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.

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.

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.

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.