Publications by authors named "Marko Hocevar"

71 Publications

Reduction of overtreatment without reduction of overdiagnosis in patients with differentiated thyroid cancer: mission impossible.

Langenbecks Arch Surg 2021 Jun 7. Epub 2021 Jun 7.

Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Purpose: Lateral neck nodal metastases are common in patients with differentiated thyroid cancer (DTC) and usually have an indolent nature. They may be detected via neck palpation or preoperative ultrasound (US) of the neck. We hypothesized that preoperative neck metastases detected with US did not affect regional recurrence or long-term survival.

Methods: A retrospective analysis of patients' records treated for DTC at our institution between January 2006 and December 2016 was performed. Information about preoperative US of the neck, treatment, demographics, staging, and histopathology was obtained. The endpoints for the study were nodal recurrence and survival. Differences in survival were analyzed between three groups of patients divided by presence or lack of preoperative US and/or palpable cervical lymph nodes (PLN). Furthermore, the prognostic value of multiple variables was tested by univariate and multivariate analysis.

Results: There were 1108 patients with DTC, 221 males and 887 females. The median age was 48.3 years (range 3 to 86), the median time of observation was 68 months (range 0 to 142). Eight hundred sixty-two patients without PLN or preoperative US represented group 1, 112 patients with PLN were in group 2, and 134 patients without PLN and with preoperative US were in group 3. Only five patients had a regional recurrence, one died due to distant metastases. There was no statistically significant difference in survival between the groups (p = 0.841) and neck US was not significantly associated with overall survival neither in univariate nor in multivariate analysis.

Conclusion: In patients with DTC, the benefits of preoperative US of cervical lymph nodes are probably limited and "less is more" approach is advised.
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http://dx.doi.org/10.1007/s00423-021-02216-7DOI Listing
June 2021

Birth cohort-specific trends of sun-related behaviors among individuals from an international consortium of melanoma-prone families.

BMC Public Health 2021 04 23;21(1):692. Epub 2021 Apr 23.

Department of Dermatology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Individuals from melanoma-prone families have similar or reduced sun-protective behaviors compared to the general population. Studies on trends in sun-related behaviors have been temporally and geographically limited.

Methods: Individuals from an international consortium of melanoma-prone families (GenoMEL) were retrospectively asked about sunscreen use, sun exposure (time spent outside), sunburns, and sunbed use at several timepoints over their lifetime. Generalized linear mixed models were used to examine the association between these outcomes and birth cohort defined by decade spans, after adjusting for covariates.

Results: A total of 2407 participants from 547 families across 17 centers were analyzed. Sunscreen use increased across subsequent birth cohorts, and although the likelihood of sunburns increased until the 1950s birth cohort, it decreased thereafter. Average sun exposure did not change across the birth cohorts, and the likelihood of sunbed use increased in more recent birth cohorts. We generally did not find any differences in sun-related behavior when comparing melanoma cases to non-cases. Melanoma cases had increased sunscreen use, decreased sun exposure, and decreased odds of sunburn and sunbed use after melanoma diagnosis compared to before diagnosis.

Conclusions: Although sunscreen use has increased and the likelihood of sunburns has decreased in more recent birth cohorts, individuals in melanoma-prone families have not reduced their overall sun exposure and had an increased likelihood of sunbed use in more recent birth cohorts. These observations demonstrate partial improvements in melanoma prevention and suggest that additional intervention strategies may be needed to achieve optimal sun-protective behavior in melanoma-prone families.
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http://dx.doi.org/10.1186/s12889-021-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063451PMC
April 2021

Completely resected stage III melanoma controversy - 15 years of national tertiary centre experience.

Radiol Oncol 2020 Oct 8;55(1):50-56. Epub 2020 Oct 8.

Department of Surgery, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Background: Two prospective randomized studies analysing cutaneous melanoma (CM) patients with sentinel lymph node (SLN) metastases and rapid development of systemic adjuvant therapy have changed our approach to stage III CM treatment. The aim of this study was to compare results of retrospective survival analysis of stage III CM patients' treatment from Slovenian national CM register to leading international clinical guidelines.

Patients And Methods: Since 2000, all Slovenian CM patients with primary tumour ≥ TIb are treated at the Institute of Oncology Ljubljana and data are prospectively collected into a national CM registry. A retrospective analysis of 2426 sentinel lymph node (SLN) biopsies and 789 lymphadenectomies performed until 2015 was conducted using Kaplan-Meier survival curves and log-rank tests.

Results: Positive SLN was found in 519/2426 (21.4%) of patients and completion dissection (CLND) was performed in 455 patients. The 5-year overall survival (OS) of CLND group was 58% . 47% of metachronous metastases group (MLNM) (p = 0.003). The 5-year OS of patients with lymph node (LN) metastases and unknown primary site (UPM) was 45% . 21% of patients with synchronous LN metastasis. Patients with SLN tumour burden < 0.3 mm had 5-year OS similar to SLN negative patients (86% . 85%; p = 0.926). The 5-year OS of patients with burden > 1.0 mm was similar to the MLNM group (49% . 47%; p = 0.280).

Conclusions: Stage III melanoma patients is a heterogeneous group with significant OS differences. CLND after positive SLNB might still remain a method of treatment for selected patients with stage III.
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http://dx.doi.org/10.2478/raon-2020-0056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877267PMC
October 2020

Diagnostic value of [F]Fluorocholine PET/CT in detection of primary medullary thyroid cancer.

Ann Nucl Med 2021 Apr 5;35(4):429-437. Epub 2021 Feb 5.

Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska cesta 7, 1000, Ljubljana, Slovenia.

Objective: Medullary thyroid cancer (MTC) is a challenging neuroendocrine malignancy where the role of nuclear medicine imaging is currently limited. This paper investigates the potential diagnostic value of [F]Fluorocholine PET/CT in primary MTC.

Methods: We prospectively enrolled 25 patients (10 male, 15 female) with suspicion for primary MTC based on fine-needle aspiration biopsy (FNAB). All patients had a baseline three phase [F]Fluorocholine PET/CT (2.5 MBq/kg): two regional head and neck and upper mediastinum studies at 5 min (first phase) and 120 min (third phase) and a whole-body PET/CT (from the skull vertex to mid-thighs) at 60 min (second phase). Any non-physiological radiotracer uptake was regarded as MTC positive. All patients referred to surgery had a preoperative neck-US. True lesion status was assessed using either histopathology, FNAB results or follow-up imaging and laboratory (calcitonin, CEA) results. Results with p < 0.05 were considered statistically significant.

Results: Nineteen of 25 patients (76%) were surgically treated and histopathology reports were obtained. Patient-based sensitivity and positive predictive value for detection of any MTC lesion using [F]Fluorocholine PET/CT were both 100%. Neck-US was more specific (100% vs 70%; p = 0.002) and had a higher positive predictive value than [F]Fluorocholine PET/CT (100% vs 55%; p = 0.018) for N1a and N1b staging. [F]Fluorocholine PET/CT had a higher sensitivity (100% vs 50%; p = 0.025) and higher negative predictive value (100% vs 81%; p = 0.026) than neck-US for N1b staging. The optimal SUV cut-off to differentiate malignant from benign neck lesions at 60 and 120 min was 2.56. Patients with M1 stage on PET/CT had higher calcitonin (median of 5,372 vs 496.6 pg/ml; p = 0.005) and CEA concentrations (median of 95.8 vs 18.65 µg/l; p = 0.034) compared to patients with M0 disease.

Conclusion: [F]Fluorocholine PET/CT appears to be a promising radiotracer for primary staging of MTC by increasing diagnostic accuracy for N staging and detecting possible distant metastatic sites at initial presentation of disease.
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http://dx.doi.org/10.1007/s12149-021-01579-7DOI Listing
April 2021

Completely resected stage III melanoma controversy - 15 years of national tertiary centre experience.

Radiol Oncol 2020 Oct 8. Epub 2020 Oct 8.

Department of Surgery, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Background Two prospective randomized studies analysing cutaneous melanoma (CM) patients with sentinel lymph node (SLN) metastases and rapid development of systemic adjuvant therapy have changed our approach to stage III CM treatment. The aim of this study was to compare results of retrospective survival analysis of stage III CM patients' treatment from Slovenian national CM register to leading international clinical guidelines. Patients and methods Since 2000, all Slovenian CM patients with primary tumour ≥ TIb are treated at the Institute of Oncology Ljubljana and data are prospectively collected into a national CM registry. A retrospective analysis of 2426 sentinel lymph node (SLN) biopsies and 789 lymphadenectomies performed until 2015 was conducted using Kaplan-Meier survival curves and log-rank tests. Results Positive SLN was found in 519/2426 (21.4%) of patients and completion dissection (CLND) was performed in 455 patients. The 5-year overall survival (OS) of CLND group was 58% vs. 47% of metachronous metastases group (MLNM) (p = 0.003). The 5-year OS of patients with lymph node (LN) metastases and unknown primary site (UPM) was 45% vs. 21% of patients with synchronous LN metastasis. Patients with SLN tumour burden < 0.3 mm had 5-year OS similar to SLN negative patients (86% vs. 85%; p = 0.926). The 5-year OS of patients with burden > 1.0 mm was similar to the MLNM group (49% vs. 47%; p = 0.280). Conclusions Stage III melanoma patients is a heterogeneous group with significant OS differences. CLND after positive SLNB might still remain a method of treatment for selected patients with stage III.
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http://dx.doi.org/10.2478/raon-2020-0056DOI Listing
October 2020

Genome-wide association meta-analyses combining multiple risk phenotypes provide insights into the genetic architecture of cutaneous melanoma susceptibility.

Nat Genet 2020 05 27;52(5):494-504. Epub 2020 Apr 27.

Department of Dermatology, Instituto Valenciano de Oncología, Valencia, Spain.

Most genetic susceptibility to cutaneous melanoma remains to be discovered. Meta-analysis genome-wide association study (GWAS) of 36,760 cases of melanoma (67% newly genotyped) and 375,188 controls identified 54 significant (P < 5 × 10) loci with 68 independent single nucleotide polymorphisms. Analysis of risk estimates across geographical regions and host factors suggests the acral melanoma subtype is uniquely unrelated to pigmentation. Combining this meta-analysis with GWAS of nevus count and hair color, and transcriptome association approaches, uncovered 31 potential secondary loci for a total of 85 cutaneous melanoma susceptibility loci. These findings provide insights into cutaneous melanoma genetic architecture, reinforcing the importance of nevogenesis, pigmentation and telomere maintenance, together with identifying potential new pathways for cutaneous melanoma pathogenesis.
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http://dx.doi.org/10.1038/s41588-020-0611-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7255059PMC
May 2020

Significance of nuclear factor - kappa beta activation on prostate needle biopsy samples in the evaluation of Gleason score 6 prostatic carcinoma indolence.

Radiol Oncol 2020 Apr 21;54(2):194-200. Epub 2020 Apr 21.

Department of Surgical Oncology, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Background The goal of our study was to find out whether the immunohistochemical expression of nuclear factor-kappa beta (NF-κB) p65 in biopsy samples with Gleason score 3 + 3 = 6 (GS 6) can be a negative predictive factor for Prostate cancer (PCa) indolence. Patients and methods Study was conducted on a retrospective cohort of 123 PCa patients with initial total PSA ≤ 10 ng/ml, number of needle biopsy specimens ≥ 8, GS 6 on biopsy and T1/T2 estimated clinical stage who underwent laparoscopic radical prostatectomy and whose archived formalin-fixed and paraffin-embedded (FFPE) prostate needle biopsy specimens were used for additional immunohistochemistry staining for detection of NF-κB p65. Both cytoplasmic and nuclear NF-κB p65 expression in biopsy cores with PCa were correlated with postoperative pathological stage, positive surgical margins, GS and biochemical progression of disease. Results After follow-up of 66 months, biochemical progression (PSA ≥ 0.2 ng/ml) occurred in 6 (5.1%) patients, 3 (50%) with GS 6 and 3 (50%) with GS 7 after radical prostatectomy. Both cytoplasmic and nuclear NF-κB p65 expressions were not significantly associated with pathological stage, positive surgical margin and postoperative GS. Patients with positive cytoplasmic NF-kB reaction had significantly more frequent biochemical progression than those with negative cytoplasmic NF-kB reaction with PSA 0.2 ng/ml as cutoff point (p = 0.015) and a trend towards more biochemical progression with PSA ≥ 0.05 ng/ml as cutoff point (p = 0.068). Conclusions Cytoplasmic expression of NF-κB is associated with more biochemical progression and might be an independent prognostic factor for recurrence-free survival (RFS), but further studies including larger patient cohorts are needed to confirm these initial results.
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http://dx.doi.org/10.2478/raon-2020-0019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276643PMC
April 2020

Surgical options in treating patients with primary hyperparathyroidism.

Radiol Oncol 2020 02 29;54(1):22-32. Epub 2020 Feb 29.

Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Background Primary hyperparathyroidism is the third most common endocrine disorder for which surgical procedure called parathyroidectomy is the most effective treatment. Since the early 20th century, parathyroid surgery has improved extensively. With the advances in preoperative imaging and with understanding the causes of disease, new and minimally invasive surgical approaches overrode the standard bilateral exploratory operations. Directed parathyroidectomy is currently the standard technique for treatment of primary hyperparathyroidism worldwide. Conclusions Surgery is the only definitive treatment of primary hyperparathyroidism. The most appropriate type of surgical procedure depends on the number and localization of the hyperactive parathyroid glands, availability of modern imaging techniques, limitation of each type of procedure and expertise.
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http://dx.doi.org/10.2478/raon-2020-0010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7087427PMC
February 2020

F-Fluorocholine PET/CT in Primary Hyperparathyroidism: Superior Diagnostic Performance to Conventional Scintigraphic Imaging for Localization of Hyperfunctioning Parathyroid Glands.

J Nucl Med 2020 04 27;61(4):577-583. Epub 2019 Sep 27.

Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia

Primary hyperparathyroidism (PHPT) is a common endocrine disorder, definitive treatment usually requiring surgical removal of the offending parathyroid glands. To perform focused surgical approaches, it is necessary to localize all hyperfunctioning glands. The aim of the study was to compare the efficiency of established conventional scintigraphic imaging modalities with emerging F-fluorocholine PET/CT imaging in preoperative localization of hyperfunctioning parathyroid glands in a larger series of PHPT patients. In total, 103 patients with PHPT were imaged preoperatively with F-fluorocholine PET/CT and conventional scintigraphic imaging methods, consisting of Tc-sestamibi SPECT/CT, Tc-sestamibi/pertechnetate subtraction imaging, and Tc-sestamibi dual-phase imaging. The results of histologic analysis, as well as intact parathyroid hormone and serum calcium values obtained 1 d after surgery and on follow-up, served as the standard of truth for evaluation of imaging results. Diagnostic performance of F-fluorocholine PET/CT surpassed conventional scintigraphic methods (separately or combined), with calculated sensitivity of 92% for PET/CT and 39%-56% for conventional imaging (65% for conventional methods combined) in the entire patient group. Subgroup analysis, differentiating single and multiple hyperfunctioning parathyroid glands, showed PET/CT to be most valuable in the group with multiple hyperfunctioning glands, with sensitivity of 88%, whereas conventional imaging was significantly inferior, with sensitivity of 22%-34% (44% combined). F-fluorocholine PET/CT is a diagnostic modality superior to conventional imaging methods in patients with PHPT, allowing for accurate preoperative localization.
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http://dx.doi.org/10.2967/jnumed.119.229914DOI Listing
April 2020

Plant protection product dose rate estimation in apple orchards using a fuzzy logic system.

PLoS One 2019 24;14(4):e0214315. Epub 2019 Apr 24.

University of Maribor, Faculty of Mechanical Engineering, Laboratory for Structure Evaluation, Maribor, Slovenia.

In the process of applying a plant protection product mixed with water (spray mixture) at the prescribed concentration with conventional sprayers for chemical protection of tree canopies in an orchard, standard models are used to express the dose rate of the plant protection product. Characteristic properties of the tree canopy in an orchard are not taken into consideration. Such models result in fixed quantities of spray mixture being sprayed through individual nozzles into a tree canopy. In this research work, an autonomous system is presented, which ensures a controlled quantity of spray mixture sprayed through the nozzles onto different tree canopy segments. The autonomous system is based on a fuzzy logic system (FLS) that includes information about the estimated leaf area to ensure more appropriate control of the spray mixture. An integral part of the FLS is a fuzzy logic controller for three electromagnetic valves operating in the pulse width mode and installed on the axial sprayer prototype. The results showed that, with the FLS, it was possible to control the quantity of spray mixture in the specific range depending on the estimated value of the leaf area, with a quantitative spray mixture average saving of 17.92%. For the phenological growth stage BBCH 91, this method represents a powerful tool for reducing the quantity of spray mixture for plant protection in the future.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214315PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481820PMC
December 2019

Cytology material is equivalent to tumor tissue in determining mutations of BRCA 1/2 genes in patients with tubo-ovarian high grade serous carcinoma.

BMC Cancer 2019 Apr 2;19(1):296. Epub 2019 Apr 2.

Department of Medical oncology, Institute of Oncology Ljubljana, Zaloška cesta 2, 1000, Ljubljana, Slovenia.

Background: High-grade serous ovarian cancer is a detrimental disease. Treatment options in patients with a recurrent disease are dependent on BRCA1/2 mutation status since only patients with known BRCA mutation are eligible for treatment with poly(ADP-ribose) polymerase inhibitors (PARPi). The aim of this study was to compare concordance of BRCA mutation analyses from cytological samples (CS) with BRCA mutation analyses from histological formalin fixed paraffin embedded (FFPE) samples.

Methods: Mutation analysis of BRCA1 and BRCA2 genes was performed in 44 women diagnosed with primary or recurrent high-grade ovarian cancer from three different samples: blood, cytological sample (ascites, pleural effusion and enlarged lymph nodes) and tumor tissue. Results from all three samples were compared.

Results: Among 44 patients, there were 15 germline mutations and two somatic mutations. A 100% concordance was found between cytological and histologic samples.

Conclusion: There is a 100% concordance in BRCA mutation testing between cytological and histologic samples. BRCA mutation testing from CS could replace testing from FFPE tissue in clinical decision making in ovarian cancer patients.

Trial Registration: The study was retrospectively registered at ISRCTN registry on 24/11/2015 - ISRCTN42408038 .
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http://dx.doi.org/10.1186/s12885-019-5535-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444857PMC
April 2019

Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT.

J Am Acad Dermatol 2019 Aug 5;81(2):386-394. Epub 2019 Feb 5.

Department of Clinical Sciences, Lund University Hospital Lund, Sweden; Department of Surgery, Lund University Hospital, Lund, Sweden.

Background: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5%-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of families with melanoma and whether performance improvements can be achieved.

Methods: In total, 2116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CIs) along with net reclassification indices (NRIs) as performance metrics.

Results: MELPREDICT performed well (AUC 0.752, 95% CI 0.730-0.775), and GenoMELPREDICT performance was similar (AUC 0.748, 95% CI 0.726-0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (P < .0001) in GenoMELPREDICT (AUC 0.772, 95% CI 0.750-0.793, NRI 0.40). Including phenotypic risk factors did not improve performance.

Conclusion: The MELPREDICT model functioned well in a global data set of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in directing these patients to receive genetic testing or cancer risk counseling.
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http://dx.doi.org/10.1016/j.jaad.2019.01.079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6634996PMC
August 2019

Quality assurance in melanoma care: The EU-MELACARE study.

Eur J Surg Oncol 2018 11 3;44(11):1773-1778. Epub 2018 Jul 3.

Veneto Institute of Oncology IOVIRCCS, Padua, Italy.

Background: A significant disparity regarding survival outcome for melanoma among European regions is well recognized and access to high quality care for European melanoma patients needs to be improved. There is an unmet need for the implementation of minimal standard of care within defined clinical pathways and Quality Assurance (QA) indicators.

Objective: The EU-MELACARE study aims to identify shared variables for cutaneous melanoma cases recorded in melanoma registries across Europe.

Material And Methods: Opinion leaders involved in melanoma data registration and care quality analysis in 34 European countries were invited to respond to an expert survey covering questions regarding the melanoma registration practice in their countries and the characteristics, coverage and variables collected by the relevant melanoma registries.

Results: Data regarding 13 melanoma registries from 11 European countries contributed to the study. The majority (61,5%) were population based registries and more than half (62%) had national coverage. The included registries collected a median of 38 variables (Interquartile Range, IRQ 21-76). We identified 24 shared variables available in >70% of registries.

Conclusions: This study provides valuable specific information on information recorded for melanoma cases are registered within Europe. A core of shared variables has been identified, which will constitute the basis for a standardized set of QA indicators for assessing and monitoring melanoma care across European countries.
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http://dx.doi.org/10.1016/j.ejso.2018.06.020DOI Listing
November 2018

F-choline PET/CT for parathyroid scintigraphy: significantly lower radiation exposure of patients in comparison to conventional nuclear medicine imaging approaches.

J Radiol Prot 2018 03 17;38(1):343-356. Epub 2018 Jan 17.

Department of Nuclear Medicine, University Medical Centre, Ljubljana, Slovenia.

Background: Parathyroid subtraction scintigraphy (PSS) is the most commonly used imaging method for localisation of hyperfunctioning parathyroid glands (HPGs) in primary hyperparathyroidism (PHP), a common endocrine disorder. Hybrid (SPECT/CT) imaging with Tc-sestaMIBI (MIBI) at an early and delayed phase (dual-phase imaging) may be the most accurate conventional imaging approach, but includes additional radiation exposure due to added CT imaging. Recently, F-choline (FCH) PET/CT was introduced for HPG imaging, which can also be performed using the dual-phase approach. To date, no studies have compared organ doses and the effective dose (ED) from conventional subtraction scintigraphy, dual-phase MIBI SPECT/CT, and FCH PET/CT in the localisation of HPGs.

Aim: In addition to the comparison of the diagnostic performance of FCH PET/CT and conventional scintigraphic imaging methods, the aim of the study was to measure the organ doses and the ED for conventional subtraction parathyroid imaging protocols, using dual-phase MIBI SPECT/CT as a potential conventional imaging method of choice and FCH dual-phase PET/CT as a potential future imaging method of choice for the localisation of HPGs. Materials, methods. Thirty-six patients referred for parathyroid imaging with a clinical indication of PHP underwent preoperative PSS and dual-phase SPECT/CT imaging with the addition of FCH PET/CT. The diagnostic performance of the imaging modalities was assessed by using histology results as a gold standard. Radiation exposure was calculated for the administered activities of radiopharmaceuticals using ICRP80 weighting factors and for CT exposure at hybrid imaging using dose-length products and the ImPACT CT Patient Dosimetry Calculator.

Results: The diagnostic performance of FCH PET/CT was significantly better than that of conventional imaging modalities (sensitivity of 97% vs 64% and 46% for MIBI SPECT/CT and PSS, respectively, with comparable specificity of over 95% for all modalities). The highest radiation exposure was caused by conventional PSS (7.4 mSv), followed by dual-phase MIBI SPECT/CT (6.8 mSv). The radiation exposure was the lowest for dual-phase FCH PET/CT imaging (2.8 mSv). The added CT imaging for both hybrid approaches did not cause significant additional radiation exposure (1.4 mSv for MIBI SPECT/CT, additional 26.4% to overall exposure; 0.8 mSv for FCH PET/CT, additional 42.4% to overall exposure).

Conclusion: In comparison to conventional scintigraphic imaging of HPGs, emerging hybrid (SPECT/CT, PET/CT) imaging techniques combine superior diagnostic performance with lower radiation exposure to patients.
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http://dx.doi.org/10.1088/1361-6498/aaa86fDOI Listing
March 2018

Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families.

J Invest Dermatol 2017 12 19;137(12):2606-2612. Epub 2017 Aug 19.

Melanoma Institute Australia, Westmead, New South Wales, Australia; Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute, New South Wales, Australia.

Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18-2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92-1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94-1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75-4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.
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http://dx.doi.org/10.1016/j.jid.2017.07.829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5701856PMC
December 2017

Genetic Counselling, BRCA1/2 Status and Clinico-pathologic Characteristics of Patients with Ovarian Cancer before 50 Years of Age.

Radiol Oncol 2017 Jun 16;51(2):187-194. Epub 2017 Mar 16.

Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Background: In Slovenia like in other countries, till recently, personal history of epithelial ovarian cancer (EOC) has not been included among indications for genetic counselling. Recent studies reported up to 17% rate of germinal BRCA1/2 mutation (gBRCA1/2m) within the age group under 50 years at diagnosis. The original aim of this study was to invite to the genetic counselling still living patients with EOC under 45 years, to offer gBRCA1/2m testing and to perform analysis of gBRCA1/2m rate and of clinico-pathologic characteristics. Later, we added also the data of previously genetically tested patients with EOC aged 45 to 49 years.

Patients And Methods: All clinical data have to be interpreted in the light of many changes happened in the field of EOC just in the last few years: new hystology stage classification (FIGO), new hystology types and differentiation grades classification, new therapeutic possibilities (PARP inhibitors available, also in Slovenia) and new guidelines for genetic counselling of EOC patients (National Comprehensive Cancer Network, NCCN), together with next-generation sequencing possibilities.

Results: Compliance rate at the invitation was 43.1%. In the group of 27 invited or previously tested patients with EOC diagnosed before the age of 45 years, five gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within the group was 18.5%. There were 4 gBRCA1 and 1 gBRCA2 mutations detected. In the extended group of 42 tested patients with EOC diagnosed before the age of 50 years, 14 gBRCA1/2 mutations were found. The gBRCA1/2m detection rate within this extended, partially selected group was 33.3%. There were 11 gBRCA1 and 3 gBRCA2 mutations detected.

Conclusions: The rate of gBRCA1/2 mutation in tested unselected EOC patients under the age of 50 years was higher than 10%, namely 18.5%. Considering also a direct therapeuthic benefit of PARP inhibitors for BRCA positive patients, there is a double reason to offer genetic testing to all EOC patients younger than 50 years. Regarding clinical data, it is important to perform their re-interpretation in everyday clinical practice, because this may influence therapeutic possibilities to be offered.
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http://dx.doi.org/10.1515/raon-2017-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5514659PMC
June 2017

Optimal scan time for evaluation of parathyroid adenoma with [(18)F]-fluorocholine PET/CT.

Radiol Oncol 2015 Dec 27;49(4):327-33. Epub 2015 Nov 27.

Department of Oncological Surgery, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

Background: Parathyroid adenomas, the most common cause of primary hyperparathyroidism, are benign tumours which autonomously produce and secrete parathyroid hormone. [(18)F]-fluorocholine (FCH), PET marker of cellular proliferation, was recently demonstrated to accumulate in lesions representing enlarged parathyroid tissue; however, the optimal time to perform FCH PET/CT after FCH administration is not known. The aim of this study was to determine the optimal scan time of FCH PET/CT in patients with primary hyperparathyroidism.

Patients And Methods: 43 patients with primary hyperparathyroidism were enrolled in this study. A triple-phase PET/CT imaging was performed five minutes, one and two hours after the administration of FCH. Regions of interest (ROI) were placed in lesions representing enlarged parathyroid tissue and thyroid tissue. Standardized uptake value (SUVmean), retention index and lesion contrast for parathyroid and thyroid tissue were calculated.

Results: Accumulation of FCH was higher in lesions representing enlarged parathyroid tissue in comparison to the thyroid tissue with significantly higher SUVmean in the second and in the third phase (p < 0.0001). Average retention index decreased significantly between the first and the second phase and increased significantly between the second and the third phase in lesions representing enlarged parathyroid tissue and decreased significantly over all three phases in thyroid tissue (p< 0.0001). The lesion contrast of lesions representing enlarged parathyroid tissue and thyroid tissue was significantly better in the second and the third phase compared to the first phase (p < 0.05).

Conclusions: According to the results the optimal scan time of FCH PET/CT for localization of lesions representing enlarged parathyroid tissue is one hour after administration of the FCH.
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http://dx.doi.org/10.1515/raon-2015-0016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4722922PMC
December 2015

Distance-Dependent Multimodal Image Registration for Agriculture Tasks.

Sensors (Basel) 2015 Aug 21;15(8):20845-62. Epub 2015 Aug 21.

Department of Computer Science, Ben-Gurion University of the Negev, Beer-Sheva 8410501, Israel.

Image registration is the process of aligning two or more images of the same scene taken at different times; from different viewpoints; and/or by different sensors. This research focuses on developing a practical method for automatic image registration for agricultural systems that use multimodal sensory systems and operate in natural environments. While not limited to any particular modalities; here we focus on systems with visual and thermal sensory inputs. Our approach is based on pre-calibrating a distance-dependent transformation matrix (DDTM) between the sensors; and representing it in a compact way by regressing the distance-dependent coefficients as distance-dependent functions. The DDTM is measured by calculating a projective transformation matrix for varying distances between the sensors and possible targets. To do so we designed a unique experimental setup including unique Artificial Control Points (ACPs) and their detection algorithms for the two sensors. We demonstrate the utility of our approach using different experiments and evaluation criteria.
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http://dx.doi.org/10.3390/s150820845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4570450PMC
August 2015

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma.

Nat Genet 2015 Sep 3;47(9):987-995. Epub 2015 Aug 3.

Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland, USA.

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10(-8)), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.
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http://dx.doi.org/10.1038/ng.3373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4557485PMC
September 2015

The effect on melanoma risk of genes previously associated with telomere length.

J Natl Cancer Inst 2014 Oct 17;106(10). Epub 2014 Sep 17.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Leeds Cancer Research UK Centre, University of Leeds, Leeds, UK (MMI, DTB, JCT, MHa, JRM, JANB, JHB); Oncogenomics (NKH), Genetic Epidemiology (NGM), Inflammatory Bowel Diseases Laboratory (GLRS), Cancer Control Group (DCW), Statistical Genetics (SM, MHL), and Molecular Epidemiology (GWM), QIMR Berghofer Medical Research Institute, Brisbane, Australia; INSERM, UMR-946, Genetic Variation and Human Diseases Unit, Paris, France (MB, FD); Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie, Paris, France (MB, FD); Cancer Epidemiology and Services Research, Sydney School of Public Health, University of Sydney, Australia (AEC); Department of Oncology, University of Cambridge, Cambridge, UK (AMD, PDPP); Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX (JEL); Centre for Genetic Origins of Health and Disease, Faculty of Medicine, Dentistry and Health Sciences, University of Western Australia, Crawley, Australia (EKM, SVW); Centre for Cancer Biomarkers CCBIO (LAA) and Gade Laboratory for Pathology (AM), Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Pathology, Haukeland University Hospital, Bergen, Norway (LAA); Department of Pathology, Molecular Pathology (PAA) and Department of Dermatology (PH), Oslo University Hospital, Rikshospitalet, Oslo, Norway; Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Service de Dermatologie, Université Paris Descartes, Paris, France (MFA); Department of Dermatology (EA) and Oncogenics Unit (EA, EF), Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv, Israel (EA); Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, Italy (GBS, EFPG); Laboratory of Genetics of Rare Hereditary Cancers, San Martino-IST Research Hospital, Genoa, Italy (GBS, EFPG); Division of Cancer Epidemiology and Gene

Telomere length has been associated with risk of many cancers, but results are inconsistent. Seven single nucleotide polymorphisms (SNPs) previously associated with mean leukocyte telomere length were either genotyped or well-imputed in 11108 case patients and 13933 control patients from Europe, Israel, the United States and Australia, four of the seven SNPs reached a P value under .05 (two-sided). A genetic score that predicts telomere length, derived from these seven SNPs, is strongly associated (P = 8.92x10(-9), two-sided) with melanoma risk. This demonstrates that the previously observed association between longer telomere length and increased melanoma risk is not attributable to confounding via shared environmental effects (such as ultraviolet exposure) or reverse causality. We provide the first proof that multiple germline genetic determinants of telomere length influence cancer risk.
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http://dx.doi.org/10.1093/jnci/dju267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196080PMC
October 2014

A patient with a painless neck tumour revealed as a carotid paraganglioma: a case report.

World J Surg Oncol 2014 Aug 20;12:267. Epub 2014 Aug 20.

Institute of Oncology Ljubljana, Zaloska 2, Ljubljana 1000, Slovenia.

Carotid paragangliomas are usually slowly enlarging and painless lateral neck masses. These mostly benign lesions are recognized due to their typical location, vessel displacement and specific blood supply, features that are usually seen on different imaging modalities. Surgery for carotid paraganglioma can be associated with immediate cerebrovascular complications or delayed neurological impairment.We are reporting the case of a 36-year-old man who presented with a painless mass on the right side of his neck 11 months after being treated for testicular cancer. After a fine-needle aspiration biopsy, he was diagnosed with a testicular cancer lymph node metastasis. Neck US and fluorine [F-18]-fluorodeoxy-D-glucose (FDG) PET-CT showed no signs of hypervascularity or vessel displacement. The patient underwent a level II to V functional neck dissection. During the procedure, suspicion of a carotid paraganglioma was raised and the tumour was carefully dissected from the walls of the carotid arteries with minimal blood loss and no cranial nerve dysfunction.The histology report revealed carotid paraganglioma with no metastasis in the rest of the lymph nodes. The patient's history of testicular germ cell tumour led to a functional neck dissection during which a previously unrecognized carotid paraganglioma was removed.Surgery for carotid PG can be associated with complications that have major impact on quality of life. A thorough assessment of the patient and neck mass must therefore be performed preoperatively in order to perform the surgical procedure under optimal conditions.
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http://dx.doi.org/10.1186/1477-7819-12-267DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4153909PMC
August 2014

Fine mapping of genetic susceptibility loci for melanoma reveals a mixture of single variant and multiple variant regions.

Int J Cancer 2015 Mar 14;136(6):1351-60. Epub 2014 Aug 14.

Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.

At least 17 genomic regions are established as harboring melanoma susceptibility variants, in most instances with genome-wide levels of significance and replication in independent samples. Based on genome-wide single nucleotide polymorphism (SNP) data augmented by imputation to the 1,000 Genomes reference panel, we have fine mapped these regions in over 5,000 individuals with melanoma (mainly from the GenoMEL consortium) and over 7,000 ethnically matched controls. A penalized regression approach was used to discover those SNP markers that most parsimoniously explain the observed association in each genomic region. For the majority of the regions, the signal is best explained by a single SNP, which sometimes, as in the tyrosinase region, is a known functional variant. However in five regions the explanation is more complex. At the CDKN2A locus, for example, there is strong evidence that not only multiple SNPs but also multiple genes are involved. Our results illustrate the variability in the biology underlying genome-wide susceptibility loci and make steps toward accounting for some of the "missing heritability."
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http://dx.doi.org/10.1002/ijc.29099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4328144PMC
March 2015

¹⁸F-Fluorocholine PET/CT for localization of hyperfunctioning parathyroid tissue in primary hyperparathyroidism: a pilot study.

Eur J Nucl Med Mol Imaging 2014 Nov 26;41(11):2083-9. Epub 2014 Jul 26.

Department for Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia,

Purpose: Primary hyperparathyroidism is a common endocrine disorder which is diagnosed biochemically and for which therapy is surgical. A prerequisite for minimally invasive surgery, which minimizes morbidity and cost, is accurate localization of the involved gland(s). The aim of this study was to evaluate the usefulness of (18)F-fluorocholine PET/CT for preoperative localization of hyperfunctioning parathyroid tissue.

Methods: (18)F-Fluorocholine PET/CT and conventional parathyroid scintigraphic imaging consisting of (99m)Tc-sestaMIBI SPECT/CT, (99m)Tc-sestaMIBI dual-phase imaging and (99m)Tc-sestaMIBI/pertechnetate subtraction imaging were performed in 24 patients. The diagnostic performance of the imaging methods was compared against histology as the gold standard and postoperative serum Ca(2+) and iPTH values.

Results: The sensitivity and specificity of (18)F-fluorocholine PET/CT were 92% and 100%, respectively, in contrast to 49% and 100%, 46% and 100%, and 44% and 100% for (99m)Tc-sestaMIBI SPECT/CT, (99m)Tc-sestaMIBI/pertechnetate subtraction imaging and (99m)Tc-sestaMIBI dual-phase imaging, respectively. Combined conventional scintigraphic imaging had a sensitivity and specificity of 64% and 100%, respectively. The performance of (18)F-fluorocholine PET/CT was superior particularly in patients with multiple lesions or hyperplasia.

Conclusion: (18)F-Fluorocholine PET/CT appears to be a promising, effective imaging method for localization of hyperfunctioning parathyroid tissue.
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http://dx.doi.org/10.1007/s00259-014-2837-0DOI Listing
November 2014

A variant in FTO shows association with melanoma risk not due to BMI.

Nat Genet 2013 Apr 3;45(4):428-32, 432e1. Epub 2013 Mar 3.

Section of Epidemiology and Biostatistics, Leeds Institute of Molecular Medicine, Leeds Cancer Research UK Centre, St. James's University Hospital, Leeds, UK.

We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 × 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanoma-susceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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http://dx.doi.org/10.1038/ng.2571DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640814PMC
April 2013

Programmable ultrasonic sensing system for targeted spraying in orchards.

Sensors (Basel) 2012 Nov 9;12(11):15500-19. Epub 2012 Nov 9.

Faculty of Agriculture and Life Sciences, University of Maribor, 2000 Maribor, Slovenia.

This research demonstrates the basic elements of a prototype automated orchard sprayer which delivers pesticide spray selectively with respect to the characteristics of the targets. The density of an apple tree canopy was detected by PROWAVE 400EP250 ultrasound sensors controlled by a Cypress PSOC CY8C29466 microcontroller. The ultrasound signal was processed with an embedded computer built around a LPC1343 microcontroller and fed in real time to electro-magnetic valves which open/close spraying nozzles in relation to the canopy structure. The analysis focuses on the detection of appropriate thresholds on 15 cm ultrasound bands, which correspond to maximal response to tree density, and this was selected for accurate spraying guidance. Evaluation of the system was performed in an apple orchard by detecting deposits of tartrazine dye (TD) on apple leaves. The employment of programmable microcontrollers and electro-magnetic valves decreased the amount of spray delivered by up to 48.15%. In contrast, the reduction of TD was only up to 37.7% at some positions within the tree crown and 65.1% in the gaps between trees. For all these reasons, this concept of precise orchard spraying can contribute to a reduction of costs and environmental pollution, while obtaining similar or even better leaf deposits.
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http://dx.doi.org/10.3390/s121115500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3522973PMC
November 2012

Inguinal or inguino-iliac/obturator lymph node dissection after positive inguinal sentinel lymph node in patients with cutaneous melanoma.

Radiol Oncol 2012 Sep 24;46(3):258-64. Epub 2012 Jul 24.

Department of Surgical Oncology, Institute of Oncology, Ljubljana, Slovenia.

Background: The aim of the study was to determine whether the presence of inguinal sentinel lymph node (SLN) metastases smaller than 2 mm (micrometastases) subdivided according to the number of micrometastases predicts additional, non-sentinel inguinal, iliac or obturator lymph node involvement in completion lymph node dissection (CLND). PATIENTS AND METHODS.: Positive inguinal SLN was detected in 58 patients (32 female, 26 male, median age 55 years) from 743 consecutive and prospectively enrolled patients with primary cutaneous melanoma stage I and II who were treated with SLN biopsy between 2001 and 2007.

Results: Micrometastases in inguinal SLN were detected in 32 patients, 14 were single, 2 were double, and 16 were multiple. Twenty-six patients had macrometastases.

Conclusions: No patient with any micrometastases or a single SLN macrometastasis in the inguinal region had any iliac/obturator non-sentinel metastases after CLND in our series. Furthermore, no patient with single SLN micrometastasis in the inguinal region had any non-sentinel metastases at all after CLND in our series. In these cases respective CLND might be omitted.
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http://dx.doi.org/10.2478/v10019-012-0041-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3472950PMC
September 2012

Lower tumour burden and better overall survival in melanoma patients with regional lymph node metastases and negative preoperative ultrasound.

Radiol Oncol 2012 Mar 22;46(1):60-8. Epub 2011 Sep 22.

Institute of Oncology Ljubljana, Department of Surgical Oncology, Slovenia.

Background: The purpose of the study was to evaluate the ability of ultrasound (US) and fine needle aspiration biopsy (FNAB) in reducing the number of melanoma patients requiring a sentinel node biopsy (SNB); to compare the amount of metastatic disease in regional lymph nodes in SNB candidates with clinically uninvolved lymph nodes and of those with US uninvolved lymph nodes; and to compare the overall survival (OS) of both groups.

Methods: Between 2000 and 2007, a SNB was successfully performed in 707 patients with melanoma. The preoperative US of the regional lymph node basins was performed in 405 SNB candidates. In 14 of these patients, the US-guided FNAB was positive and they proceeded directly to lymph node dissection. In 391 patients, the preoperative US was either negative (343 patients) or suspicious (48 patients) (US group). In the remaining 316 patients the preoperative US was not performed (non-US group).

Results: The proportion of macrometastatic sentinel lymph nodes (SN), number of metastatic lymph nodes per patient and proportion of nonsentinel lymph node metastases were found to be lower in the US group compared to the non-US group. The smaller tumour burden of the US group was reflected in a significantly better OS of patients with SN metastases.

Conclusions: The preoperative US of regional lymph nodes spares some patients with melanoma from undergoing a SNB. Patients with regional metastases and a negative preoperative US have a significantly lower tumour burden in comparison to those with clinically negative lymph nodes, which is also reflected in a better OS.
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http://dx.doi.org/10.2478/v10019-011-0028-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423764PMC
March 2012

Novel BRCA1 and BRCA2 pathogenic mutations in Slovene hereditary breast and ovarian cancer families.

Int J Oncol 2012 Nov 21;41(5):1619-27. Epub 2012 Aug 21.

Department of Molecular Diagnostics, Institute of Oncology Ljubljana, Ljubljana, Slovenia.

The estimated proportion of hereditary breast and ovarian cancers among all breast and ovarian cancer cases is 5-10%. According to the literature, inherited mutations in the BRCA1 and BRCA2 tumour-suppressor genes, account for the majority of hereditary breast and ovarian cancer cases. The aim of this report is to present novel mutations that have not yet been described in the literature and pathogenic BRCA1 and BRCA2 mutations which have been detected in HBOC families for the first time in the last three years. In the period between January 2009 and December 2011, 559 individuals from 379 families affected with breast and/or ovarian cancer were screened for mutations in the BRCA1 and BRCA2 genes. Three novel mutations were detected: one in BRCA1 - c.1193C>A (p.Ser398*) and two in BRCA2 - c.5101C>T (p.Gln1701*) and c.5433_5436delGGAA (p.Glu1811Aspfs*3). These novel mutations are located in the exons 11 of BRCA1 or BRCA2 and encode truncated proteins. Two of them are nonsense while one is a frameshift mutation. Also, 11 previously known pathogenic mutations were detected for the first time in the HBOC families studied here (three in BRCA1 and eight in BRCA2). All, except one cause premature formation of stop codons leading to truncation of the respective BRCA1 or BRCA2 proteins.
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http://dx.doi.org/10.3892/ijo.2012.1595DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3583621PMC
November 2012