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Background: It is believed that chemotherapy (ChT) is ineffective in papillary thyroid carcinoma (PTC). The aim of our retrospective chart review was to find out if neoadjuvant ChT before thyroid surgery had any effect on the size of primary tumors in patients with PTC., Methods: The study included 16 patients (13 women, 3 men; median age 63.5 years) with PTC, who were treated with neoadjuvant ChT from 1988 to 2005. Poorly differentiated PTC, classical PTC, a follicular variant of PTC, and a Hürthle cell variant of PTC were diagnosed in 5, 5, 3, and 3 cases, respectively. The mean tumor diameter was 9.67 cm. Seven patients had a pT4 tumor. Regional and distant metastases were detected in 10 and 7 patients, respectively. ChT consisted of vinblastine in 11 cases, vinblastine with adriamycin in 2 cases, and other schedules in 3 cases. Four patients were also treated with preoperative external irradiation., Results: Altogether, 40 cycles of ChT were given. After ChT, the tumor size decreased in all 16 patients: by >50% in 7 (44%) patients and by <50% in 9 patients. R0, R1, and R2 resection was performed in 2, 10, and 4 cases, respectively. The median survival time of our patients was 88 months. Six patients are still alive; two died of causes not related to carcinoma, while eight patients died of PTC., Conclusions: Neoadjuvant ChT before thyroid surgery may be effective in patients with locally advanced PTC. After neoadjuvant ChT, in 44% of patients, the tumor size decreased by >50%.

Background: It is believed that chemotherapy (ChT) is ineffective in follicular thyroid carcinoma (FTC) and Hürthle cell thyroid carcinoma (HCTC). The aim of our retrospective study was to find out whether neodjuvant ChT before thyroid surgery had any effect on the size of primary tumor in patients with FTC or HCTC., Methods: The study included 29 patients (20 women, 9 men; mean age: 60.8 years) with FTC or HCTC who had T3 or T4 tumor and were treated with neoadjuvant ChT from 1979 to 2004. A mean tumor diameter was 9.3 cm. Extrathyroid growth of tumor was present in 15 patients. Regional and distant metastases were detected in 6 and 12 patients, respectively. With respect to the site of metastatic spread, the lung was involved in eight patients and the skeleton in five. ChT consisted of vinblastine in 19 cases, vinblastine with adriamycin in 5 cases, or other ChT regimens in 5 cases., Results: Altogether, 67 cycles of ChT were given and tumor size decreased by >50% in 13 patients (=45%). ChT was effective in patients with FTC and HCTC in 47% and 43%, respectively. In the patients with and without distant metastases, the primary tumor size decreased by >50% in 17% and 65% (p=0.02), respectively. R0, R1, and R2 resection was performed in 15, 10, and 4 cases, respectively. Histopathology revealed that ChT (i.e., wide areas of tumor necrosis) was effective in seven patients (24%). The 5- and 10-year cause-specific survivals of the patients were 77% and 47%, while the 5- and 10-year disease-free intervals were 57% and 46%, respectively. Six patients are alive (median survival: 162 months), four of them have no evidence of disease, six patients died of other causes (median survival: 101 months), while 17 patients died of FTC or HCTC (median survival: 72 months). Among them, 16 died of distant metastases, while only one succumbed to locoregional recurrence and distant metastases., Conclusions: ChT before surgical procedure may be effective in order to decrease the tumor size in FTC or HCTC in 45% of patients.

Objective: To explore whether the combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycin could be an effective alternative treatment to surgery in verrucous carcinoma (VC) of the head and neck., Methods: Combined radiochemotherapy was used in 12 patients with previously untreated VC. They were irradiated to equivalent tumor dose of 44-70 Gy (median, 56 Gy) and had > or = 2 courses of concomitant chemotherapy. Chemotherapy regimen consisted of prolonged intravenous infusions of Vinblastine 2 mg (day 1); Methotrexate 50 mg (day 2); Bleomycin 15 mg (days 2 and 3), and repetition at 2-3 week intervals., Results: Eleven of 12 patients were cured of VC, and one died of purulent meningitis associated with intracranial extension of VC from the oral cavity. Of 11 patients cured of VC, eight had advanced tumors. The median follow-up of cured patients was 3.6 years (range, 1.4-13.6 years). All the patients developed mucositis of grade > or = 3, whereas no serious late side-effects were recorded., Conclusions: Combined radiochemotherapy with Vinblastine, Methotrexate, and Bleomycine is highly effective in the treatment of VC of the head and neck. It could be successfully used in the patients with inoperable VC or as an alternative to surgery., (2005 Wiley-Liss, Inc.)

Background: Multivariate studies concerning the prognosis of patients with anaplastic carcinoma of the thyroid gland are scarce. The aim of our study was to determine the prognostic factors associated with survival of patients with anaplastic carcinoma in Slovenia, an iodine-deficient region., Methods: This retrospective study was carried out on a group of 188 patients (130 female, 58 male; median age 68 years) with anaplastic carcinoma of the thyroid who had been treated at a tertiary care centre from 1972 to 2003. For each patient, data on gender, age, disease history, extent of disease, morphological characteristics, mode of therapy, and survival were collected. Statistical correlation between possible prognostic factors and survival was analysed by univariate and Cox's multivariate analysis. Treatment modality was not included in the analysis to avoid selection bias., Results: The median survival of all the patients was 3 (+/-0.36) months. Overall 1-year survival of our patients was 13%, and 2-year survival was 6%. Multivariate analysis showed that the patients' age, performance status, tumour growth, tumour extension and distant metastases were independent prognostic factors for the survival., Conclusion: Patients younger than 71 years, with a good performance status and slowly growing tumours confined to the thyroid, and without distant metastases, had the best prognosis.

It is generally believed that Hürthle cell thyroid carcinoma (HCTC) does not accumulate radioactive iodine (RAI). The aim of our retrospective study was to find out if, after thyroid surgery and RAI ablation of the thyroid remnant, the metastatic or recurrent HCTC accumulates RAI. We reviewed the charts of 48 patients with histopathologically verified HCTC, who were treated at the Institute of Oncology in Ljubljana, Slovenia, from 1972 to 2000. In 16 patients (11 women, five men; 47-77 years old), who had distant metastases at presentation (eight patients) or recurrence (eight patients), whole-body RAI scanning was performed after the withdrawal of thyroid hormone replacement. Whenever RAI uptake was confirmed, the therapy with 5.6 GBq of RAI was performed. In 11 of 16 patients, the uptake (range 0.1-12%) of RAI was confirmed. Altogether, 46 therapeutic applications of RAI were given. We conclude that whole-body scanning with RAI should be performed in HCTC. RAI may be effective in the treatment of HCTC.

Information on the in vivo antitumor efficiency of the combination of Vinca alkaloids in animal tumor models, especially vinblastine (VLB) with cisplatin [cis-diamminedichloroplatinum(II); CDDP] is very limited. Therefore, the aim of our study was to explore whether antitumor schedule dependence exists for the combination of CDDP and VLB on i.p. Ehrlich ascites tumors in mice. Animals were treated 3 days after tumor transplantation with VLB (0.006 mg/kg) or CDDP (0.05 mg/kg) alone, VLB followed by CDDP, and CDDP followed by VLB. The time interval between i.p. injections of the drugs was 24 h. Cell number was measured by counting viable cells using the trypan blue exclusion assay, cell platinum content by electrothermal atomic absorption spectrometry, DNA distribution pattern using flow cytometry, apoptosis by flow-cytometric terminal deoxynucleotidyl transferase dUTP nick-end labeling assay, and cell morphology. Combination of CDDP and VLB resulted in additive interaction when VLB preceded CDDP as determined from cell survival data 24 h after completion of the therapy and in increased platinum content (two times) compared with the same combination in a reverse schedule (CDDP given before VLB), which resulted in antagonism. None of the treatment combinations induced apoptosis. We propose that the observed increase in antitumor effectiveness is mainly due to higher platinum accumulation in tumor cells, which we unambiguously demonstrated by measurement of platinum content in the tumor cells, leading to increased cytotoxicity as well as to cell cycle-dependent effects of VLB and CDDP.

Vinblastine (VLB) previously has been shown to perturb tumor blood flow, but the effect of these perturbations on tissue oxygenation is not known. The recent development of electron paramagnetic resonance (EPR) oximetry now has made it feasible to measure the effects of changes of perfusion on the pO(2) in tumors and normal tissues as a function of time and dose. We measured changes in tumor perfusion by Patent blue staining, tumor blood volume and microvascular permeability by contrast-enhanced magnetic resonance imaging, and tumor oxygenation by EPR in s.c. SA-1 murine tumors. We found that treatment with VLB induced dose-dependent reduction in tumor perfusion. One hour after i.p. treatment of mice with 2.5 mg/kg VLB, tumor perfusion was reduced to 20% of the pretreatment value and returned to close to original values within 48 h. A transient tumor blood flow-modifying effect of VLB was demonstrated also by contrast-enhanced magnetic resonance imaging; reduction of tumor blood volume and microvascular permeability was found. Reduced tumor oxygenation was found as measured by EPR oximetry, with the same time course of changes in tumor blood flow. Tumor oxygenation was reduced to 50% of pretreatment value 1 h after the treatment with 2.5 mg/kg VLB and returned to pretreatment levels within 24 h after the treatment. Although the directions of the changes in perfusion and oxygenation were similar, they were quantitatively different. Reduction in oxygenation of normal tissues, muscle, and subcutis also occurred but was smaller and returned to pretreatment values more quickly compared to the changes induced in the tumors. In conclusion, the present study demonstrates that VLB causes a profound reduction in tumor blood flow and oxygenation, which may have implications in controlling side effects of therapy and the planning of combined treatment with VLB, either with other chemotherapeutic drugs or with radiotherapy.

Aims: Multivariate studies of the diagnosis, treatment and prognosis of patients with follicular carcinoma of the thyroid gland are relatively scarce. The aim of our multivariate analysis was to study the factors associated with survival of patients with follicular carcinoma in Slovenia, in an iodine-deficient region., Methods: This retrospective study was carried out in a group of 154 patients (113 women, 41 men; median age 61 years) with follicular carcinoma of the thyroid treated at the Institute of Oncology in Ljubljana between 1972-1992. Data on patient gender, age, disease history, extent of disease, morphological characteristics, mode of therapy and survival were collected. Statistical correlations between possible prognostic factors and survival were analysed by univariate and Cox's multivariate analysis., Results and Conclusions: The 10-year survival of the 154 patients was 60%. Multivariate analysis showed that tumour differentiation, primary tumour size, vascular invasion, distant metastases, regional lymph-node metastases, histological tumour type and age were independent prognostic factors for survival. The best prognosis was found in patients with well-differentiated T1 or T2 tumours, without extensive vascular invasion, without distant or regional metastases and aged under 46 years. Patients with Hürthle-cell type carcinomas had better prognosis than those with the follicular type. The worst prognosis was found in patients with poorly differentiated T4 tumours, with extensive vascular invasion, with distant or regional metastases and aged over 60 years., (Copyright 1999 Harcourt Publishers Ltd.)

Aims: There is no reliable diagnostic test for pre-operative differentiation between benign and malignant follicular and Hurthle cell neoplasms. Measurements of serum thyroglobulin (Tg) are currently only used post-operatively as a marker of recurrent disease or distant metastases in the follow-up of patient with differentiated thyroid cancer. In this study pre-operative serum Tg measurements were performed with the aim of investigating whether Tg levels differ in benign and malignant follicular and Hurthle cell neoplasms., Methods: In 516 patients who underwent thyroid surgery at the Institute of Oncology in Ljubljana, Slovenia, from 1990 to 1996, serum Tg concentration was measured in addition to the standard pre-operative tests (fine-needle aspiration biopsy, ultrasonography, 99mTc scanning and hormonal profile). After the operation, patients were divided into 11 groups based on their histological diagnosis (papillary cancer--classic, papillary cancer--follicular variant, papillary cancer oncocytic variant, occult papillary cancer, follicular adenoma, follicular cancer, Hurthle cell adenoma, Hurthle cell cancer, anaplastic cancer, medullary cancer, nodular goiter) and the serum Tg values of the different groups were compared., Results: In groups of patients with follicular and Hurthle cell cancer, median Tg values were higher (2895 and 638.5 ng/ml) and, statistically, differed significantly from the serum Tg values in all other groups (P<0.01). Sensitivities and specificities of the tests were 71.8% and 80.4% for follicular cancer and 55.6% and 83.8% for Hurthle cell cancer, while positive and negative predictive values were 75.6% and 77.1% for follicular cancer and 75% and 68.4% for Hurthle cell cancer., Conclusions: These results indicate that pre-operative serum Tg measurements might be an important additional diagnostic tool in the pre-operative work-up of patients with thyroid tumours.

Sixty fine needle aspiration biopsy samples of the medullary carcinoma of the thyroid, 49 primary and 11 recurrent/metastatic, were reexamined in order to determine diagnostic features and value of auxiliary techniques. In the smears, tumor cells were present either as single cells or in loose cohesive groups; in about one third of cases, three-dimensional groups predominated. Cells were of different shapes round-to-oval, polyhedral and spindle. The aspirates contained one or all three cell types. Large mononucleated cells were present in 47/60 cases and, in addition, in 34 of these multinucleated cells with nuclei arrayed in semicircular rows were present. Plasmacytoid and dendritic cells, observed in 58/60 cases, appear to be an important diagnostic feature. Red cytoplasmic granules and amyloid deposits could serve as an additional diagnostic clue. Among the auxiliary techniques, the demonstration of calcitonin and CEA immunoreactive cells proved to be the most helpful.

Vinblastine (VELBE) is one of the first chemotherapeutic agents used in the treatment of malignancies. To explore the effectiveness of various treatment regimens, bolus versus 24-hour continuous VELBE treatment was tested on an EAT tumor model in mice. Continuous VELBE infusion was simulated by splitting the bolus VELBE dose into 4 fractions, injected at 8-hour intervals. A comparison of antitumor effectiveness between bolus and split dose VELBE treatment was determined by three assays: cell survival, tumor growth delay and animal survival. The cell survival curves of both bolus and split dose VELBE treatments indicated a biphasic response with an initial fast reduction in cell survival followed by a plateau. However, split dose treatment was significantly more effective than bolus treatment at all doses tested (p < 0.001). Tumor growth delay of the split dose VELBE treatment was 6.9 days and of the bolus VELBE treatment 3.0 days, indicating that the split dose treatment is approximately 2-times more effective (p < 0.001). Median survival time of mice treated with split VELBE dose (24.0 days) was significantly longer compared to that of mice treated with bolus VELBE dose (16.5 days) (p < 0.001). The median survival time of control untreated mice (16.0 days) and bolus treated mice did not differ (p = 0.24). Our study shows that at the same VELBE dose the split dose VELBE treatment is more effective than VELBE administered in bolus.

Objective: To analyze the diagnostic problems with fine needle aspiration biopsy in anaplastic thyroid carcinoma (ATC) and to describe the cytomorphologic characteristics in 113 cases., Study Design: A retrospective analysis of 113 fine needle aspirates and 67 surgical specimens from 113 patients with ATC admitted to the Institute of Oncology, Ljubljana, in 1972-1992., Results: In a series of 113 fine needle aspirates of ATC, 3 (2.7%) were inadequate, 3 (2.7%) suboptimal and 107 (94.7%) diagnostic of malignancy. On reexamination, 96/107 (89.7%) were diagnosed as ATC, 6 (5.6%) as differentiated thyroid carcinoma, and 5 (4.6%) as a malignant tumor not otherwise specified. As to the predominant cell population, fine needle aspirates showed three different cell patterns: (1) pleomorphic cell (43 cases), (2) round cell (33 cases), and (3) spindle cell pattern (7 cases). In the present retrospective analysis we identified three main reasons for inadequate or nonrepresentative fine needle aspiration biopsy sampling: (1) tumor regressive changes (necrosis, hemorrhage, leukocytic infiltration), (2) extensive tumor fibrosis, and (3) distinct differentiated and anaplastic patterns in the same tumor., Conclusions: The major diagnostic problem with fine needle aspiration biopsy (FNAB) of ATC is related to sample quality. Cytomorphologic features of ATC are highly specific and easy to recognize. Due to the simple technique and high diagnostic accuracy, FNAB is the method of choice in patients with ATC.

Marginal vacuoles (MV) found in Giemsa-stained fine-needle aspirates of the thyroid gland have been observed in toxic and also in non-toxic goiters. The aim of our retrospective study was to disclose the incidence and diagnostic significance of MV in 46 smears from 43 patients with primary and/or metastatic follicular thyroid carcinoma (FTC). Typical MV, MV-like structures, or both were found in 14 of 36 specimens (39%) of the primary tumor and in four of seven specimens (57%) obtained from metastases of FTC. No association between the appearance of MV/MV-like structures and degree of tumor differentiation was demonstrated. On the other hand, MV or/and MV-like structures were more frequently (69%) documented in hyperthyroid patients (P < 0.05). Accordingly, our study demonstrated relatively frequent appearance of MV or MV-like structures in FTC independent of tumor differentiation. Their appearance, however, seems to be associated with hyperthyroidism.

Cell membranes can be targets of some anti-cancer drugs. Therefore, the purpose of this study was to determine whether vinblastine (VLB) can also affect the tumor cell membrane. On the in vivo SA-1 tumor model, alteration of cell membrane fluidity (measured by electron paramagnetic resonance, EPR), cytotoxicity and morphological changes of the SA-1 tumor cells after VLB treatment were studied. The cytotoxic effect of VLB was biphasic, with an initial fast increase in cytotoxicity followed by a plateau. The surviving cells had increased membrane fluidity and were morphologically changed. The dose-response curve of VLB on membrane fluidity was also biphasic with an initial fast increase in membrane fluidity followed by a plateau. Since dose-response curves of VLB cytotoxicity and its effect on membrane fluidity were similar, there was a high correlation between both effects. The effect of VLB on membrane fluidity was the most pronounced at 24 h and 48 h after treatment. The results of this study indicate that VLB affects cell membrane by increasing the membrane fluidity of SA-1 tumor cells in vivo in a dose-and time-dependent manner. Therefore, this finding may be beneficially implemented also in priming cells for other cytotoxic drugs and for appropriate timing of drug sequence in combined schedules.