Pheochromocytoma Or Paraganglioma Research Articles

Evaluation of pharmacokinetics, safety, and efficacy of [211At] meta-astatobenzylguanidine ([211At] MABG) in patients with pheochromocytoma or paraganglioma (PPGL): A study protocol.

Pheochromocytoma, or paraganglioma (PPGL), is a tumor that arises from catecholamine-producing chromaffin cells of the adrenal medulla or paraganglion. Systemic therapy, such as the combination of cyclophosphamide, vincristine, and dacarbazine or therapeutic radiopharmaceuticals such as [131I] meta-iodobenzylguanidine (MIBG), may be administered in cases of locally advanced tumors or distant metastases. However, the current therapies are limited in terms of efficacy and implementation. [211At] meta-astatobenzylguanidine (MABG) is an alpha-emitting radionuclide-labeled ligand that has demonstrated remarkable tumor-reducing effects in preclinical studies, and is expected to have a high therapeutic effect on pheochromocytoma cells. We are currently conducting an investigator-initiated first-in-human clinical trial to evaluate the pharmacokinetics, safety, and efficacy of [211At] MABG. Patients with locally unresectable or metastatic PPGL refractory to standard therapy and scintigraphically positive [123I] MIBG aggregation are being recruited, and a 3 + 3 dose escalation design was adopted. The initial dose of [211At] MABG is 0.65 MBq/kg, with a dose escalation in a 1:2:4 ratio in each cohort. Dose-limiting toxicity is observed for 6 weeks after a single bolus dose of [211At] MABG, and the patients are observed for 3 months to explore safety and efficacy profiles. The primary endpoint is dose-limiting toxicity to determine both maximum tolerated and recommended doses. The secondary endpoints include radiopharmacokinetics, urinary radioactive excretion rate, urinary catecholamine response rate, objective response rate, progression free survival, [123I] MIBG scintigraphy on reducing tumor accumulation, and quality of life. jRCT2021220012 registered on 17 June 2022.

Nuclear medicine practice in Japan: a report of the ninth nationwide survey in 2022.

Subcommittee on Survey of Nuclear Medicine Practice in Japan has performed a nationwide survey of nuclear medicine practice every 5years since 1982 to survey contemporary nuclear medicine practice and its changes over the years. The subcommittee sent questionnaires, including the number and category of examinations as well as the kind of the radiopharmaceuticals during the 30days of June 2022 to all nuclear medicine institutes in Japan. The total numbers of them for the year 2022 were estimated depends on the 1-month data. A total of 1095 institutes responded to the survey, including 364 positron emission tomography (PET) centers. The recovery rate was 90.6%. The number of gamma cameras installed was 1299 in total, with 2.5% decrease in 5years. Dual-head cameras and hybrid SPECT/CT scanners accounted for 83.8% and 35.5%, respectively. The number of single-photon tracer studies in 2022 was 1.11million which means increase in 2.7% in 5years. Bone scintigraphy was a leading examination (31.0%), followed by myocardial scintigraphy (27.1%) and cerebral perfusion study (23.8%) in order. The percentage of SPECT studies showed an increase from 63.5% in previous survey to 66.8% in this survey. PET centers have also increased from 389 to 412, as compared with the previous one. One hundred and twenty-two PET centers have installed one or two in-house cyclotrons. Increasing trends of the PET studies were observed from 1992 to 2017, the trend changed and PET studies showed 1.5% decrease in 5years. 18F-FDG accounted for 98.6% (610,497 examinations). PET examinations using 11C-methionine, 13N-NH3 and 11C-PIB have decreased, with 1624, 2146 and 525 examinations, respectively in 2022. The total number of nuclear medicine examination was eventually increased by 1.0%. Therapies for pheochromocytoma or paraganglioma (PPGL) with 131I-MIBG and for neuroendocrine tumor with 177Lu-DOTA-TATE were newly started, however, a total number of targeted radionuclide therapy was decreased by 17.7% because 131I-radioiodine and 223Ra targeted therapies were decreased and supply of some radioisotopes was discontinued. 131I-radioiodine targeted therapy showed a decrease in 5years (- 15.9%), including 4099 patients for thyroid cancer. The number of out-patient thyroid bed ablation therapy with 1110MBq of 131I was also decreased to 1015 per year. The number of admission rooms specialized for radionuclide targeted therapy increased from 157 to 160. The number of 223Ra targeted therapies for castration-resistant metastatic prostate cancer (mCRPC) was 1041 patients. This survey was performed during COVID-19 pandemic, however, total number of nuclear medicine examinations was almost same as previous survey (+ 1.0%). Radionuclide therapies with 131I-MIBG and 177Lu-DOTA-TATE were newly started, and new radionuclide therapy will be available in future, therefore, the development of radionuclide therapy will be continued. We are convinced that this survey report is useful in understanding the current status of the nuclear medicine practice in Japan, and in devising the new strategy to strengthen a role ofnuclear medicine.

Plasma Metanephrines Yield Fewer False-Positive Results Than Urine Metanephrines in Patients With Obstructive Sleep Apnea.

Obstructive sleep apnea (OSA) is associated with increased nocturnal sympathetic activity. In OSA patients, elevations in metanephrines may lead to false-positive tests when evaluating for pheochromocytoma or paraganglioma (PPGL). To evaluate whether morning plasma metanephrines would lead to fewer false-positive results than 24-hour urinary metanephrines in OSA patients. Patients undergoing polysomnography for suspected OSA were recruited. Plasma free and 24-hour urinary metanephrines were measured by HPLC-MS/MS. Patients with elevated levels had repeat measurements, abdominal imaging, and follow-up to diagnose or exclude a PPGL. Seventy-six patients completed polysomnography and biochemical testing; 68 (89.5%) patients had OSA, of whom 19 (27.9%) had elevated plasma and/or urinary metanephrines. On follow-up, one patient had a bladder paraganglioma, while PPGL was excluded in the remaining patients. OSA patients had more false-positive urinary metanephrines (17 of 67, 25.4%) than plasma metanephrines (2 of 67, 3.0%), P < .01, and this was more common in severe OSA (13 of 34, 38.2%), compared to moderate/mild OSA (4 of 33, 12.1%), P < .01. Both plasma and urinary metanephrines decreased after treatment with continuous positive airway pressure. On multivariable analysis, severe OSA, obesity, and family history of hypertension were positive predictors for false-positive urinary metanephrines in patients with suspected OSA. In OSA patients, plasma metanephrines are less likely to yield false-positive results for the diagnosis of PPGL than 24-hour urinary metanephrines. In patients with suspected OSA, obesity, or a family history of hypertension, plasma metanephrines may be the preferred first-line test to avoid unnecessary anxiety or follow-up.

CHANGES IN BLOOD COUNT INDUCED BY DOXAZOSIN TREATMENT IN SUBJECTS WITH PHEOCHROMOCYTOMA

Objective: Not only pre-treatment with with alfa-receptor antagonists and high-sodium diet, but also intravenous fluid administration immediately before surgery are recommended to minimalize per- and postoperative complications in subjects with pheochromocytoma or paraganglioma (PPGL). Aim of this study was to search for changes in blood count induced by doxazosin. Design and method: We studied PPGL subjects treated with doxazosin before operation and approximately one year after tumor removal. We measured count of blood elements – leukocytes, erythrocytes, thrombocytes, and hemoglobin level before initiation of treatment with doxazosin, during the treatment, and after tumor removal. Diagnosis of PPGL was based on elevated levels of plasma metanephrines preoperatively and was confirmed by histopathology. Results: In this retrospective study, we included 40 subjects with PPGL (15 males and 25 females, 51.8±14 years). Average doxazosin dose was 3.4±1.6 mg and median of duration of doxazosin treatment was 41 (25; 55) days. Leukocyte count decreased from 8.5±2.8 G/L to 7±2 G/L (P&lt;0.001) after doxazosin treatment and to 6.5±1.6 G/L/l (P&lt;0.001 vs. preoperatively) after surgery. Erythrocyte count decreased from 4.7±0.5 T/L to 4.3±0.5 T/L after doxazosin treatment (P = 0.01) and returned back after surgery: 4.6±0.3 T/L (P = 0.04 vs. after doxazosin). Similar results were found for hemoglobin levels: decrease from 140±15 g/L to 130±16 g/L (P&lt;0.001) after doxazosin and increase after surgery to 140±14 g/L (P&lt;0.001 vs. after doxazosin), and for hematocrit values: decrease from 0.42±0.04 to 0.39±0.04 (P&lt;0.001) after doxazosin and increase after surgery to 0.41±0.05 (P&lt;0.001). Platelets decreased significantly from 296±75 G/L to 263±78 G/L (P&lt;0.001) after doxazosin and to 239±63 G/L after tumor removal (P = 0.02 vs. after doxazosin). Conclusions: These data show that doxazosin pretreatment before surgery was accompanied with a significant decrease in red blood cell count, and hemoglobin level and hematocrit compared to values before initiation of doxazosin treatment and after surgery (the highest decrease of hemoglobin value after doxazosin was almost 30 g/l). We conclude that routine fluid administration before PPGL surgery is not supported by presented data.

Abstract 133: Rewinding the tape of life: somatic profiling in Von Hippel-Lindau (VHL) disease reveals evolutionary contingency and constraints

Abstract Whether cancer evolution follows a deterministic route prescribed by host factors (germline genetics and/or environment) or proceeds along multiple alternative trajectories due to the stochastic nature of evolution is unknown. Patients with VHL disease have a pathogenic germline mutation in VHL (3p25) and tumorigenesis occurs when the wild-type copy of VHL is lost. Patients develop multiple clonally independent tumors including clear cell renal cell carcinoma (ccRCC), pheochromocytoma or paraganglioma (PPGL) and pancreatic neuroendocrine tumors (pNET), offering an opportunity to test repeatability of evolutionary trajectories between and within patients. We performed deep targeted exome sequencing, in 1520 tumors (993 solid ccRCC; 156 cystic ccRCC; 135 mixed solid/cystic ccRCC; 236 extra-renal) from 130 patients with VHL disease to evaluate somatic variants and copy number alterations, ploidy and chromosomal complexity. Tumor phenotype was evaluated from pathology reports and longitudinal growth kinetics from diagnostic MRI data. Analysis of 889 tumor samples is complete and profiling of the full cohort will be presented at the 2023 AACR meeting. Within clonally independent tumors, we performed two tests to assess for evidence of convergence between tumors from the same patient. First, we tested for parallel events in canonical ccRCC drivers. We found significant enrichment of somatic VHL variants occurring in one patient with a germline whole VHL gene deletion encompassing neighboring BRK1. Contiguous BRK1 loss is associated with less aggressive ccRCC phenotype and our findings suggest a specific constraint in this patient. We next assessed for evidence of convergence by measuring the genetic distance of copy number and mutational profiles between and within patients with resampling and permutation. Similar somatic profiles between tumors were only detected in 1/76 patients whose tumors were characterized by infrequent somatic alterations beyond 3p loss indicating little evidence of convergence. Cystic ccRCCs represent an indolent phenotype not associated with metastasis that may progress to solid tumors over time; we found mixed tumors closely resemble somatic profiles of solid tumors whereas cysts were characterized by infrequent copy number gains and low chromosomal complexity. We also identified cysts with specific losses (chr16, chr17, chr19p) mutually exclusive with 3p LOH suggestive of VHL-loss independent cyst formation. In solid ccRCCs, we found chromosomal complexity and loss of specific chromosomal loci (9p and/or 14q) are associated with diameter potentially reconciling the observation linking risk of metastasis to tumor diameter in VHL-related ccRCC. In summary, within the constrained setting of VHL-related ccRCC, evolution is dominated by chance although specific patient and phenotype specific constraints are observed. Citation Format: Scott T. Shepherd, Alex Coulton, Cathy D. Vocke, Chris J. Ricketts, Mark Ball, Fiona Byrne, Yuliia Dovga, Annika Fendler, Barber Taja, Olga O'Neill, Lina Gerontogianni, Gavin Kelly, Laura S. Schmidt, Daniel R. Crooks, Kirstin Choo, Rabindra Gautam, Zoe Blake, Krista Reynolds, Kevin Litchfield, Maria Merino, Marston W. Linehan, Samra Turajlic. Rewinding the tape of life: somatic profiling in Von Hippel-Lindau (VHL) disease reveals evolutionary contingency and constraints [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 133.

Unique Characteristics of Patients with Von Hippel-Lindau Disease Defined by Various Diagnostic Criteria.

Von Hippel-Lindau (VHL) disease diagnosis is based on two criteria sets: International criteria (IC, two hemangioblastomas, one hemangioblastoma plus one visceral lesion, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion); or Danish criteria (DC, two clinical manifestations, or VHL family history/pathogenic variant plus hemangioblastoma/visceral lesion). We aimed to compare the characteristics of patients with VHL-related pancreatic neuroendocrine tumor (vPNET) meeting either the clinical Danish criteria only (DOC) or IC to those with sporadic PNET (sPNET). The cohort included 33 patients with VHL (20 vPNETs) and 65 with sPNET. In terms of genetic testing and family history of VHL, 90.0% of the patients with vPNET in the IC group had a germline VHL pathogenic variant, and 70.0% had a family history of VHL vs. 20% and 10% in the DOC group, respectively (p < 0.05 for both). Patients with vPNET were younger at diagnosis compared with sPNET (51.6 ± 4.1 vs. 62.8 ± 1.5 years, p < 0.05). Patients in the IC group were younger at diagnosis with VHL, vPNET, pheochromocytoma, or paraganglioma (PPGL) and renal-cell carcinoma (RCC) than those in the DOC group (p < 0.05 for all comparisons). The most prevalent presenting manifestations were hemangioblastoma (42.8%) and PPGL (33.3%) vs. RCC (58.3%) and PNET (41.7%) in the IC vs. DOC groups. In conclusion, patients with vPNET meeting DOC criteria show greater similarity to sPNET. We suggest performing genetic testing, rather than solely using clinical criteria, for establishing the diagnosis of VHL.

Retinal arterial remodeling in patients with pheochromocytoma or paraganglioma and its reversibility following surgical treatment.

Structural abnormalities in resistance arteries are a hallmark of patients with hypertension. In hypertensive patients with pheochromocytoma or paraganglioma (PPGL), it is still a matter of debate whether structural vascular changes are because of elevated blood pressure (BP) or to toxic effects of elevated circulating catecholamines. Hence, the aim of our study was to assess whether catecholamine excess and/or elevated BP affect the structure of small retinal arteries in patients with catecholamine-producing tumors. The study included 27 patients with PPGL and 27 hypertensive patients. All patients underwent biochemical tests for catecholamine excess, echocardiography and analyses of scanning-laser-Doppler-flowmetry (SLDF) both at baseline and 12 months following surgical resection of PPGL. Baseline retinal arterial diameter, arterial wall thickness and wall cross sectional area (WCSA) were higher in patients with PPGL as compared with subjects without PPGL (arterial diameter: 110 ± 16.5 vs. 99.5 ± 10.8 μm, wall thickness: 16.3 ± 6.0 vs. 13.5 ± 4.0 μm, WCSA: 4953.9 ± 2472.8 vs. 3784.1 ± 1446.3 μm, P < 0.05). Significant correlations were noted between wall thickness and WCSA and echocardiographic parameters assessing diastolic and systolic function of left ventricle. No correlations between retinal parameters, BP level and plasma concentrations of metanephrines were observed. In patients with PPGL, there were postoperative decreases in wall thickness (16.4 ± 15.8 vs. 14.8 ± 4.7 μm; P = 0.011) and WLR (0.42 ± 0.13 vs. 0.37 ± 0.10; P = 0.003) at 12 months after surgical removal of tumors. This is the first study to demonstrate that catecholamine excess is related to thickening of retinal arteries independent of BP and reversible after surgical cure. These data support a role of catecholamines in vascular remodeling in PPGL patients.

RESULTS OF GENETIC TESTING IN PATIENTS WITH PHEOCHROMOCYTOMA/PARAGANGLIOMA

Objective:More than 20 genes associated with the development of pheochromocytoma or paraganglioma (PPGL) have been described so far. In previous studies, mutation rate of involved genes reached up to 30–40% depending of studied populations. Aim of the study was to search for mutations of PPGL-relate

Long-term survival and safety from a multi-center, open-label, pivotal phase 2 study of iobenguane I 131 in patients (Pts) with unresectable, locally advanced or metastatic pheochromocytoma or paraganglioma (PPGL).

4108 Background: PPGL, rare neuroendocrine tumors with a 5-yr survival rate as low as 12%, have a high unmet need for effective treatment options. AZEDRA, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131-MIBG), is the first and only FDA- approved therapeutic radiopharmaceutical agent indicated for the treatment of adult and pediatric pts with iobenguane scan positive, unresectable, locally advanced or metastatic PPGL who require systemic anticancer therapy. Methods: Pts with advanced disease who were heavily pre-treated and were ineligible for curative surgery or chemotherapy received a dosimetric dose followed by up to two therapeutic doses (each at 296 MBq/kg to a max of 18.5 GBq). The primary endpoint, defined as the proportion of pts with at least 50% reduction of all antihypertensive medication(s) lasting ≥6 months, was met and previously reported. Updated secondary endpoints including overall survival (OS) and safety are reported. Results: A dosimetric dose of HSA I-131-MIBG was administered to 74 pts. Of those, 68 pts received one therapeutic dose and 50 received two doses of HSA I-131-MIBG. Clinical benefit rates (objective tumor responses defined by RECIST 1.0 and stable disease) were observed in 71.4% and 98.0% of pts receiving one and two therapeutic doses, respectively. As of Jan 25, 2019, median OS for all pts was 41.1 months (95% CI 31.1, 91.2). Median OS was 17.5 months (95% CI 4.0, 31.5) and 48.7 months (95% CI 33.2, 91.2) in pts receiving one and two doses, respectively. A tail of survival was observed, with OS of 73.1% at 2 yrs and 44.2% at 4 yrs. The most common (≥50%) adverse events were nausea, fatigue, and myelosuppression. Myelosuppressive events resolved within 4-8 wks without requiring stem cell transplantation. Late radiation toxicity included 8 pts with secondary malignancies (myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), colon cancer, and lung carcinoma) of which MDS, ALL and AML were considered related to I-131 radiotherapy. Conclusions: Updated results from this pivotal phase 2 study suggest that HSA I-131-MIBG is an efficacious and safe treatment for advanced PPGL. Clinical trial information: NCT00874614.

OR29-4 Pregnancy Outcomes in Women with Pheochromocytoma and Paraganglioma: An International Multi-Center Study

Background: Unrecognized or newly diagnosed pheochromocytoma (PHEO) or paraganglioma (PGL) during pregnancy may lead to adverse maternal and fetal outcomes. Recommendations for the management of women with PHEO or PGL (PPGL) during pregnancy are limited by the scarcity of published literature. Objective: To describe the presentation, management and outcomes of women with active PPGL during pregnancy and to identify predictors of unfavorable maternal and fetal outcomes. Methods: international retrospective multi-center study, 1968-2018. Results: Seventy-nine women with active PPGL had 89 pregnancies at a median age of 28 yrs (range, 16-46). At the time of pregnancy, 37 (42%) women had unilateral PHEO, 11 (12%) bilateral PHEO, 26 (29%) PGL, 8 (9)% multifocal disease and 7 (8%) metastatic PPGL. Of 51 patients evaluated for a predisposing mutation, 38 were positive (12 SDHB, 11 VHL, 8 RET, 7 other). Median tumor size was 6 cm (range, 1.9-29). Of 74 patients with available data on function, 65 (88%) had functioning PPGL. Of 89 pregnancies, only 13 (15%) patients had a known PPGL prior to pregnancy (8 with known metastases), while in 42 (47%) pregnancies, PPGL was diagnosed during pregnancy at a median gestation of 16 weeks (range, 2-38) and during 34 (38%) pregnancies, PPGL remained unrecognized until postpartum, diagnosed at a median of 9 weeks (range, 0-78) after delivery. PPGL surgery was performed in 72 women: 14 intrapartum at median gestation week 16 (range, 13-26) and 58 postpartum at a median of 36 weeks (range, 0-270) after pregnancy. Of 41 pregnancies with antepartum diagnosis of PHEO not treated with surgery, 25 (61%) were managed with medical therapy and 15 (39%) were closely monitored. Delivery was by C-section in 39 (44%) pregnancies (38 healthy babies, one death delivered at 22 weeks) and vaginal in 35 (39%) with no adverse maternal or fetal outcomes. Elective abortion was pursued in 5 (6%) pregnancies. Intrauterine fetal demise occurred in 6 (7%) pregnancies at a median of 21 weeks gestation (range, 11-28), all in women with unrecognized functioning PPGL. Adverse maternal outcomes occurred in 3 (3%) pregnancies, all in unrecognized functioning PPGL resulting in 1 death (at gestation week 38) and 2 severe cardiovascular complications (immediately postpartum). The most significant predictor of an unfavorable pregnancy outcome was postpartum diagnosis of PHEO, with an odds ratio of 16.6 (95% CI, 2-140, P=0.001), but not maternal age, tumor size, presence of metastases, antepartum surgery for PHEO, or known PHEO syndrome. Conclusion: The majority of pregnancies in women with active PPGL had excellent outcomes, even in women with metastatic or functional disease, especially when PPGL was diagnosed before or during pregnancy, allowing for appropriate management. However, unrecognized and untreated PPGL was associated with 16-fold higher risk of either maternal or fetal complications.

Study of germline mutations in patients with pheochromocytoma and paraganglioma in a tertiary level university hospital: Which patients have been studied and what results have been found?

IntroductionCurrent clinical practice guidelines recommend that a genetic study is considered in all patients diagnosed with pheochromocytoma or paraganglioma (PPGL). Our study objective was to know how many patients with PPGL undergo genetic studies at a non-specialized university hospital, the clinical factors involved in the decision to make the study, how many patients are found germline mutation, which are the affected genes, and what variables are related to presence of mutations. Material and methodsAll patients diagnosed with PPGL at a tertiary university hospital from 2010 to 2015 were enrolled. Age and sex, tumor location and multiplicity, hormone secretion, presence of a clinical syndrome, family history, and medical department in charge were recorded and used to compare patients with (GEN+) and without (GEN−) genetic study, as well as patients with (MUT+) and without (MUT−) germline mutations. ResultsThirty-nine patients were enrolled (21 females and 18 males with a mean age of 53.9±17.8 years). A genetic study was performed in 54% of patients with PPGL. These were younger, were more frequently seen by endocrinologists, and had more often a family history related to PPGL, multiple PPGLs, or hormonally functional tumors. Unilateral head and neck paragangliomas were less common. Germline mutations (3 RET, 3 SDHB, 1 SDHD) were found in 33% of patients, who were younger and more frequently had a clinical syndrome, multiple PPGLs. and a family history of PPGL. ConclusionAlthough current clinical practice guidelines recommend that genetic studies are considered in all patients diagnosed with PPGL, studies was requested for 54% of such cases in our healthcare area. Predisposing germline mutations were found in 33% of studies.

Estudio de mutaciones germinales en pacientes con feocromocitomas y paragangliomas atendidos en un hospital universitario de tercer nivel: ¿qué pacientes se estudian y qué resultados se encuentran?

IntroductionCurrent clinical practice guidelines recommend that a genetic study is considered in all patients diagnosed with pheochromocytoma or paraganglioma (PPGL). Our study objective was to know how many patients with PPGL undergo genetic studies at a non-specialized university hospital, the clinical factors involved in the decision to make the study, how many patients are found germline mutation, which are the affected genes, and what variables are related to presence of mutations. Material and methodsAll patients diagnosed with PPGL at a tertiary university hospital from 2010 to 2015 were enrolled. Age and sex, tumor location and multiplicity, hormone secretion, presence of a clinical syndrome, family history, and medical department in charge were recorded and used to compare patients with (GEN+) and without (GEN-) genetic study, as well as patients with (MUT+) and without (MUT-) germline mutations. ResultsThirty-nine patients were enrolled (21 females and 18 males with a mean age of 53.9±17.8 years). A genetic study was performed in 54% of patients with PPGL. These were younger, were more frequently seen by endocrinologists, and had more often a family history related to PPGL, multiple PPGLs, or hormonally functional tumors. Unilateral head and neck paragangliomas were less common. Germline mutations (3 RET, 3 SDHB, 1 SDHD) were found in 33% of patients, who were younger and more frequently had a clinical syndrome, multiple PPGLs. and a family history of PPGL. ConclusionAlthough current clinical practice guidelines recommend that genetic studies are considered in all patients diagnosed with PPGL, studies was requested for 54% of such cases in our healthcare area. Predisposing germline mutations were found in 33% of studies.

Impact of Surgical Resection of the Primary Tumor on Overall Survival in Patients With Metastatic Pheochromocytoma or Sympathetic Paraganglioma.

To determine whether primary tumor resection in patients with metastatic pheochromocytoma or paraganglioma (PPG) is associated with longer overall survival (OS). Patients with metastatic PPG have poor survival outcomes. The impact of surgical resection of the primary tumor on OS is not known. We retrospectively studied patients with metastatic PPG treated at the University of Texas, MD Anderson Cancer Center from January 2000 through January 2015. Kaplan-Meier analysis with log-rank tests was used to compare OS among patients undergoing primary tumor resection and patients not treated surgically. Propensity score method was applied to adjust for selection bias using demographic, clinical, biochemical, genetic, imaging, and pathologic information. A total of 113 patients with metastatic PPG were identified. Eighty-nine (79%) patients had surgery and 24 (21%) patients did not. Median OS was longer in patients who had surgery than in patients who did not [148 months, 95% confidence interval (CI) 112.8-183.2 months vs 36 months, 95% CI 27.2-44.8 months; P < 0.001].Fifty-three (46%) patients had synchronous metastases; of these patients, those who had surgery had longer OS than those who did not (85 months, 95% CI 64.5-105.4 months vs 36 months, 95% CI 29.7-42.3 months; P < 0.001). Patients who had surgery had a similar ECOG performance status to the ones who did not (P = 0.1798, two sample t test; P = 0.2449, Wilcoxon rank sum test). Univariate and propensity score analysis confirmed that patients treated with surgery had longer OS than those not treated surgically irrespective of age, race, primary tumor size and location, number of metastatic sites, and genetic background (log-rank P < 0.001).In patients with hormonally active tumors (70.8%), the symptoms of catecholamine excess improved after surgery. However, the tumor burden was a more important determinant of OS than hormonal secretion. Primary tumor resection in patients with metastatic PPG appeared to be associated with improved OS. In patients with hormonally active tumors, surgical resection led to better blood pressure control.

Azedra (iobenguane I 131) in patients with malignant, recurrent and/or unresectable pheochromocytoma or paraganglioma (PPGL): Updated efficacy and safety results from a multi-center, open-label, pivotal phase 2 study.

4005Background: AZEDRA, a high-specific-activity iodine-131 meta-iodobenzylguanidine (HSA I-131 MIBG), has been developed for the treatment of iobenguane-avid malignant (metastatic) or recurrent or...

Perioperative hemodynamics and outcomes of patients on metyrosine undergoing resection of pheochromocytoma or paraganglioma

IntroductionTo describe outcomes of patients with metyrosine (MET) pretreatment for abdominal surgical resection of pheochromocytoma or paraganglioma (PCC/PGL) compared with patients who had phenoxybenzamine (PBZ) pretreatment. MethodsRetrospective review of perioperative outcomes for PCC/PGL patients treated with MET and propensity-matched comparison of MET and PBZ (MET + PBZ) with PBZ alone. ResultsMET preparation was given in 63 cases (26 laparoscopic and 37 open, of which 55 also received PBZ). All patients had wide perioperative hemodynamic oscillations. Patients with open procedures required more intravenous fluids and blood transfusions; 35% required postoperative vasopressor infusions for hypotension and 38% developed acute kidney injury. One laparoscopic procedure required postoperative vasopressor infusion, and 12% of patients developed acute kidney injury. Forty-five MET + PBZ patients were propensity-matched with PBZ-only patients. Intraoperatively, MET + PBZ patients had lower minimum systolic and diastolic blood pressures than PBZ-only patients (median systolic, 74 vs 80 mm Hg, P = 0.01; median diastolic, 42 vs 46 mm Hg, P = 0.005) and larger intraoperative blood pressure oscillations (median systolic range, 112 vs 93 mm Hg, P = 0.06; median diastolic range, 58 vs 51 mm Hg, P = 0.02). Postoperative vasopressor infusion use was similar between MET + PBZ and PBZ only (16% vs 11%, P = 0.76). Major outcomes were not different between regimens. ConclusionLarge hemodynamic oscillations were present in our PCC/PGL patients treated with MET + PBZ. These patients had a wider range of intraoperative blood pressure variations than PBZ-only patients. No differences in postoperative comorbid outcomes were found between MET + PBZ and PBZ-only groups.

Recurrent, bilateral, and metastatic pheochromocytoma in a young patient with Beckwith-Wiedemann syndrome: A genetic link?

Beckwith-Wiedemann syndrome (BWS) is a genetic disorder at chromosome 11p15 that leads to increased activity of insulin-like growth factor-2 (IGF2) and reduced activity, with no active copy of the inhibitor of cell proliferation, CDKN1C, resulting in excessive growth and increased risk of tumour formation. Isolated cases of patients with Beckwith-Wiedemann syndrome and pheochromocytoma are reported in the literature; however, none have described a molecular or cytogenetic evaluation for associated genetic abnormalities.We present a case of an adolescent female with Beckwith-Wiedemann syndrome who developed recurrent, bilateral, and metastatic pheochromocytoma despite low-risk histopathology. Genotyping studies, which evaluated for genetic predisposition to pheochromocytoma or paraganglioma (PHEO/PGL), including the PGLNext sequencing panel of 12 associated genes, and a whole genome comparative genome hybridization microarray, were performed. Genomic studies were unexpectedly negative. Additionally, the histopathology of the PHEO/PGL of our patient had low-risk features, which is unusual in cases of metastases, occurring in less than 4% of cases.1 This case suggests that the BWS in itself could predispose to formation of a PHEO/PGL phenotype with aggressive behaviour. The following manuscript summarizes the case report, reviews pertinent literature, and proposes a possible mechanism for this association.

Pheochromocytoma and paraganglioma in patients with neurofibromatosis type 1.

Individuals with neurofibromatosis type 1 (NF1) are at an increased risk of developing a pheochromocytoma or paraganglioma (PHEO/PGL). However, the best case detection strategy is unknown. Our objectives were to describe the prevalence, clinical presentation and outcomes of PHEO/PGL associated with NF1 and formulate case detection testing recommendations for PHEO/PGL. A retrospective cohort study from 1959 to 2015, Tertiary medical centre. We studied 41 patients with NF1 and PHEO/PGL who were identified using the PHEO/PGL and NF1 databases: 3289 and 1415 patients, respectively. Our main outcome measures were prevalence of PHEO/PGL in NF1 and occurrence of bilateral, recurrent, or metastatic disease and method of PHEO/PGL detection (symptoms vs incidental vs biochemical case detection testing). The prevalence of PHEO/PGL in patients with NF1 was 2·9%. The 41 patients included 23 men (56%) and 18 women. The median age at diagnosis was 41·0 years (range 14-67). The median tumour size was 3·4 cm (range 0·8-9·5). Bilateral PHEO was identified in 17% (n = 7) of patients, all women. Metastatic or recurrent disease occurred in 7·3% (n = 3). In the last 25 years, PHEO/PGL was diagnosed after incidental finding on computed imaging in 31% of patients (n = 11). Only three patients (7·3%) had PHEO/PGL discovered because of biochemical case detection testing. We recommend patients with NF1 have biochemical case detection testing for PHEO/PGL every 3 years starting at age 10 to 14 years. Biochemical case detection testing should also be carried out prior to elective surgical procedures and conception.

Risk of catecholaminergic crisis following glucocorticoid administration in patients with an adrenal mass: a literature review.

Glucocorticoids as diagnostic or therapeutic agents have been reported to carry an increased risk of catecholaminergic crisis (CC) in patients with pheochromocytoma or paraganglioma (PPGL). We searched literature databases using the following terms: pheochromocytoma, paraganglioma, adrenal incidentaloma, steroids, glucocorticoids, dexamethasone suppression test (DST), hypertensive crisis, cosyntropin and CRH. From all published case reports (1962-2013), we reviewed medical history, presenting symptoms, dose and route of steroid administration, location and size of adrenal mass, biochemical phenotype and outcome. Twenty-five case reports describing a CC were identified. Three patients with an adrenal incidentaloma suffered a CC following high-dose DST, and in one case, this was fatal. In two of these patients, biochemical testing missed the diagnosis, and in the third, a DST was done despite elevated urinary metanephrines. No CC has been reported for patients undergoing a low-dose DST. Three of 16 patients who received therapeutic glucocorticoids and four of six patients following cosyntropin testing died. No specific biochemical phenotype was related to adverse events. Although a causal relationship cannot be established from this review, it seems prudent to exclude a PPGL in patients with a large incidentaloma or when high-dose DST is considered in a patient with an incidentaloma of any size. Our literature review does not support the need for biochemical testing for PPGL prior to a low-dose (1 mg) DST. Finally, before starting therapeutic glucocorticoids, any clinical signs or symptoms of a potential PPGL should prompt reliable biochemical testing to rule out a PPGL.

Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma.

Choosing effective therapy for patients with malignant pheochromocytoma or paraganglioma (PPGL) is problematic and none of the options are curative. Although combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine (CVD) is an established treatment option, only a limited number of case series have been reported in the literature. To determine the efficacy of CVD in patients treated at Tokyo Women's Medical University. Retrospective review of patients treated with CVD between 1989 and 2012 was conducted. Demographics, clinical presentation, imaging, and laboratory reports were reviewed and analyzed. Efficacy of CVD was ascertained from the biochemical and tumor responses. Twenty-three patients fulfilled study criteria and 6 of these were excluded due to inadequate follow-up or discontinuance by poor general condition or adverse effects. Thus, 17 cases were included in the study. The age and duration of the disease before initiation of CVD were 54.7 ± 12.0 years and 9.1 ± 8.1 years, respectively. The follow-up period after initiation of CVD ranged from 12 to 192 months (median, 60 months). Complete or partial biochemical and/or partial tumor response was achieved in 47.1 % (responders). No significant biochemical or tumor response was seen in 23.5 % and deterioration in biochemical and tumor outcomes was seen in 29.4 % (non-responders). No patient showed complete biochemical and tumor responses. In responders, these effects were documented within 4 months after initiation of CVD with a progression-free survival of 31 to 60 months (median, 40 months). Age at the first diagnosis with PPGL was younger (P < 0.05) and the lag time to eventual diagnosis of malignant disease was longer (P < 0.05) in responders than those in non-responders. The responders had improvements in hypertension and impaired glucose tolerance. Although CVD chemotherapy is not curative for patients with malignant PPGL, it does provide approximately half of the patients with biochemical, tumor, and hypertension benefits.

Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution

Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.