Evaluation of bone mineral density (BMD) and trabecular bone score (TBS) in pheochromocytoma and paraganglioma; a multi-centric case-control study from India.

Pheochromocytoma and paraganglioma (PPGL) have been associated with low bone mineral density (BMD) due to excess sympathetic system stimulation. Our study revealed low BMD and TBS (trabecular bone score) in cases compared to matched controls. Plasma-free nor-metanephrine and hypertension duration found to be most consistent predictive factors. PURPOSE: Pheochromocytoma and paraganglioma (PPGL) have been associated with low bone mineral density (BMD) and increased fracture risks. Sympathetic nervous system stimulation has been shown to increase bone resorption and decrease bone formation via ß2 receptors. Chronic inflammation and increased cytokine production add to more bone loss. TBS (trabecular bone score) is an established surrogate marker for bone histomorphometry. BMD and TBS data in pheochromocytoma and PPGL are scarce. The aim was to assess the BMD and TBS in pheochromocytoma and PPGL and look for clinical and biochemical predictors. METHODS: This case-control study had sample size of 58 (29 cases and controls each). BMI-, age-, and sex-matched controls were taken for comparison. Both cases and controls had undergone DXA scan and BMD {Z-scores and bone mineral concentration (BMC) in g/cm2} and TBS were analyzed. Detailed clinical histories and relevant biochemistry values were noted. RESULTS: The mean age of our case population was 29.5 ± 9.4 years with a mean age of HTN onset at 26.86 ± 6.6 years. Lumbar spine BMC (0.86 ± 0.14 vs 0.96 ± 0.15; p = 0.036), femoral neck Z-score (- 1.23 ± 1.07 vs - 0.75 ± 0.97; p = 0.003), and whole body BMC (0.91 ± 0.14 vs 1.07 ± 0.11; p = 0.000) were significantly low in cases compared to controls. Similarly, TBS was significantly lower in cases compared to controls (1.306 ± 0.113 vs 1.376 ± 0.083; p = 0.001). CONCLUSION: This study establishes both low bone mass and poor bone quality in an Indian pheochromocytoma and PPGL patient's cohort. Plasma-free nor-metanephrine and duration of hypertension were found to be most consistent predictive factors in multivariate regression analysis.

Deteriorated bone microarchitecture caused by sympathetic overstimulation in pheochromocytoma and paraganglioma.

PURPOSE: Despite the potentially destructive effect of sympathetic activity on bone metabolism, its impact on bone microarchitecture, a key determinant of bone quality, has not been thoroughly investigated. This study aims to evaluate the impact of sympathetic activity on bone microarchitecture and bone strength in patients with pheochromocytoma and paraganglioma (PPGL). METHODS: A cross-sectional study was conducted in 38 PPGL patients (15 males and 23 females). Bone turnover markers serum procollagen type 1 N-terminal propeptide (P1NP) and ß-carboxy-terminal crosslinked telopeptide of type 1 collagen (ß-CTX) were measured. 24-h urinary adrenaline (24hUE) and 24-h urinary norepinephrine levels (24hUNE) were measured to indicate sympathetic activity. High-resolution peripheral quantitative computed tomography (HR-pQCT) was conducted to evaluate bone microarchitecture in PPGL patients and 76 age-, sex-matched healthy controls (30 males and 46 females). Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry (DXA) simultaneously. RESULTS: PPGL patients had a higher level of ß-CTX. HR-pQCT assessment revealed that PPGL patients had notably thinner and more sparse trabecular bone (decreased trabecular number and thickness with increased trabecular separation), significantly decreased volume BMD (vBMD), and bone strength at both the radius and tibia compared with healthy controls. The deterioration of Tt.vBMD, Tb.Sp, and Tb.1/N.SD was more pronounced in postmenopausal patients compared with the premenopausal subjects. Moreover, subjects in the highest 24hUNE quartile (Q4) showed markedly lower Tb.N and higher Tb.Sp and Tb.1/N.SD at the tibia than those in the lowest quartile (Q1). Age-related bone loss was also exacerbated in PPGL patients to a certain extent. CONCLUSIONS: PPGL patients had significantly deteriorated bone microarchitecture and strength, especially in the trabecular bone, with an increased bone resorption rate. Our findings provide clinical evidence that sympathetic overstimulation may serve as a secondary cause of osteoporosis, especially in subjects with increased sympathetic activity.

Risk of metastatic pheochromocytoma and paraganglioma in SDHx mutation carriers: a systematic review and updated meta-analysis.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are tumours that arise from chromaffin cells. Some genetic mutations influence PPGL, among which, those in genes encoding subunits of succinate dehydrogenase (SDHA, SDHB, SDHC and SDHD) and assembly factor (SDHAF2) are the most relevant. However, the risk of metastasis posed by these mutations is not reported except for SDHB and SDHD mutations. This study aimed to update the metastatic risks, considering prevalence and incidence of each SDHx mutation, which were dealt formerly all together. METHODS: We searched EMBASE and MEDLINE and selected 27 articles. The patients included in the studies were divided into three groups depending on the presence of PPGL. We checked the heterogeneity between studies and performed a meta-analysis using Hartung-Knapp-Sidik-Jonkman method based on a random effect model. RESULTS: The highest PPGL prevalence was for SDHB mutation, ranging from 23% to 31%, and for SDHC mutation (23%), followed by that for SDHA mutation (16%). The lowest prevalence was for SDHD mutation, ranging from 6% to 8%. SDHAF2 mutation showed no metastatic events. The PPGL incidence showed a tendency similar to that of its prevalence with the highest risk of metastasis posed by SDHB mutation (12%-41%) and the lowest risk by SDHD mutation (~4%). CONCLUSION: There was no integrated evidence of how SDHx mutations are related to metastatic PPGL. However, these findings suggest that SDHA, SDHB and SDHC mutations are highly associated and should be tested as indicators of metastasis in patients with PPGL.

Intrarenal hemodynamics and kidney function in pheochromocytoma and paraganglioma before and after surgical treatment.

PURPOSE: Current evidence regarding renal involvement in pheochromocytoma and paraganglioma (PPGL) is scant. More accurate diagnostic methods, such as renal Doppler ultrasound for intrarenal hemodynamic studies, may provide more detailed information on renal function. It might be postulated that renal function in PPGL patients might be altered by high blood pressure and excess secretion of catecholamines. The aim of this prospective study was to assess intrarenal blood flow parameters in PPGL patients included in the prospective monoamine-producing tumour (PMT) study and to evaluate the effects of normalisation of catecholamine production after surgical treatment on long-term renal function. MATERIALS AND METHODS: Seventy consecutive patients (aged 46.5 ± 14.0 years) with PPGL were included. Forty-eight patients from the PMT study cohort, matched for age, gender, blood pressure level and presence of hypertension, served as a control group. Renal artery doppler ultrasound spectral analysis included mean resistance index (RRI) and pulsatility index (PI). Forty-seven patients completed 12 months follow-up. RESULTS: There were no differences in renal parameters such as RRI, PI and kidney function between PPGL and non-PPGL patients as assessed by renal ultrasound, serum creatinine, eGFR and albumin excretion rate. No correlations between kidney function parameters, intrarenal doppler flow parameters and plasma catecholamines were observed in PPGL patients. At 12 months after surgery, no differences in creatinine level, eGFR, albumin excretion rate, RI and PI were found as compared to baseline results. CONCLUSIONS: In contrast to patients with other forms of secondary hypertension, our study did not show differences in intrarenal blood flow parameters and renal function between PPGL and non-PPGL subjects. Intrarenal hemodynamics and renal function did not change after normalisation of catecholamine levels by surgical treatment.

Simple, rapid, and cost-effective microextraction by the packed sorbent method for quantifying of urinary free catecholamines and metanephrines using liquid chromatography-tandem mass spectrometry and its application in clinical analysis.

Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors arising from adrenal and extra-adrenal chromaffin cells. They produce excessive amounts of catecholamines and their metabolites. A newly analytical procedure based on the semi-automated microextraction by packed sorbent (MEPS) technique, using a digitally controlled syringe (eVol) combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS), was developed to quantify free urinary catecholamines and metanephrines. The important parameters affecting MEPS performance, namely the type of sorbent material (porous graphitized carbon (PGC), polar enhanced polymer (PEP), cation-exchange (CX) and C18), number of extraction cycles, and elution solvent system, were evaluated. The optimal experimental conditions involved the loading of sample mixture in seven extraction cycles through a C18 sorbent in a MEPS syringe, followed by using elution solutions (water/acetonitrile/formic acid, 95/4.75/0.25). The entire sample preparation took about 4 min. Chromatographic separation was well achieved with an HSS PFP column using the gradient elution. The linearity range of the method was 0.167-33.4 ng/mL for epinephrine, 0.650-130 ng/mL for norepinephrine, 1.53-306 ng/mL for dopamine, 1.34-268 ng/mL for metanephrine, 3.43-686 ng/mL for normetanephrine, and 1.33-265 ng/mL for 3-methoxytyramine. The intra- and interassay precisions were ≤ 12.8%, and the respective accuracies were 88.4-112.0% and 89.0-109.5%. The carryover and sample stability without acidification were also investigated. Validation using clinical urine specimens showed that the proposed method had higher sensitivity compared with other urinary biochemical tests. The developed MEPS-LC-MS/MS method was simple, fast, and cost-effective; it helped to obtain information about multiple metabolites. It is applicable in routine clinical laboratories for the screening of PPGL. Graphical abstract.

Anti-Tumor Activity vs. Normal Cell Toxicity: Therapeutic Potential of the Bromotyrosines Aerothionin and Homoaerothionin In Vitro.

Novel strategies to treat cancer effectively without adverse effects on the surrounding normal tissue are urgently needed. Marine sponges provide a natural and renewable source of promising anti-tumor agents. Here, we investigated the anti-tumor activity of Aerothionin and Homoaerothionin, two bromotyrosines isolated from the marine demosponge Aplysina cavernicola, on two mouse pheochromocytoma cells, MPC and MTT. To determine the therapeutic window of these metabolites, we furthermore explored their cytotoxicity on cells of the normal tissue. Both metabolites diminished the viability of the pheochromocytoma cell lines significantly from a concentration of 25 µM under normoxic and hypoxic conditions. Treatment of MPC cells leads moreover to a reduction in the number of proliferating cells. To confirm the anti-tumor activity of these bromotyrosines, 3D-pheochromocytoma cell spheroids were treated with 10 µM of either Aerothionin or Homoaerothionin, resulting in a significant reduction or even complete inhibition of the spheroid growth. Both metabolites reduced viability of normal endothelial cells to a comparable extent at higher micromolar concentration, while the viability of fibroblasts was increased. Our in vitro results show promise for the application of Aerothionin and Homoaerothionin as anti-tumor agents against pheochromocytomas and suggest acceptable toxicity on normal tissue cells.

Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients.

PURPOSE: MDH2 (malate dehydrogenase 2) has recently been proposed as a novel potential pheochromocytoma/paraganglioma (PPGL) susceptibility gene, but its role in the disease has not been addressed. This study aimed to determine the prevalence of MDH2 pathogenic variants among PPGL patients and determine the associated phenotype. METHODS: Eight hundred thirty patients with PPGLs, negative for the main PPGL driver genes, were included in the study. Interpretation of variants of unknown significance (VUS) was performed using an algorithm based on 20 computational predictions, by implementing cell-based enzymatic and immunofluorescence assays, and/or by using a molecular dynamics simulation approach. RESULTS: Five variants with potential involvement in pathogenicity were identified: three missense (p.Arg104Gly, p.Val160Met and p.Ala256Thr), one in-frame deletion (p.Lys314del), and a splice-site variant (c.429+1G>T). All were germline and those with available biochemical data, corresponded to noradrenergic PPGL. CONCLUSION: This study suggests that MDH2 pathogenic variants may play a role in PPGL susceptibility and that they might be responsible for less than 1% of PPGLs in patients without pathogenic variants in other major PPGL driver genes, a prevalence similar to the one recently described for other PPGL genes. However, more epidemiological data are needed to recommend MDH2 testing in patients negative for other major PPGL genes.

Anti-Tumorigenic and Anti-Metastatic Activity of the Sponge-Derived Marine Drugs Aeroplysinin-1 and Isofistularin-3 against Pheochromocytoma In Vitro.

Over 10% of pheochromocytoma and paraganglioma (PPGL) patients have malignant disease at their first presentation in the clinic. Development of malignancy and the underlying molecular pathways in PPGLs are poorly understood and efficient treatment strategies are missing. Marine sponges provide a natural source of promising anti-tumorigenic and anti-metastatic agents. We evaluate the anti-tumorigenic and anti-metastatic potential of Aeroplysinin-1 and Isofistularin-3, two secondary metabolites isolated from the marine sponge Aplysina aerophoba, on pheochromocytoma cells. Aeroplysinin-1 diminished the number of proliferating cells and reduced spheroid growth significantly. Beside these anti-tumorigenic activity, Aeroplysinin-1 decreased the migration ability of the cells significantly (p = 0.01), whereas, the invasion capacity was not affected. Aeroplysinin-1 diminished the high adhesion capacity of the MTT cells to collagen (p < 0.001) and, furthermore, reduced the ability to form spheroids significantly. Western Blot and qRT-PCR analysis showed a downregulation of integrin ß1 that might explain the lower adhesion and migration capacity after Aeroplysinin-1 treatment. Isofistularin-3 showed only a negligible influence on proliferative and pro-metastatic cell properties. These in vitro investigations show promise for the application of the sponge-derived marine drug, Aeroplysinin-1 as anti-tumorigenic and anti-metastatic agent against PPGLs for the first time.

Opposing effects of HIF1α and HIF2α on chromaffin cell phenotypic features and tumor cell proliferation: Insights from MYC-associated factor X.

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 HIF2α and HIF1α, 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 HIF2α and mature phenotypic features and the other with high expression of HIF2α 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 Hif2α, overexpression of the gene led to immature phenotypic features, failure of dexamethasone to induce differentiation and increased proliferation. HIF1α had opposing actions to HIF2α 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 HIF2α 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.

Opposing effects of cannabidiol in patient-derived neuroendocrine tumor, pheochromocytoma/paraganglioma primary cultures.

CONTEXT: Treatment options for advanced neuroendocrine tumors (NETs), pheochromocytomas and paragangliomas (together PPGLs) are still limited. In recent years, anti-tumor effects of cannabinoids have been reported; however, there are only very limited data available in NETs or PPGLs. OBJECTIVE: Investigation of the effects of cannabidiol (CBD) on patient-derived human NET/PPGL primary cultures and on NET/PPGL cell lines. METHODS: We established primary cultures derived from 46 different patients with PPGLs (n = 35) or NETs (n = 11) who underwent tumor resection at two centers. Treatment of patient primary cultures with clinically relevant doses (5 µM) and slightly higher doses (10 µM) of CBD was performed. RESULTS: We found opposing effects of 5 µM CBD: significant anti-tumor effects in 5/35 (14%) and significant tumor-promoting effects in 6/35 (17%) of PPGL primary cultures. In terms of anti-tumor effects, cluster 2-related PPGLs showed significantly stronger responsivity to CBD compared to cluster 1-related PPGLs (p = 0.042). Of the cluster 2-related tumors, NF1 PPGLs showed strongest responsivity (4/5 PPGL primary cultures with a significant decrease in cell viability were NF1-mutated). We also found opposing effects of 10 µM CBD in PPGLs and NETs: significant anti-tumor effects in 9/33 of PPGL (27%) and 3/11 of NET (27%) primary cultures, significant tumor-promoting effects in 6/33 of PPGL (18%) and 2/11 of NET (18%) primary cultures. CONCLUSIONS: We suggest a potential novel treatment option for some NETs/PPGLs, but also provide evidence for caution when applying cannabinoids as supportive therapy for pain or appetite management to cancer patients, and possibly as health supplements.

Adrenal pheochromocytoma impacts three main pathways: cysteine-methionine, pyrimidine, and tyrosine metabolism. / è‚¾ä¸Šè ºå—œé“¬ç»†èƒžç˜¤å½±å“ä¸‰æ¡ä¸»è¦ä»£è°¢é€šè·¯ï¼šåŠèƒ±æ°¨é ¸-è›‹æ°¨é ¸ä»£è°¢ã€å˜§å•¶ä»£è°¢å’Œé ªæ°¨é ¸ä»£è°¢é€šè·¯.

Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.

Right adrenal giant cystic pheochromocytoma: A case report.

A 78-year-old woman was referred to our institution for evaluation and treatment of a mass on her right adrenal gland measuring 12 × 11 × 10 cm. Twenty-four-hour urine analysis revealed a total metanephrine level over 3 times the upper limit of normal. Scintigraphy using 123I-metaiodobenzylguanidine was positive. The mass was resected en bloc by laparotomy after a laparoscopic attempt was unsuccessful. Histopathologic examination revealed a pheochromocytoma of the right adrenal gland, weighing 576 g. The Grading System for Adrenal Pheochromocytoma and Paraganglioma score was 6, and the histology of the tumor was a moderately differentiated type.

External Beam Radiotherapy in Advanced Pheochromocytoma and Paraganglioma: An Observation of a Rare Abscopal Effect.

Metastatic pheochromocytoma and paraganglioma are incurable, and effective treatment of systemic symptoms resulting from catecholamine excess and local symptoms from tumor growth are crucial to prolong survival and improve quality of life. We report the first case of metastatic pheochromocytoma wherein external beam radiotherapy (EBRT) demonstrated efficacy in both target and nontarget lesions, demonstrating the "abscopal effect." EBRT reduced tumor volume and catecholamine secretion and improved catecholamine excess-related complications, including glycemic control. EBRT is an effective treatment option for metastatic pheochromocytoma and paraganglioma because of its minimal invasiveness, safety, and potential for the rare abscopal effect.

Paraganglioma with High Levels of Dopamine, Dopa Decarboxylase Suppression, Dopamine ß-hydroxylase Upregulation and Intra-tumoral Melanin Accumulation: A Case Report with a Literature Review.

Object Exclusively dopamine-producing pheochromocytoma/paraganglioma (PPGL) is an extremely rare subtype. In this condition, intratumoral dopamine ß-hydroxylase (DBH), which controls the conversion of norepinephrine from dopamine, is impaired, resulting in suppressed norepinephrine and epinephrine production. However, the rarity of this type of PPGL hampers the understanding of its pathophysiology. We therefore conducted genetic and immunohistological analyses of a patient with an exclusively dopamine-producing paraganglioma. Methods Paraganglioma samples from a 52-year-old woman who presented with a 29.6- and 41.5-fold increase in plasma and 24-h urinary dopamine, respectively, but only a minor elevation in the plasma norepinephrine level was subjected to immunohistological and gene expression analyses of catecholamine synthases. Three tumors carrying known somatic PPGL-related gene variants (HRAS, EPAS1) were used as controls. Whole-exome sequencing (WES) was also performed using the patient's blood and tumor tissue. Results Surprisingly, the protein expression of DBH was not suppressed, and its mRNA expression was clearly higher in the patient than in the controls. Furthermore, dopa decarboxylase (DDC), which governs the conversion of 3,4-dihydroxyphenyl-L-alanine (L-DOPA) to dopamine, was downregulated at the protein and gene levels. In addition, melanin, which is synthesized by L-DOPA, accumulated in the tumor. WES revealed no PPGL-associated pathogenic germline variants, but a missense somatic variant (c.1798G>T) in CSDE1 was identified. Conclusion Although pre-operative plasma L-DOPA was not measured, our histological and gene expression analyses suggest that L-DOPA, rather than dopamine, might have been overproduced in the tumor. This raises the possibility of pathophysiological heterogeneity in exclusively dopamine-producing PPGL.

Early short-term effects on catecholamine levels and pituitary function in patients with pheochromocytoma or paraganglioma treated with [177Lu]Lu-DOTA-TATE therapy.

Purpose: While there are reports of treatment-related endocrine disruptions and catecholamine surges in pheochromocytoma/paraganglioma (PPGL) patients treated with [177Lu]Lu-DOTA-TATE therapy, the spectrum of these abnormalities in the immediate post-treatment period (within 48 hours) has not been previously evaluated and is likely underestimated. Methods: The study population included patients (≥18 years) enrolled in a phase 2 trial for treatment of somatostatin receptor (SSTR)-2+ inoperable/metastatic pheochromocytoma/paraganglioma with [177Lu]Lu-DOTA-TATE (7.4 GBq per cycle for 1 - 4 cycles). Hormonal measurements [adrenocorticotropic hormone (ACTH), cortisol, thyroid stimulating hormone (TSH), free thyroxine (FT4), follicle stimulating hormone (FSH), luteinizing hormone (LH), testosterone, estradiol, growth hormone, prolactin], catecholamines, and metanephrines were obtained on days-1, 2, 3, 30, and 60 per cycle as per trial protocol, and were retrospectively analyzed. Results: Among the 27 patients (age: 54 ± 12.7 years, 48.1% females) who underwent hormonal evaluation, hypoprolactinemia (14.1%), elevated FSH (13.1%), and elevated LH (12.5%) were the most frequent hormonal abnormalities across all 4 cycles combined. On longitudinal follow-up, significant reductions were noted in i. ACTH without corresponding changes in cortisol, ii. TSH, and FT4, and iii. prolactin at or before day-30 of [177Lu]Lu-DOTA-TATE. No significant changes were observed in the gonadotropic axis and GH levels. Levels of all hormones on day-60 were not significantly different from day-1 values, suggesting the transient nature of these changes. However, two patients developed clinical, persistent endocrinopathies (primary hypothyroidism: n=1 male; early menopause: n=1 female). Compared to day-1, a significant % increase in norepinephrine, dopamine, and normetanephrine levels were noted at 24 hours following [177Lu]Lu-DOTA-TATE dose and peaked within 48 hours. Conclusions: [177Lu]Lu-DOTA-TATE therapy is associated with alterations in endocrine function likely from radiation exposure to SSTR2+ endocrine tissues. However, these changes may sometimes manifest as clinically significant endocrinopathies. It is therefore important to periodically assess endocrine function during [177Lu]Lu-DOTA-TATE therapy, especially among symptomatic patients. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03206060?term=NCT03206060&draw=2&rank=1, identifier NCT03206060.

Lutathera® Orphans: State of the Art and Future Application of Radioligand Therapy with 177Lu-DOTATATE.

Lutathera® is the first EMA- and FDA-approved radiopharmaceutical for radioligand therapy (RLT). Currently, on the legacy of the NETTER1 trial, only adult patients with progressive unresectable somatostatin receptor (SSTR) positive gastroenteropancreatic (GEP) neuroendocrine neoplasms (NET) can be treated with Lutathera®. Conversely, patients with SSTR-positive disease arising from outside the gastroenteric region do not currently have access to Lutathera® treatment despite several papers in the literature reporting the effectiveness and safety of RLT in these settings. Moreover, patients with well-differentiated G3 GEP-NET are also still "Lutathera orphans", and retreatment with RLT in patients with disease relapse is currently not approved. The aim of this critical review is to summarize current literature evidence assessing the role of Lutathera® outside the approved indications. Moreover, ongoing clinical trials evaluating new possible applications of Lutathera® will be considered and discussed to provide an updated picture of future investigations.

Preclinical evaluation of targeted therapies in Sdhb-mutated tumors.

Therapies for metastatic SDHB-dependent pheochromocytoma and paraganglioma (PPGL) are limited and poorly efficient. New targeted therapies and identification of early non-invasive biomarkers of response are thus urgently needed for these patients. We characterized an in vivo allograft model of spontaneously immortalized murine chromaffin cells (imCC) with inactivation of the Sdhb gene by dynamic contrast-enhanced MRI (DCE-MRI) and 18FDG-PET. We evaluated the response to several therapies: IACS-010759 (mitochondrial respiratory chain complex I inhibitor), sunitinib (tyrosine kinase inhibitor with anti-angiogenic activity), talazoparib (poly ADP ribose polymerase (PARP) inhibitor) combined or not to temozolomide (alkylating agent), pharmacological inhibitors of HIF2a (PT2385 and PT2977 (belzutifan)) and molecular inactivation of HIF2a (imCC Sdhb-/- shHIF2a). Multimodal imaging was performed, including magnetic resonance spectroscopy (1H-MRS) to monitor the level of succinate in vivo. The allografted model of Sdhb-/- imCC reflected SDHB-deficient tumors, with increased angiogenesis and a particular avidity for 18FDG. After 14 days of treatment, IACS-010759, sunitinib and talazoparib at high doses allowed a significant reduction of the tumor volumes. In contrast to the tumor growth inhibition observed in Sdhb-/- shHIF2a imCC tumors, pharmacological inhibitors of HIF2a (PT2385 and belzutifan) showed no antitumor action in this model, alone or in combination with sunitinib. 1H-MRS, but not DCE-MRI, enabled the monitoring response to sunitinib, which was the best treatment in this study, promoting a decrease in succinate levels detected in vivo. This study paves the way for new therapeutic options and reveals a potential new early biomarker of response to treatment in SDHB-dependent PPGL.

Prognostic factors for refractory pheochromocytoma and paraganglioma after 131I-metaiodobenzylguanidine therapy.

OBJECTIVE: Given the rarity of refractory pheochromocytoma and paraganglioma (PPGL), outcomes and prognostic factors after 131I-metaiodobenzylguanidine (131I-mIBG) treatment still remain unclear. Therefore, this study evaluated whether baseline characteristics at initial 131I-mIBG therapy and imaging response to repeated 131I-mIBG therapy could be prognostic factors for refractory PPGL. METHODS: All patients [n = 59 (male/female = 35/24), median age; 49.3 years] with refractory PPGL who received 131I-mIBG therapy at our institution between September 2009 and September 2019 were retrospectively reviewed for the effects of the following factors on overall survival: age, sex, hypertension, diabetes mellitus, palpitations, constipation, cancer pain, catecholamines values, past history of therapy (external beam radiation for bone metastasis, operation, and chemotherapy), metastasis sites, and response to 131I-mIBG treatments. RESULTS: Throughout the follow-up period, 18 patients died from disease exacerbation. The estimated 5- and 10-year survival rates were 79.4% and 67.2% from the initial diagnoses of refractory PPGL and 68.5% and 49.9% from the first 131I-mIBG therapy, respectively. The multivariate Cox proportional hazards model showed that progressive disease (PD) [hazard ratio (HR) 96.3, P = 0.011] and constipation (HR 8.2, P = 0.024) were adverse prognostic factors for overall survival after initial 131I-mIBG therapy. The log-rank test demonstrated that PD in response to 131I-mIBG therapies (P < 0.0001) and constipation (P < 0.01) were correlated with poor survival rates. CONCLUSIONS: Response to repeated 131I-mIBG treatment can be a strong predictor of prognosis after initial 131I-mIBG therapy for refractory PPGL. Repeated 131I-mIBG therapy may be a good option for controlling refractory PPGL.

Comprehensive analysis of tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2): A potential novel pan-cancer immune checkpoint.

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

Comprehensive analysis of the novel omicron receptor AXL in cancers.

The SARS-CoV-2 is constantly mutating, and the new coronavirus such as Omicron has spread to many countries around the world. Anexelekto (AXL) is a transmembrane protein with biological functions such as promoting cell growth, migration, aggregation, metastasis and adhesion, and plays an important role in cancers and coronavirus disease 2019 (COVID-19). Unlike angiotensin-converting enzyme 2 (ACE2), AXL was highly expressed in respiratory system cells. In this study, we verified the AXL expression in cancer and normal tissues and found AXL expression was strongly correlated with cancer prognosis, tumor mutation burden (TMB), the microsatellite instability (MSI) in most tumor types. Immune infiltration analysis also demonstrated that there was an inextricable link between AXL expression and immune scores in cancer patients, especially in BLCA, BRCA and CESC. The NK-cells, plasmacytoid dendritic cells, myeloid dendritic cells, as one of the important components of the tumor microenvironment, were highly expressed AXL. In addition, AXL-related tumor neoantigens were identified and might provide the novel potential targets for tumor vaccines or SARS-Cov-2 vaccines research in cancer patients.