Clinical Practice Guidance: Surveillance for phaeochromocytoma and paraganglioma in paediatric succinate dehydrogenase gene mutation carriers

The succinate dehydrogenase (SDH) enzyme complex functions as a key enzyme coupling the oxidation of succinate to fumarate in the citric acid cycle. Inactivation of this enzyme complex results in the cellular accumulation of the oncometabolite succinate, which is postulated to be a key driver in tumorigenesis. Succinate accumulation inhibits 2‐oxoglutarate‐dependent dioxygenases, including DNA and histone demethylase enzymes and hypoxic gene response regulators. Biallelic inactivation (typically resulting from one inherited and one somatic event) at one of the four genes encoding the SDH complex (SDHA/B/C/D) is the most common cause for SDH deficient (dSDH) tumours. Germline mutations in the SDHx genes predispose to a spectrum of tumours including phaeochromocytoma and paraganglioma (PPGL), wild type gastrointestinal stromal tumours (wtGIST) and, less commonly, renal cell carcinoma and pituitary tumours. Furthermore, mutations in the SDHx genes, particularly SDHB, predispose to a higher risk of malignant PPGL, which is associated with a 5‐year mortality of 50%. There is general agreement that biochemical and imaging surveillance should be offered to asymptomatic carriers of SDHx gene mutations in the expectation that this will reduce the morbidity and mortality associated with dSDH tumours. However, there is no consensus on when and how surveillance should be performed in children and young adults. Here, we address the question: “What age should clinical, biochemical and radiological surveillance for PPGL be initiated in paediatric SDHx mutation carriers?”.     

Nationwide Qualitative Study of Practice Leader Perspectives on What It Takes to Transform into a Patient-Centered Medical Home

BackgroundDespite widespread adoption of patient-centered medical home (PCMH), little is known about why practices pursue PCMH and what is needed to undergo transformation.ObjectiveExamine reasons practices obtained and maintained PCMH recognition and what resources were needed.DesignQualitative study of practice leader perspectives on PCMH transformation, based on a random sample of primary care practices engaged in PCMH transformation, stratified by US region, practice size, PCMH recognition history, and practice use of Consumer Assessment of Healthcare Providers and Systems (CAHPS®) PCMH survey.Participants105 practice leaders from 294 sampled practices (36% response rate).ApproachContent analysis of interviews with practice leaders to identify themes.ResultsMost practice leaders had local control of PCMH transformation decisions, even if practices adopted quality initiatives under the direction of an organization or network. Financial incentives, being in a statewide effort, and the intrinsic desire to improve care or experiences were the most common reasons practice leaders decided to obtain PCMH recognition and pursue associated care delivery changes. Leadership support and direction were highlighted as essential throughout PCMH transformation. Practice leaders reported needing specialized staff knowledge and significant resources to meet PCMH requirements, including staff knowledgeable about how to implement PCMH changes, track and monitor improvements, and navigate implementation of simultaneous changes, and staff with specific quality improvement (QI) expertise related to evaluating changes and scaling-up programs.ConclusionPCMH efforts necessitated support and assistance to frontline, on-site practice leaders leading care delivery changes. Such change efforts should include financial incentives (e.g., direct payment or additional reimbursement), leadership direction and support, and internal or external staff with experience with the PCMH application process, implementation changes, and QI expertise in monitoring process and outcome data. Policies that recognize and meet the needs of on-site practice leaders will better promote primary care practice transformation and move practices further toward their PCMH transformation goals.Electronic supplementary materialThe online version of this article (10.1007/s11606-020-06052-1) contains supplementary material, which is available to authorized users.KEY WORDS: practice transformation, quality improvement, leadership, primary care     

Evaluation and management of TMDs, Part 1. History, epidemiology, classification, anatomy, and patient evaluation

The study of temporomandibular disorders has undergone many changes throughout its history. Focus on the structure and function of the TMJ continues to improve our understanding of these complex disorders. A more standardized classification system allows practitioners and researchers to discuss findings in a common language. With improved patient evaluation techniques, the clinician can establish a proper working differential diagnosis and begin focusing attention on treatment planning.     

Plasma concentrations of morphine,morphine-6-glucuronide and morphine-3-glucuronide and their relationship with analgesia and side effects in patients with cancer-related pain

Morphine, the recommended drug for the management of moderate to severe cancer pain, is metabolized predominantly to the glucuronides morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G). The quantitative clinical importance of these metabolites following the administration of oral morphine is unclear. This study investigates the relationship between plasma concentrations of morphine (M), M6G, M3G and clinical effects in patients receiving sustained release oral morphine for cancer-related pain. Peak and trough plasma concentrations of morphine and its metabolites were determined by high-performance liquid chromatography (HPLC). At corresponding time points, pain [Visual Analogue Scales (VAS), Verbal Rating Scales (VRS), Pain Relief Scores (PRS)] and toxicity (VAS and VRS) were assessed. Renal and liver function tests were performed. Forty-six patients were included in the study. There was a significant correlation between dose and both peak and trough plasma M, M6G and M3G (r > 0.60, P < 0.001 for each). Differences between peak and trough M, M6G, M3G, M+M6G, M6G:M, M3G:M and M3G:M6G were all significant (P < 0.001 for each). Pain was generally well controlled in the group, with a median VAS of 15 mm at the peak blood sampling time point. The differences between peak and trough values for VAS pain, VAS nausea and VAS drowsiness were not statistically significant (P = 0.078, 0.45 and 0.099, respectively). There were no differences in peak or trough morphine and metabolite concentrations or ratios between patients with low (< median) or high pain scores. Similarly, there was no significant relationship between high and low plasma concentrations and clinical effect. This study did not identify a simple relationship between plasma concentrations of morphine, morphine metabolites or metabolite ratios and clinical effects in patients with cancer and pain who were receiving chronic oral morphine therapy. Although overall pain control was good, there was marked interpatient variability in the dose of morphine and the plasma concentrations necessary to achieve this degree of analgesia.     

Haploidentical Peripheral Blood Stem Cell Transplantation Demonstrates Stable Engraftment in Adults with Sickle Cell Disease

We report on the screening and development of haploidentical hematopoietic stem cell transplantation (HSCT) for adult patients with clinically aggressive sickle cell disease (SCD) at our institution. Of 50 adult SCD patients referred for HSCT between January 2014 and March 2017, 20% were denied by insurance. Of 41 patients initially screened, 10% lacked an available haploidentical donor, 29% had elevated donor-specific antibodies (DSAs), and 34% declined to proceed to HSCT. All 10 patients who were transplanted received peripheral blood stem cells. The initial 2 were conditioned with alemtuzumab/total body irradiation (TBI) 3?Gy followed by post-transplant cyclophosphamide and failed to engraft. The next 8 patients received the regimen developed at Johns Hopkins University with TBI 3?Gy. Granulocyte colony-stimulating factor was administered from day +12 in those with HbS < 30%. All 8 patients engrafted with a median time to neutrophil >.5 × 10⁹/L of 22 days (range, 18 to 23). One patient subsequently lost the graft, and 7 (87.5%) maintained >95% donor cell chimerism at 1-year post-HSCT. Two patients developed acute graft-versus-host disease (GVHD) of at least grade II. One had chronic GVHD and died >1 year after HSCT of unknown causes. With a median follow-up of 16 months (range, 11 to 29), 7 patients (87.5%) are alive. Our findings suggest that limited insurance coverage, high rate of DSAs, and patient declining HSCT may limit the availability of haploidentical HSCT in adult SCD patients. The modified Hopkins regimen used here demonstrates high engraftment and low morbidity rates and should be tested in larger, multicenter, prospective clinical trials.     

Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain

OBJECTIVE: To determine the prevalence of hypovitaminosis D in primary care outpatients with persistent, nonspecific musculoskeletal pain syndromes refractory to standard therapies. PATIENTS AND METHODS: In this cross-sectional study, 150 patients presented consecutively between February 2000 and June 2002 with persistent, nonspecific musculoskeletal pain to the Community University Health Care Center, a university-affiliated inner city primary care clinic in Minneapolis, Minn (45 degrees north). Immigrant (n = 83) and nonimmigrant (n = 67) persons of both sexes, aged 10 to 65 years, from 6 broad ethnic groups were screened for vitamin D status. Serum 25-hydroxyvitamin D levels were determined by radioimmunoassay. RESULTS: Of the African American, East African, Hispanic, and American Indian patients, 100% had deficient levels of vitamin D (< or = 20 ng/mL). Of all patients, 93% (140/ 150) had deficient levels of vitamin D (mean, 12.08 ng/mL; 95% confidence interval, 11.18-12.99 ng/mL). Nonimmigrants had vitamin D levels as deficient as immigrants (P = .48). Levels of vitamin D in men were as deficient as in women (P = .42). Of all patients, 28% (42/150) had severely deficient vitamin D levels (< or = 8 ng/mL), including 55% of whom were younger than 30 years. Five patients, 4 of whom were aged 35 years or younger, had vitamin D serum levels below the level of detection. The severity of deficiency was disproportionate by age for young women (P < .001), by sex for East African patients (P < .001), and by race for African American patients (P = .006). Season was not a significant factor in determining vitamin D serum levels (P = .06). CONCLUSION: All patients with persistent, nonspecific musculoskeletal pain are at high risk for the consequences of unrecognized and untreated severe hypovitaminosis D. This risk extends to those considered at low risk for vitamin D deficiency: nonelderly, nonhousebound, or nonimmigrant persons of either sex. Nonimmigrant women of childbearing age with such pain appear to be at greatest risk for misdiagnosis or delayed diagnosis. Because osteomalacia is a known cause of persistent, nonspecific musculoskeletal pain, screening all outpatients with such pain for hypovitaminosis D should be standard practice in clinical care.