Mortality after surgery for primary hyperparathyroidism: results from a nationwide cohort.

BACKGROUND: Contemporary patients with primary hyperparathyroidism are often diagnosed with mildly raised serum calcium levels. Previous studies have reported increased mortality in patients with primary hyperparathyroidism. This retrospective cohort study aimed to examine whether contemporary patients operated for primary hyperparathyroidism have higher mortality than the general population, and whether mortality in these patients is associated with serum calcium concentration, adenoma weight or multiglandular disease. METHODS: Patients from a Swedish national cohort consisting of patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery 2003-2013, were matched with population controls. The National Patient Register, the Swedish Cause of Death Register, and socioeconomic data were cross-linked. End of follow-up was 10 years after surgery, 31 December 2015, or emigration. Mortality was analysed by standardized mortality ratio, Kaplan-Meier survival estimates, and univariable and multivariable Cox regression. Multiple imputation by chained equations was performed on missing data. RESULTS: After exclusions, there were 5009 patients with primary hyperparathyroidism and 14 983 controls. Multivariable Cox regression analysis adjusted for age, sex, Charlson Co-morbidity Index, marital status, level of education, disposable income, and period of surgery showed lower mortality in patients than controls (hazard ratio (HR) 0.83, 95 per cent c.i. 0.75 to 0.92). In univariable Cox regression of mortality in patients, serum calcium concentration (mmoles per litre) was associated with mortality (HR 2.20, 1.53 to 3.16). This association remained in multivariable Cox regression after multiple imputation (HR 1.79, 1.19 to 2.70). CONCLUSION: Mortality was not increased in patients operated for primary hyperparathyroidism compared with controls in a contemporary setting. Preoperative serum calcium concentration might, however, influence survival.

Mortality in patients with permanent hypoparathyroidism after total thyroidectomy.

BACKGROUND: Permanent hypoparathyroidism remains the most common adverse outcome after total thyroidectomy, but long-term effects of hypoparathyroidism are unknown. The aim was to investigate mortality in patients with permanent hypoparathyroidism after total thyroidectomy. METHODS: Data from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery were linked with the Swedish National Prescription Register for Pharmaceuticals and the Swedish National Inpatient Register. Patients who underwent total thyroidectomy between 1 July 2005 and 30 June 2014 for benign thyroid disease, and who used active vitamin D for at least 6 months after surgery, were classified as having permanent hypoparathyroidism and included in the study cohort. Risk of death was assessed using Cox regression analysis, adjusting for age, sex, thyrotoxicosis and co-morbidity. RESULTS: There were 4899 patients, with a mean(s.d.) age of 46·3(15·8) years; 83·1 per cent were women, and 2932 patients (59·8 per cent) had thyrotoxicosis. In all, 246 patients (5·2 per cent) were classified as having permanent hypoparathyroidism. Mean(s.d.) follow-up was 4·4(2·4) years, and 109 patients (2·2 per cent) died during follow-up. Compared with patients without permanent hypoparathyroidism, the risk of death was significantly higher among patients with permanent hypoparathyroidism after total thyroidectomy (adjusted hazard ratio 2·09, 95 per cent c.i. 1·04 to 4·20). CONCLUSION: Permanent hypoparathyroidism after total thyroidectomy for benign disease is common and associated with an increased risk of death.

Patients presenting at the emergency department with acute abdominal pain are less likely to be admitted to inpatient wards at times of access block: a registry study.

BACKGROUND: Also known as access block, shortage of inpatient beds is a common cause of emergency department (ED) boarding and overcrowding, which are both associated with impaired quality of care. Recent studies have suggested that access block not simply causes boarding in EDs, but may also result in that patients are less likely to be admitted to the hospital from the ED. The present study's aim was to investigate whether this effect remained for patients with acute abdominal pain, for which different management strategies have emerged. Access block was defined in terms of hospital occupancy and the appropriateness of ED discharges addressed as 72 h revisits to the ED. METHODS: As a registry study of ED administrative data, the study examined a population of patients who presented with acute abdominal pain at the ED of a 420-bed hospital in southern Sweden during 2011-2013. Associations between exposure and outcomes were addressed in contingency tables and by logistic regression models. RESULTS: Crude analysis revealed a negative association between access block and the probability of inpatient admission (38.6 % admitted at 0-95 % occupancy, 37.8 % at 95-100 % occupancy, and 35.0 % at ≥ 100 % occupancy) (p < .001). No significant associations between exposure and 72 h revisits emerged. Multivariable models indicated an odds ratio of inpatient admission of 0.992 (95 % CI: 0.986-0.997) per percentage increase in hospital occupancy. CONCLUSIONS: Study findings indicate that patients with acute abdominal pain are less likely to be admitted to the hospital from the ED at times of access block and that other management strategies are employed instead. No association with 72 h revisits was seen, but future studies need to address more granular outcomes in order to clarify the safety aspects of the effect.

Hyperparathyroidism and new onset diabetes after renal transplantation.

BACKGROUND: Secondary hyperparathyroidism persists after renal transplantation in a substantial number of patients. Primary hyperparathyroidism and secondary hyperparathyroidism are both associated with abnormalities in glucose metabolism, such as insufficient insulin release and glucose intolerance. The association of hyperparathyroidism and diabetes after renal transplantation has, as far as we know, not been studied. Our aim was to investigate whether hyperparathyroidism is associated with new-onset diabetes mellitus after transplantation (NODAT) during the first year posttransplantation. STUDY DESIGN: In a retrospective study, we analyzed data on patient characteristics, treatment details, and parathyroid hormone (PTH) in 245 adult nondiabetic patients who underwent renal transplantation between January 2000 and June 2011. RESULTS: The first year cumulative incidence of NODAT was 15%. The first serum PTH value after transplantation was above normal range in 74% of the patients. In multiple logistic regression analysis, PTH levels above twice normal range (>13.80 pmol/L) were significantly associated with NODAT (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.13-15.92; P = .03) compared with PTH within normal range (≤6.9 pmol/L). Age between 45 and 65 years (OR, 2.80; 95% CI, 1.07-7.36; P = .04) compared with age <45 years was also associated with NODAT. CONCLUSION: We found a strong association between hyperparathyroidism and NODAT in the first year after renal transplantation. Both conditions are common and have a negative impact on graft and patient survivals. Our results should be confirmed in prospective studies.

Interstitial laser thermotherapy (ILT) of breast cancer.

AIM: To find out if ILT can be used as radical treatment of breast cancer. METHOD: Twenty-four patients, aged 39-84 (mean 61), with invasive breast cancer were treated with ILT. All underwent mammography, ultrasound and core biopsy before treatment. The tumour was an invasive ductal carcinoma in 15 patients, a lobular carcinoma in eight and lobular-ductal cancer in one. Average tumour diameter was 14 mm on ultrasound (5-35). Patients were treated in the outpatient clinics under local anaesthesia. Probes were placed under ultrasound guidance, in 19 patients, and ILT was performed with a diode laser at a steady-state temperature of 48 degrees C for 30 min using temperature feedback control. Standard surgical excision was performed 12 (4-23) days after ILT and was preceded by Doppler ultrasound. RESULTS: Treatment-induced necrosis of invasive cancer was 33% (range 0-100) and was complete in three patients. At follow-up before surgery, the extent of laser damage could not be judged with ultrasound, although abolished tumour blood flow was demonstrated after treatment resulting in large necroses. Efficacy of treatment varied negatively with tumour size. The inefficacy of ILT was mainly due to the underestimation of tumour size by mammography and ultrasound and the shortcomings of these methods to demonstrate tumour borders, tumour irregularity and carcinoma in situ (CIS). ILT was well tolerated. Five patients had breast tenderness, and three patients had pain, during the first day after treatment. Small skin necroses were observed in two patients. CONCLUSION: Small breast cancers can be treated radically with ILT. The method may become useful in the treatment of breast cancer but needs further refinement, even for small well-defined breast cancers, if it is going to be employed for radical treatment.

Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response.

Previous studies in our laboratory have shown that interstitial laser thermotherapy (ILT) of an experimental liver tumour is superior to surgical excision, at least partly due to a laser-induced immunological effect. The aim of the present study was to investigate the time-response relationship of the ILT-induced immunisation and the cellular response of macrophages and lymphocytes. A dimethylhydrazine-induced adenocarcinoma was transplanted into the liver of syngeneic rats. Rats with tumour were treated 6-8 days later (tumour size 0.25-0.40 cm(3)) with ILT of tumour or resection of the tumour-bearing lobe. Two groups of rats without tumour were treated with resection of a normal liver lobe or ILT of normal liver. A challenging tumour was implanted into the liver of each rat 2, 5 or 10 weeks after primary treatment. Rats were killed 6, 12 and 48 days (or earlier due to their condition) after challenge (n = 8 in all groups). Immunohistochemical techniques were used to determine lymphocytes (CD8, CD4) and macrophages (ED1, ED2) in rats having had treatment of a primary tumour. Interstitial laser thermotherapy of the first tumour was followed by eradication of challenging tumour and absence of tumour spread. This contrasted with rapid growth and spread of challenging tumour in the other groups. In the challenging vital tumour tissue and in the interface between the tumour and surroundings, the number of ED1 macrophages and CD8 lymphocytes was higher in rats having been treated with the ILT of tumour than in those having undergone resection of the tumour-bearing lobe. The number of ED2 macrophages and CD4 lymphocytes was low and did not vary between these two groups. Interstitial laser thermotherapy elicited an immune response that eradicated a challenging tumour and was associated with increased numbers of tumour-infiltrating macrophages and CD8 lymphocytes.

Interstitial laser thermotherapy of a rat liver adenocarcinoma.

The aim of this study was to compare interstitial laser thermotherapy with excision of a liver tumour. A dimethylhydrazine-induced adenocarcinoma was implanted into the left lateral lobe of the rat liver, and treatment was performed 8 days later. Rats were treated with resection of the tumour-bearing lobe or underwent interstitial laser thermotherapy, which was performed at a steady-state temperature of 46°C for 30 min, 3 mm from the tumour margin. The incidence and extent of intraperitoneal spread was smaller after laser thermotherapy than after resection, with no difference in local control. Using inoculation of tumour cell suspensions into the lateral and the median lobes of the liver simultaneously and treating the lateral lobe tumour only, we found that laser thermotherapy reduced take and growth of the untreated tumour in the median lobe indicating that laser thermotherapy may induce immunologic effects. It is concluded that interstitial laser thermotherapy reduces spread of liver tumour as compared to resection. It is suggested that this can be at least partly explained by a laser-induced immunologic effect.

Electrically mediated drug delivery for treatment of an adenocarcinoma transplanted into rat liver.

BACKGROUND: In this study, electrochemotherapy (ECT), i.e. tumour treatment based on local augmentation of intracellular drug delivery from short, intense electric pulses, was evaluated in rats with an adenocarcinoma implanted into the liver. Tumour response and concentrations of macrophages and T-lymphocytes (CD4 and CD8) in and around the tumour were measured. MATERIALS AND METHODS: Rats were treated with permeabilizing electric pulses, bleomycin, or both, eight days after implantation of the tumour, while one group received sham treatment. RESULTS: Treatment with electric pulses and bleomycin resulted in a significantly reduced lesion volume and 92% cure rate (12 out of 13, p<0.0002 compared to the other treatment groups). The highest concentration of CD8 lymphocytes was found in tumours treated with electric pulses and bleomycin. Macrophages were found mainly in tumours treated with electric pulses, with or without bleomycin. CONCLUSION: Electrochemotherapy using millisecond exponential pulses and bleomycin is efficient in a rat liver tumour model and appears to stimulate the host's immune system.

Production of steroids by human ovarian surface epithelial cells in culture: possible role of progesterone as growth inhibitor.

OBJECTIVE: The purpose was to investigate whether normal ovarian surface epithelial cells, harvested from premenopausal and postmenopausal women, are capable of steroid production, and to evaluate effects of estradiol and progesterone on growth regulation of such cells. METHODS: Ovarian surface epithelial cells were obtained by brushing of the ovarian surface of 9 premenopausal and 10 postmenopausal women undergoing surgery for benign gynecological diseases. The conditioned media after culture, with and without addition of FSH and LH, were analyzed for estradiol and progesterone. The proliferative effects of the steroids were analyzed using two different culture models, nonconfluent cells and confluent cells, and two different detection methods, [(3)H]thymidine incorporation and a colorimetric method assaying cell number. RESULTS: The normal ovarian surface epithelial cells were found to secrete both estradiol and progesterone, a production that was not regulated by FSH or LH. Addition of steroids to the cultured cells did not induce any overall significant growth effects. However, progesterone significantly inhibited the growth of ovarian surface epithelial cells from three of the patients. Enhanced thymidine incorporation was observed in the presence of the progesterone receptor antagonist Org 31710 in the nonconfluent cultures of cells from postmenopausal women, but no effect of an estrogen receptor antagonist was observed. CONCLUSIONS: The normal ovarian surface epithelium is capable of steroid production, which is also often observed in tissue from ovarian epithelial tumors. Progesterone appeared to be a negative regulator of ovarian surface epithelial growth, while estradiol had no effect.

Higher levels of soluble E-cadherin in cyst fluid from malignant ovarian tumours than in benign cysts.

A major diagnostic dilemma in the clinical gynaecological oncology setting is to preoperatively determine whether a complex ovarian mass is benign or malignant. The cell-cell adhesion molecule E-cadherin has previously been localised in biopsies from both benign and malignant epithelial ovarian tumours. In this study, soluble E-cadherin levels was measured with ELISA-technique in peripheral blood, ascites and cystic fluids from patients (n = 33) undergoing surgery for ovarian cystic masses. The levels of soluble E-cadherin were significantly higher in cystic fluid from cystadenocarcinomas (p < 0.001) and borderline tumours (p < 0.05) as compared to cystic fluid from cystadenomas. In ascites fluid and peripheral blood no significant differences were seen. However, ratios of cystic fluid/peripheral blood levels were significantly higher in cystadenocarcinoma (p < 0.001) and borderline tumours (p < 0.05) as compared to benign tumours. In conclusion, measurements of soluble E-cadherin in cystic fluid from patients presenting with complex ovarian masses may be beneficial in increasing the accuracy of preoperative diagnosis.

Diverse effects of FSH and LH on proliferation of human ovarian surface epithelial cells.

The purpose of this study was to evaluate the effects of FSH and LH on growth regulation of normal ovarian surface epithelial (OSE) cells harvested from both premenopausal and postmenopausal women. Ovarian surface epithelial cells were obtained through brushing of the ovarian surface during surgery. FSH and LH were added to the OSE cultures and the proliferative effects were analysed using two different culture models, non-confluent and confluent cells, and two different detection methods, [(3)H]thymidine incorporation and a colorimetric cell number assay. FSH lowered the OSE proliferation under non-confluent conditions (10-27%), and the inhibitory effect was most pronounced among cells from postmenopausal women (P: < 0.01). In the confluent model only cells from postmenopausal women showed significantly (P: < 0.05) decreased proliferation. No effects of LH on OSE cells were detected. The unexpected results of an anti-proliferative effect of FSH on OSE, and the absence of effect by LH, do not support the theory that gonadotrophins are directly involved in ovarian carcinogenesis through an enhanced proliferation of OSE cells.

Gonadotropin- and cytokine-regulated expression of the chemokine interleukin 8 in the human preovulatory follicle of the menstrual cycle.

Interleukin 8 (IL-8) is a chemotactic cytokine involved in the recruitment and activation of neutrophils as well as in cell proliferation and angiogenesis. Because these events are essential components of folliculogenesis, ovulation, and subsequent repair of the ruptured follicle, the presence and regulation of IL-8 in the human follicle of the menstrual cycle was investigated. The concentrations of IL-8 were higher in follicular fluids from dominant follicles of late follicular/ovulatory phase compared with those of midfollicular phase. IL-8 was detected in the media from cultured granulosa and theca cells, with 10-fold higher levels in the theca cell cultures. Exposure to FSH and LH increased the IL-8 secretion from granulosa cells, but no effect was seen in theca cell cultures. Estradiol and progesterone did not affect IL-8 secretion from any cell type. The cytokines IL-1alpha and IL-1beta, but not tumor necrosis factor alpha, enhanced IL-8 secretion from both cell types. IL-8 levels in cultures of granulosa-lutein cells from hyperstimulated in vitro fertilization cycles were not affected by either gonadotropins or steroids. These data provide evidence that ovarian IL-8 is gonadotropin and cytokine induced and may be involved in the hormonally regulated stages of follicular development and ovulation.

Upregulation of interleukin-8 and polarized epithelial expression of interleukin-8 receptor A in ovarian carcinomas.

BACKGROUND: The chemokine interleukin-8 is present in a variety of tumor types with suggested effects on proliferation, migration, and angiogenesis. Elevated levels of interleukin-8 are present in cyst fluids from malignant ovarian tumors. The origin and potential targets for this chemokine in ovarian tumors were investigated in this study. METHODS: Interleukin-8 and its receptors were analyzed in 26 ovarian samples, including both normal and neoplastic tissue, with immunohistochemistry, Western blotting, and in situ hybridization. RESULTS: The mRNA for IL-8 was detected in higher amounts in the epithelial compartments compared to stromal areas, while the IL-8 protein was present in both epithelial and stromal areas, and in cystic formations of the tumors. The tissue levels of IL-8 protein increased with lower differentiation of the tumors. Both types of IL-8 receptors were detected in most specimens. A typical expression pattern for IL-8 receptor A was detected, with expression only on the luminal side of the epithelial tumor cells, while IL-8 receptor B was more evenly distributed in the tissue. CONCLUSIONS: An increased synthesis of IL-8 during dedifferentiation of the tumor, and a typical expression pattern of the IL-8 receptor A were detected, indicating a function for IL-8 in biology of epithelial ovarian cancer.

The expression of CCAAT/enhancer binding protein (C/EBP) in the human ovary in vivo: specific increase in C/EBPbeta during epithelial tumour progression.

The CCAAT/enhancer binding protein (C/EBP) family of transcription factors is involved in metabolism and differentiation of cells, especially in rodent liver cells and adipocytes. Their roles in vivo and in particular during pathophysiological conditions in humans are largely unknown. We have investigated the presence of C/EBPalpha, -beta, -delta and -zeta in normal ovaries and in epithelial ovarian tumours of different stages. Immunohistochemical experiments demonstrated that C/EBPalpha and C/EBPbeta were preferentially expressed in epithelial/tumour cells irrespective of stage or grade of the tumour. C/EBPbeta was located in the nuclei of the cells, in contrast to C/EBPalpha, which was present only in the cytoplasm of these cells. The nuclear localization of C/EBPbeta indicates an active role of this transcription factor in tumour cells, whereas the cytoplasmic distribution suggests a more passive function of C/EBPalpha. C/EBPdelta and -zeta demonstrated a more diverse distribution with predominant localization to epithelial cells, but stromal distribution was also noted. The intracellular distribution was confined to both the nucleus and the cytoplasm for C/EBPdelta and -zeta. Western blotting demonstrated that C/EBPalpha, -beta, -delta and -zeta were present in a majority of the samples. The amount of C/EBPbeta increased markedly with malignancy, i.e. with degree of dedifferentiation, while the other members of the C/EBP family displayed a more constant expression level. These results demonstrate an association between the expression of members of the C/EBP family and the formation of epithelial ovarian tumours, with C/EBPbeta as a potential marker for these tumours. As C/EBPbeta is known to be expressed during proliferation of cells in vitro, it may participate in the proliferative process of ovarian epithelial tumour cells in vivo and play a central role in tumour progression.

Changes in local hepatic blood perfusion during interstitial laser-induced thermotherapy of normal rat liver measured by interstitial laser Doppler flowmetry.

Interstitial laser Doppler flowmetry was used to measure the effect of interstitial laser-induced thermotherapy on local blood perfusion in normal rat liver in the peripheral treatment region elevated to hyperthermic temperatures. The Nd:YAG laser emitting at 1064 nm was utilised as heat generation source. The plane-cut tip of an optical fibre was placed in the middle of the exteriorised left liver lobe. Blood perfusion and temperature were measured in the liver parenchyma 4 mm from the laser fibre. The temperature at the location of the liver temperature sensor was maintained at 41 or 44°C during 30 min by regulating the power of the heating laser. The laser Doppler signal was recorded during and after heat treatment, for a total time of 60 min. At 41°C, a significant increase in perfusion up to 1.3 times the initial value was observed 2-16 min after start of treatment. At 44°C, perfusion decreased continuously during and after treatment, and was significantly different from control 40 min after start of treatment. The results may be valuable in assessing the thermal response of tissues surrounding the target in interstitial laser-induced thermotherapy of liver tumours during conditions of normal blood flow.

Evaluation of the effects of DNase treatment on signal specificity in RT-PCR and in situ RT-PCR.

In this study, the effects of DNase treatment on the specificity of reverse transcription (RT)-PCR have been investigated on different samples, containing RNA, DNA, DNA/RNA and DNA/cDNA. This was to evaluate the possibilities of getting specific results in a direct in situ RT-PCR. All DNA targets in the samples were eliminated after 1 h of DNase treatment. However, some DNA fragments still remained after both 1 h and overnight DNase treatment. When these fragments served as primers for amplification, nonspecific smears resulted. In samples containing small amounts of RNA, the RNA was affected by overnight treatment with DNase. Our conclusion is that the direct in situ RT-PCR is an unreliable method because the necessary DNase treatment induces nonspecific amplification, and no size-separation is possible. We conclude that the best way to perform an in situ RT-PCR is to hybridize with a labeled specific probe after amplification is completed.

Comparison between interstitial laser thermotherapy and excision of an adenocarcinoma transplanted into rat liver.

The aim of this study was to compare interstitial laser thermotherapy with excision of a liver tumour. A dimethylhydrazine-induced adenocarcinoma was transplanted (implanted if not stated otherwise) into the left lateral lobe of the rat liver, and treatment was performed 8 days later. In the main experiment, rats were treated with resection of the tumour-bearing lobe or underwent interstitial laser thermotherapy, which was performed at a steady-state temperature of 46 degrees C for 30 min, 3 mm from the tumour margin. The incidence and extent of intraperitoneal spread was smaller after laser thermotherapy than after resection of the tumour-bearing lobe, with no difference in local control. Metastatic spread after resection of the median liver lobe was similar to that observed after sham procedures for thermotherapy or resection, suggesting that the advantage of thermotherapy was not due to a difference in surgical trauma. Additional studies showed that laser thermotherapy reduced intraperitoneal spread when treatment was suboptimal or in a tumour inoculation model and suggested that immunological mechanisms might be involved. It is concluded that interstitial laser thermotherapy reduces spread of liver tumour compared with resection.

Feedback interstitial diode laser (805 nm) thermotherapy system: ex vivo evaluation and mathematical modeling with one and four-fibers.

BACKGROUND AND OBJECTIVE: In this study a newly developed microprocessor controlled power regulation and thermometry system integrated with a diode laser (805 nm wavelength) was evaluated with respect to temperature distribution, effectiveness of regulation, and ability to predict temperature distributions by computer simulation. STUDY DESIGN/MATERIALS AND METHODS: Experiments were performed in ground bovine muscle using either a single laser fiber or four-fibers. The target temperature at one (feedback) thermistor, placed 5 mm from one of the laser fibers, was set to 50 degrees C and was maintained by means of stepwise power regulation. The temperature distribution was monitored using multiple thermistor probes. A numerical model based on the bioheat equation was used to calculate the temperature distributions. RESULTS: Temperature regulation was excellent with a tendency towards better regulation in the four-fiber than in the single-fiber experiments. Agreement between calculated and measured temperatures was good. The coagulated (> 55 degrees C) and hyperthermic (> 45 degrees C) volumes were 6 and 10-11 times larger, respectively, with four-fibers than with a single fiber. CONCLUSION: It is concluded that the stepwise power regulation system was efficient in maintaining a stable target temperature. The results indicate that the system can produce lesion volumes adequate for treating a relatively large tumor in a single session and that computer simulation may be useful for predicting temperature distribution.