Svante Jansson

Improved survival of patients with papillary thyroid cancer after surgical microdissection.

Abstract. A total of 195 patients had surgery for papillary thyroid cancer. The mean age at operation was 50 years. A microdissection technique was used for total thyroidectomy and lymph node clearance. Postoperative radioiodine tests showed no uptake or an uptake close to the background activity in 77% of the examined patients. By counting the lymph nodes removed at surgery we were able to check on the quality of the lymph node dissection. Men had a higher incidence (70%) of lymph node metastases than women (45%). Only 4% of the patients had radioiodine ablation of the thyroid remnant. The median follow-up time was 13 years. None of the patients below 45 years of age at surgery died of thyroid cancer. In the older age group eight patients died of thyroid cancer at a mean age of 75 years. Five of those who died of a thyroid carcinoma had distant metastases at diagnosis. Among patients with resectable disease, three (1.6%) died of thyroid cancer, all of whom had lived for more than 17 years after surgery. Hence longer follow-up is needed before we know the final mortality in our series. The results suggest that surgical technique and strategy can positively influence the survival of patients with papillary thyroid cancer.

Neoadjuvant, adjuvant and palliative treatment of gastrointestinal stromal tumours (GIST) with imatinib : a centre-based study of 17 patients

Malignant gastrointestinal stromal tumours (GIST) have a poor prognosis. Since these tumours are resistant to conventional radiation and chemotherapy, surgery has been the mainstay of treatment. However, surgery is usually inadequate for the treatment of malignant GIST. Imatinib, a KIT tyrosine kinase inhibitor, has recently been found to have a dramatic antitumour effect on GIST. In this centre-based study of 17 consecutive patients with high-risk or overtly malignant GIST, imatinib was used in three different settings – palliatively, adjuvantly, and neoadjuvantly. The treatment was found to be safe and particularly effective in tumours with activating mutations of exon 11 of the KIT gene. Clinical response to imatinib treatment correlated morphologically to tumour necrosis, hyalinisation, and reduced proliferative activity. The value of neoadjuvant imatinib treatment was illustrated in one case.

Orthotopic liver or multivisceral transplantation as treatment of metastatic neuroendocrine tumors

Liver transplantation can be a therapeutic option for individual patients with neuroendocrine tumors metastatic only to the liver. In this consecutive series of 15 patients (5 multivisceral and 10 orthotopic liver transplantations) with well‐differentiated carcinoids, or endocrine pancreatic tumors, we allowed higher proliferation rate (Ki67 <10%), large tumor burden, and higher age than previous studies. Liver transplantation offered good relief of symptoms, long disease‐free intervals, and potential cure in individual patients. The survival of grafts and patients compared well with transplantation for benign disease. The overall 5‐year survival was 90%. The recurrence‐free survival of both multivisceral and liver transplantation related to the time after transplantation (about 20% at 5 years) despite inclusion of patients with higher risk. In conclusion, the critical prognosticators for long‐term outcome still remain to be defined. The experience with multivisceral transplantation for patients with endocrine tumors of the pancreatic head is still limited. Liver Transpl 13:327–333, 2007.

Effect of Surgery on Cardiovascular Risk Factors in Mild Primary Hyperparathyroidism

CONTEXT Mild primary hyperparathyroidism (pHPT) seems to have a good prognosis, and indications for active treatment (surgery) are widely discussed. The extraskeletal effects of PTH, such as insulin resistance, arterial hypertension, and cardiovascular (CV) risk, may however be reversible by operation. OBJECTIVE Our aim was to study biochemical markers of bone turnover, indices of the metabolic syndrome, and various risk markers for CV disease in patients with mild pHPT randomized to observation without surgery or operative treatment and followed for 2 yr. DESIGN/SETTING/PATIENTS A total of 116 patients (mean age, 63 +/- 8 yr; 19 men and 97 women) who on May 1, 2008, had performed the 2-yr visit in a randomized study on mild pHPT (serum calcium at baseline, 2.69 +/- 0.11 mmol/liter) and where frozen samples were available from baseline and follow-up participated in the study. RESULTS Calcium and PTH levels were normalized after surgery, and biochemical markers of bone turnover decreased by 35%, followed by a significant increase in BMD in the spine (2.7%; P < 0.01) and femoral neck (1.1%; P < 0.02) compared with the observation group. No significant differences were observed between the groups for blood pressure, markers of insulin resistance, detailed cholesterol metabolism, adipokines, or parameters of inflammation and CV surrogate markers. CONCLUSIONS We observed expected effects on biochemical markers of bone turnover and bone mass after surgical treatment of mild pHPT, with stable values in the group randomized to observation. For a variety of measures of the metabolic syndrome, adipokines, and CV risk factors, no benefit of operative treatment could be demonstrated. Neither did we observe any deleterious effects of conservative management in the 2-yr perspective.

Indications and Results of Liver Transplantation in Patients with Neuroendocrine Tumors

Metastases from neuroendocrine (NE) tumors of the gastrointestinal tract, carcinoids, and endocrine pancreatic tumors (EPTs) can be confined to the liver for long periods and may exhibit slow growth. When considering liver transplantation (LTx) for patients with NE tumors, the expected results with conventional treatment must be weighed against the risk of LTx and immunosuppression. The following indications for LTx may be considered for patients with metastatic NE tumors limited to the liver: (1) tumors not accessible to curative surgery or major tumor reduction; (2) tumors not responding to medical or interventional treatment; and (3) tumors causing life-threatening hormonal symptoms. We excluded patients with poorly differentiated NE carcinoma or well differentiated NE carcinoma with a high proliferation index (Ki 67 > 10%). Over 4 years (1997–2001) we have performed transplants in nine patients (five with EPTs, four with carcinoids) with a mean ± SEM follow-up of 22 ± 5 months (range 4–45 months). Seven patients underwent orthotopic LTx and two multivisceral LTx. Eight patients are alive, six without clinical evidence of disease. Four patients developed recurrent tumors 9 to 36 months after LTx; two were detected at an early stage and underwent resection with curative intent. One patient with multivisceral Tx died after 4 months of posttransplant lymphoproliferative disease without tumor recurrence. In selected series LTx can offer good control of hormonal symptoms, a relatively long disease-free interval, and in individual cases potential cure.

Survival of patients with disseminated midgut carcinoid tumors after aggressive tumor reduction

Abstract. Sixty-four consecutive patients with disseminated midgut carcinoids were treated during an 8-year period according to a single clinical protocol aimed at aggressive tumor reduction by surgery alone or with subsequent hepatic artery embolization. All patients had markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) levels (581 ± 79 μmol/24 h) and hormonal symptoms. Fourteen patients (22%) reached anatomic and biochemical cure by surgery alone. At follow-up, the mean 5-HIAA levels were still normal after 69.0 ± 6.2 months; two patients had died from unrelated causes. With the introduction of somatostatin receptor scintigraphy, subclinical disease was diagnosed in 7 of these 14 patients. Forty patients with bilobar hepatic disease underwent embolization in combination with octreotide. In this group, 5-HIAA levels were still reduced by 55% after 71 ± 11 months of follow-up, and the 5-year survival was 56%, estimated from the total death hazard function. After embolization, two subgroups could be identified with marked differences in their long-term response to treatment. Ten patients were not embolized owing to complicating diseases. The 5-year survival for the entire series was 58%. A significantly increased risk of cardiovascular deaths was seen, which underlines the importance of total survival analysis in a disease with multiple hormonal effects. It is concluded that an active surgical approach must be recommended to patients with the midgut carcinoid syndrome. In patients with bilobar hepatic disease, embolization combined with octreotide treatment markedly reduced the 5-HIAA excretion and suggested a prolonged 5-year survival.

Cytotoxic treatment of adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare, aggressive tumor that is often detected in an advanced stage. Medical treatment with the adrenotoxic drug mitotane has been used for decades, but critical prospective trials on its role in residual disease or as an adjuvant agent after surgical resection are still lacking. The concept of a critical threshold plasma level of the drug must be confirmed in controlled studies. Because individual responsiveness cannot be predicted, the use mitotane is still advised for nonresectable disease. In case of Cortisol or other steroid overproduction, several drugs (e.g., ketoconazole or aminoglutethimide) may be used. Chemotherapy with single agents (e.g., doxorubicin or cisplatin) have been disappointing, with low response rates (< 30%) and a short response duration. Part of this refractoriness may be explained by the fact that ACC tumors express the multidrug-resistance gene MDR-1. Chemotherapy with multiple agents has been tested in smaller series and has resulted in significant side effects. The best results were achieved by the combination of etoposide, doxorubicin, and cisplatin associated with mitotane, achieving a response rate of 54%, including individual complete responses. To be able to make progress in treating advanced ACC disease, adjuvant multicenter trials must be encouraged. When mitotane-based therapies are used, monitored drug levels are mandatory.RésuméLe cancer de la corticosurrénale (CCS) est une tumeur rare mais agressive, détectée souvent à un stade avancé. Le traitement médical par le mitotane, une drogue adrénotoxique, est utilisée depuis plusieurs décennies, mais, on manque d’essais prospectifs critiques sur son rôle dans la maladie résiduelle ou comme agent adjuvant après résection chirurgicale. Le concept d’un niveau plasmatique dont le seuil critique doit être confirmé par des études contrôlées. Puisqu’on ne peut prédire la réponse individuelle, le mitotane est toujours conseillé dans les maladies nonréséquables. En cas d’hyperproduction de Cortisol, ou d’autres Steroides, d’autres drogues, comme par exemple, le cétoconazole ou l’aminogluthétimide peuvent être utilisées. La monochimiothérapie, avec par exemple la doxorubicine et le cisplatine, est décevante avec un taux de réponse bas (<30%) et une durée de réponse courte. Une partie de cette non-réonse peut être expliquée par le fait que les CCS expriment un gène de résistance multidrogues, le MDR-1. La plurichimiothérapie a été testée dans de plus petites séries avec des effets secondaires importants. Les meilleurs résultats ont été avec la combinaison d’étoposide, de doxorubicine et de cisplatine associés au mitotane: le taux de réponse a été de 54%, avec quelques réponses individuelles complètes. Pour faire des progrès dans le CCS avancé, il faut encourager des essais multicentriques de traitement adjuvant. En cas de thérapie utilisant le mitotane, il faut obligatoirement monitorer le taux des drogues.ResumenEl carcinoma adrenocortical (CAC) es un tumor agresivo poco frecuente que comûnmente se détecta cuando ya esta en etapas avanzadas de su desarrollo. Desde hace décadas se practica tratamiento médico con una droga adrenotöxica, el mitotane, pero no se dispone de ensayos clînicos prospectivos que soporten su valor en enfermedad residual o como adyuvante de la resection quirürgica. También se hace necesario confirmar el concepto de nivelés criticos de la droga mediante estudios controlados. Puesto que no es posible predecir la respuesta individual, todavia se aconseja el uso del mitotane en casos de enfermedad no resecable. Cuando hay superproduction de Cortisol o de otros esteroides, se pueden utilizar algunas drogas como el Ketoconazol o la aminoglutetimida. La quimioterapia con agentes ûnicos, por ejemplo doxorubicina y el cisplatino, ha sido decepcionante, por las bajas tasas (<30%) y la corta duration de la respuesta. Parte de tal situation refractaria puede explicarse por el hecho de que los CAC expresan el gen MDR-1 de resistencia multidroga. La quimioterapia con agentes multiples ha sido ensayada en series mas pequenas, con efectos secundarios significatives. Los mejores resultados se logran con la combination de etopösido, doxorubicina y cisplatino asociada con mitotane, alcanzando una tasa de respuesta del 54%, incluyendo respuestas complétas. Para lograr progreso en el manejo del CAC avanzado se debe estimular la realization de ensayos multi-institucionales. La monitoria de los nivelés de droga son obligatorios cuando se usan terapias con base en mitotane.

Radioiodine ablation and therapy in differentiated thyroid cancer under stimulation with recombinant human thyroid-stimulating hormone

We investigated whether recombinant human TSH (rhTSH) safely and effectively induces uptake of high-dose 131-iodine (131I) to ablate thyroid remnant or treat disease, in patients with well-differentiated thyroid carcinoma. Eleven consecutive patients unable to tolerate thyroid hormone withdrawal received one im injection of 0.9 mg rhTSH on 2 consecutive days before receiving 4000 MBq (~108 mCi) radioiodine orally. Eight patients received one, and 3 patients 2 courses. Our series comprised 7 women and 4 men (mean age, 78 yr, range: 56–87 yr). Ten patients had undergone total or near-total thyroid-ectomy up to 19 yr earlier. rhTSH-stimulated single course radioiodine with the intention to ablate thyroid remnant was performed in 3 patients, with following estimation of radioiodine uptake and TG measurements. Of another 8 patients given this treatment palliatively, 5 had radiological, clinical and/or laboratory response, including: 80% decreased pathological uptake between treatment courses; pronounced decrease in bone pain; diminished symptoms; improved physical condition and quality of life; lower serum TG concentration; and/or normalization of TG recovery test. Two patients with small lung metastases on computed tomography had no detectable radioiodine uptake or other response; they also lacked uptake after withdrawal-stimulated radioiodine treatment. Despite being elderly and frail, patients generally tolerated treatment well; rhTSH caused nausea in one patient and transiently increased pain in bone and soft tissue lesions in another. We conclude that rhTSH-stimulated high-dose radioiodine for remnant ablation or tumor treatment is safe, feasible and seemingly effective, enhancing quality of life and offering reasonable palliation in patients with advanced disease.

Long‐term outcome of a large series of patients surgically treated for pheochromocytoma

Objective.  To analyse the morbidity, mortality and long‐term outcome in a consecutive series of surgically treated patients with pheochromocytoma (PC), or paraganglioma (PG), from the western region of Sweden between 1950 and 1997.

Liver Transplantation for Treatment of Metastatic Neuroendocrine Tumors

Abstract: Liver transplantation can be considered a therapeutic option for patients with neuroendocrine tumors only metastatic to the liver. Important selection criteria are well‐differentiated tumors and a low proliferation rate (Ki67 <10%). In this series, orthopic liver transplantation offered good relief of symptoms and long disease‐free intervals with initial survival of grafts and patients as in benign disease. The experience with multivisceral transplantation is still limited.