Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: long-term survival in its adjuvant use.

BACKGROUND: To evaluate the efficacy of streptozocin and o.p'DDD (SO) in adrenocortical cancer (ACC) patients since other chemotherapeutic regimens have limited effects. PATIENTS AND METHODS: We performed a phase II study with SO therapy in 40 ACC patients (median age 44 years). Oral o,p'DDD administration (1-4 g/d, every day) was given together with intravenous streptozocin (1 g/d for five days, thereafter 2 g once every three weeks). 5HT3-receptor blocker was used as standard premedication for streptozocin. RESULTS: The SO therapy was found to have significant effects on disease-free interval (P = 0.02) as well as on survival (P = 0.01) in adjuvantly treated cases (n = 17) in comparison to the patients who did not get any therapy after complete resection (n = 11). Complete or partial response was obtained in 36.4% of patients with measurable disease (n = 22). The overall two-year and five-year survival rates were 70% and 32.5%, respectively. The presence of metastases at diagnosis was identified as a poor prognostic factor (P = 0.02). CONCLUSIONS: The present study necessitates further randomized clinical study of SO therapy in the treatment of ACC, mainly as adjuvant treatment immediately after curative intended surgery, and could be developed into a regular treatment regimen.

Risk factors for postoperative hypocalcemia after surgery for primary hyperparathyroidism.

HYPOTHESIS: A variety of clinical and biochemical variables may be associated with hypocalcemia after surgery for parathyroid adenoma. DESIGN: A prospective study of patients who underwent surgery for solitary parathyroid adenoma. SETTING: A university hospital department of surgery. PATIENTS: Eighty-six consecutive patients who underwent surgery for solitary parathyroid adenoma. INTERVENTION: Parathyroidectomy according to the principles of unilateral neck exploration. MAIN OUTCOME MEASURES: Clinical and biochemical risk factors for early (< or =4 days after surgery) and late (1 year after surgery) postoperative symptomatic and biochemical hypocalcemia. RESULTS: Twenty-two patients developed early symptomatic hypocalcemia. The difference in total serum calcium levels between patients, with and without early symptomatic hypocalcemia, was evident on the third and fourth postoperative days. Serum level of osteocalcin greater than 6.0 microg/L, bilateral neck exploration, and history of cardiovascular disease were risk factors for symptomatic hypocalcemia (odds ratios [95% confidence intervals]: 4.4 [1.4-14.1], 3.8 [1.3-11.6], and 0.1 [0.02-0.60], respectively). Patients with up to 1 risk factor had a possibility of only 7% to develop early symptomatic hypocalcemia. One year after surgery, 16 patients had low levels of total serum calcium (late biochemical hypocalcemia) and were asymptomatic. Preoperative intermittent hypercalcemia was associated with an increased risk for late biochemical hypocalcemia (odds ratio, 3.9; 95% confidence interval, 1.0-16.3). CONCLUSIONS: Clinical and biochemical risk factors for early and late postoperative hypocalcemia in patients who underwent surgery for solitary parathyroid adenoma were found. A clinically useful prognostic index for early symptomatic hypocalcemia was constructed using these risk factors.

Measurement of parathyroid hormone in patients with primary hyperparathyroidism undergoing first and reoperative surgery.

BACKGROUND: The distinction between solitary parathyroid adenoma and hyperplasia can sometimes be difficult during surgery for primary hyperparathyroidism (pHPT), especially in patients who have undergone previous thyroid or parathyroid surgery. The use of intraoperative parathyroid hormone (PTH) monitoring as a possible diagnostic tool was therefore investigated. METHODS: Intraoperative levels of PTH were measured in 119 patients during 121 operations (including 14 reoperations) for pHPT. The mean(s.d.) preoperative serum calcium level was 2.79(0.21) mmol/l. Blood samples were drawn before, and at 5 and 15 min after, excision of the first enlarged parathyroid gland. PTH was analysed electively in 61 patients and on-line by a modified assay for intact PTH in 48 patients. Both procedures were used in ten patients. RESULTS: The mean(s.d.) decline in PTH concentration in 101 patients with primary exploration due to solitary adenoma was 63(17) per cent after 5 min (n=84) and 83(10) per cent after 15 min. The patients with primary exploration because of multiglandular disease (n=6) were correctly predicted not to have parathyroid adenoma. CONCLUSION: Measurement of PTH levels during surgery for pHPT is a highly sensitive method for differentiating between single and multiple gland disease. The on-line monitoring of PTH is clinically useful in patients who have undergone previous neck surgery. Its role in pHPT surgery at primary exploration should be evaluated in prospective trials.

Increased biochemical markers of bone formation and resorption in primary hyperparathyroidism with special reference to patients with mild disease.

OBJECTIVES: To evaluate the impact on bone turnover of primary hyperparathyroidism (pHPT) with special reference to patients with mild pHPT, using biochemical markers of bone formation and resorption. DESIGN: A longitudinal study of patients with pHPT before and one year after surgical treatment. SETTING: The Departments of Internal Medicine and Surgery, Lund University Hospital. SUBJECTS: Forty consecutive patients with pHPT. Thirty of these patients had mild pHPT and are reported separately. Data on bone mineral was also compared to a reference population. INTERVENTION: All patients were operated upon and restudied one year later. MAIN OUTCOME MEASURES: Bone resorption and formation was studied by means of the serum concentrations of the telopeptide of the carboxyterminal region of type 1 collagen (ICTP) and of alkaline phosphatase (ALP), osteocalcin and the carboxyterminal propeptide of type 1 procollagen (PICP), respectively. Bone density was measured at the distal radius by single photon absorptiometry (SPA). RESULTS: Bone formation markers consistently decreased after parathyroid surgery: ALP from 3.51 +/- 0.23 to 2.94 +/- 0.21 microkat L(-1) (P < 0.05), osteocalcin from 6.15 +/- 0.53 to 2.89 +/- 0.23 microg L(-1) (P < 0.001) and PICP from 126.4 +/- 10.9 to 96.0 +/- 6.5 microg L(-1) (P < 0.001). In parallel, the ICTP concentration, reflecting bone resorption, decreased from 5.10 +/- 0.54 to 3.94 +/- 0.34 microg L(-1) (P < 0.001). There was not any significant change in distal radius bone mineral 1 one year after surgery. In the subgroup of patients classified as mild pHPT, a significant decrease was noted for osteocalcin, PICP and for ICTP but not for ALP, without significant changes in variables reflecting distal radius bone mineral content. Glomerular filtration rate was inversely correlated to serum levels of intact PTH, ionized calcium, alkaline phosphatase, osteocalcin and ICTP and directly correlated to the 1.25-dihydroxy-vitamin D concentrations. CONCLUSIONS: pHPT is associated with substantial changes in circulating levels of biochemical markers of bone formation and resorption. These findings are also present in patients with mild pHPT. Renal function should be considered in the evaluation of the impact of pHPT on bone turnover.

Sestamibi versus thallium subtraction scintigraphy in parathyroid localization: a prospective comparative study in patients with predominantly mild primary hyperparathyroidism.

BACKGROUND: Technetium 99m sestamibi was recently introduced for the preoperative localization of abnormal parathyroid glands in patients with primary hyperparathyroidism with promising results. However, the sensitivity of sestamibi and thallium to detect abnormal parathyroid glands is partly dependent on the gland size. In this study we compared the sensitivity of sestamibi subtraction scintigraphy with thallium subtraction scintigraphy in patients with predominantly mild increase in serum calcium level. METHODS: Thirty-nine patients with primary hyperparathyroidism were included. The mean (+/-SD) serum level of calcium was 2.75 +/- 0.17 mmol/L. In 28 (72%) of the patients the serum level of calcium was less than 2.85 mmol/L. These patients were classified as having mild abnormalities in serum calcium. All patients were investigated before operation with both sestamibi and thallium subtraction scintigraphy. RESULTS: In two patients autonomous thyroid adenomas precluded subtraction scintigraphy. Sestamibi subtraction scintigraphy correctly localized 31 (86%) of 36 parathyroid adenomas compared with only 17 (47%) of 36 by thallium subtraction scintigraphy (p < 0.001). There was one false-positive result in the sestamibi group because of a thyroid adenoma, and two of the scans were negative. Both the sestamibi and the thallium subtraction scintigraphy localized one single enlarged gland in all three patients with multiple gland involvement. In no case was multiglandular disease predicted. CONCLUSIONS: Sestamibi subtraction scintigraphy is superior to thallium subtraction scintigraphy and has a high sensitivity to localize a solitary parathyroid adenoma in patients with mild increase in serum calcium level. The sensitivity decreases in patients with multiglandular parathyroid disease and concomitant thyroid nodular abnormalities.

Persistent elevated serum levels of intact parathyroid hormone after operation for sporadic parathyroid adenoma: evidence of detrimental effects of severe parathyroid disease.

BACKGROUND: A significant number of patients with primary hyperparathyroidism (pHPT) who are surgically treated have increased serum levels of intact parathyroid hormone (PTH) during long-term follow-up despite normocalcemia. The cause and significance of this finding remain to be established. METHODS: A total of 82 patients operated on for sporadic parathyroid adenoma were investigated before and at 8 weeks and 1 year after operation with serum levels of intact PTH, bone mineral content, and biochemical variables known to reflect PTH activity. RESULTS: All patients had low or normal serum levels of calcium during follow-up. At 8 weeks after operation 20 (24%) patients had increased serum levels of PTH. These patients had severe parathyroid disease and low levels of 25(OH) vitamin D before operation. In contrast to patients with normal levels of PTH after operation, they did not have an elevated bone mineral content but had elevated levels of serum creatinin. At 1 year after operation 13 patients had elevated serum levels of PTH. Compared with patients with normal serum levels of PTH, they were older and had an increased frequency of cardiovascular disease and biochemical indications of compromised renal function. They did not have an elevated bone mineral content. CONCLUSIONS: Persistently increased serum levels of PTH indicate harmful effects of pHPT even after surgical cure, especially in elderly patients with severe disease before operation. The results in this investigation therefore favor early treatment of pHPT.

Side localization of parathyroid adenomas by simplified intraoperative venous sampling for parathyroid hormone.

Side localization of parathyroid adenomas was performed by venous sampling for intact parathyroid hormone (PTH) in 20 consecutive patients with primary hyperparathyroidism (pHPT) after induction of anesthesia. The results were thus available during surgery. Nineteen of the patients had solitary parathyroid adenoma, and one had hyperplasia. There was no complication to the procedure. A lateralizing PTH gradient for a parathyroid adenoma was obtained in 13 patients. At surgery 12 of them (92%) were proved correct; that is, the adenoma was localized on the same side. Thus the technique correctly lateralized the adenoma in 12 of 19 patients (63%). We therefore conclude that the method of intraoperative venous sampling for intact PTH is safe, and the predictive value of a lateralizing gradient is high. It could therefore be used as an adjunct to surgical skill and noninvasive localization procedures in selected cases, for instance in patients with prior neck surgery and hypercalcemic crisis.

Dynamic Octreotide scintigraphy in neuroendocrine tumours.

The purpose of the present study was to investigate the optimal time for scintigraphy after injection of the radio-labelled somatostatin analogue, Octreotide. A secondary purpose was to evaluate the value of SPECT. One SPECT study and up to 4 whole body scans were performed in 22 patients with neuroendocrine tumours 0.5, 5, 24 and 48 hours after an injection of 110 MBq In-DTPA Octreotide. A total of 98 scintigrams were studied. A pathological uptake was found in 19 of the 22 patients. In 3 cases, early scintigrams (0.5 and 5 hours after injection) were of the most value whereas late scintigrams (24 and 48 hours) were the best in 4 cases. SPECT was found to be of value in 13 of 21 cases. For correct interpretation of Octreotide scintigraphy it is necessary to obtain both early and late scintigrams as well as a SPECT study.

Neuroendocrine metastases of the liver.

Neuroendocrine liver metastases are rare, yet they represent an entity that has attracted much attention lately. The protracted course of neuroendocrine tumors and the hormone origin of their typical incapacitating symptoms constitute a logical basis for well founded and bespoke treatment. Demonstration of the liver secondaries is best done by ultrasonography (US) and contrast-enhanced computed tomography (CT), which on the whole have replaced the invasive angiography techniques. By use of histochemical and molecular biologic methods the exact nature of the tumor can be typified in tissue samples obtained percutaneously, laparoscopically, or surgically. Localization of nonpalpable metastases of the liver is best done by intraoperative US. Surgical removal of liver metastases is curative in some cases and is usually effective in relieving the symptoms. Also, palliative debulking or cytoreductive surgery is often worthwhile as it offers a chance of prolonged survival and symptom relief. Similar benefits are achieved by ischemic therapy preferably by temporary dearterialization, which in our department is done on an outpatient basis using a specially designed (externally controlled) occluder applied during a single laparotomy that includes debulking when appropriate as well as cholecystectomy. Hormonal therapy with somatostatin analogs may be used as a single treatment or in combination with ischemic therapy. It has an ensured symptom-reducing effect, whereas its influence on tumor growth is unsettled. Lately similar effects have been ascribed to human leukocyte interferon. In conclusion the specific characteristics of neuroendocrine tumors and the available treatment arsenal favor an active treatment approach in patients who have developed liver metastases.

Combined doxorubicin, hyperfractionated radiotherapy, and surgery in anaplastic thyroid carcinoma. Report on two protocols. The Swedish Anaplastic Thyroid Cancer Group.

BACKGROUND: Anaplastic carcinoma of the thyroid (ACT) rarely can be cured, but every effort should be made to improve prognosis and, above all, prevent death due to suffocation or large local tumor ulceration. METHODS: From 1984 to 1992, 33 consecutive patients with ACT were treated prospectively according to a combined treatment program consisting of hyperfractionated radiotherapy, doxorubicin, and debulking surgery. Preoperative radiotherapy was administered to a target dose of 30 Gy and postoperatively to a total dose of 46 Gy. Radiotherapy was performed 5 days a week. The daily fraction was 1.0 Gy x 2 until 1988, after which it was 1.3 Gy x 2. Otherwise, the therapy remained unchanged. Twenty milligrams of doxorubicin were administered intravenously per week. Debulking surgery was possible in 23 patients (70%). RESULTS: No patient failed to complete the protocol because of toxicity. There were no signs of local recurrence in 16 patients (48%). In only eight patients (24%) was death attributed to local failure. In four patients, survival with no evidence of disease exceeded 2 years. Improvement in local tumor control was marginally significant (P = 0.08) in the 17 patients treated in the latter part of the study, with no sign of local disease in 11 patients and deaths due to local failure in only 2 patients. The improved local control could not be attributed to any differences between the two series. CONCLUSION: Combination modality treatment of ACT is feasible and effective despite the patients' advanced age and locally advanced disease. There was a tendency for local control to be improved after accelerated radiotherapy.

Diagnostic laparoscopy reduces unnecessary appendicectomy in fertile women.

OBJECTIVE: To assess the value of laparoscopy in the accurate diagnosis of appendicitis in women of child-bearing age. DESIGN: Prospective randomised trial. SETTING: University hospital, Kuwait. SUBJECTS: 100 patients who fulfilled the inclusion criteria between July 1988 and March 1990. INTERVENTIONS: 50 patients were randomised to have diagnostic laparoscopy followed by appendicectomy if necessary, and the other 50 to have immediate appendicectomy. MAIN OUTCOME MEASURES: Avoidance of unnecessary appendicectomy, length of operating time, and length of stay in hospital. RESULTS: 19 of 50 patients in the study group did not require appendicectomy (38%). One patient required an emergency operation for an ectopic pregnancy. Of the remaining 30, only 4 of the removed appendixes showed no histological abnormality (13%). There were no complications of laparoscopy. CONCLUSION: Laparoscopy is a safe and effective way of diagnosing acute appendicitis and should be used more often.

Primary hyperparathyroidism due to solitary adenoma. A comparative multicentre study of early and long-term results of different surgical regimens.

Surgical regimens for treatment of solitary parathyroid adenoma were compared in a multicentre study in five departments of surgery in the United States and Europe. Three hundred and twenty-five patients fulfilled the inclusion criteria. Eight years after the operation 272 patients (84%) were available for follow-up investigation. Severe postoperative hypocalcaemia (less than 2.00 mmol) was significantly more common after bilateral than unilateral exploration (p less than 0.001), and in women (p less than 0.01). Neither age nor preoperative serum calcium concentration was related to the severity of postoperative hypocalcaemia. At follow-up, 96% of the patients who had had unilateral, and 89% of those who had had Bilateral exploration had remained normocalcaemic without further treatment. Of the patients who had had incisional biopsies of normal glands 8% had hypercalcaemia and 8% had hypocalcaemia. Of patients operated on without a biopsy being taken or who had had one whole normal gland removed 1% were hypercalcaemic and 4% were hypocalcaemic. Early and late hypocalcaemia are reduced by atraumatic handling of the normal parathyroid gland without increasing the risk of persistent or recurrent hypercalcaemia.

The influence of different degrees of chronic lymphocytic thyroiditis on thyroid function after surgery for benign, non-toxic goitre.

Of 220 patients, surgically treated for benign, non-toxic goitre with unilateral procedures during a six-year period, 201 could be followed up, on average, 8 years postoperatively. Twenty-four patients were treated with thyroxine immediately postoperatively ("recurrence prophylaxis"); in the other patients thyroxine was only given in cases of hypothyroidism (significant increase of S-TSH). Occurrence of lymphoid infiltration in the removed lobe was subjectively quantified according to a five point scale. Five of the 15 patients with pronounced inflammation developed hypothyroidism whereas 5 of the 137 patients without inflammation had hypothyroidism (p less than 0.05). There was a significant difference in S-TSH postoperatively between patients with no or, only a slight degree of, chronic inflammation, and patients with pronounced inflammation. This study indicates that histologic grading of lymphocytic infiltration in the thyroid gland may be useful for predicting the risk of postoperative hypothyroidism.

Current trends in the surgical treatment of solitary parathyroid adenoma. A questionnaire study from 53 surgical departments in 14 countries.

Current trends in the surgical treatment of primary hyperparathyroidism due to solitary parathyroid adenoma were evaluated in a questionnaire study. Response was obtained from 53 departments highly active in endocrine surgery in 14 countries (response rate 95%). Intraoperative histologic examination is widely (70%) regarded as necessary, but utilized more in North America and Scandinavia (87%) than elsewhere (45%). Intraoperative fat staining is used in one-third of the departments. Excisional biopsy including one whole gland is preferred by 32% to multiple incisional biopsies. Gross inspection of three normal parathyroid glands without histologic identification is favoured in 21% of the departments, while 31% prefer bilateral exploration and incisional biopsy. When an adenoma is found on the first side to be explored, 17% advocate bilateral exploration with incisional biopsy of all three normal glands, whereas unilateral exploration with excisional or incisional biopsy of the ipsilateral normal gland is preferred by a similar percentage.

Drain vs. no drain in primary thyroid and parathyroid surgery.

The need for drainage after primary thyroid or parathyroid surgery was evaluated in a prospective study in which 100 consecutive patients were randomly allocated to drainage or no drainage. Seroma developed in the wound in seven of the 50 patients without drainage and in two of the 50 with drainage. There were no residual effects of the seromas, which resolved spontaneously. The incidence of wound complication was unrelated to the surgeon's opinion on the need for drainage. The study provided no statistical report for routine use of drains in primary thyroid or parathyroid surgery.

Angiogenic activity of normal and pathologic human thyroid tissue.

Thyroid tissue was collected from 60 patients during operations for various thyroid conditions. The tissue's angiogenic capacity was assessed in a chick chorioallantoic membrane preparation. Angiogenic activity was observed in 22 (85%) of 26 solitary follicular neoplasms, in none of ten papillary carcinomas and in one of seven glands with Graves' disease (all pretreated with propranolol). Of 17 glands with euthyroid multinodular colloid goitre, three (18%) showed angiogenic activity. No angiogenic activity was detected in normal thyroid tissue from 26 patients. Angiogenic activity of diseased human thyroid does not seem to be a marker of thyroid malignancy.

Indications for thyroxine therapy after surgery for nontoxic benign goitre.

Of 287 consecutive patients, surgically treated at our department for benign, nontoxic goitre during a six-year period, 261 could be followed up, on average, 8.0 years postoperatively. Unilateral surgical procedures had been used in 199 patients, subtotal thyroidectomy in 62. 29 patients were treated with thyroxine (T4) immediately postoperatively ("recurrence prophylaxis"); in the other patients thyroxine was only given in cases of hypothyroidism (significant increase of s-TSH). 26 patients had a goitre recurrence 0.5-10 years after surgery; of these 3 had got T4 as "recurrence prophylaxis" and 23 had not. There was no significant difference between patients with and without T4 postoperatively regarding the rate of recurrence. Of 55 patients treated with subtotal thyroidectomy, 33 had postoperative latent (n = 26) or manifest (n = 7) hypothyroidism. Only 13 of 177 patients operated on unilaterally developed hypothyroidism; two of these had Hashimoto's thyroiditis. All cases of hypothyreosis except 4 were detected within the first 12 months of follow-up. This study indicates that routine use of thyroxine as prophylaxis against recurrence after surgery for benign nontoxic goitre can be strongly questioned and that the risk of hypothyroidism is high after subtotal thyroidectomy.

Mortality in patients surgically treated for primary hyperparathyroidism due to solitary adenoma.

In a multicentre study including 5 surgical departments in Europe and USA the results of surgical treatment in primary hyperparathyroidism (HPT) due to single adenoma were analysed. At long term follow-up 60 out of 282 patients operated on for solitary parathyroid adenoma were found to be dead. The average age at operation was 69.2 years and the time of survival after surgery 3.9 years. The cumulative relative survival in patients aged 60-64 years was reduced by 18% (P less than 0.01) as compared to a control group corrected for nationality, age and gender. In patients above the age of 65 no such reduction could be demonstrated. The operative mortality was 1% and attributed to cardiac failures. Late mortality was caused by cardiovascular conditions in 52% and by malignant disease in 15%. None of these figures were statistically different from the age, gender and nation corrected control group. Among the miscellaneous causes of death were two patients who committed suicide during the first postoperative year. The results indicate that surgery for parathyroid adenoma can be performed with low morbidity and mortality.

Preoperative treatment of thyrotoxicosis in developing countries: a comparative study of carbimazole and propranolol.

Preoperative management of treatment in thyrotoxicosis was investigated in a comparative study of carbimazole and propranolol in 41 consecutive patients collected during a 3-year period. The groups included 20 and 21 patients respectively, of equal sex and age distribution and of similar severity. The length of the preoperative treatment was significantly reduced in the propranolol pretreated patients (P greater than 0.001). Intraoperative blood loss, postoperative function with regard to the thyroid, parathyroids and vocal cords were similar in both groups. Three and two patients respectively had permanent hypothyroidism requiring thyroxin treatment. In patients with therapy compliance problems treatment with propranolol would entail a definite advantage, particularly in developing countries.

Splenic implants: evaluation with radionuclide methods.

The viability of omental splenic implants placed in 16 patients who had undergone splenectomy was assessed with 37 technetium-99m tin colloid studies and five studies with Tc-99m-labeled denatured red blood cells (RBCs). Indications for splenectomy included trauma in eight patients, schistosomal (Bilharzial) portal hypertension in six, splenic artery aneurysm in one, and Wiskott-Aldrich syndrome in one. Studies were done within the 1st month and at various intervals up to 13 months after surgery. Implants in five of eight trauma patients were seen during the 1st month, and implants in seven of seven were seen after 6 months (one patient could not be followed up). Three of six implants in cases of portal hypertension were seen in the 1st month and four of four at 6 months (two patients were not followed up). In two of the five studies with denatured RBCs, Tc-99m tin colloid study was also done 48 hours later; in these cases denatured RBCs were more successful in showing the implants. The authors conclude that radioisotopic procedures are valuable in following up the viability of splenic implants. The "take" of splenic implants in patients with schistosomiasis is equally successful to that in trauma patients.