Focused parathyroidectomy without intraoperative parathormone testing is safe after pre-operative localization with 18F-Fluorocholine PET/CT.

A focused surgical approach based on pre-operative localization replaced the classical four-gland exploration in patients with primary hyperparathyroidism (PHP). Sestamibi scanning and ultrasound are most often used localization modalities with reported sensitivity of 54-100% for identification of single gland disease. The aim of this study was to analyze the results of pre-operative localization with 18F-Fluorocholine PET/CT (FCh-PET) in patients with PHP. A retrospective review of 151 patients with PHP who underwent surgery after pre-operative localization with FCh-PET was performed. Only a focused parathyroidectomy without ioPTH testing had been done in patients with single adenoma on FCh-PET. Primary outcome was operative failure, defined as persistent PHP. According to pre-operative FCh-PET 126 (83,4%) patients had single adenoma, 22 (14,5%) multiglandular disease and the test was negative in only two patients. Intraoperative failure experienced 4/126 patients (3,3%) with single adenoma. Removed parathyroid glands were normal in three and hyperplastic in one patient with intraoperative failure. A limited bilateral neck exploration with ioPTH testing was used in 14/22 patients with double adenoma and a classical four-gland exploration without ioPTH testing was used in 8/22 patients with more than two pathological glands according to pre-operative FCh-PET. Intraoperative failure experienced 2/22 patients (9,1%). In two patients with negative FCh-PET a classical four-gland exploration without ioPTH testing was used and one experienced intraoperative failure. A preoperative localization with FCh-PET is a reliable test in patients with PHP. Patients with a single adenoma on FCh-PET can safely undergo a focused parathyroidectomy without ioPTH testing.

A predictive tool to estimate the risk of axillary metastases in breast cancer patients with negative axillary ultrasound.

BACKGROUND: Sentinel node biopsy (SNB) is the "gold standard" in axillary staging in clinically node-negative breast cancer patients. However, axillary treatment is undergoing a paradigm shift and studies are being conducted on whether SNB may be omitted in low-risk patients. The purpose of this study was to evaluate the risk factors for axillary metastases in breast cancer patients with negative preoperative axillary ultrasound. METHODS: A total of 1,395 consecutive patients with invasive breast cancer and SNB formed the original patient series. A univariate analysis was conducted to assess risk factors for axillary metastases. Binary logistic regression analysis was conducted to form a predictive model based on the risk factors. The predictive model was first validated internally in a patient series of 566 further patients and then externally in a patient series of 2,463 patients from four other centers. All statistical tests were two-sided. RESULTS: A total of 426 of the 1,395 (30.5 %) patients in the original patient series had axillary lymph node metastases. Histological size (P < 0.001), multifocality (P < 0.001), lymphovascular invasion (P < 0.001), and palpability of the primary tumor (P < 0.001) were included in the predictive model. Internal validation of the model produced an area under the receiver operating characteristics curve (AUC) of 0.731 and external validation an AUC of 0.79. CONCLUSIONS: We present a predictive model to assess the patient-specific probability of axillary lymph node metastases in patients with clinically node-negative breast cancer. The model performs well in internal and external validation. The model needs to be validated in each center before application to clinical use.

Residual melanoma after an excisional biopsy is an independent prognostic factor for local recurrence and overall survival.

UNLABELLED: The aim of this study was to evaluate the effect of a residual melanoma after an excisional biopsy on prognosis of patients with cutaneous melanoma. PATIENTS AND METHODS: Between 2000 and 2007 sentinel lymph node biopsy with wide reexcision of a primary melanoma site was successfully performed in 692 patients (315 male and 377 female; mean age 55.7 years) at the Institute of Oncology Ljubljana, Slovenia. Clinicopathological data of all patients were extracted from a prospective institutional melanoma database and the frequency of local recurrences and survival were compared between patients with residual melanoma and those without it. For a statistical analysis univariate and multivariate analyses were used. RESULTS: Only 25 (3.6%) patients had a residual melanoma. There was no difference in mean tumor thickness (3.9 and 2.8 mm) and ulceration (40% and 34%) of the primary melanoma between patients with and without residual melanoma. However, a number of local recurrences (16% versus 2.7%) and a number of metastases in sentinel lymph nodes (44% versus 22%) were significantly higher and a 5-year survival was significantly lower (64% versus 87.5%) in patients with residual melanoma. Breslow thickness, ulceration, positive SLNB and residual melanoma were independent prognostic factors for overall survival. CONCLUSIONS: Residual melanoma is very rare after an excisional biopsy of the primary melanoma. However, when present it indicates a higher probability of local recurrence and a worse overall survival.

Geographical distribution of Slovenian BRCA1/2 families according to family origin: implications for genetic screening.

Knowledge of the geographical distribution of highly recurrent mutations may be useful for efficient screening in cancer families. Since the cloning of the BRCA1/2 genes, it is known that the wide spectrum of deleterious mutations shows high ethnic and geographic heterogeneity. In this study, we have tested probands from 582 breast/ovarian cancer families and positioned all 156 BRCA1/2 families on the map according to the family origin. We observed that high-risk families with the same recurrent mutation present a typical geographical distribution and that different recurrent mutations may show different distribution patterns. We then evaluated the genetic screening implications of this heterogeneous prevalence of the most recurrent mutations found [300T>G(c.181T>G), 1806C>T(c.1687C>T), 969ins7(c.844_850dupTCATTAC), 5382insC(c.5266dupC), 235G>A(c.116G>A) in BRCA1 and IVS16-2A>G(c.7806-2A>G) in BRCA2]. On the basis of these results, specific testing procedures for new incident cases may be offered according to their family origins and, according to the information regarding clusters revealed in this study, the individuals (especially those at low risk), originating from regions with clusters, might be screened preferentially for cluster mutations and analysis may be simplified according to the family origin.

International multicenter tool to predict the risk of four or more tumor-positive axillary lymph nodes in breast cancer patients with sentinel node macrometastases.

Recently, many centers have omitted routine axillary lymph node dissection (ALND) after metastatic sentinel node biopsy in breast cancer due to a growing body of literature. However, existing guidelines of adjuvant treatment planning are strongly based on axillary nodal stage. In this study, we aim to develop a novel international multicenter predictive tool to estimate a patient-specific risk of having four or more tumor-positive axillary lymph nodes (ALN) in patients with macrometastatic sentinel node(s) (SN). A series of 675 patients with macrometastatic SN and completion ALND from five European centers were analyzed by logistic regression analysis. A multivariate predictive model was created and validated internally by 367 additional patients and then externally by 760 additional patients from eight different centers. All statistical tests were two-sided. Prevalence of four or more tumor-positive ALN in each center's series (P = 0.010), number of metastatic SNs (P < 0.0001), number of negative SNs (P = 0.003), histological size of the primary tumor (P = 0.020), and extra-capsular extension of SN metastasis (P < 0.0001) were included in the predictive model. The model's area under the receiver operating characteristics curve was 0.766 in the internal validation and 0.774 in external validation. Our novel international multicenter-based predictive tool reliably estimates the risk of four or more axillary metastases after identifying macrometastatic SN(s) in breast cancer. Our tool performs well in internal and external validation, but needs to be further validated in each center before application to clinical use.

Multicentre validation of different predictive tools of non-sentinel lymph node involvement in breast cancer.

Sentinel lymph node (SN) biopsy offers the possibility of selective axillary treatment for breast cancer patients, but there are only limited means for the selective treatment of SN-positive patients. Eight predictive models assessing the risk of non-SN involvement in patients with SN metastasis were tested in a multi-institutional setting. Data of 200 consecutive patients with metastatic SNs and axillary lymph node dissection from each of the 5 participating centres were entered into the selected non-SN metastasis predictive tools. There were significant differences between centres in the distribution of most parameters used in the predictive models, including tumour size, type, grade, oestrogen receptor positivity, rate of lymphovascular invasion, proportion of micrometastatic cases and the presence of extracapsular extension of SN metastasis. There were also significant differences in the proportion of cases classified as having low risk of non-SN metastasis. Despite these differences, there were practically no such differences in the sensitivities, specificities and false reassurance rates of the predictive tools. Each predictive tool used in clinical practice for patient and physician decision on further axillary treatment of SN-positive patients may require individual institutional validation; such validation may reveal different predictive tools to be the best in different institutions.

Haematomas after percutaneus vacuum-assisted breast biopsy.

PURPOSE: Clinically apparent haematomas are among most frequent complications after vacuum-assisted breast biopsy (VABB). We evaluated the prevalence and persistence of sonographically (US) detected haematomas and other tissue changes at the biopsy site after VABB. MATERIALS AND METHODS: We examined 48 women who underwent stereotactic 11G needle VABB; the majority of them had mammographically detected microcalcifications. US examination of the breast biopsy site was performed one week after the VABB in 48 patients, and in 45 patients once again three weeks after the VABB. In 13/45 patients US-guided fine needle aspiration biopsy (FNAB) of the changes visualised was performed 3 weeks after the biopsy. RESULTS: One week after the VABB, a haematoma at the biopsy site was detected in 45/48 (94 %) patients (mean length 16.3 mm, mean width 3.6 mm). Three weeks after the VABB, haematoma was detected in 25/45 patients (55 %) (mean length 9.3 mm, mean width 2.7 mm), and architectural distortion in 13/45 patients (29 %), in 7/45 patients (16 %), no changes were found. In 13 patients in whom FNAB (fine needle aspiration biopsy) was performed, haematoma was found in 6/13, fat necrosis in 3/13, reactive changes in 2/13, whereas 2/13 samples were unsatisfactory. CONCLUSION: The changes at the biopsy site can be seen by US in most of the patients one and three weeks after the VABB. These changes could potentially be used for US guidance and localisation of microcalcifications in patients requiring surgical biopsy.

The hTERT mRNA in plasma samples of early breast cancer patients, non-cancer patients and healthy individuals.

One of the most important changes, which make cancer cells immortal, is reactivation of the telomerase enzyme. Human telomerase is composed of at least two subunits, hTERT and hTR. Many investigators have already detected telomerase mRNA in bodily fluids. The first aim of our study was to find out if there is a difference in the appearance frequency of detectable hTERT mRNA in plasma of early breast cancer patients, non-cancer patients and healthy individuals. The second aim was to determine whether surgical removal of the tumor affects the presence of hTERT mRNA in plasma of early breast cancer patients. 87 patients with early breast cancer, 22 non-cancer patients and 21 healthy individuals were included in the study. From early breast cancer patients, two blood samples were collected, the first prior and the second 24 hours after the surgical removal of the tumor. From other individuals one blood sample was collected. The presence or absence of hTERT mRNA was determined from all blood samples. 47% of early breast cancer patients, 32% of non-cancer patients and 5% of healthy individuals tested positive for the presence of hTERT mRNA in plasma. The difference between early breast cancer patients and healthy individuals was statistically significant (p<0,001). Among early breast cancer patients, 26% were positive for the presence of plasma hTERT mRNA before and after the surgical removal of the tumor, 21% were positive before and negative after, 36% were negative before and after and 17% were negative before and positive after the surgical removal of the tumor. In conclusion, we found statistically significant difference of hTERT mRNA presence in plasma of early breast cancer patients when compared to healthy individuals. Second, we found that hTERT mRNA in plasma of early breast cancer patients is affected by the surgical removal of the tumor.

Performance of opportunistic breast cancer screening in Slovenia.

The purpose of the study was to assess performance indicators of opportunistic breast screening carried out in one of the Primary Breast Diseases Centers (PBDC) and to find out if these indicators meet the standards set in "European guidelines for quality assurance in mammographic screening". The records of 1,896 asymptomatic women, aged between 50 and 69 years who attended PBDC for the first time in the period from October 15 1998 to October 15 2002, were reviewed. In all of them, clinical examination and mammography was done. If necessary, non-invasive additional imaging was also performed in the PBDC. If malignancy could not be excluded, the women were referred to the Institute of Oncology (IO) for additional invasive diagnostic procedures. The data on these findings were collected from the records of the IO. We compared our results with the recommended values of performance indicators valid for organized screening programs as determined by "European guidelines". Of 1,896 women, 415 (22%) were recalled for additional imaging. In 335/415 women the suspicion for malignancy was excluded with noninvasive diagnostic methods. Invasive diagnostic procedures were applied in 80/415 women. Carcinomas were detected in 23 women, the majority of them (96%) were non palpable. All carcinomas were ductal; 9 (39%), 7 (30.5%), 7 (30.5%) were grade 1, 2 and 3, respectively. One carcinoma was preinvasive; 20 had the tumor size T1, 1 had T2, while in one the size was not specified. The axillary lymph nodes were negative in 14/23 (61%) women with invasive carcinoma and positive in 5/23 (22%). Surgery of the axilla was considered unnecessary in 4/23 (17%). Diagnostic sensitivity in presented cohort was 96%, specificity 79%. After a negative mammogram 1 interval cancer was detected. Compared to the "European guidelines" we achieved satisfactory results in the number and size of detected and interval cancers, but the analysis showed a higher recall rate with too many false-positive results. Efforts should target lowering the recall rate without reducing the cancer detection rate. Compared to Slovenian average, a large percentage of localized breast cancers in our study claim for organized breast cancer screening program in Slovenia at earliest convenience.

Aggressiveness of therapy and prognosis of patients with Hürthle cell papillary thyroid carcinoma.

Hürthle cell papillary thyroid carcinoma (HCPTC) has been studied separately from other types of thyroid carcinoma in relatively few studies. The aim of our study was to determine the factors associated with the survival of patients with HCPTC in Slovenia, an iodine-deficient region. A total of 1552 patients with thyroid carcinoma were seen at our institute during the period of 1976-2003; of them, 42 patients (33 females, 9 males; age 10-85 years, median 56.5 years) had histopathologically verified HCPTC. The data on the patients' gender, age, disease history, extent of disease, morphologic characteristics, therapy, locoregional control, disease-free interval, and survival were collected. The statistical correlation between possible prognostic factors and the disease-free interval and survival was analyzed by chi2 test and log rank analysis. The tumor diameter ranged from 1 to 9 cm (median, 3 cm). Extrathyroid tumor growth was found in 19 patients, lymph node metastases in 13 patients, and distant metastases in 2 patients. Primary treatment consisted of total or near-total thyroidectomy (39 patients), lobectomy (2 patients), radioiodine ablation of the thyroid remnant (37 patients), external irradiation (14 patients), and chemotherapy (3 patients). Locoregional recurrence was diagnosed in four patients, and dissemination in 1 patient during the follow-up period of 0.75-20 years (median, 5.5 years). Three patients died of thyroid carcinoma during the follow-up period. The 5-year and 10-year survivals were 94% and 87%, respectively. The 5-year and 10-year disease-free intervals were 93% and 81%, respectively. The factors correlated with the survival were: age, extrathyroid tumor growth, primary tumor stage, and regional and distant metastases. Although extrathyroidal tumor growth was found in 45% of the patients with HCPTC, our patients had a favorable prognosis. Long-term survival and locoregional control of disease are likely after the radical tumor resection, radioiodine ablation of the thyroid remnant, and external irradiation.

The reliability and accuracy of intraoperative imprint cytology of sentinel lymph nodes in breast cancer.

OBJECTIVE: Sentinel lymph node (SLN) biopsy is a new component of the surgical treatment of breast cancer that accurately predicts axillary status. In this study the authors evaluated the accuracy of intraoperative imprint cytology (IC) in comparison with definitive histologic evaluation of SLN in breast cancer patients. METHODS: A total 413 women with breast carcinoma and clinically negative axillary nodes underwent breast surgery and SLN biopsy. Mapping of SLN involved injection of (99m)Technecium labelled human albumin nanocolloid particles and Patent Blue dye. At the Department of Pathology, SLNs were bisected along its major axis. Both halves were imprinted 2-4 times on the slides and immediate staining with Hemacolor (Merck Germany) was performed for intraoperative examination. Imprint node negative women underwent no further surgery, while node positive women proceeded to full axillary clearance. Histological analysis of the SLN involved serial sectioning of the whole node with H&E and immunostaining for cytokeratin. RESULTS: Definitive histology revealed metastases (pN+) in 159/413 patients (38.5%): 69 (16.7%) macro metastases, 57 (13.8%) micro metastases, and 33 (8%) women with only isolated IHC positive cells or positive cell groups smaller than 0.2 mm (pNO sn+). The other 254 women had negative SLN biopsy. Imprint cytology detected 54/69 macro metastases, and 4/57 micro metastases. In the group with negative SLN (254), 2 cases were ''false positives''. CONCLUSIONS: Imprint of SLN biopsy can identify a negative axilla with high accuracy (specificity 99.2%). Overall sensitivity is only 36.5%, but macrometastases are detected in 77% which is important for performing ALDN in one session with operation of primary tumour.

Radioguided occult lesion localization (ROLL) of the nonpalpable breast lesions.

Standard localization techniques of the nonpalpable breast lesions (guide wire, carbon, skin marking) have several disadvantages. Radioguided occult lesion localization (ROLL) was recently proposed as a better alternative resulting in wider surgical margins and lower average specimen weight. The aim of our study was to compare ROLL to our previously published series of the standard guidewire localization, performed at the Institute of Oncology Ljubljana. ROLL was performed in 110 nonpalpable breast lesions. Human serum albumin macroaggregats, marked with 1.8-5.5 MBq 99mTc was injected in the nonpalpable lesion. During surgery the radioactive breast tissue was excised using hand held gamma probe. Nonpalpable breast lesions were excised in all 110 patients. The definitive histology revealed 32 invasive carcinomas, 19 DCIS, 5 LCIS in and 54 benign breast lesions. Mean specimen weight was 40 g which is less in comparison to 53 g of the guidewire series (p=0.002). Surgical margins were clear in 36/51 (70%) invasive breast cancer or DCIS patients and close or involved in 15/51 (30%) patients. Compared to the guidewire series, where 41/92 (44%) margins were clear and 51/92 (56%) were close or involved, the difference was statistically significant (p=0.005). ROLL proved to be superior to guidewire localization in our series, allowing excision of the nonpalpable breast lesion with wider surgical margins despite lower average specimen weight.

Role of imprint cytology in the intraoperative evaluation of sentinel lymph nodes for malignant melanoma.

Controversy exists over the utility of different methods for intra-operative sentinel lymph node (SLN) evaluation in patients with malignant melanoma (MM). The aim of this study was to evaluate the role of intra-operative imprint cytology (IC) in patients with MM. 215 SLNs from 99 patients with MM were examined by IC and results compared with the results of permanent sections. 24 patients had MM deposits in their SLNs and this was confirmed by histological examination. Intraoperative IC was positive in 11 of these patients (46% sensitivity). In addition, there were three false-positive IC diagnoses (79% positive predictive value); one of these was due to contamination during the sectioning of the SLN. The specificity and the negative predictive values of the IC were 96 and 85%, respectively. IC is a valuable method of intra-operative SLN evaluation which can spare approximately half of the patients with clinically occult regional metastases from a second surgical procedure. However, special care must be taken to avoid false-positive results due to contamination.

Breast biopsy with wire localization: factors influencing complete excision of nonpalpable carcinoma.

Our aim was to find out the factors influencing the complete excision of nonpalpable carcinoma. During a 2-year period, 215 patients (median age 55 years) underwent biopsy after wire localization of 222 nonpalpable breast lesions. Mammographic, surgical and pathological factors were correlated with the outcome of surgery using contingence tables in SPSS statistical software. A total of 96 carcinomas were diagnosed: 38 in situ and 58 invasive carcinomas. Surgical margins were clear in 43, close in 20 and involved in 33 cases. Factors correlated with clear surgical margins are mammographically spicular lesion, cytologically proven carcinoma, excision of more than 50 g of tissue, carcinoma smaller than 10 mm, invasive carcinoma without in situ component, and unicentric ductal carcinoma in situ ( p<0.05). Complete excision of multifocal in situ carcinoma or invasive carcinoma with extensive in situ component, which are diagnosed on mammogram as suspicious microcalcifications, remains a puzzling surgical task.