Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma.

Background: Pheochromocytoma and paraganglioma (PHEO/PGL) are rare neuroendocrine tumors which may cause potentially life-threatening complications, with about a third of cases found to harbor specific gene mutations. Thus, early diagnosis, treatment, and meticulous monitoring are of utmost importance. Because of low incidence of succinate dehydrogenase complex subunit A (SDHA)-related metastatic PHEO/PGL, currently there exists insufficient clinical information, especially with regards to its diagnostic and treatment characteristics. Methods: Ten patients with SDHA-related metastatic PHEO/PGL were followed-up prospectively and/or retrospectively between January 2010-July 2018. They underwent biochemical tests (n = 10), 123I-MIBG (n = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with 68Ga-DOTATATE (n = 10), 18F-FDG (n = 10), and 18F-FDOPA (n = 6). Results: Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PHEO/PGL, making them appear sporadic. Nine out of 10 patients showed abnormal PHEO/PGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. Per patient detection rates of 68Ga-DOTATATE (n = 10/10), 18F-FDG (n = 10/10), 18F-FDOPA (n = 5/6) PET/CT, and 123I-MIBG (n = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 123I-MIBG positive patients had minimal 123I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on 18F-FDG PET/CT, implying that diagnosis and treatment with 123/131I-MIBG is not a good option. 68Ga-DOTATATE PET/CT was found to be superior or equal to 18F-FDG PET/CT in 7 out of 10 patients and hence, is recommended for evaluation and follow-up of these patients. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, 131I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed disease progression. Conclusion: In our cohort of patients, SDHA-related metastatic PHEO/PGL followed a disease-course similar to that of SDHB-related metastatic PHEO/PGL, showing highly aggressive behavior, similar imaging and biochemical phenotypes, and suboptimal response to conventional therapies. Therefore, we recommend careful surveillance of the affected patients and a search for effective therapies.

Update of Pheochromocytoma Syndromes: Genetics, Biochemical Evaluation, and Imaging.

Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare commonly benign neuroendocrine tumors that share pathology features and clinical behavior in many cases. While PCCs are chromaffin-derived tumors that arise within the adrenal medulla, PGLs are neural-crest-derived tumors that originate at the extraadrenal paraganglia. Pheochromocytoma-paraganglioma (PPGL) syndromes are rapidly evolving entities in endocrinology and oncology. Discoveries over the last decade have significantly improved our understanding of the disease. These include the finding of new hereditary forms of PPGL and their associated susceptibility genes. Additionally, the availability of new functional imaging tools and advances in targeted radionuclide therapy have improved diagnostic accuracy and provided us with new therapeutic options. In this review article, we present the most recent advances in this field and provide an update of the biochemical classification that further reflects our understanding of the disease.

MEN4 and CDKN1B mutations: the latest of the MEN syndromes.

Multiple endocrine neoplasia (MEN) refers to a group of autosomal dominant disorders with generally high penetrance that lead to the development of a wide spectrum of endocrine and non-endocrine manifestations. The most frequent among these conditions is MEN type 1 (MEN1), which is caused by germline heterozygous loss-of-function mutations in the tumor suppressor gene MEN1 MEN1 is characterized by primary hyperparathyroidism (PHPT) and functional or nonfunctional pancreatic neuroendocrine tumors and pituitary adenomas. Approximately 10% of patients with familial or sporadic MEN1-like phenotype do not have MEN1 mutations or deletions. A novel MEN syndrome was discovered, initially in rats (MENX), and later in humans (MEN4), which is caused by germline mutations in the putative tumor suppressor CDKN1B The most common phenotype of the 19 established cases of MEN4 that have been described to date is PHPT followed by pituitary adenomas. Recently, somatic or germline mutations in CDKN1B were also identified in patients with sporadic PHPT, small intestinal neuroendocrine tumors, lymphoma and breast cancer, demonstrating a novel role for CDKN1B as a tumor susceptibility gene for other neoplasms. In this review, we report on the genetic characterization and clinical features of MEN4.

Derivation and Validation of a Geriatric-Sensitive Perioperative Cardiac Risk Index.

BACKGROUND: Surgical patients aged 65 and over face a higher risk of cardiac complications from noncardiac surgery. The Revised Cardiac Risk Index (RCRI) and the Gupta Myocardial Infarction or Cardiac Arrest (MICA) calculator are widely used to predict this risk, but they are not specifically designed to predict MICA in geriatric patients. Our hypothesis is that a new geriatric-sensitive index, derived from geriatric data, will capture this population's unique response to risk factors. METHODS AND RESULTS: The model was developed using the NSQIP (National Surgical Quality Improvement Program) 2013 geriatric cohort (N=584,931) (210,914 age ≥65) and validated on the NSQIP 2012 geriatric cohort (N= 485,426) (172,905 age ≥65). Least Angle Shrinkage and Selection Operator regression was used for initial variable selection. The Geriatric-Sensitive Cardiac Risk Index (GSCRI) was then evaluated in the 2012 data set. The area under the curve (AUC) was compared among the GSCRI, RCRI, and Gupta MICA in the 2012 data set. The GSCRI had an AUC of 0.76 in the validation cohort among geriatric patients. When the Gupta MICA was tested on geriatric patients in the validation cohort, a significant deterioration (≈17%) was noted, as well as a significant underestimation of the risk. The GSCRI AUC of 0.76 in the geriatric subset was significantly greater (P<0.001) than those in the RCRI (AUC=0.63) or Gupta MICA (AUC=0.70) models, outperforming the RCRI and Gupta MICA models in geriatric patients by 13% and 6%, respectively, with a ΔAUC and P-value of 0.13 (P<0.001), and 0.06 (P<0.001). CONCLUSIONS: The GSCRI is a significantly better predictor of cardiac risk in geriatric patients undergoing noncardiac surgery.

The Crossroads of Geriatric Cardiology and Cardio-Oncology.

Cancer and cardiovascular disease (CVD) are two major causes of mortality in older adults. With improved survival and outcomes from cancer and CVD, the role of the geriatrician is evolving. Geriatricians provide key skills to facilitate patient-centered and value-based care in the growing older population of cancer patients (and survivors). Cancer treatment in older adults is particularly injurious with respect to complications stemming from cancer therapy and as well as to CVD related to cancer therapy in the context of physiologic aging. To best meet their natural potential as caregiving leaders, geriatricians must hone skills and insights pertaining to oncologic and cardiovascular care, insights that can inform and enhance key management expertise. In this paper, we will review common chemotherapy and radiation-induced cardiovascular complications, screening recommendations, and advance the concept of a geriatric, cardiology, and oncology collaboration. We assert that geriatricians are well suited to a leadership role in the care of older cardio-oncology patients and in the education of primary care physicians and subspecialists on geriatric principles.