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Background: The spread of COVID-19 poses an unprecedented challenge to care delivery in post-disaster and conflict situations. In Mozambique, the 2019 cyclone Idai and the violence by Non-State-Armed-Groups devastated the province of Sofala and Cabo Delgado respectively and led to the displacement of thousands of people living in poor and overcrowded conditions. The pandemic has further aggravated the situation. Doctors with Africa CUAMM (University college for aspiring missionary doctors) implemented surveillance activities in these regions between October 2020 and September 2021. The aim of this study is to give an overview of the prevalence of malaria, malnutrition, COVID-19 related symptoms and access to HIV testing. Methods: Data were collected in targeted internally displaced people (IDP) sites in Sofala and Cabo Delgado province between 31st January and 25th September 2021. The tool used enabled to assess COVID-19 symptoms, risk of HIV infection, malaria cases and malnutrition in children under five. Results: The project reached 93 503 people. During the study period, 13.6% people reported at least one symptom suggestive of COVID-19 infection. Malaria Rapid Diagnostic Tests (RDT) were administered to 86% of the recruited people (n =?), with a positive diagnosis in the 4.5% of them (n =?). Among the recruited Internally Displaced Persons (IDP), 23.1% were considered eligible for HIV screening, but only 1.4% were referred for testing. Acute malnutrition was found in 6.3% of children screened and, among these, a higher prevalence of concurrent COVID-19 symptoms was reported. Discussion: Our study highlights the importance of mass clinical screening for COVID-19 infection in this target population to enact prevention behavior, although this may not be enough, due to the pivotal role played by asymptomatic transmissions. Considering the overlap of the symptoms of COVID-19 and malaria, a combined diagnostic algorithm is urgently needed to avoid underdiagnosing mala

Item does not contain fulltext, The biochemical phenotype of paragangliomas (PGLs) is highly dependent on the underlying genetic background and tumor location. PGLs at extra-adrenal locations usually do not express phenylethanolamine N-methyltransferase (PNMT), the enzyme required for epinephrine production, which was explained by the absence of glucocorticoids. PGLs with pathogenic variants (PVs) in Harvey rat sarcoma viral oncogene homolog (HRAS) can occur in or outside of the adrenal, but always synthesize epinephrine independently of the localization. Here, we characterize the signaling pathways through which PVs in HRAS influence PNMT expression. Catecholamines, cortisol, and transcriptional features of PGL tissues with known genetic background were analyzed. Genetically modified rat pheochromocytoma cells carrying PVs in Hras were generated and analyzed for regulation of Pnmt expression. Elevated epinephrine contents in PGLs with PVs in HRAS were accompanied by enrichment in mitogen-activated protein kinase (MAPK) signaling compared to PGLs with PVs in genes that activate hypoxia pathways. In vitro, Hras PVs increased Pnmt expression and epinephrine biosynthesis through increased phosphorylation of stimulatory protein 1 via MAPK signaling. Here, we provide a molecular mechanism that explains the PV-dependent epinephrine production of PGLs.

If we focus our attention on seven main features of COVID-19 infection (heterogeneity, fragility, lack of effective treatments and vaccines, "miraculous cures", psychological suffering, deprivation, and globalization), we may establish parallelism with the challenges faced in the steep road to the understanding and treatment of neoplastic diseases. How the similarities between these two conditions can help us cope with the emergency effort represented by the management of cancer patients in the COVID-19 era, today and in the future? In a manner similar to the Cancer Moonshot initiative in the United States, we can hypothesize a multinational moonshot project towards the management of cancer patients during COVID-19 pandemic. In particular, we believe that the main road to elaborate meaningful scientific evidence is represented by the collection of all the data on COVID-19 and cancer comorbidity that are and will become available in cancer centers, coupled with the design of large clinical studies. To address this goal, it is essential to identify the entity that can produce this scientific evidences and the potentially most successful research strategy to undertake. The largest Italian organization for cancer research, Alliance Against Cancer (Alleanza Contro il Cancro, ACC), is called to play a scientific leadership in addressing these challenges, which requires the coordination of oncology teams at regional, national, and international levels. To fulfill this commitment, ACC will create a liaison with health government agencies in order to develop "dynamic"indications able to fight such an unpredictable pandemic.

Item does not contain fulltext, PURPOSE: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. EXPERIMENTAL DESIGN: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). RESULTS: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Deltabetametastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity. CONCLUSIONS: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020-30. (c)2015 AACR.

Item does not contain fulltext, PURPOSE: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. EXPERIMENTAL DESIGN: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). RESULTS: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Deltabetametastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity. CONCLUSIONS: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020-30. (c)2015 AACR.

Item does not contain fulltext, PURPOSE: Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors, associated with highly variable postoperative evolution. The scarcity of reliable PPGL prognostic markers continues to complicate patient management. In this study, we explored genome-wide DNA methylation patterns in the context of PPGL malignancy to identify novel prognostic markers. EXPERIMENTAL DESIGN: We retrospectively investigated DNA methylation patterns in PPGL with and without metastases using high-throughput DNA methylation profiling data (Illumina 27K) from two large, well-characterized discovery (n = 123; 24 metastatic) and primary validation (n = 154; 24 metastatic) series. Additional validation of candidate CpGs was performed by bisulfite pyrosequencing in a second independent set of 33 paraffin-embedded PPGLs (19 metastatic). RESULTS: Of the initial 86 candidate CpGs, we successfully replicated 52 (47 genes), associated with metastatic PPGL. Of these, 48 CpGs showed significant associations with time to progression even after correcting for SDHB genotype, suggesting their value as prognostic markers independent of genetic background. Hypermethylation of RDBP (negative elongation factor complex member E) in metastatic tumors was further validated by bisulfite pyrosequencing [Deltabetametastatic-benign = 0.29, P = 0.003; HR, 1.4; 95% confidence interval (CI), 1.1-2.0; P = 0.018] and may alter transcriptional networks involving (RERG, GPX3, and PDZK1) apoptosis, invasion, and maintenance of DNA integrity. CONCLUSIONS: This is the first large-scale study of DNA methylation in metastatic PPGL that identifies and validates prognostic markers, which could be used for stratifying patients according to risk of developing metastasis. Of the three CpGs selected for further validation, one (RDBP) was clearly confirmed and could be used for stratifying patients according to the risk of developing metastases. Clin Cancer Res; 21(13); 3020-30. (c)2015 AACR.

Alliance Against Cancer (ACC) was established in Rome in 2002 as a consortium of six Italian comprehensive cancer centers (Founders). The aims of ACC were to promote a network among Italian oncologic institutions in order to develop speci c, advanced projects in clinical and translational research. During the following years, many additional full and associate members joined ACC, that presently includes the National Institute of Health, 17 research-oriented hospitals, scienti c and patient organizations. Furthermore, in the last three years ACC underwent a reorganiza- tion process that redesigned the structure, governance and major activities. The present goal of ACC is to achieve high standards of care across Italy, to implement and harmonize principles of modern personalized and precision medicine, by developing cost e ective processes and to provide tailored information to cancer patients. We herein summarize some of the major initiatives that ACC is currently developing to reach its goal, including tumor genetic screening programs, establishment of clinical trial programs for cancer patients treated in Italian cancer centers, facili- tate their access to innovative drugs under development, improve quality through an European accreditation process (European Organization of Cancer Institutes), and develop international partnerships. In conclusion, ACC is a growing organization, trying to respond to the need of networking in Italy and may contribute signi cantly to improve the way we face cancer in Europe.

Item does not contain fulltext, CONTEXT: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations. OBJECTIVE: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations. DESIGN, SETTING, AND PATIENTS: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites. MAIN OUTCOME MEASURE: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations. RESULTS: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases. CONCLUSIONS: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Item does not contain fulltext, Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2alpha and HIF1alpha, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2alpha and mature phenotypic features and the other with high expression of HIF2alpha and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2alpha, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1alpha had opposing actions to HIF2alpha in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2alpha in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.

Item does not contain fulltext, CONTEXT: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations. OBJECTIVE: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations. DESIGN, SETTING, AND PATIENTS: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites. MAIN OUTCOME MEASURE: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations. RESULTS: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases. CONCLUSIONS: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Item does not contain fulltext, Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2alpha and HIF1alpha, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2alpha and mature phenotypic features and the other with high expression of HIF2alpha and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2alpha, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1alpha had opposing actions to HIF2alpha in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2alpha in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.

Item does not contain fulltext, Pheochromocytomas and paragangliomas (PPGLs) are catecholamine-producing chromaffin cell tumors with diverse phenotypic features reflecting mutations in numerous genes, including MYC-associated factor X (MAX). To explore whether phenotypic differences among PPGLs reflect a MAX-mediated mechanism and opposing influences of hypoxia-inducible factor (HIF)s HIF2alpha and HIF1alpha, we combined observational investigations in PPGLs and gene-manipulation studies in two pheochromocytoma cell lines. Among PPGLs from 140 patients, tumors due to MAX mutations were characterized by gene expression profiles and intermediate phenotypic features that distinguished these tumors from other PPGLs, all of which fell into two expression clusters: one cluster with low expression of HIF2alpha and mature phenotypic features and the other with high expression of HIF2alpha and immature phenotypic features due to mutations stabilizing HIFs. Max-mutated tumors distributed to a distinct subcluster of the former group. In cell lines lacking Max, re-expression of the gene resulted in maturation of phenotypic features and decreased cell cycle progression. In cell lines lacking Hif2alpha, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1alpha had opposing actions to HIF2alpha in both cell lines, supporting evolving evidence of their differential actions on tumorigenic processes via a MYC/MAX-related pathway. Requirement of a fully functional MYC/MAX complex to facilitate differentiation explains the intermediate phenotypic features in tumors due to MAX mutations. Overexpression of HIF2alpha in chromaffin cell tumors due to mutations affecting HIF stabilization explains their proliferative features and why the tumors fail to differentiate even when exposed locally to adrenal steroids.

Item does not contain fulltext, CONTEXT: Mutations of succinate dehydrogenase A/B/C/D genes (SDHx) increase susceptibility to development of pheochromocytomas and paragangliomas (PPGLs), with particularly high rates of malignancy associated with SDHB mutations. OBJECTIVE: We assessed whether altered succinate dehydrogenase product-precursor relationships, manifested by differences in tumor ratios of succinate to fumarate or other metabolites, might aid in identifying and stratifying patients with SDHx mutations. DESIGN, SETTING, AND PATIENTS: PPGL tumor specimens from 233 patients, including 45 with SDHx mutations, were provided from eight tertiary referral centers for mass spectrometric analyses of Krebs cycle metabolites. MAIN OUTCOME MEASURE: Diagnostic performance of the succinate:fumarate ratio for identification of pathogenic SDHx mutations. RESULTS: SDH-deficient PPGLs were characterized by 25-fold higher succinate and 80% lower fumarate, cis-aconitate, and isocitrate tissue levels than PPGLs without SDHx mutations. Receiver-operating characteristic curves for use of ratios of succinate to fumarate or to cis-aconitate and isocitrate to identify SDHx mutations indicated areas under curves of 0.94 to 0.96; an optimal cut-off of 97.7 for the succinate:fumarate ratio provided a diagnostic sensitivity of 93% at a specificity of 97% to identify SDHX-mutated PPGLs. Succinate:fumarate ratios were higher in both SDHB-mutated and metastatic tumors than in those due to SDHD/C mutations or without metastases. CONCLUSIONS: Mass spectrometric-based measurements of ratios of succinate:fumarate and other metabolites in PPGLs offer a useful method to identify patients for testing of SDHx mutations, with additional utility to quantitatively assess functionality of mutations and metabolic factors responsible for malignant risk.

Item does not contain fulltext, PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Item does not contain fulltext, PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Item does not contain fulltext, PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Item does not contain fulltext, PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

Item does not contain fulltext, PURPOSE: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. RESULTS: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. CONCLUSIONS: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients.

Item does not contain fulltext, PURPOSE: Radionuclide imaging of phaeochromocytomas (PCCs) and paragangliomas (PGLs) involves various functional imaging techniques and approaches for accurate diagnosis, staging and tumour characterization. The purpose of the present guidelines is to assist nuclear medicine practitioners in performing, interpreting and reporting the results of the currently available SPECT and PET imaging approaches. These guidelines are intended to present information specifically adapted to European practice. METHODS: Guidelines from related fields, issued by the European Association of Nuclear Medicine and the Society of Nuclear Medicine, were taken into consideration and are partially integrated within this text. The same was applied to the relevant literature, and the final result was discussed with leading experts involved in the management of patients with PCC/PGL. The information provided should be viewed in the context of local conditions, laws and regulations. CONCLUSION: Although several radionuclide imaging modalities are considered herein, considerable focus is given to PET imaging which offers high sensitivity targeted molecular imaging approaches.

In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and proliferation, and in genes found to be differentially expressed in thyroid carcinoma. A total of 768 SNPs in 97 genes were genotyped in a Spanish series of 615 cases and 525 controls, the former comprising the largest collection of patients with this pathology from a single population studied to date. SNPs in an LD block spanning the entire FOXE1 gene showed the strongest evidence of association with papillary thyroid carcinoma susceptibility. This association was validated in a second stage of the study that included an independent Italian series of 482 patients and 532 controls. The strongest association results were observed for rs1867277 (OR[per-allele] = 1.49; 95%CI = 1.30-1.70; P = 5.9x10(-9)). Functional assays of rs1867277 (NM_004473.3:c.-283G>A) within the FOXE1 5' UTR suggested that this variant affects FOXE1 transcription. DNA-binding assays demonstrated that, exclusively, the sequence containing the A allele recruited the USF1/USF2 transcription factors, while both alleles formed a complex in which DREAM/CREB/alphaCREM participated. Transfection studies showed an allele-dependent transcriptional regulation of FOXE1. We propose a FOXE1 regulation model dependent on the rs1867277 genotype, indicating that this SNP is a causal variant in thyroid cancer susceptibility. Our results constitute the first functional explanation for an association identified by a GWAS and thereby elucidate a mechanism of thyroid cancer susceptibility. They also attest to the efficacy of candidate gene approaches in the GWAS era.

Since insulin increases renal sodium reabsorption, hyperinsulinaemia in insulin-treated insulin-dependent diabetes mellitus might lead to sodium retention and, in turn, increase atrial natriuretic factor (ANF) values. We investigated ANF levels in insulin-dependent diabetes mellitus with and without hypertension. We infused saline (2mmol/kg per 90 min) in nine normotensive Controls, eight normotensive diabetics, seven hypertensive Controls and six hypertensive diabetics during the imposition of a euglycaemic glucose clamp with an artificial pancreas. Baseline ANF values were higher in the normotensive and hypertensive diabetics than in the normotensive and hypertensive Controls. During a sodium load the sodium excretion rate increased significantly in Controls but not in the diabetic groups. The ANF pattem was similar, values being significantly increased in Controls and unchanged in diabetic patients. We conclude that euglycaemic, slightly hyperinsulinaemic, insulin-dependent diabetes mellitus patients with and without hypertension are characterized by higher baseline ANF values and an impaired response to an acute saline load as shown by the sodium excretion rate and the plasma ANF concentration.