Tumour-induced osteomalacia: 18 months of 2-weekly burosumab treatment

Summary: Tumour-induced osteomalacia (TIO) is due to an overproduction of fibroblast growth factor 23 (FGF23) by mesenchymal tumours, causing hypophosphatemia, osteomalacia and muscle weakness. TIO is usually cured by tumour resection, but neoplasms may be unidentifiable and unresectable or the patient may refuse surgery. In these cases, medical treatment with oral phosphate and calcitriol is mandatory, but it is not fully effective and it is associated with low compliance. Burosumab, a human MAB against FGF23 employed to treat X-linked hypophosphatemia (XLH), has recently been approved for TIO in the USA. Maximum burosumab dose in XLH is 90 mg administered for 2 weeks; there are no data on clinical efficacy and safety of this dose in TIO. We reported the case of a 73 years old male with multiple non-traumatic fractures, low bone mineral density, pain and reduced independence of activities of daily living. Biochemical evaluation showed hypophosphatemia, high alkaline phosphatase (ALP) and C-terminal telopeptide (CTX) and normal albumin-corrected total calcium and parathyroid hormone. Tubular phosphate reabsorption was low (80%), whereas C-terminal tail of FGF23 (cFGF23) was elevated. A 68Ga-DOTATOC PET was performed, identifying a lesion in the first left rib. The patient refused surgery; therefore, burosumab therapy was started. After 18 months of treatment (maximum dose: 60 mg administered for 2 weeks), plasma phosphate normalized and ALP levels improved (138 U/L). Patient clinical symptoms as well as pain severity and fatigue improved. Neither adverse events nor tumour progression was reported during follow-up except for a painless fracture of the second right rib. Learning points: Our case shows efficacy and safety of burosumab treatment administered every 2 weeks in a tumour-induced osteomalacia (TIO) patient. After 18 months of treatment at a maximum dose of 60 mg every 2 weeks, we found plasma phosphate normalization and ALP reduction as well as improvement in clinical symptoms and fatigue. Neither adverse events nor tumour progression was reported during follow-up, except for a painless fracture of the second right rib

Object-based image analysis for historic maps classification

Heritage maps represent fundamental information for the study of the evolution of a region, especially in terms of landscape and ecologic features. Historical maps present two kinds of hurdle before they can be used in a modern GIS: they must be geometrically corrected to correspond to the datum in use and they must be classified to exploit the information they contain. This study deals the latter problem: the Historical Cadaster Map, created between 1851 and 1861, for the Trentino region in the North of Italy is available as a collection of maps in the ETRS89/UTM 32N datum. The map is a high resolution scan (230 DPI, 24 bit) of the original map and has been used in several ecological studies, since it provides detailed information not only about land property but also about land use. In the past the cadaster map has been manually digitized and for each area a set of attributes has been recorded. Since this approach is time consuming and prone to errors, automatic and semi-automatic procedures have been tested. Traditional image classification techniques, such as maximum likelihood classification, supervised or un-supervised, pixelwise and contextual, do not provide satisfactory results for many reasons: map colors are very variable within the same area, symbols and characters are used to identify cadaster parcels and locations, lines, drawn by hand on the original map, have variable thickness and colors. The availability of FOSS tools for the Object-based Image Analysis (OBIA) has made possible the application of this technique to the cadaster map. This paper describes the use of GRASS GIS and R for the implementation of the OBIA approach for the supervised classification of the historic cadaster map. It describes the determination of the optimal segments, the choice of their attributes and relevant statistics, and their classification. The result has been evaluated with respect to a manually digitized map using Cohens Kappa and the analysis of the confusion matrix. The result of the OBIA classification has also been compared to the classification of the same map using maximum likelihood classification, un-supervised and supervised, both pixelwise and contextual. The OBIA approach has provided very satisfactory results with the ability to automatically remove the background and symbols and characters, creating a ready to be used classified map. This study highlights the effectiveness of the OBIA processing chain available in the FOSS4G ecosystem, and in particular the added value of the interoperability between GRASS GIS and R

Modeling of forest landscape evolution at regional level: a FOSS4G approach

In the last decades the Alpine landscape has dramatically changed due to social and economic factors. The most visible impact has been the reduction of the population for mid and high altitude villages and the shrinking of the part of the land used for agriculture and grazing, with a progressive reduction of pastures and meadows and the expansion of the forested areas. For these reasons, a dataset describing the forest, meadows and pasture coverage for the Trentino region, in the eastern Italian Alps, has been created. A set of heterogeneous sources has been selected so that maps and images cover the longest possible time span on the whole Trentino region with comparable quality, creating a Land Use/Land Cover (LULC) map based on historical maps from 1859 to 1936 and aerial images from 1954 to 2015. The achieved accuracy ranges from 98% for historical maps to 94% for aereal imagery. The analysis of selected landscape metrics provided preliminary results about the forest distribution and patterns of recolonization during the last 155 years. It has been possible to create future scenarios for the forest evolution for the next 85 years. Given the large number of maps involved, the great flexibility provided by FOSS for spatial analysis, such as GRASS, R, QGIS and GAMA and the possibility of scripting all the operations have played a pivotal role in the success both in the creation of the dataset and in the extraction and modeling of land use change

Neck paraganglioma and follicular lymphoma: A case report

Background: Paragangliomas and pheochromocytomas are sympathetic or parasympathetic tumors derived from the paraganglia and the adrenal medulla, respectively. Paragangliomas and pheochromocytomas can be sporadic or familial, the latter frequently being multifocal and possibly due to succinate dehydrogenase complex genes mutations. In addition, 12% of sporadic paragangliomas are related to covered succinate dehydrogenase complex mutations. The importance of identifying succinate dehydrogenase complex mutations is related to the risk for these patients of developing multiple tumors, including non-endocrine ones, showing an aggressive clinical presentation. Case presentation: We report the case of a 45-year-old Caucasian man with an indolent mass in his neck. Ultrasound of his neck, magnetic resonance imaging, and 1,4,7,10-tetraazacyclododecane-N(I),N(II),N(III),N(IIII)-tetraacetic acid(D)-Phe(1)-thy(3)-octreotide (68Ga-DOTATOC) positron emission tomography-computed tomography and endocrine work-up were consistent with a carotid body paraganglioma with concomitant nodal enlargement in several body regions, which turned out to be a follicular lymphoma at histology. He was found to carry a germline Succinate dehydrogenase subunit B gene (SDHB) mutation. Conclusion: It is crucial to look for a second malignancy in the case of a paraganglioma demonstrating succinate dehydrogenase complex germline mutations

Radiomics in the characterization of lipid-poor adrenal adenomas at unenhanced CT: time to look beyond usual density metrics

Objectives: In this study, we developed a radiomic signature for the classification of benign lipid-poor adenomas, which may potentially help clinicians limit the number of unnecessary investigations in clinical practice. Indeterminate adrenal lesions of benign and malignant nature may exhibit different values of key radiomics features. Methods: Patients who had available histopathology reports and a non-contrast-enhanced CT scan were included in the study. Radiomics feature extraction was done after the adrenal lesions were contoured. The primary feature selection and prediction performance scores were calculated using the least absolute shrinkage and selection operator (LASSO). To eliminate redundancy, the best-performing features were further examined using the Pearson correlation coefficient, and new predictive models were created. Results: This investigation covered 50 lesions in 48 patients. After LASSO-based radiomics feature selection, the test dataset’s 30 iterations of logistic regression models produced an average performance of 0.72. The model with the best performance, made up of 13 radiomics features, had an AUC of 0.99 in the training phase and 1.00 in the test phase. The number of features was lowered to 5 after performing Pearson’s correlation to prevent overfitting. The final radiomic signature trained a number of machine learning classifiers, with an average AUC of 0.93. Conclusions: Including more radiomics features in the identification of adenomas may improve the accuracy of NECT and reduce the need for additional imaging procedures and clinical workup, according to this and other recent radiomics studies that have clear points of contact with current clinical practice. Clinical relevance statement: The study developed a radiomic signature using unenhanced CT scans for classifying lipid-poor adenomas, potentially reducing unnecessary investigations that scored a final accuracy of 93%. Key Points: • Radiomics has potential for differentiating lipid-poor adenomas and avoiding unnecessary further investigations. • Quadratic mean, strength, maximum 3D diameter, volume density, and area density are promising predictors for adenomas. • Radiomics models reach high performance with average AUC of 0.95 in the training phase and 0.72 in the test phase

Radioligand therapy (RLT) as neoadjuvant treatment for inoperable pancreatic neuroendocrine tumors: a literature review

In the last 10 years, several literature reports supported radioligand therapy (RLT) in neoadjuvant settings for pancreatic neuroendocrine tumors (PanNETs). Indeed, primary tumor shrinkage has been frequently reported following RLT in unresectable or borderline resectable PanNETs. Moreover, RLT-induced intratumoral modifications facilitate surgery, both on primary tumor and metastasis, having a great impact on progression free survival (PFS), overall survival (OS) and quality of life (QoL). However, prospective controlled investigations are necessary to confirm preliminary data and to define the best RLT scheme and the ideal patient that, in a multidisciplinary approach, should be referred to neoadjuvant RLT

HUMAN-WILDLIFE CONFLICT AND ROAD COLLISIONS WITH UNGULATES. A RISK ANALYSIS AND DESIGN SOLUTIONS IN TRENTINO, ITALY

This study investigates wildlife vehicle collisions with wild ungulates in the Italian Autonomous Province of Trento (PAT) located in the Eastern Italian Alps with a consistent anthropic population and pervasive summer and winter tourism. Both the populations of wild ungulates and vehicular traffic are increasing as well as road collisions leading to animals killed, vehicles damaged and human injuries and fatalities. The purpose of this work was to use FOSS4G to identify the road sections with a high number of collisions and then propose and design practical engineering solutions tailored to each of these hotspots. QGIS 3.16.6, GRASS 7.8.5 and GRASS 8.2 were used to standardize the data set, process georeferenced road collision with ungulates registered by local authorities, perform the hotspot analysis and the final maps. Field surveys were carried out to investigate the local morphology at each hotspot and once the more appropriate practical solutions were chosen, a specific detailed project was proposed including its costs. A cost benefit analysis comparing the cost of the infrastructures with the cost of roadkills shows that the infrastructures are effective in reducing the costs in the medium-long term. The construction of the five proposed infrastructures would reduce deer investments by 6% (about 250 collisions avoided in five years). Such solutions should be more numerous and widely distributed in order to have a greater impact. This FOSS4G procedure can be replicated elsewhere to plan the position of crossing structures, and for application to EU funds, thus mitigating Human-wildlife conflicts (HWC)

Combination of ultrasound and molecular testing in malignancy risk estimate of Bethesda category IV thyroid nodules: results from a single-institution prospective study

Purpose: Malignancy prediction in indeterminate thyroid nodules is still challenging. We prospectively evaluated whether the combination of ultrasound (US) risk stratification and molecular testing improves the assessment of malignancy risk in Bethesda Category IV thyroid nodules. Methods: Ninety-one consecutively diagnosed Bethesda Category IV thyroid nodules were prospectively evaluated before surgery by both ACR- and EU-TIRADS US risk-stratification systems and by a further US-guided fine-needle aspiration cytology (FNAC) for the following molecular testing: BRAFV600E, N-RAS codons 12/13, N-RAS codon 61, H-RAS codons 12/13, H-RAS codon 61, K-RAS codons 12/13, and K-RAS codon 61 point-mutations, as well as PAX8/PPARγ, RET/PC1, and RET/PTC 3 rearrangements. Results: At histology, 37% of nodules were malignant. No significant association was found between malignancy and either EU- or ACR-TIRADS. In total, 58 somatic mutations were identified, including 3 BRAFV600E (5%), 5 N-RAS 12/13 (9%), 13 N-RAS 61 (22%), 7 H-RAS 12/13 (12%), 11 H-RAS 61 (19%), 6 K-RAS 12/13 (10%), 8 K-RAS 61 (14%) mutations and 2 RET/PTC1 (4%), 0 RET/PTC 3 (0%), 3 PAX8/PPARγ (5%) rearrangements. At least one somatic mutation was found in 28% and 44% of benign and malignant nodules, respectively, although malignancy was not statistically associated with the outcome of the mutational test. However, the combination of ACR-, but not EU-, TIRADS with the presence of at least one somatic mutation, was significantly associated with malignant histology (P = 0.03). Conclusion: US risk stratification and FNAC molecular testing may synergistically contribute to improve malignancy risk estimate of Bethesda category IV thyroid nodules

MTOR, p70S6K, AKT, and ERK1/2 levels predict sensitivity to mTOR and PI3K/mTOR inhibitors in human bronchial carcinoids

Bronchial carcinoids (BCs) are rare neuroendocrine tumors that are still orphans of medical treatment. Human BC primary cultures may display resistance to everolimus, an inhibitor of the mammalian target of rapamycin (mTOR), in terms of cell viability reduction. Our aim was to assess whether the novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor NVP-BEZ235 is effective in everolimus-resistant human BC tissues and cell lines. In addition, we searched for possible markers of the efficacy of mTOR inhibitors that may help in identifying the patients who may benefit from treatment with mTOR inhibitors, sparing them from ineffective therapy. We found that NVP-BEZ235 is twice as potent as everolimus in reducing cell viability and activating apoptosis in human BC tissues that display sensitivity to mTOR inhibitors, but is not effective in everolimus-resistant BC tissues and cell lines that bypass cyclin D1 downregulation and escape G0/G1 blockade. Rebound AKT activation was not observed in response to treatment with either mTOR inhibitor in the 'resistant' BC cells. In addition to total mTOR levels, putative markers of the sensitivity of BCs to mTOR inhibitors are represented by AKT, p70S6K (RPS6KB2), and ERK1/2 (MAPK3/1) protein levels. Finally, we validated these markers in an independent BC group. These data indicate that the dual PI3K/mTOR inhibitor NVP-BEZ235 is more potent than everolimus in reducing the proliferation of human BC cells. 'Resistant' cells display lower levels of mTOR, p70S6K, AKT, and ERK1/2, indicating that these proteins may be useful as predictive markers of resistance to mTOR and PI3K/mTOR inhibitors in human BCs. \ua9 2013 Society for Endocrinology