Analysis of and prognostic information from disseminated tumour cells in bone marrow in primary breast cancer: a prospective observational study.

BACKGROUND: Disseminated tumour cells (DTCs) in the bone marrow of patients with breast cancer have been identified as an independent predictor of poor prognosis in patients with non-metastatic disease. This prospective study aimed to evaluate the presence and prognostic value of DTCs in the bone marrow of female patients with primary breast cancer. METHODS: Between 1999 and 2003, bone marrow aspirates were obtained from patients at the time of surgery for primary invasive breast cancer. DTCs in bone marrow were identified using monoclonal antibodies against cytokeratins for detection of epithelial cells. The detection of DTCs was related to clinical follow-up with distant disease-free survival (DDFS) and breast cancer-specific survival as endpoints. Bone marrow aspirates from adult healthy bone marrow donors were analysed separately. RESULTS: DTCs were analysed in 401 patients, and cytokeratin-positive cells were found in 152 of these (38%). An immunofluorescence (IF) staining procedure was used in 327 patients, and immunocytochemistry (IC) was performed in 74 patients. The IF-based method resulted in 40% DTC-positive cases, whereas 30% were positive using IC (p = 0.11). The presence of DTCs in bone marrow was not significantly related to patient or tumour characteristics. The presence of DTCs was not a prognostic factor for DDFS (IF: hazards ratio [HR], 2.2; 95% confidence interval [CI], 0.63-2.2; p = 0.60; IC: HR, 0.84; 95% CI, 0.09-8.1; p = 0.88). Significant prognostic factors were lymph node metastases, oestrogen receptor positivity, Nottingham histological grade, and tumour size using Cox univariate analysis. The analyses were positive for epithelial cells in bone marrow from adult healthy donors in 19 (25%) samples. CONCLUSIONS: The detection of DTCs in bone marrow in primary breast cancer was previously shown to be a predictor of poor prognosis. We were not able to confirm these results in a prospective cohort including unselected patients before the standard procedure was established. Future studies with a standardised patient protocol and improved technique for isolating and detecting DTCs may reveal the clinical applications of DTC detection in patients with micrometastases in the bone marrow.

Fusion of the SEC31L1 and ALK genes in an inflammatory myofibroblastic tumor.

Inflammatory myofibroblastic tumor (IMT) is a neoplasm composed of myofibroblastic spindle cells and infiltrating inflammatory cells. Cytogenetic analyses have revealed that a subgroup of IMT, in particular among children and young adults, harbors clonal chromosomal rearrangements involving chromosome band 2p23. Further, molecular genetic studies have shown that these rearrangements target the ALK gene, serving as the 3'-partner in fusion genes with various translocation partners. In the present study, we describe the finding of a novel SEC31L1/ALK fusion gene in an intraabdominal IMT of a young man. G-band analysis revealed a translocation t(2;4)(p23;q21) and subsequent fluorescence in situ hybridization with locus-specific probes strongly indicated disruption of the ALK locus on chromosome 2. Immunostaining with monoclonal mouse anti-human CD246 ALK Protein showed diffuse cytoplasmic positivity. Using reverse primers for the ALK-gene, we could, by 5'-RACE methodology, amplify a single 1.2 kb fragment. Sequence analysis showed that the fragment was a hybrid cDNA product in which nt 3012 of SEC31L1 (NM_016211), located in band 4q21, was fused in-frame to nt 4080 of ALK (NM_004304). RT-PCR with two sets of primer pairs specific for SEC31L1 and ALK amplified two transcripts, which at sequencing corresponded to two types of chimeric SEC31L1/ALK transcripts. In the long, type I, transcript nt 3012 of SEC31L1 (NM_016211) was fused in-frame to nt 4080 of ALK. In the short, type II, transcript nt 2670 of SEC31L1 was fused in-frame to nt 4080 of ALK. Genomic PCR and subsequent sequencing showed that the breakpoints were located in intron 23 of SEC31L1 and intron 20 of ALK.

Characterization of normal breast tissue heterogeneity using time-resolved near-infrared spectroscopy.

In recent years, extensive efforts have been made in developing near-infrared optical techniques to be used in detection and diagnosis of breast cancer. Variations in optical properties of normal breast tissue set limits to the performance of such techniques and must therefore be thoroughly examined. In this paper, we present intra- and intersubject as well as contralateral variations of optical and physiological properties in breast tissue as measured by using four-wavelength time-resolved spectroscopy (at 660, 786, 916 and 974 nm). In total, 36 volunteers were examined at five regions at each breast. Optical properties (absorption, mu(a), and reduced scattering, mu'(s)) are derived by employing diffusion theory. The use of four wavelengths enables determination of main tissue chromophores (haemoglobin, water and lipids) as well as haemoglobin oxygenation. Variations in all evaluated properties seen over the entire breast are approximately twice those for small-scale heterogeneity (millimetre scale). Intrasubject variations in optical properties are almost in all cases below 20% for mu'(s), and 40% for mu(a). Overall variations in water, lipid and haemoglobin concentrations are all in the order of 20%. Oxygenation is the least variable of the quantities evaluated, overall intrasubject variations being 6% on average. Extracted physiological properties confirm differences between pre- and post-menopausal breast tissue. Results do not indicate systematic differences between left and right breasts.

Patients with elevated serum parathyroid hormone levels after parathyroidectomy: showing signs of decreased peripheral parathyroid hormone sensitivity.

We have previously shown that patients with elevated levels of parathyroid hormone (PTH) after surgery for parathyroid adenoma have normal parathyroid and renal function but demonstrate signs of remineralization of cortical bone, decreased calcium absorption, and low levels of vitamin D. We hypothesized that decreased peripheral PTH sensitivity could also be of importance for this condition. Thirteen patients operated on for a solitary parathyroid adenoma, with a mean +/- SD preoperative serum level of calcium of 2.72 +/- 0.12 mmol/L, were investigated 6 weeks after surgery with a standardized PTH (1-34) infusion test for 6 hours. The eight patients with elevated PTH levels had less increase in serum levels of ionized calcium (0.02 +/- 0.03 mmol/L) than did the five patients with normal PTH levels (0.06 +/- 0.02 mmol/L) (p < 0.05). Patients with elevated PTH also showed less decrease in serum phosphate levels (p < 0.05) and a trend to a larger decrease in the excretion of urinary calcium (p = 0.08). The increase in 1,25-dihydroxyvitamin D(3) did not differ between the two groups of patients. Thus patients operated on for parathyroid adenoma with postoperatively elevated serum PTH levels showed decreased peripheral sensitivity to PTH.

Preoperative normal level of parathyroid hormone signifies an early and mild form of primary hyperparathyroidism.

Contemporary patients are often diagnosed with mild or intermittent hypercalcemia. In addition, most studies demonstrate patients with parathyroid (PTH) levels in the upper normal range. The aim of the present investigation was to define subgroups of patients with mild primary hyperparathyroidism (pHPT), which could be of importance in the decision for or against surgical treatment. Two-hundred and eleven patients, operated for pHPT were investigated with biochemical variables known to reflect PTH activity, renal function, and bone mineral content. The preoperative diagnosis of pHPT was based on the presence of hypercalcemia combined with an inappropriate serum concentration of PTH. The mean age of the patients was 64 +/- 14 years and the mean serum level of calcium was 2.78 +/- 0.19 mmol/L. One hundred and sixty-two patients (77%) had raised levels of calcium and PTH the day before surgery (overt pHPT), 25 patients (12%) had a normal level of calcium and a raised PTH level (normal calcium group), and 20 patients (9%) had a raised level of calcium and a normal level of PTH (normal PTH group). In four patients the level of calcium and PTH was normal. Between-group analysis demonstrated no major difference in symptom and signs of pHPT. Except for lower adenoma weight, patients in the normal calcium group did not essentially differ from the patients in the overt pHPT group. However, patients in the normal PTH group were a decade younger, and had better renal function, lower bone turnover, and a preserved bone density compared with patients in the overt pHPT group. In conclusion, the data from the present investigation show that pHPT patients with a preoperative normal PTH level have an early and mild form of the disease. Furthermore, the serum calcium concentration does not reflect disease severity in pHPT.

Unilateral versus bilateral neck exploration for primary hyperparathyroidism: a prospective randomized controlled trial.

OBJECTIVE: To compare unilateral and bilateral neck exploration for primary hyperparathyroidism in a prospective randomized controlled trial. SUMMARY BACKGROUND DATA: Based on the assumption that unilateral neck exploration for a solitary parathyroid adenoma should reduce operating time and morbidity, a variety of minimally invasive procedures have challenged the idea that bilateral neck exploration is the gold standard for the surgical treatment of primary hyperparathyroidism. However, to date, no open prospective randomized trial has been published comparing unilateral and bilateral neck exploration. METHODS: Ninety-one patients with the preoperative diagnosis of primary hyperparathyroidism were randomized to unilateral or bilateral neck exploration. Preoperative scintigraphy and intraoperative parathyroid hormone measurement guided the unilateral exploration. Gross morphology and frozen section determined the extent of parathyroid tissue resection in the bilateral group. The primary end-point was the use of postoperative medication for hypocalcemic symptoms. RESULTS: Eighty-eight patients (97%) were cured. Histology and cure rate did not differ between the two groups. Patients in the bilateral group consumed more oral calcium, had lower serum calcium values on postoperative days 1 to 4, and had a higher incidence of early severe symptomatic hypocalcemia compared with patients in the unilateral group. In addition, for patients undergoing surgery for a solitary parathyroid adenoma, unilateral exploration was associated with a shorter operative time. The cost for the two procedures did not differ. CONCLUSIONS: Patients undergoing a unilateral procedure had a lower incidence of biochemical and severe symptomatic hypocalcemia in the early postoperative period compared with patients undergoing bilateral exploration. Unilateral neck exploration with intraoperative parathyroid hormone assessment is a valid surgical strategy in patients with primary hyperparathyroidism with distinct advantages, especially for patients with solitary parathyroid adenoma.

Multifactorial risk profile for bone fractures in primary hyperparathyroidism.

Primary hyperparathyroidism (pHPT) is associated with an increased fracture risk, and decreased bone density thus has been considered an indication for surgery. However, many pHPT patients have a multifactorial risk profile for osteoporosis and bone fractures. The aim of the present study was to evaluate variables associated with fracture risk within the group of pHPT patients. A series of 203 consecutive patients operated for pHPT were investigated with bone mineral content and biochemical and clinical risk factors for bone fracture. Seventeen patients (8%) had a history of at least one bone fracture up to 5 years before pHPT surgery. Twenty-six patients (13%) had a history of at least one fracture during the 10-year period prior to surgery. In the univariate analyses corticosteroid treatment, serum levels of alkaline phosphatase, 25-hydroxyvitamin D3, type I collagen telopeptide, and bone mineral content were found to be associated with a history of bone fractures up to 10 years before surgery. Additionally, age and menopausal status were of importance for fractures during the 10-year-period, whereas a history of cardiovascular disease was important for fractures during the 5-year-period prior to surgery. Multivariate analyses showed that serum level of PTH was independently associated with bone fractures during the 5-year period prior to pHPT surgery and further that serum level of 25-hydroxyvitamin D3 was associated with fractures up to 10 years before surgery. In conclusion, serum levels of 25-hydroxyvitamin D3 and PTH were independently associated with a history of bone fractures in pHPT. These variables should be considered when evaluating patients for parathyroid surgery.

Low parathyroid hormone levels after thyroid surgery: a feasible predictor of hypocalcemia.

BACKGROUND: Selecting patients with a low risk of hypocalcemia is mandatory if patients are to be discharged on the first day after bilateral thyroidectomy. This study investigated the predictive value of intraoperative parathyroid hormone (PTH). METHODS: Thirty-eight patients underwent total or near-total thyroidectomy. Patients with or without biochemical and symptomatic hypocalcemia were compared regarding intraoperative PTH levels and previously suggested risk factors. The accuracy of intraoperative PTH to predict patients at risk for postoperative hypocalcemia was compared with a calcium concentration of less than 2.00 mmol/L (8.0 mg/dL) on the first postoperative day. RESULTS: PTH levels after resection of the second lobe, age, and number of parathyroid glands identified intraoperatively were independently associated with the reduction in serum calcium concentration measured at nadir on the first or second postoperative day. PTH levels after resection of the second lobe were lower among patients who developed biochemical (P <.001) and symptomatic hypocalcemia (P <.01) compared with those who did not. Low levels of intraoperative PTH identified the 3 patients who required intravenous calcium during the first 24 postoperative hours. An intraoperative PTH level below reference range and a calcium concentration of less than 2.00 mmol/L measured 1 day postoperatively both predicted biochemical hypocalcemia with a similar sensitivity (90% vs 90%) and specificity (75% vs 82%). Intraoperative PTH was slightly better than a serum calcium concentration of less than 2.00 mmol/L on postoperative day 1 to predict symptomatic hypocalcemia, with a sensitivity of 71% vs 52% and a specificity of 81% vs 76%, respectively. CONCLUSIONS: Parathyroid gland insufficiency is the main determinant of transient hypocalcemia after bilateral thyroid surgery. Low intraoperative PTH levels during thyroid surgery are therefore a feasible predictor of postoperative hypocalcemia.

Measurement of intraoperative parathyroid hormone predicts long-term operative success.

HYPOTHESIS: A decrease in the intraoperative parathyroid hormone (PTH) level predicts long-term operative success. DESIGN: A case series of consecutive patients undergoing parathyroidectomy with intraoperative PTH measurement. SETTING: A university hospital. PATIENTS AND INTERVENTION: One hundred two patients with sporadic primary hyperparathyroidism underwent parathyroidectomy according to the principles of unilateral exploration with intraoperative PTH measurement. MAIN OUTCOME MEASURES: Longitudinal effects on levels of serum calcium and PTH. RESULTS: In 94 of 98 patients who underwent primary exploration because of a solitary adenoma, intraoperative PTH decreased at least 60% 15 minutes after gland excision. The 4 cases in which PTH fell to less than 60% were classified as false negatives. Patients examined for multiglandular disease (n = 4) were correctly predicted not to have an adenoma. Twenty-two patients (22%) were unavailable for 5-year follow-up. These patients were followed up for 2 months to 48 months (median, 24 months), and none developed recurrent primary hyperparathyroidism. Of the remaining 80 patients (78%), all but 1 patient had normal or slightly decreased serum calcium levels (mean +/- SD, 9.24 +/- 0.4 mg/dL [2.31 +/- 0.10 mmol/L]) at 5-year follow-up. One patient with hypercalcemia (10.6 mg/dL [2.65 mmol/L]) was interpreted to have developed renal failure with secondary hyperparathyroidism. Thirty-four patients had elevated serum PTH levels at least once during the postoperative study period, with normal or slightly decreased calcium concentrations. The prediction of late postoperative normocalcemia by means of intraoperative PTH measurement had an overall accuracy of 95%. CONCLUSIONS: The measurement of intraoperative PTH during surgery for primary hyperparathyroidism accurately differentiates between single- and multiple-gland disease and ensures good long-term results.