Updated and new perspectives on diagnosis, prognosis, and therapy of malignant pheochromocytoma/paraganglioma.

Malignant pheochromocytomas/paragangliomas are rare tumors with a poor prognosis. Malignancy is diagnosed by the development of metastases as evidenced by recurrences in sites normally devoid of chromaffin tissue. Histopathological, biochemical, molecular and genetic markers offer only information on potential risk of metastatic spread. Large size, extraadrenal location, dopamine secretion, SDHB mutations, a PASS score higher than 6, a high Ki-67 index are indexes for potential malignancy. Metastases can be present at first diagnosis or occur years after primary surgery. Measurement of plasma and/or urinary metanephrine, normetanephrine and metoxytyramine are recommended for biochemical diagnosis. Anatomical and functional imaging using different radionuclides are necessary for localization of tumor and metastases. Metastatic pheochromocytomas/paragangliomas is incurable. When possible, surgical debulking of primary tumor is recommended as well as surgical or radiosurgical removal of metastases. I-131-MIBG radiotherapy is the treatment of choice although results are limited. Chemotherapy is reserved to more advanced disease stages. Recent genetic studies have highlighted the main pathways involved in pheochromocytomas/paragangliomas pathogenesis thus suggesting the use of targeted therapy which, nevertheless, has still to be validated. Large cooperative studies on tissue specimens and clinical trials in large cohorts of patients are necessary to achieve better therapeutic tools and improve patient prognosis

The +276 G/T Single Nucleotide Polymorphism of the Adiponectin Gene Is Associated With Coronary Artery Disease in Type 2 Diabetic Patients

OBJECTIVE —Two single nucleotide polymorphisms (SNPs) at the adiponectin locus (+45T>G and +276G>T) have been associated with low circulating adiponectin levels, insulin resistance, and type 2 diabetes. We investigated whether these genetic markers are determinants of coronary artery disease (CAD) in type 2 diabetic patients. RESEARCH DESIGN AND METHODS —A total of 376 consecutive type 2 diabetic patients were studied: 142 case subjects with coronary stenosis >50% or previous myocardial infarction and 234 control subjects with no symptoms, no electrocardiogram (ECG) signs of myocardial ischemia, and a normal ECG stress test ( n = 189) and/or ( n = 45) with coronary stenosis ≤50%. RESULTS —No association with CAD was observed for the +45 SNP ( P = 0.48). By contrast, a significant association was observed for the +276 SNP, with T/T homozygotes having a lower risk of CAD than carriers of other genotypes (adjusted odds ratio [OR] 0.13 [95% CI 0.037–0.46], P = 0.002). A similarly protective effect of the +276 T/T genotype was observed in 110 case and 45 control subjects for whom the CAD status had been determined by angiography (0.04 [0.006–0.30], P = 0.002).  Serum adiponectin, although clearly related to several features of the proatherogenic/insulin-resistant phenotype, was not different between control subjects and CAD patients (26 ± 17 vs. 25 ± 13 μg/ml). CONCLUSIONS —In conclusion, the +276 G>T polymorphism is a determinant of CAD risk in type 2 diabetic patients. This marker may assist in the identification of diabetic individuals at especially high risk of CAD, so that preventive programs can be targeted at these subjects

Prognostic and monitoring value of circulating tumour cells in adrenocortical carcinoma: a preliminary monocentric study.

Adrenocortical carcinoma (ACC), a rare and aggressive neoplasia, presents poor prognosis when metastatic at diagnosis and limited therapies are available. Specific and sensitive markers for early diagnosis and a monitoring system of therapy and tumor evolution are urgently needed. The liquid biopsy represents a source of tumor material within a minimally invasive blood draw that allows the recovery of circulating tumor cells (CTCs). CTCs have been recently shown to be detectable in ACC. In the present paper, we evaluated the prognostic value of CTCs obtained by size-filtration in a small pilot cohort of 19 ACC patients. We found CTCs in 68% of pre-surgery and in 38% of post-surgery blood samples. In addition, CTC clusters (CTMs) and cancer associated macrophages (CAMLs) were detectable in some ACC patients. The median number of CTCs significantly decreased after the mass removal. Finally, stratifying patients in high and low pre-surgery CTC number groups, assuming the 75th percentile CTC value as cut-off, CTCs significantly predicted patients’ overall survival (log rank = 0.005), also in a multivariate analysis adjusted for age and tumor stage. In conclusion, though preliminary and performed in a small cohort of patients, our study suggests that CTC number may represent a promising marker for prognosis and disease monitoring in ACC

A case of carotid body paraganglioma and haemangioblastoma of the spinal cord in a patient with the N131K missense mutation in the VHL gene

The article describes paraganglioma case in woman with von Hippel–Lindau disease. She was found to be a carrier of a rare germline mutation in the VHL gene (393C>A; N131K). The patient developed large, untypical for von Hippel–Lindau disease, carotid body paraganglioma at the common carotid artery bifurcation. The carotid body paraganglioma coexisted with the haemangioblastoma situated intramedullary in region C5/C6. The haemangioblastoma reached the right-sided dorsal part of the spinal cord in section C5/C6. It produced radicular symptoms within C5/C6, followed by the later paresis of the right limbs. The haemangioblastoma was resected completely. Twelve months after the operation, the spinal symptoms receded and the carotid body paraganglioma still was asymptomatic. The current case of carotid body paraganglioma in patient with the 393C>A (N131K) missense mutation in the VHL gene, supports association of this specific mutation and VHL disease type 2, and suggests its correlation with susceptibility to paragangliomas

A multicenter epidemiological study on second malignancy in non-syndromic pheochromocytoma/paraganglioma patients in Italy

SIMPLE SUMMARY: As no previous studies had assessed the risk of second malignant tumors in patients with pheochromocytomas/paragangliomas (PPGLs), we aimed to evaluate whether these patients could have an increased risk of additional malignancy, comparing them with patients in the general population who had a first malignancy and developed a second malignant tumor. We demonstrated that PPGL patients had higher incidence of additional malignant tumors and the risk of developing a second malignant tumor increased with age at diagnosis. As the main tumors were prostate, colorectal and lung/bronchial cancers in males, and breast cancer, differentiated thyroid cancer and melanoma in females, our findings could have an impact on the surveillance strategy. ABSTRACT: No studies have carried out an extensive analysis of the possible association between non-syndromic pheochromocytomas and paragangliomas (PPGLs) and other malignancies. To assess >the risk of additional malignancy in PPGL, we retrospectively evaluated 741 patients with PPGLs followed-up in twelve referral centers in Italy. Incidence of second malignant tumors was compared between this cohort and Italian patients with two subsequent malignancies. Among our patients, 95 (12.8%) developed a second malignant tumor, which were mainly prostate, colorectal and lung/bronchial cancers in males, breast cancer, differentiated thyroid cancer and melanoma in females. The standardized incidence ratio was 9.59 (95% CI 5.46–15.71) in males and 13.21 (95% CI 7.52–21.63) in females. At multivariable analysis, the risk of developing a second malignant tumor increased with age at diagnosis (HR 2.50, 95% CI 1.15–5.44, p = 0.021 for 50–59 vs. 60- vs. <50-year). In patients with available genetic evaluation, a positive genetic test was inversely associated with the risk of developing a second tumor (HR 0.25, 95% CI 0.10–0.63, p = 0.003). In conclusion, PPGLs patients have higher incidence of additional malignant tumors compared to the general population who had a first malignancy, which could have an impact on the surveillance strategy

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

Genome Instability and Cance

An ultrahot Neptune in the Neptune desert

About one out of 200 Sun-like stars has a planet with an orbital period shorter than one day: an ultra-short-period planet (Sanchis-ojeda et al. 2014; Winn et al. 2018). All of the previously known ultra-short-period planets are either hot Jupiters, with sizes above 10 Earth radii (Re), or apparently rocky planets smaller than 2 Re. Such lack of planets of intermediate size (the "hot Neptune desert") has been interpreted as the inability of low-mass planets to retain any hydrogen/helium (H/He) envelope in the face of strong stellar irradiation. Here, we report the discovery of an ultra-short-period planet with a radius of 4.6 Re and a mass of 29 Me, firmly in the hot Neptune desert. Data from the Transiting Exoplanet Survey Satellite (Ricker et al. 2015) revealed transits of the bright Sun-like star \starname\, every 0.79 days. The planet's mean density is similar to that of Neptune, and according to thermal evolution models, it has a H/He-rich envelope constituting 9.0^(+2.7)_(-2.9)% of the total mass. With an equilibrium temperature around 2000 K, it is unclear how this "ultra-hot Neptune" managed to retain such an envelope. Follow-up observations of the planet's atmosphere to better understand its origin and physical nature will be facilitated by the star's brightness (Vmag=9.8)

Toi-1235 b: A keystone super-earth for testing radius valley emergence models around early m dwarfs

Small planets on close-in orbits tend to exhibit envelope mass fractions of either effectively zero or up to a few percent depending on their size and orbital period. Models of thermally-driven atmospheric mass loss and of terrestrial planet formation in a gas-poor environment make distinct predictions regarding the location of this rocky/non-rocky transition in period-radius space. Here we present the confirmation of TOI-1235 b ($P=3.44$ days, $r_p=1.738^{+0.087}_{-0.076}$ R$_{\oplus}$), a planet whose size and period are intermediate between the competing model predictions, thus making the system an important test case for emergence models of the rocky/non-rocky transition around early M dwarfs ($R_s=0.630\pm 0.015$ R$_{\odot}$, $M_s=0.640\pm 0.016$ M$_{\odot}$). We confirm the TESS planet discovery using reconnaissance spectroscopy, ground-based photometry, high-resolution imaging, and a set of 38 precise radial-velocities from HARPS-N and HIRES. We measure a planet mass of $6.91^{+0.75}_{-0.85}$ M$_{\oplus}$ which implies an iron core mass fraction of $20^{+15}_{-12}$% in the absence of a gaseous envelope. The bulk composition of TOI-1235 b is therefore consistent with being Earth-like and we constrain a H/He envelope mass fraction to be $<0.5$% at 90% confidence. Our results are consistent with model predictions from thermally-driven atmospheric mass loss but not with gas-poor formation, which suggests that the former class of processes remain efficient at sculpting close-in planets around early M dwarfs. Our RV analysis also reveals a strong periodicity close to the first harmonic of the photometrically-determined stellar rotation period that we treat as stellar activity, despite other lines of evidence favoring a planetary origin ($P=21.8^{+0.9}_{-0.8}$ days, $m_p\sin{i}=13.0^{+3.8}_{-5.3}$ M$_{\oplus}$) that cannot be firmly ruled out by our data

TOI-1235 b: A Keystone Super-Earth For Testing Radius Valley Emergence Models Around Early M Dwarfs

Small planets on close-in orbits tend to exhibit envelope mass fractions of either effectively zero or up to a few percent depending on their size and orbital period. Models of thermally driven atmospheric mass loss and of terrestrial planet formation in a gas-poor environment make distinct predictions regarding the location of this rocky/nonrocky transition in period–radius space. Here we present the confirmation of TOI-1235 b (P = 3.44 days, ${r}_{{\rm{p}}}={1.738}_{-0.076}^{+0.087}$ ${R}_{\oplus }$), a planet whose size and period are intermediate between the competing model predictions, thus making the system an important test case for emergence models of the rocky/nonrocky transition around early M dwarfs (R s = 0.630 ± 0.015 ${R}_{\odot }$, M s = 0.640 ± 0.016 ${M}_{\odot }$). We confirm the TESS planet discovery using reconnaissance spectroscopy, ground-based photometry, high-resolution imaging, and a set of 38 precise radial velocities (RVs) from HARPS-N and HIRES. We measure a planet mass of ${6.91}_{-0.85}^{+0.75}$ ${M}_{\oplus }$, which implies an iron core mass fraction of ${20}_{-12}^{+15}$% in the absence of a gaseous envelope. The bulk composition of TOI-1235 b is therefore consistent with being Earth-like, and we constrain an H/He envelope mass fraction to be \u3c0.5% at 90% confidence. Our results are consistent with model predictions from thermally driven atmospheric mass loss but not with gas-poor formation, suggesting that the former class of processes remains efficient at sculpting close-in planets around early M dwarfs. Our RV analysis also reveals a strong periodicity close to the first harmonic of the photometrically determined stellar rotation period that we treat as stellar activity, despite other lines of evidence favoring a planetary origin ($P={21.8}_{-0.8}^{+0.9}$ days, ${m}_{{\rm{p}}}\sin i={13.0}_{-5.3}^{+3.8}$ ${M}_{\oplus }$) that cannot be firmly ruled out by our data