Angiography-proven liver metastases explain low efficacy of lymph node dissections in medullary thyroid cancer patients.

AIM: To report the role of liver angiography in the staging of medullary thyroid cancer (MTC) patients. MATERIAL AND METHODS: Sixty MTC patients with persistent or recurrent hypercalcitonemia (n=49), a characteristic general symptom (diarrhea, n=4) or a normal basal calcitonin level without general symptoms (n=7) were investigated by dynamic liver CT, MRI and angiography between 06/1998 and 06/2002. RESULTS: Dual-phase CT and MRI investigations identified hepatic metastases with relatively low frequency (8/58 on MRI, and 7/60 on CT). Angiography indicated liver involvement in 54/60 cases. The hepatic metastases were typically multiple, hypervascular, small foci (only 13 foci measured >/=10 mm). With one exception significant disease progression was not observed over 5 years of follow-up. CONCLUSIONS: Liver angiography is a powerful tool to reveal hepatic metastases in MTC patients. Frequent, inoperable liver metastases in hypercalcitoninemic MTC patients demonstrate that secondary lymph node dissection is an inefficient technique for restoration of a normal calcitonin level.

Molecular genetic diagnostic program of multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma syndromes in Hungary.

Medullary thyroid carcinoma (MTC) occurs usually in sporadic form, but about a quarter of the cases are hereditary and appear as part of one of the multiple endocrine neoplasia type 2 (MEN2) syndromes. Mutations in the RET protooncogene are known to be the cause of the MEN2A and familial medullary thyroid carcinoma (FMTC) syndromes in the majority of the families. Direct DNA testing allows prophylactic thyroidectomy to be offered to individuals carrying a mutation in the above codons, and in mutation-negative cases it reduces the yearly screening-related burden on family members at risk of the disease. By DNA sequencing and PCR-restriction fragment length polymorphisms, 65 MTC probands were examined for mutations in residues 609, 611, 618, 620 of exon 10, and in residues 634, 768, 804 of exons 11, 13, and 14 respectively of the RET protooncogene. In our study, mutations in the above codons were detected in all of the 14 clinically MEN2A and FMTC families. One of these mutations, TGC609 TCC has not been reported previously. Of the 14 probands with the mutation, 25 relatives also had the identified mutation and 18 relatives proved to be non-carriers. Among the 51 probands with clinically sporadic MTC, none was found to carry a mutation in the above positions even if indirect signs of MTC, pheochromocytoma or hyperparathyroidism could be detected in some families. The frequency of the TGC634AGC mutation is unexpectedly high in our samples, which can probably be attributed to a founder effect. We conclude that screening for mutations in these codons is effective in families fulfilling the strict clinical criteria of MEN2A or FMTC.

A retrospective analysis of different modalities for treatment of primary orbital non-Hodgkin's lymphomas.

We have reviewed 37 patients with primary orbital lymphoma, using the Ann Arbor criteria and the Working Formulation and its modification. Thirty-one patients had stage I disease, four stage II, one stage III and one stage IV. The male to female ratio was 2.7:1. There were 34 low-grade tumours (including 24 mantle zone) and three intermediate-grade. Patients were divided into three groups according to their primary treatment. Group 1: radiotherapy (17 cases); Group 2: surgery alone (13 cases); Group 3: chemotherapy (seven cases). Patients were followed up from 5 months to 24.3 years, with a mean and median of 7.6 and 6.2 years, respectively. The BMDP software package was used for survival estimation (Kaplan-Meier) and determination of prognostic variable (univariate Cox regression). Local relapse-free survival at 10 years was 100% in Group 1, 0% in Group 2 and 42% in Group 3 with a statistically significant difference (p < 0.01) in favour of radiotherapy. Statistically significant good prognostic features were: complete remission (CR) in response to initial treatment, primary radiotherapy and older age. For stage I cases, there was no difference in distant relapse-free survival in the three groups. The overall cause-specific survival for stage I patients at 10 years was 100% for each group and at 20 years was 100, 67 and 0% for Groups 1, 2 and 3. The difference between the primary radiotherapy and chemotherapy-treated groups was significant at the p = 0.08 level. Statistically significant prognostic factors were early stage, low-grade histology and primary radiotherapy. In one patient, ptosis and diplopia appeared after surgery. One case of glaucoma required enucleation, one patient suffered severe dry eye syndrome. All patients (11/11) in whom the lens received direct radiation developed cataracts of different degrees if follow-up was long enough. Cataract formation was prevented by adequate lens shielding. One patient in CR from a stage I low-grade tumour died from chemotherapy-induced marrow aplasia. Primary orbital lymphoma is an indolent, usually stage I disease, showing low to intermediate-grade histology. After biopsy the best treatment is 30 (low-grade) to 40 Gy (intermediate-grade) carefully planned, lens-sparing megavoltage radiation without adjuvant chemotherapy.

Three-dimensional photon radiotherapy planning for laryngeal and hypopharyngeal cancers. 1. Conventional rotational technique.

Three-dimensional dose distributions have been computed for the photon radiation therapy of laryngeal and hypopharyngeal cancers, using biaxial and eccentric rotatory techniques. Treatment plans obtained under various conditions of irradiation with a 15 MV linear accelarator (MEVATRON 77, Siemens) are analysed and compared. Dose delivery to the tumour and the degree of spinal cord protection are evaluated for both treatment techniques. The eccentric plan is somewhat superior to the biaxial one, suggesting a justifiable preference to use this method in the radiation treatment of these tumours. Simulations show that extreme care is needed in positioning the axis: an accuracy of +/- 3 mm is required in the sagittal plane.

Three-dimensional photon radiotherapy planning for laryngeal and hypopharyngeal cancers. 2. Conformation treatment planning using a multileaf collimator.

Three-dimension dose distributions have been computed for 15 MV X-ray radiation therapy (MEVATRON 77, Siemens) of laryngeal and hypopharyngeal cancers using isocentric rotational technique with multileaf collimator. Using a new concave contour tracing algorithm, satisfactory dose delivery to the target volume and efficient protection of the normal tissues can be achieved.

Survival chance in papillary thyroid cancer in Hungary: individual survival probability estimation using the Markov method.

PURPOSE: The typically benign, but occasionally rapidly fatal clinical course of papillary thyroid cancer has raised the need for individual survival probability estimation, to tailor the treatment strategy exclusively to a given patient. MATERIALS AND METHODS: A retrospective study was performed on 400 papillary thyroid cancer patients with a median follow-up time of 7.1 years to establish a clinical database for uni- and multivariate analysis of the prognostic factors related to survival (Kaplan-Meier product limit method and Cox regression). For a more precise prognosis estimation, the effect of the most important clinical events were then investigated on the basis of a Markov renewal model. The basic concept of this approach is that each patient has an individual disease course which (besides the initial clinical categories) is affected by special events, e.g. internal covariates (local/regional/distant relapses). On the supposition that these events and the cause-specific death are influenced by the same biological processes, the parameters of transient survival probability characterizing the speed of the course of the disease for each clinical event and their sequence were determined. The individual survival curves for each patient were calculated by using these parameters and the independent significant clinical variables selected from multivariate studies, summation of which resulted in a mean cause-specific survival function valid for the entire group. On the basis of this Markov model, prediction of the cause-specific survival probability is possible for extrastudy cases, if it is supposed that the clinical events occur within new patients in the same manner and with the similar probability as within the study population. RESULTS: The patient's age, a distant metastasis at presentation, the extent of the surgical intervention, the primary tumor size and extent (pT), the external irradiation dosage and the degree of TSH suppression proved to be statistically significant and independent prognostic factors with regard to cause-specific survival in multivariate studies. During follow-up, 14, 14, 9 and 12% of the patients underwent local/regional/distant relapses or thyroid cancer-related death, respectively. Through use of the above six independent clinical variables and the parameters relating to the four clinical events and their interrelations, mean cause-specific survival probabilities of 88, 83 and 78% were determined at 10, 20 and 30 years, respectively. The survival-predicting software (PATHYPRE) written on the basis of the biostatistical model is available through Internet connections on the home page of the National Institute of Oncology, Budapest (www.oncol.hu). CONCLUSION: Prediction of the individual survival probability for extrastudy cases affords a rationale for individualization of the treatment of papillary thyroid cancer patients.

External audit on the clinical practice and medical decision-making at the departments of radiotherapy in Budapest and Vienna.

PURPOSE: To present an example of how to study and analyze the clinical practice and the quality of medical decision-making under daily routine working conditions in a radiotherapy department, with the aims of detecting deficiencies and improving the quality of patient care. METHODS: Two departments, each with a divisional organization structure and an established internal audit system, the University Clinic of Radiotherapy and Radiobiology in Vienna (Austria), and the Department of Radiotherapy at the National Institute of Oncology in Budapest (Hungary), conducted common external audits. The descriptive parameters of the external audit provided information on the auditing (auditor and serial number of the audit), the cohorts (diagnosis, referring institution, serial number and intention of radiotherapy) and the staff responsible for the treatment (division and physician). During the ongoing external audits, the qualifying parameters were (1) the sound foundation of the indication of radiotherapy, (2) conformity to the institution protocol (3), the adequacy of the choice of radiation equipment, (4) the appropriateness of the treatment plan, and the correspondence of the latter with (5) the simulation and (6) verification films. Various degrees of deviation from the treatment principles were defined and scored on the basis of the concept of Horiot et al. (Horiot JC, Schueren van der E. Johansson KA, Bernier J, Bartelink H. The program of quality assurance of the EORTC radiotherapy group. A historical overview. Radiother. Oncol. 1993,29:81-84), with some modifications. The action was regarded as adequate (score 1) in the event of no deviation or only a small deviation with presumably no alteration of the desired end-result of the treatment. A deviation adversely influencing the result of the therapy was considered a major deviation (score 3). Cases involving a minor deviation (score 2) were those only slightly affecting the therapeutic end-results, with effects between those of cases with scores 1 and 3. Non-performance of the necessary radiotherapeutic procedures was penalized by the highest score of 4. Statistical evaluation was performed with the BMDP software package, using variance analysis. RESULTS: Bimonthly audits (six with a duration of 4-6 h in each institution) were carried out by three auditors from the evaluating departments; they reviewed a total of 452 cases in Department A, and 265 cases in Department B. Despite the comparable staffing and instrumental conditions, a markedly higher number (1.5 times) of new cases were treated in Department A, but with a lower quality of radiotherapy, as adequate values of qualifying parameters (1-6) were more frequent for the cases treated in Department B (85.3%, 94%, 83.4%, 28.3%, 41.9% and 81.1%) than for those in Department A (67%, 83.4%, 87.8%, 26.1%, 33.2% and 17.7%). The responsible division (including staff and instrumentation), the responsible physician and the type of the disease each exerted a highly significant effect on the quality level of the treatment. Statistical analysis revealed a positive influence of the curative (relative to the palliative/symptomatic) intention of the treatment on the level of quality, but the effect of the first radiotherapy (relative to the second or further one) was statistically significant in only one department. At the same time, the quality parameters did not vary with the referring institution, the auditing person or the serial number of the audit. CONCLUSION: The external audit relating to the provision of radiotherapeutic care proved feasible with the basic conformity and compliance of the staff and resulted in valuable information to take correction measures.

Second malignancies after treatment for Hodgkin's disease.

The occurrence of treatment-related second malignancy following Hodgkin's disease (HD) has now been recognized as a major problem. The purpose of this study was to review our experience with second malignancies in patients treated for Hodgkin's disease, comparing the results with the international literature data. Six hundred and sixty five patients with HD were treated in our department, between 1978 and 1996. Second neoplasm developed in 32 cases (4.8%). Seven secondary hematological malignancies were observed: four acute nonlymphocytic leukemias, two non-Hodgkin's lymphomas and one chronic myeloid leukemia. Among patients with second hematological malignancies, the mean age at diagnosis of HD was 44 years and the mean interval until the development of second malignancy was 6.1 years. Five patients received chemo- and radiotherapy and in two cases chemotherapy was used. Three of the seven patients are alive. Twenty-five patients have had solid tumors, affecting lung (5), breast (3), colon (3), stomach (2), urinary bladder (2), head-and-neck (1), thyroid gland (1), esophagus (1), liver (1), pancreas (1), furthermore, three sarcomas and two malignant melanomas were observed. Their mean age at the diagnosis of HD was 46 years and the mean period of latency was 8.3 years. Chemotherapy was applied to nine patients, 16 patients received both chemo- and radiotherapy. Eleven patients had solid tumors in the region irradiated earlier. Ten out of the 25 patients are alive, three patients' present state is unknown. Since alkylating agents increase the risk of leukemia and irradiation contributes mainly to other malignancies, future treatment protocols should attempt to reduce the most serious consequence of therapy without compromising the survival. It is necessary to investigate the impact of additional risk factors. Careful, lifelong observation is indicated for patients with HD, with special attention given to new clinical signs and symptoms.

Radiation myelopathy with partial functional recovery: PET evidence of long-term increased metabolic activity of the spinal cord.

Postoperative telecobalt irradiation was performed with a biologically effective extrapolated response dose of 165 Gy2 delivered to the spinal cord of a papillary thyroid cancer patient. Incomplete cervical transection developed, followed by a gradual functional improvement, which is still continuing 8 years after radiotherapy. Between the 6th and 8th years of the clinical course, positron emission tomography investigations demonstrated an increased 18F-deoxyglucose accumulation and (15)O-butanol perfusion, but negligible 11C-methionine uptake in the irradiated spinal cord segment. We suggest that the increased metabolism and perfusion, and the lack of detectable protein synthesis may be related to the increased energy demands of action potential conduction, due to the higher than normal density of sodium channels along demyelinated axons displaying restored conduction.

FDG PET imaging in hereditary thyroid cancer.

AIM: To report the role of different imaging methods in staging individuals with multiple endocrine neoplasia 2A (MEN2A) or familial medullary thyroid carcinoma (FMTC). MATERIAL AND METHODS: Fourteen newly diagnosed gene carriers underwent cervical ultrasound scanning (US), cervical and mediastinal CT, MRI and whole-body meta-[131I]iodobenzylguanidine (MIBG) scintigraphy and [18F]fluorodeoxyglucose (FDG) PET scanning. RESULTS: US identified seven true primary cancer. CT and MRI located only tumors > or =5 mm in diameter. MIBG scintigraphy and FDG PET could not identify MTC foci within the thyroid. Whole-body FDG PET identified two true-positive and one false-positive lymph node metastases. MIBG scintigraphy did not identify lymph node metastases. Total thyroidectomy was performed in 12 cases, and subtotal thyroidectomy in two subjects. CONCLUSIONS: Whole-body FDG PET and cervical US help stage individuals carrying mutant genes verifying MEN2A or FMTC.

A case of bilateral testicular lymphoma.

Authors report on a 75-year-old man with bilateral testicular lymphoma. He complained of painless right testicular enlargement. Orchidectomy was indicated by ultrasound examination and the diagnosis (large cell, non-Hodgkin lymphoma B-cell origin) was established by histology and immunohistochemistry. Two months later, the left testis enlarged, orchidectomy was performed, and a lymphoma with identical histology was found. PET revealed retroperitoneal spread of the tumor. Irradiation (18 Gy) was applied. Three months later, because of gastric metastases of the lymphoma the patient underwent CVP and CAVP (Cyclophosphamide, Adriablastin, Vincristin, Prednisolone) chemotherapy. Despite of the repeated courses, eleven months after the primary diagnosis the patient died due to of multiple metastases.

Cytogenetic study of radiation burden in thyroid disease patients treated with external irradiation or radioiodine.

Where clinically permitted, either external irradiation or radioiodine therapy is usually recommended for the treatment of differentiated thyroid cancer patients. The choice depends on the treatment philosophy of the responsible physician. This paper describes an attempt to clarify the radiation burden on the lymphocytes in consequence of these two therapeutic modalities. An analysis was made of the extent to which exposure to local neck irradiation (25 x 2 Gy) or radioiodine therapy (1734-2600 MBq) causes chromosomal aberrations in the lymphocytes of thyroid disease patients after total or subtotal thyroidectomy. External irradiation caused many more chromosomal aberrations than 131I therapy did, but analysis of the distribution of the aberrations suggested a homogeneous dose distribution only in 131I-treated and thyroidectomized cancer patients. In thyrotoxic patients with intact thyroid glands, the lower therapy doses (185-595 MBq) caused a significantly higher frequency of aberrations than that observed in thyroid cancer patients, and the dose distribution in the lymphocytes was inhomogeneous. Thus, in the modelling of accidental environmental radioiodine exposure, thyroid patients with small if any residual thyroids are not a suitable group.

Calcitonin-secreting ovarian strumal carcinoid.

A 3-mm strumal carcinoid was found incidentally in a mature ovarian cystic teratoma of a 38-year-old woman followed up for more than 9 years. Although the thyroid component disclosed a typical normal light microscopic appearance, no thyroglobulin and thyroxine were detected immunohistochemically. Immunoreactive calcitonin was demonstrated within the tumour cells. The close relationship between functionally imperfect thyroid tissue and a neuroendocrine marker-secreting tumour seems to be concordant with the theory of the existence of a pluripotential stem cell capable of differentiating multidirectionally.

A novel technique with a flexible applicator for MRI-based brachytherapy of cervical cancer.

PURPOSE: To introduce a novel technique for magnetic resonance (MR)-based 3-dimensional planned high-dose rate intracervical brachytherapy (BT). MATERIALS AND METHODS: During 2002, 16 patients received external beam radiotherapy and BT as part of radiochemotherapy for cervical cancer. A special adjustable applicator device was designed and used for BT. The isodose distribution was calculated from MR images with the applicator in place. RESULTS: The planning target volume coverage was adequate and the radiation burden on the organs at risk was within acceptable limits. Complete regression was achieved in two patients (12.5%), and partial regression in ten (62.5%) patients. The overall response rate for the complex treatment was 93.75%. In three cases the disease was considered to be stable. CONCLUSION: The MR-compatible, flexible applicator allows safe and reproducible cervical radiotherapy with no added discomfort or hazard for the patient.

Hypoglycemia activates compensatory mechanism of glucose metabolism of brain.

The effect of plasma glucose concentration on the cerebral uptake of [18F]-fluorodeoxy-D-glucose (FDG) was studied in a broad concentration range in a rabbit brain model using dynamic FDG PET measurements. Hypoglycemic and hyperglycemic conditions were maintained by manipulating plasma glucose applying i.v. glucose or insulin load. FDG utilization (K) and cerebral glucose metabolic rate (CGMR) were evaluated in a plasma glucose concentration range between 0.5 mM and 26 mM from the kinetic constant k1, k2, k3 obtained by the Sokoloff model of FDG accumulation. A decreasing set of standard FDG uptake values found with increasing blood glucose concentration was explained by competition between the plasma glucose and the radiopharmacon FDG. A similar trend was observed for the forward kinetic constants k1, and k3 in the entire concentration range studied. The same decreasing tendency of k2 was of a smaller magnitude and was reverted at the lowest glucose concentrations where a pronounced decrease of this backward transport rate constant was detected. Our kinetic data indicate a modulation of the kinetics of carbohydrate metabolism by the blood glucose concentration and report on a special mechanism compensating for the low glucose supply under conditions of extremely low blood glucose level.

[Results of radiotherapy in the year of the Röntgen centenary]. / Sugárterápiás eredmények a Röntgen-centenárium évében.

In 1996, the three leading radiation oncology periodicals (Int. J. Radiat. Oncol. Biol. Phys.--USA, Radiother. Oncol.--Europe, and Strahlenther. Onkol.--Germany) published 681 papers. Among the different topics, the clinical subjects accounted for almost half (46%) of the total number of publications, followed by radiation physics/techniques (18%) and radiation biology (17%). The 13% of editorials/review articles reflects a considerable endeavor towards integration; the contribution of papers relating to professional organization amounted to 2%. The fact that 1996 was the centennial year of the discovery of the Röntgen rays explains the reasonable proportion (4%) of historical reviews. Within the special topics, prostatic cancer and breast cancer were the two most frequent issues. Dose escalation was the most important tool applied to improve the results of the radiation therapy of tumors with unfavorable prognostic signs or radioresistance. The increase in the applied dose was made possible by a decrease in the planning target volume (PTV), 3D forward and inverse radiation treatment planning, a combination of tomographic (CT/MRI/US) diagnostic methods (image registration/fusion), optimizing algorithms, computer-controlled delivery of radiation dose and electronic portal imaging with in vivo dosimetry. In contrast, the trends in the radiotherapy of tumors with favorable long-term survival (e.g. Hodgkin's disease and seminoma) include a decreased dose and PTV reduction to diminish the late, radiation-related morbidity. Fractionation has remained the only tool of radiobiology routinely used in the everyday clinical practice. A comparison of the results and achievements in the special fields reveals that radiation physics/techniques clearly outstrip clinical subjects and especially radiation biology, as they allow direct and instant exploitation of the advantages offered by computers. It is highly probable, however, that, subsequent to a wider use of computers in clinical subjects and radiation biology, this situation will change.

[Tridimensional radiation treatment planning]. / Háromdimenziós besugárzástervezés.

The effectiveness of radiotherapy and the possibility that the patient will be cured are basically determined by the accuracy of the therapy planning and the treatment. The tumour with its environment is a three-dimensional (3D) phenomenon, and therefore 3D radiation treatment planning and performance are needed for adequate coverage of the target volume (tumour+safety zone). The prerequisities of the elaboration of the 3D radiotherapy planning were as follows: the availability of high-performance hardware, the establishment of interactive computer graphics, and the development and direct integration into the therapy planning process of the digitalized information derived from diagnostic imaging, and especially computer tomography. The introduction of 3D treatment planning will mean the modernization of the radiotherapy, the accuracy of which may permit more cures, i. e. more patients will recover their ability to work.

[Clinical observations on breast cancer in males]. / Klinikai megfigyelések férfi emlörákban.

The analysis of clinical parameters of seventeen male breast cancer patients clearly demonstrate the correlation between prognosis and size of primary tumour as well as regional spread. The localization of the tumour in the breast is not correlated to survival. Intelligent hormonal therapy contributes to improving of survival. Detections of plasma FSH, LH, testosterone, 17 beta estradiol levels are useful in examining of pathomechanism, revealing relapse, and monitoring hormonal therapy.

[External irradiation of differentiated thyroid cancer: 30 follow up]. / A differenciált pajzsmirigyrákok külsö sugárkezelése: 30 év követés.

UNLABELLED: Following surgery which left no macroscopic residue 114 patients with differentiated thyroid cancer (58 papillary, 56 follicular) were subgrouped on the basis of the dose of prophylactic postoperative external radiation applied: group I--an adequate dose of radiation (greater than or equal to 4500 cGy of telecobalt, greater than or equal to 4000 R of orthovolt therapy); group II--an inadequate dose of radiation (including non-irradiated patients). Local/regional relapse-free survival (LRRFS), distant metastatic relapse-free survival (DMRFS) and total cause-specific survival (TCSS) were calculated by means of life-table analysis for both histologic types separately. Results. 1. TCSS and LRRFS were significantly (p less than 0.001) better for group I in papillary cancer. No difference was found in DMRFS. 2. LRRFS was significantly (p less than 0.001) better for group I in follicular cancer. No differences were found in TCSS and DMRFS. CONCLUSIONS: 1. The prophylactic postoperative external irradiation is an effective method for survival prolongation in papillary cancer, the local/regional recurrences thereby being reduced. 2. External irradiation, in conjunction with radioiodine treatment, should be considered in the postoperative management of follicular cancer to diminish local/regional relapse.

[PATHYPRE: Pascal program for the estimation of the individual course of patients with papillary thyroid cancer]. / PATHYPRE: Pascal-program a papillaris pajzsmirigyrákos betegek individuális kórlefolyásának becslésére.

Individual survival probability estimation provided by mathematical models based on cases with a known clinical course is of great help as concerns the treatment strategy decision relating to malignant tumours. Data on four hundred Hungarian papillary thyroid cancer patients were used together with the Markov method to construct a survival model (Orv. Hetil. 1996 137: 1067-1078,) for prediction of the individual clinical course of newly diagnosed cases for 30 years following surgical intervention. Input data included the age, the primary tumour size and extent (pT), distant metastasis at presentation, the extent of the surgical intervention, the external irradiation dosage and the degree of TSH suppression. From the input data, the PATHYPRE program can estimate the individual local/regional/distant relapse-free survival probabilities and overall cause-specific survival probability. The survival probabilities may be predicted for variations in the treatment parameters, and thus the model helps in the selection of the most appropriate therapy for the patient. The PATHYPRE software is available through the Internet connections on the home page of the National Institute of Oncology, Budapest (www.oncol.hu).