Cardiovascular changes in patients with primary aldosteronism after surgical or medical treatment.

BACKGROUND: Data on the cardiovascular middle-term follow-up of patients with primary aldosteronism (PA) are scanty. AIM: To detect the cardiovascular effects of surgery in patients with aldosterone (ALD)-producing adenoma (APA) and of pharmacotherapy in those with bilateral adrenal hyperplasia (BAH), a prospective study involving 60 consecutive patients with PA was performed. MATERIAL/ METHODS: Clinical, biochemical, and cardiovascular assessment was obtained before and after (31.5±4.4 months) surgery or proper medical treatment (32.1±5.0 months) in 19 and 41 patients, respectively. RESULTS: As expected, plasma ALD normalized in all operated patients, while in the other group it did not change. Systolic and diastolic blood pressure decreased (p<0.001) after both treatments. However, absolute and percentage reduction was significantly more pronounced (p<0.01) in operated than in non-operated patients. Left ventricular (LV) mass showed significant reduction after surgery (LV mass g/m(2), p<0.0007; LV mass g/m(2.7), p<0.01), but no change after medical treatment, so that the differences between absolute and percentage values at follow- up were statistically significant (p<0.01) between groups. Basal LV mass/m(2.7) was positively associated with age (p<0.009), body mass index (p<0.0008), drug number (p<0.03), and ALD/plasma renin activity ratio (p<0.01). Allocating the patients according to plasma ALD and cardiac parameters, patients who presented ALD reduction during the study also had a decrement in cardiac mass (p<0.04). CONCLUSIONS: Our data indicate that in patients with PA the removal of ALD excess by surgery in APA is effective in reducing blood pressure and in improving cardiac parameters, while anti-hypertensive therapy in BAH shows less positive impact on cardiovascular system.

Video-assisted surgery: what is its role in the treatment of thyroid carcinoma?

Thyroid carcinoma can be divided in two main groups, differentiated, with a good prognosis and an average 10 years survival ranging from 70% to 95%, and undifferentiated which is lethal in few months. Differentiated thyroid carcinoma can be distinguished in those variants coming from follicular cells (papillary and follicular) and those from C cell (medullary carcinoma). Surgical approach represents the first step in the treatment of thyroid carcinoma. Minimally-invasive endoscopic technique can be applied only to a minority of case, the so called ''low risk'' carcinoma according to AGES and AMES criteria. During the last ten years many different endoscopic approaches have been proposed for the treatment of thyroid carcinoma and the minimally invasive videoassisted (MIVAT) by Prof Miccoli is undoubtly the one which resulted to be the most successful and spread all over the world. Through a 1.5 cm central skin incision 2 cm above the sternal notch MIVAT allows to perform a total thyroidectomy for low risk papillary carcinoma with a completeness similar to that of conventional thyroidectomy. Using the same central access it is also possible to perfom a prophylactic central neck dissection for RET gene positive carriers. A lateral neck minimally invasive videoassisted lymphadenectomy is under development for those patients with low risk papillary carcinoma and isolated lateral lymph node metastasis.

Papillary thyroid cancer, although strongly associated with lymphocytic infiltration on histology, is only weakly predicted by serum thyroid auto-antibodies in patients with nodular thyroid diseases.

OBJECTIVE: We evaluated the association between thyroid autoimmunity and thyroid cancer in a retrospective series of unselected thyroid nodules submitted to fine-needle aspiration (FNA) cytology. DESIGN: Anti-thyroid antibodies (TAb) were measured in patients with multinodular goiter (MNG) and single/isolated thyroid nodule (S/I) submitted to FNA. Thyroid lymphocytic infiltration (LI) on histology was studied in a subgroup of patients submitted to thyroidectomy; 13,021 patients were included: on cytology 622 had papillary thyroid cancer (c- PTC) and 12,399 benign thyroid nodular diseases (c-BTN). LI was evaluated in histological samples of 688 patients: 304 with PTC (h-PTC) and 384 with BTN (h-BTN). RESULTS: TAb prevalence was not different in c-BTN and c-PTC (38.7% vs 35.6%). TAb were more frequent in c-BTN than c-PTC in females with MNG (40.1% vs 32.5%, p=0.02), and in c-PTC than in c-BTN in males with S/I (31.2% vs 20.4%, p=0.02) and, although not significantly, in females younger than 30 yr (35.1% vs 30.7%). The frequency and severity of LI was significantly higher in h-PTC than h-BTN, both in MNG (82.5% vs 45.0%, p<0.001) and S/I (85.6% vs 71.0%, p<0.001), but a higher number of patients with h-PTC had negative circulating TAb, despite the presence of moderate/severe LI. CONCLUSIONS: TAb are weakly associated to PTC in males and young females, while they are more frequent in older females with BTN. The frequency and severity of LI is significantly higher in PTC than in BTN, but in cancer patients TAb are frequently negative, despite the evidence of histological thyroiditis. These data suggest that different kinds of immune response may be involved in PTC and BTN.

Endoscopic bilateral neck exploration versus quick intraoperative parathormone assay (qPTHa) during endoscopic parathyroidectomy: A prospective randomized trial.

BACKGROUND: Quick intraoperative parathormone assay (qPTHa) during paratyroidectomy has become a standard procedure for patients with primary hyperparathyroidism (PHPT). This paper aims to compare endoscopic bilateral neck exploration (BE) versus focused parathyroidectomy plus qPTHa during minimally invasive video-assisted parathyroidectomy (QM). The endpoints of the study are the mean operative time and outcome of the surgical procedure (PTH and calcemia normalization at one and six months postoperatively). METHODS: Forty patients with PHPT, positive to preoperative localization studies (ultrasonography evaluation and (99)Tc-MIBI scan) for a single parathyroid adenoma, were randomly allotted into two groups. In the first group (QM), 20 patients (17 women, three men, mean age 57.6 years) underwent focused endoscopic parathyroidectomy (MIVAP tecnicque) plus qPTHa . In the second group (BE) 20 patients (17 women, three men, mean age 59.6 years) underwent endoscopic parathyroidectomy plus bilateral exploration in order to check the integrity of the remaining glands. RESULTS: There were no significant differences between groups at baseline. No conversion to cervicotomy was required. No postoperative complications were reported. The mean operative time was 32.0 vs 33.1 min [BE and QM group respectively, p = not significant (ns)]. A second macroscopically enlarged gland was removed in four patients in the BE group. Only one out of four glands was reported to be hyperplastic in the final histology. All patients were discharged on the first postoperative day. Calcemia levels were normalized in all patient of both groups, despite persistently high level of serum PTH in one patient in the QM group. CONCLUSIONS: BE can be performed endoscopically, avoiding both the time necessary for qPTHa and its cost, with the same effectiveness, but might in few cases lead to the unjustified removal of parathyroid glands slightly enlarged but not necessarily pathologic.

Perspectives and lessons learned after a decade of minimally invasive video-assisted thyroidectomy.

Minimally invasive video-assisted thyroidectomy (MIVAT) was introduced in our department in 1998. The procedure is based on a unique incision in the central neck, 2 cm above the sternal notch, using small conventional retractors and 2-mm reusable instruments. Hemostasis is achieved by using a Harmonic scalpel. 1,320 (1,136 female and 184 male, ratio 4:1) patients have undergone MIVAT since June 1998. Lobectomy was carried out in 421 patients, while 899 patients underwent total thyroidectomy. In 21 cases (RET oncogene mutation carriers), MIVAT was associated with central compartment lymph node clearance. Mean operative time of lobectomy was 32.3 min (range 20-120 min); for total thyroidectomy it was 44.1 min (range 30-130). Mean time for video-assisted central compartment lymphadenectomy was 57 min. Conversion to standard cervicotomy was required in 30 cases (2.2%); operative complications included transient unilateral recurrent nerve palsy in 35 cases (2.65%) and definitive unilateral recurrent nerve palsy in 15 cases (1.13%). Thirty-eight patients exhibited hypoparathyroidism, which corresponds to 4.2% of total thyroidectomies performed, but only 2 showed permanent hypoparathyroidism. MIVAT can be considered a safe operation offering significant cosmetic advantages and has possible new promising indications such as prophylactic thyroidectomy in RET gene mutation carriers.

Role of frozen section associated with intraoperative cytology in comparison to FNA and FS alone in the management of thyroid nodules.

AIMS: The utilization of fine needle aspiration (FNA) biopsy is an accurate and cost-effective method in the diagnosis of thyroid diseases. However, the non-diagnostic cases and cases of suspicious carcinoma remain a dilemma, and in these cases thyroidectomy is usually recommended, even if only 15-20% of these patients really need a thyroidectomy. To avoid unnecessary surgical treatment, frozen section (FS) is usually performed. This method is well recognized, but is not useful for the diagnosis of follicular lesions. Therefore, many authors have tried to increase the specificity and sensibility of intraoperative examination, supporting it with an intraoperative cytological technique (IC). To clarify the role of intraoperative exam (FS and IC), also comparing to FNA, we have reviewed our own experiences. METHODS: In a period covering 6 years (2000-2005), FS was performed in 1,472 cases out of 11,420 total thyroidectomy operations. FS diagnosis and definitive diagnosis, were reviewed and confirmed, moreover, FNA diagnosis and definitive diagnosis were also considered and all intraoperatory cytological slides were reviewed. Diagnostic accuracy was assessed for FNA and FS with or without intraoperative cytology. We compared 1,472 FS diagnoses with their definitive histological diagnosis; 728 FNA out of 1,472 patients with definitive histological diagnosis, and 564 FS associated with IC out of 1,472 patients with definitive diagnosis. RESULTS: The diagnostic accuracy of these three methods were, respectively, 88.8%, 88.8% and 95.7%. CONCLUSION: We can assert that FS associated with IC remains the most accurate technique in the surgical management of thyroid nodules.

Video-assisted central compartment lymphadenectomy in a patient with a positive RET oncogene: initial experience.

BACKGROUND: Prophylactic surgery for patients carrying a positive RET proto-oncogene proved to be highly effective in curing those likely to experience the development of a medullary carcinoma. Video-assisted procedures have been proved feasible for central compartment dissection. METHODS: A total of 15 patients (7 men and 8 women) with a positive RET proto-oncogene underwent total thyroidectomy and central compartment lymphadenectomy via a video-assisted approach. The mean age of the patients was 32.5 years. The echographically estimated mean volume was 10.3 ml, and the mean diameter of the main nodule was 8.8 mm. Preoperative ultrasound showed an absence of lateral neck lymph node involvement in all cases. No drain was used. Direct laryngoscopy was performed in all cases 1 month after surgery. RESULTS: The mean operative time was 67.3 min. A transient hypoparathyroidism occurred in one patient, and a permanent hypoparathyroidism occurred in another patient. No laryngeal nerve palsy was present. All the patients were discharged on postoperative day 1. Histology showed a medullary carcinoma in 10 patients and diffuse C-cell hyperplasia in 5 patients. The mean number of lymph nodes removed was 5.1. None of these nodes proved to be metastatic. Calcitonin levels were undetectable in all six patients who had a follow-up period longer than 1 year. CONCLUSION: Video-assisted central compartment lymphadenectomy was proved to be effective and safe. The procedure demonstrated a complication rate comparable with that for the conventional procedure, a better cosmetic outcome, and less postoperative pain. Although the video-assisted access proved to be a valid option for the treatment of patients carrying a positive RET proto-oncogene, a greater number of cases with a longer follow-up period is necessary to estimate the impact of the video-assisted approach on central neck lymphadenectomy.

The impact of thyroidectomy on parathyroid glands: a biochemical and clinical profile.

INTRODUCTION: An evaluation of PTH levels during thyroid surgery may reflect the functional status of the parathyroids and be useful in identifying patients at risk for hypocalcemia. This study aims to monitor the parathyroid function during total thyroidectomy through intra-operative serial samples for calcium and PTH. MATERIALS AND METHODS: Forty-seven patients undergoing total thyroidectomy for different diseases were selected for the study. Patients underwent serum PTH and calcium sampling at the induction of anesthesia (T0) and after the first (T1) and the second (T2) lobectomy. Serum calcium was also drafted 24 h after the operation. RESULTS: Mean PTH at T0, T1, and T2 was, respectively: 32.1 pg/ml, 19.6 pg/ml, and 11.5 pg/ml. PTH was significantly higher at T0 when compared to T1 (p<0.0001). It was also significantly higher at T1 than at T2 (p<0.0001). At T1 PTH levels were below the normal range in 20/47 cases (42.5%) and at T2 in 31/47 cases (66%). Twenty-four h after surgery, 8 patients (17%) demonstrated a biochemical hypocalcemia. A PTH value at T0 in the upper (>70 pg/ml) or in the lower (<20 pg/ml) limits of the normal range was statistically related to post-operative hypocalcemia (p=0.017). DISCUSSION: The study seems to confirm that serum PTH during thyroidectomy does not represent a sensitive tool in precociously identifying hypocalcemic patients. Nevertheless, before surgery, a PTH concentration at the higher or lower normal limit may help to identify patients "at risk" of developing hypocalcemia.

[New technologies in thyroid surgery. Endoscopic thyroid surgery]. / Le nuove tecnologie nella chirurgia tiroidea. Chirurgia endoscopica della tiroide.

The onset of cervicoscopy dates back to the first endoscopic parathyroidectomy in 1996. This operation, along with its several variants, has become a valid option widespread in many important centres. Later on, endoscopic or video assisted thyroidectomy was introduced in spite of the limits imposed by the mass of the gland to remove. It is indicated for a minority of patients for this reason but both parathyroidectomy and thyroidectomy showed some important advantages with respect to conventional surgery, advantages demonstrated also in prospective studies. They are mainly represented by a better cosmetic outcome and a less distressful postoperative course. These approaches proved to be safe and feasible in any surgical background: their complication rate is the same as traditional open surgery in the neck. Very promising seems to be the videoscopic access to neck lymph nodes (central and lateral compartments) whereas other fields of application such as carotid artery surgery and spine surgery still remain object of experimental studies. As far as the lateral neck dissection is concerned the technique is going to be standardized in our centre as a variant of the well known video assisted approach adding a 5 mm trocar placed in the supraclavicular space. By consequence, cervicoscopy has to be considered an important surgical tool which can be further improved but which also has an excellent potentiality.

[Surgical timing in bleeding liver adenoma: case report]. / Timing chirurgico nell'adenoma epatico sanguinante: case report.

The diagnosis of liver adenoma, which etiopathogenesis most often involves a prolonged assumption of estrogen (90% of adenomas occurs in women after more than 5 years of estrogen therapy), always imposes a surgical resection. The reason depend from neoplasia characteristics like the malignant evolution (4%) and the high risk of abdominal/intratumoral bleeding (30-50%), that increases during pregnancy and postpartum period. Regression of lesion after discontinuation of hormone therapy is rare and does not remove the degeneration and/or haemorrhagic risk. Liver resection should be performed with appropriate selective endovascular embolization, considering that an inept emergency surgery may impose a greater risk ot the liver, exposing the patient to major risk of morbidity and mortality. The correct timing from embolization to elective surgery is not yet standardized in the literature. The surgeon's personal experience and mainly a careful patient follow-up suggest the timing of surgery after embolization. The authors relate their own experience about the therapeutic strategy and surgical timing in a case of bleeding liver adenoma.

Metastatic breast cancer: an updating.

This article reports on recent advances on metastatic breast cancer. Detection, prognostic factors, predictors of response to therapy and therapy, with particular regard to targeted therapies, were examined. DETECTION: Unlike current guidelines that yet do not routinely recommend intensive clinical-instrumental post-operative follow-up of breast cancer patients, relatively large data collected in the last decades have shown that an intensive post-operative follow-up with 'dynamic evaluation' of a suitable tumour marker panel precedes a few months as average the clinical and/or instrumental sign of a pending relapse in most relapsed patients and largely limits the use of the common instrumental examinations. PROGNOSIS AND THERAPY PREDICTORS: Disease-free interval (DFI)24 months and disease confined to bony skeleton are prognostic factors more often correlated with relatively poor or prolonged survival, respectively. Estrogen receptor (ER) expression in primary tumour and at the relapse correlates strongly with response to salvage hormone therapy and data from large trials showed that 38-59% of ER and/or PR+ post-menopausal patients had clinical benefit from first line tamoxifen or aromatase inhibitors. An inverse correlation of ER with epidermal growth factor receptor (EGFR) has been found. The co-expression of HER-2/neu and/or elevated serum HER-2/neu protein level were associated with a low rate and shorter duration of response of ER+ patients to first line hormone therapy. Accordingly, ER-EGFR- compared with ER-EGFR+ tumours are usually more responsive to endocrine therapy. High class III beta-tubulin expression or fall in insulin-like growth factor binding protein-3 (IGFBP-3) from baseline levels have been found to significantly predict resistance to chemotherapeutic agents. THERAPY: Liposomes as carrier of doxorubicin (Caelix, Evacet, Myocet) is one approach to decrease the anthracycline-related cardiac toxicity. Weekly paclitaxel or docetaxel and oral formulation of vinorelbine and 5-fluorouracil (5-FU) (capecitabine) provide new effective and well tolerated options that reach greater dose intensity and cumulative dose than with the conventional schedules. As to the so called 'tailored' or targeted therapies, the more potent and highly selective third generation of aromatase inhibitors (letrozole, anastrozole, exemestane) targeting ER+ tumours by estrogen deprivation, challenge tamoxifen as current standard first line therapy in postmenopausals. One pilot study showed that stimulation of cellular immunity by the addition of beta-interferon-interleukin-2 sequence in patients on clinical benefit on first line tamoxifen significantly prolonged median overall survival (OS) and duration of response compared to that observed in similar patients only treated with tamoxifen. Trastuzumab, a humanised monoclonal antibody to extracellular domain of HER-2, plus conventional chemotherapy has become a standard of care for women with overexpressing HER-2 tumours. Bevacizumab is a recombinant humanised monoclonal antibody to vascular endothelial growth factor (VEGF) that in refractory metastatic breast cancer doubled the response rate of capecitabine although it did not affect survival. Finally, the so called 'oligometastatic' and a few stage IV diseases are conditions amenable to be rendered with no evidence of disease (NED) after local surgery and/or radiation. In both, as well as in complete responders to chemotherapy, minimal residual disease (m.r.d.) likely continues to be present. Recent data suggest that 'biological' therapy (immunomodulators and/or retinoids with or without hormone therapy), might be suitable to be successfully tested in these patients as maintenance treatment given soon after local intervention or chemotherapy.

Unusual association of adrenal pheochromocytoma and para-aortic neurofibroma in pregnancy.

The association of pheochromocytoma (PHEO) and pregnancy is uncommon and life threatening for both the fetus and the mother. Early diagnosis and treatment is essential to decrease maternal and fetal mortality and to differentiate the disease from the more common pre-eclampsia. While medical treatment should be started immediately after diagnosis, the timing of surgical treatment is still debated. We describe the case of a 27-yr-old woman in the 18th week of pregnancy who showed a biochemical pattern typical of PHEO and, by imaging studies, 2 tumors with the same characteristics: the first localized on the right adrenal gland, the second at the right renal hilum. The patient underwent surgery because of suspicion of malignant PHEO with local metastasis, while histology revealed a rare association of a solitary PHEO and para-aortic neurofibroma, both tumors embryologically deriving from a common cell precursor.

Overall prognosis in younger patients with colorectal carcinoma.

AIM: Prognosis of colorectal cancer in younger patients is a controversial issue. While survival after curative resection seems not worse than in older patients, few data are available about the overall survival of younger patient with colorectal cancer irrespective of receiving a curative treatment or not. In this study we have reviewed our experience with patients under 45 years of age affected by colorectal cancer. METHODS: A total of 358 patients with colorectal cancer were operated on between 2001 and 2005. Nineteen patients were younger than 45. Schedules were reviewed as to palliative vs curative resection, Duke's classification, tumor grading, and compared with data from patients older than 45. RESULTS: Though no significant difference in survival can be detected after curative resection, fewer patients less than 45 years are eligible to be treated curatively. Significantly worse tumor grading and rates of curative resection make for a poorer prognosis in younger patients when compared with older ones. CONCLUSIONS: Prognosis for colorectal cancer in the overall group of patients less than 45 years is worse than in older patients. Younger patients more frequently present with distant metastases or peritoneal carcinosis which preclude the possibility of a curative treatment.

Type I interferons modulate the expression of thyroid peroxidase, sodium/iodide symporter, and thyroglobulin genes in primary human thyrocyte cultures.

We evaluated in primary human thyrocyte cultures the effect of interferon (IFN)-alpha and -beta on the expression of thyroid peroxidase (TPO), sodium/iodide symporter (NIS), and thyroglobulin (Tg) as well as T(4) release. Human thyrocyte cultures were carried out with fresh normal thyroid tissue. Gene and protein expression of Tg, TPO, and NIS were assessed by RT-PCR and Western blot analysis after 24, 48, and 72 h of treatment with TSH alone (10 mIU/ml) and in combination with IFN alpha or -beta (10(4) U/ml). IFN inhibited the TSH-stimulated gene expression of Tg, TPO, and NIS in a time-dependent manner without significant differences between IFN alpha and -beta. Moreover, the addition of both type I IFNs clearly reduced the TSH-stimulated protein expression of Tg, TPO, and NIS after 72 h of exposure. Finally, this down-regulation was associated with a reduction of T(4) release by almost 50%. In conclusion, our study shows that both IFN alpha and -beta down-regulate the TSH-stimulated expression of Tg, TPO, and NIS as well as T(4) release. Indeed, the development of hypothyroidism during type I IFN therapy may be related, at least in part, to an abnormal expression and function of key proteins involved in iodine uptake and organification.

Alignment/phylogeny of the papain superfamily of cysteine proteases.

An alignment/phylogeny of the papain superfamily of cysteine proteases was created using an initial structure-based alignment followed by successive iterations of sequence alignment and phylogenetic inference. The iterative approach resulted in significant improvements in the alignment/phylogeny. There were three groups of cysteine proteases that were distantly related and which could be aligned against each other only in the active site regions: the papain group, which included such stereotypical cysteine proteases as cathepsins B, C, H, L and S; and the bleomycin hydrolase and calpain groups. There was one bacterial sequence in each of the bleomycin hydrolase and calpain groups. The former probably arose by lateral gene transfer, the latter possibly by direct evolution from an ancestral protease predating the eukaryote/prokaryote divergence. The phylogeny of the papain group indicated that many families diverged almost simultaneously early during eukaryotic evolution. In mammals there are at least 12 distinct families of cysteine proteases, possibly many more, including at least two as yet uncharacterized enzymes.

Serum haptoglobin: a novel marker of adiposity in humans.

Haptoglobin (Hp) is a glycoprotein involved in the acute phase response to inflammation. Our previous findings indicate that Hp mRNA and protein are present in the adipose tissue of rodents and that Hp gene expression is up-regulated in obese models. The aim of the present study was to establish whether Hp could be considered a marker of obesity in humans. In 312 subjects, serum Hp was correlated directly with body mass index (BMI), leptin, C-reactive protein (CRP), and age. In a multivariate stepwise regression analysis, BMI and CRP were independent determinants of serum Hp in females, with BMI having the strongest effect. CRP and age were independent determinants of serum Hp in males, although explaining only a modest percentage of the total variability. Serum Hp was positively associated with body fat, as assessed by dual-energy x-ray absorptiometry, both in female and in male groups. The level of significance improved when serum Hp was analyzed against fat mass adjusted for lean mass. Finally, Northern and Western blot analyses performed in biopsies of sc abdominal fat from 20 obese individuals showed the presence of Hp mRNA and protein in the human adipose tissue. In conclusion, serum Hp constitutes a novel marker of adiposity in humans, and the adipose tissue likely contributes to determine its levels.

Determining transition states from kinetic isotope effects.

BEBOVA-based TS determination has been very successful in elucidating enzyme mechanisms at a level of detail that would be otherwise inaccessible. The resulting TS structures have been used successfully as the basis for designing TS mimics as enzyme inhibitors with dissociation constants to 10(-11) M. The structure interpolation approach has systematized the process of finding a TS, increasing both the speed and the accuracy of TS determination. The combination of information from several TSs into a unified model increases the accuracy of the process significantly and results in an extremely sensitive probe of changes in TS with varying reaction conditions (i.e., enzymatic vs nonenzymatic reactions, different enzymes, or different nucleophiles). The TS determination process is summarized in Fig. 15.

Minimally invasive parathyroid surgery.

Several minimally invasive procedures have been described over the past 3 years for the treatment of sporadic primary hyperparathyroidism (PHPT). These techniques (totally endoscopic, video assisted and radio guided) have been demonstrated to be feasible and safe, but the surgeon should be well trained to obtain the best results with these approaches. Not all patients are eligible for minimally invasive procedures. The results are comparable to those of conventional surgery with advantages in terms of cosmetic result and reduced post-operative pain. These procedures should be considered to be a valid option by surgeons dealing with patients with primary hyperparathyroidism.