pts were in age group (4-16) yrs-179 pts. Supratentorial tumors were diagnosed in 118 pts vs. infratentorial 94 pts. Therapy involved surgery, postoperative radiotherapy with or without chemotherapy. Survival rates were calculated using Caplan-Meier method and differences between curves with log-rank test. During the follow-up period from 1 to 9 year (Me = 3 yrs) 5-year disease free survival rate was 55.7%. 79 pts failed to therapy. There was no statistically significant difference in survival according to sex (p = 0.123) and age (p = 0.367). Pts with supratentorial tumors had statistically significant better survival (p = 0.036). Pts with histologic type low grade astrocitomas had statistically significant better survival than malignant gliomas, ependymomas and PNET (p = 0.0001). Surgery, postoperative radiotherapy and chemotherapy in selected cases are efficient therapeutic approach for pediatric brain tumors.

[Diffusion and perfusion magnetic resonance imaging in evaluation of primary glial brain tumors].

INTRODUCTION: Diffusion (DWI) and perfusion (PWI) imaging can give important data about physiological characteristics of tissue, which complete morphologic findings from conventional MRI. The aim of this study is to estimate the value of these MRI technics in evaluation of primary glial brain tumors. MATERIALS AND METHODS: The significance of DWI and PWI in differentiation of histologically proven low- and high-grade gliomas was estimated in 48 patient with diagnosed brain gliomas. ADC and rCBV values were compared by aplication of Mann-Whitney test, and logistic regression analysis was used to determine which of these two parameters contributed the most in increasing the diagnostic accuracy, ia. its sensitivity, specificity and predictive velues. ROC curves were constructed to determine threshold values for differentiation of low- from high-grade lesions. RESULTS: Statistical significance were showed between mean values of rCBV for low-grade (0.82) and high-grade (5.32) gliomas, which was not found for values of ADC parameters. Threshold rCBV value of 1.23 was determinated for discrimination between low- and high-grade gliomas with a sensitivity of 83.2% and a specificity of 77.5%. CONCLUSION: Conventional MRI combined with PWI increases the accuracy in determination of glioma grade.

The effect of combined therapy with ritodrine, erythromycin and verapamil on the frequency of micronuclei in peripheral blood lymphocytes of pregnant women.

The main aim of this study was to investigate the genotoxic effect of combined pharmacotherapy applied in post-operative treatment of cervical cerclage in pregnant women over six days. This study included 19 phenotypically healthy pregnant women in mid-trimester with a diagnosis of cervical insufficiency, mean age 28+/-5.33. The frequency of micronuclei (MN) was estimated in peripheral blood lymphocytes of patients before surgical intervention and after the end of applied pharmacotherapy by application of cytokinesis block micronucleus (CBMN) test. Mean value of baseline MN frequency was 6.84+/-2.91 MN/1000 binucleated cells, and after the end of the applied therapy, 10.32+/-4.27 MN/1000 binucleated cells (P<0.001) were found. The data of cell proliferation index showed that the combined therapy did not induce significant difference in cell kinetics (P>0.05). Our results showed that combined pharmacotherapy treatment over six days significantly increased the frequency of MN in peripheral blood lymphocytes of pregnant women.

Micronucleus frequency in women with genital Chlamydia Trachomatis infection before and after therapy.

The main aim of the present study was to investigate the influence of infection with the intracellular bacterium Chlamydia trachomatis, and subsequent treatments with oral doxycycline or azithromycin on the frequency of micronuclei (MN) in peripheral blood lymphocytes of adult female patients receiving standard doses of these drugs. The frequency of micronuclei was measured in the lymphocytes of 38 newly diagnosed adult women with genital C. trachomatis infection. Samples were taken before and after the therapy, and from 50 healthy control females. The therapy was taken orally during 10 days at 2 x 100 mg per day, and then for another 10 days at 1 x 100 mg per day for doxycycline, and as a single dose of 1g for azithromycin. Isolated lymphocytes from all subjects were cultured by use of the whole-blood method and blocked in metaphase with cytochalasin B (Cyt B). One thousand binucleate cells per subject were scored according to published criteria. The frequency of micronuclei was not significantly higher in samples of infected females before therapy, compared with the baseline frequency in healthy control females (p > 0.05). In patients who received doxycycline, the micronucleus frequency after the end of therapy was significantly higher than before treatment (p < 0.001). The mean frequency of micronuclei in females after the end of the therapy with azithromycin did not show an increase (p > 0.05). The application of linear regression analysis showed that the difference in micronucleus frequency before and after therapy (effect of the antibiotics) was affected by the therapy type. Age and smoking did not affect micronucleus frequency in analyzed samples of patients (p = 0.078, 0.579). We conclude that C. trachomatis infection does not induce micronuclei in peripheral blood lymphocytes of infected adult female patients. Therapy with doxycycline significantly increases the micronucleus frequency in lymphocytes of treated patients, but treatment with azithromycin does not induce micronuclei.

Successful treatment of extranodal Hodgkin's lymphoma in a patient with longstanding hairy cell leukemia.

Purine analogs, particularly pentostatin and cladribine, are highly effective in hairy cell leukemia (HCL). Both of these drugs induce responses in approximately 80-95% of patients. However, it is not yet determined if treatment with these drugs can induce second malignancies. Hodgkin's lymphoma is very rare as a second malignancy and there are only 3 reported cases concerning the association of this lymphoma with HCL. We describe a patient with longstanding HCL in complete remission after cladribine, in whom extranodal Hodgkin's lymphoma appeared 8 years after the diagnosis of HCL. Magnetic resonance imaging revealed diffuse intra-osseal neoplastic infiltration of the corpora of the whole spinal column and extra-osseal propagation from the fifth thoracic vertebra into the spinal canal with spinal cord compression. Histological and immunohistochemical analysis of the extradural tumor, which was completely excised, disclosed nodular sclerosis Hodgkin's lymphoma with typical Reed-Sternberg cells that were positive for CD30, CD15, bcl-6, Ki67, p53, EBV LPM-1 and IgG, and negative for CD45, CD20, DBA44, kappa, lambda light chains and IgM. In addition, immunohistochemical analysis of the bone marrow in 1999 showed infiltration with positivity for IgM and negative for kappa light chains and IgG. These findings (expression of different immunoglobulins and light chains on the cells) suggest an independent origin of these 2 B-cell neoplasms. After neurosurgery the patient received 6 courses of the MP-ABVD protocol and achieved a complete remission, which has lasted 16 months thus far.

The use of thoracodorsal nerve transfer in restoration of irreparable C5 and C6 spinal nerve lesions.

There are only a few reports on the use of thoracodorsal nerve (TDN) transfer to the musculocutaneous or axillary nerves in cases of directly irreparable brachial plexus injuries. In this study, we analysed outcome and time-course of recovery in correlation with recipient nerves and type of nerve transfer (isolated or in combination with other collateral branches) for 27 patients with transfer to the musculocutaneous or axillary nerves. Using this nerve as donor, we obtained useful functional recovery in all 12 cases for the musculocutaneous nerve, and in 14 (93.3%) of 15 nerve transfers for the axillary nerve. Although, we found no significant statistical difference between analysed patients according to the percentage of recoveries and mean values, we established a better quality and shorter time of recovery for the musculocutaneous nerve. According to obtained results, we consider that transfer may be a valuable method in reconstruction after directly irreparable C5 and C6 spinal nerve lesions.

Cancer pain (classification and pain syndromes).

Inspite the new informations about the physiology and biochemistry of pain, it remains true that pain is only partially understood. Cancer pain is often experienced as several different types of pain, with combined somatic and neuropathic types the most frequently. If the acute cancer pain does not subside with initial therapy, patients experience pain of more constant nature, the characteristics of wich vary with the cause and the involved sites. Chronic pain related to cancer can be considered as tumor-induced pain, chemotherapy-induced pain, and radiation therapy-induced pain. Certain pain mechanisms are present in cancer patients. These include inflammation due to infection, such as local sepsis or the pain of herpes zoster, and pain due to the obstruction or occlusion of a hollow organ, such as that caused by large bowel in cancer of colon. Pain also is commonly due to destruction of tissue, such as is often seen with bony metastases. Bony metastases also produce pain because of periostal irritation, medullary pressure, and fractures. Pain may be produced by the growth of tumor in a closed area richly supplied with pain receptors (nociceptors). Examples are tumors growing within the capsule of an organ such as the pancreas. Chest pain occurring after tumor of the lung or the mediastinum due to invasion of the pleura. Certain tumors produce characteristic types of pain. For example, back pain is seen with multiple myeloma, and severe shoulder pain and arm pain is seen with Pancoast tumors.

[Nerve transfer in brachial plexus injuries--comparative analysis of surgical procedures]. / Nervni transfer kod povreda brahijalnog pleksusa--komparativna analiza hirurskih procedura.

Nerve transfer is the only possibility for nerve repair in cases of the brachial plexus traction injuries with spinal roots avulsion. From 1980. until 2000. in Institute of Neurosurgery, Clinical Center of Serbia, nerve transfer has been performed in 127(79%) of 159 patients with traction injuries of brachial plexus, i.e., 204 reinnervation procedures has been performed using different donor nerves. We achieved good or satisfactory arm abduction and full range or satisfactory elbow flexion through reinnervation of the axillary and musculocutaneous nerve using different donor nerves in 143 of 204 reinnervations, which presents general rate of useful functional recovery in 70.1% of cases. Mean values of the rate of useful functional recovery in individual modalities of nerve transfer in our series are 50.1% for intercostal and/or spinal accessory nerve transfer, 64.5% for plexo-plexal nerve transfer, 81.7% for regional nerve transfer, and 87.1% for combine nerve transfer.

[Transplantation in peripheral nerve injuries]. / Transplantacija kod povreda perifernih nerava.

Autologous nerve grafting is the most commocommnlynly used operative technique in delayed primary, or secondary nerve repair after the peripheral nerve injuries. The aim of this procedure is to overcome nerve gaps that results from the injury itself, fibrous and elastic retraction forces, resection of the damaged parts of the nerve, position of the articulations and mobilisation of the nerve. In this study we analyse the results of operated patients with transections and lacerations of the peripheral nerves from 1979 to 2000 year. Gunshot injuries have not been analyzed in this study. The majority of the injuries were in the upper extremity (more than 87% of cases). Donor for nerve transplantation had usually been sural nerve, and only occasionally medial cutaneous nerve of the forearm was used. In about 93% of cases we used interfascicular nerve grafting, and cable nerve grafting was performed in the rest of them. Most of the grafts were 1 do 5 cm long (70% of cases). Functional recovery was achieved in more than 86% of cases, which is similar to the results of the other authors. Follow up period was minimum 2 years. We analyzed the influence of different factors on nerve recovery after the operation: patient's age, location and the extent (total or partial) of nerve injury, the length of the nerve graft, type of the nerve, timing of surgery, presence of multiple nerve injuries and associated osseal and soft tissue injuries of the upper and lower extremities.

Restoration of upper arm function in traction injuries to the brachial plexus.

BACKGROUND: Restoration of upper arm function presents the main priority in nerve repair of brachial plexus traction injuries. The results are predominantly influenced by the level and extent of injury, and the type of surgical procedure. The purpose of this study is to evaluate influence of these factors on final outcome. METHODS: Study included 91 surgically treated patients, including 71 patients with avulsions of one or more spinal nerve roots and 20 with peripheral traction injuries. We performed 120 nerve transfers, 25 nerve graftings and 29 neurolyses on different nerve elements depending on the type of nerve damage. Analysis of motor recovery for elbow flexion and arm abduction, isolated or in combination, was done. FINDINGS: Recovery of elbow flexion was obtained in 75% nerve transfers, and in 68,7% nerve graftings in peripheral traction injuries. Recovery of arm abduction was obtained in 78,5% nerve transfers, and in 44,4% nerve graftings in peripheral traction injuries. Neurolysis was successful in all cases. Generally, the quality of recovery was better for the musculocutaneous nerve. Useful global upper arm function was obtained in 49,3% of patients with avulsion of spinal nerve roots, and in 55% of patients with peripheral traction injuries. INTERPRETATION: Regarding upper arm function the prognosis of surgically treated patients with traction injuries to the brachial plexus is generally similar in cases with central or peripheral level of injury. However, nerve transfers of collateral branches seem to be superior to nerve grafting and may be another possibility for repair in cases with extensive nerve gaps.

[Micronuclei and ageing in a sample of Yugoslavian population]. / Microiadra i starenie. Issledovanie na vyborke zhitelei Iugoslavii.

OBJECTIVE: Instability in the organization and expression of the genetic material has been hypothesized as the basic mechanism of ageing. Aim of this study was to quantify the effect of ageing on spontaneous micronuclei (MN) frequency in peripheral blood lymphocytes. METHOD: Analysis of Yugoslavian population sample (164 tested individuals, age 0-62 years) has performed by application of cytokinesis-block technique (CB). RESULTS: There was an increase of MN frequency with age, from newborns to 40-year-old persons. The total average of MN frequency per 1000 analyzed binuclear cells amounts to 8.03 +/- 0.42, with variation from 0 to 26 MNs. In a sample of 29 newborns the recorded average MN frequency was 6.91 +/- 0.81, while among 69 persons 25-39 years old, the MN frequency was 9.16 +/- 1.00. The lowest average MN frequency, however, was noted in the sample of 34 tested individuals 40 to 62 years of age. CONCLUSION: An increase with age in MN frequency has been observed in samples of studied individuals from newborns to 40-year-old persons. A decrease of MN frequency in older groups could be explained by a gradual decrease of proliferative cell capacities.

Concurrent accelerated hyperfractionated radiation therapy and carboplatin/etoposide in patients with malignant glioma: long-term results of a phase II study.

PURPOSE: Feasibility, antitumor activity and toxicity of accelerated hyperfractionated radiation therapy (Acc Hfx RT) and concurrent carboplatin/etoposide (CBDCA/VP 16) chemotherapy were investigated in patients with malignant glioma. MATERIAL AND METHODS: Seventy-nine patients with either glioblastoma multiforme (GBM) (n = 61) or anaplastic astrocytome (AA) (n = 18) entered into a phase II study on the use of Acc Hfx RT with 60 Gy in 40 fractions in 20 treatment days over 4 weeks and concurrent CBDCA, 200 mg/m2, and VP 16, 200 mg/m2, both given once weekly during the RT course. RESULTS: The median survival time for all 79 patients was 14 months (11 and 44 months for GBM and AA patients, respectively), while the 2- and 4-year survival was respectively 33% and 11% for all patients, 13% and 1.6% for GBM patients, and 100% and 44% for AA patients (p < 0.0001). The median time to progression for all patients was 12 months (9 and 40 months for GBM and AA, respectively), while the 2- and 4-year progression-free survival (PFS) was respectively 28% and 10% (all patients), 10% and 1.7% (GBM) and 89% and 39% (AA) (p < 0.0001). Multivariate analysis showed that age, performance status, and preoperative size of tumor influenced survival in GBM. Only 5 (6%) patients experienced grade 3 leukopenia and 6 (8%) patients experienced grade 3 thrombocytopenia. No late RT-induced toxicity was observed to date. CONCLUSIONS: Although Acc Hfx RT/CBDCA + VP 16 was feasible and little toxic, it failed to improve survival/progression-free survival over that obtained with other currently used regimens. These results do not justify the investigation of this regimen in a phase III trial.

Results of nerve transfers to the musculocutaneous and axillary nerves.

OBJECTIVE: Nerve transfers in cases of brachial plexus traction injuries with avulsion of spinal nerve roots or irreparable proximal lesions of spinal nerves have been attempted using a variety of donor nerves. The purpose of this study was to analyze the results of nerve transfers to the musculocutaneous and axillary nerves, using collateral branches of the brachial plexus, upper intercostal nerves, or the accessory nerve. METHODS: This study included 62 patients with brachial plexus traction injuries who were surgically treated using various nerve transfer techniques. The follow-up periods were at least 3 years. Analysis of motor recovery was performed according to the type of donor nerve, the age of the patient, and the timing of surgery. RESULTS: The rates of recovery for the musculocutaneous and axillary nerves were 50% and 63.2% with intercostal nerve transfers, 65% and 75% with accessory nerve transfers, and 90.4% and 86.9% with nerve transfers of collateral branches, respectively. Despite the obviously better outcomes with the latter technique, a significant difference was found only in comparison with intercostal nerve transfers for the musculocutaneous nerve (P = 0.007). With respect to the quality of recovery, we found a significant difference between the latter type and the other two types of nerve transfers only for the musculocutaneous nerve (P = 0.027 for intercostal nerve transfers and P = 0.05 for accessory nerve transfers). There was no significant difference in results obtained using the thoracodorsal and medial pectoral nerves as donors. CONCLUSION: Our findings suggest that nerve transfer of collateral branches when possible, such as in cases involving upper brachial plexus palsy, may be the method of choice, yielding better results.

Short-course radiotherapy in elderly and frail patients with glioblastoma multiforme. A phase II study.

PURPOSE: To evaluate efficacy of short-course radiotherapy (RT) in elderly (> or = 60 years) and frail [Karnofsky performance status (KPS) 50-70] patients with glioblastoma multiforme (GBM). MATERIALS AND METHODS: Between January 1987 and June 1993, a total of 47 elderly and frail patients with histological diagnosis of GBM entered into a phase II study. RT alone was administered with tumor dose of 45 Gy in 15 daily fractions in 15 treatment days in 3 weeks to a target volume described as tumor visible on CT scan and a 2-cm margin. RESULTS: Forty-four patients were evaluable for this analysis. There were 15 (34%) CR and 11 (25%) PR, making the overall response rate of 60%. Median duration of response was 9 months (range, 2-36 months). Improvement in pretreatment performance status was observed in 20/44 (45%) patients, 5 of which improved their KPS for 20%. Median survival time is 9 months, and 1-4 year survival rates are 39%, 6.8%, 4.5%, and 0, respectively, while median time to tumor progression is 8 months, and 1-4 year progression-free survival rates are 30%, 4.5%, 4.5%, and 0, respectively. Females did significantly better than males, patients with KPS 60-70 did significantly better than those with KPS 50, patients having tumors 4-5 cm did significantly better than those with tumors 6-8 cm as well as did those with more radical surgery when compared to those with biopsy only. On multivariate analysis, only tumor size and extent of surgery were found to independently influence survival. Acute toxicity was generally assessed as mild. One of the 12 (8%) autopsied patients had RT-induced brain necrosis. CONCLUSION: This shortened RT appears to be an effective tool in palliation of elderly and frail patients with GBM. Further studies with more patients are needed before testing it against more aggressive treatment approaches in this patient population.