Which Ultrasound Characteristics Predict Lymphatic Spread of Papillary Thyroid Cancer?

INTRODUCTION: The 2015 American Thyroid Association guidelines recommend lymph node mapping US in patients with definitive cytological evidence of thyroid cancer. Suspicious lymph node features on imaging including enlarged size (>1 cm in any dimension), architectural distortion, loss of fatty hilum, and microcalcifications often prompt evaluation with fine needle aspiration. There is no universally agreed upon model for determining which ultrasound characteristics most strongly correlate with metastatic disease. METHODS: A retrospective review of patients with confirmed papillary thyroid cancer (PTC) undergoing lymph node mapping ultrasound from 2013 to 2019 was performed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value were calculated for each individual ultrasound characteristic as well as for characteristic combinations. RESULTS: Data from 119 lymph nodes were included. Malignant lymph nodes were more likely to be enlarged (71% versus 61%, P < 0.001) and to have each individual suspicious feature. Loss of fatty hilum had the highest sensitivity (89%) but was not specific (19%) for metastatic disease. Architectural distortion was found to have the highest specificity (87%). A combination of the four features was found to have higher specificity (97%) and PPV (88%) than any individual feature or combination of two/three features. CONCLUSIONS: A combination of four sonographic features correlates with metastatic PTC to lymph nodes and has the highest specificity and PPV for malignancy. A risk stratification model based on these features may lead to better classification of ultrasound findings in PTC patients with concern for nodal metastases.

CaMKIIδ post-translational modifications increase affinity for calmodulin inside cardiac ventricular myocytes.

Persistent over-activation of CaMKII (Calcium/Calmodulin-dependent protein Kinase II) in the heart is implicated in arrhythmias, heart failure, pathological remodeling, and other cardiovascular diseases. Several post-translational modifications (PTMs)-including autophosphorylation, oxidation, S-nitrosylation, and O-GlcNAcylation-have been shown to trap CaMKII in an autonomously active state. The molecular mechanisms by which these PTMs regulate calmodulin (CaM) binding to CaMKIIδ-the primary cardiac isoform-has not been well-studied particularly in its native myocyte environment. Typically, CaMKII activates upon Ca-CaM binding during locally elevated [Ca]free and deactivates upon Ca-CaM dissociation when [Ca]free returns to basal levels. To assess the effects of CaMKIIδ PTMs on CaM binding, we developed a novel FRET (Förster resonance energy transfer) approach to directly measure CaM binding to and dissociation from CaMKIIδ in live cardiac myocytes. We demonstrate that autophosphorylation of CaMKIIδ increases affinity for CaM in its native environment and that this increase is dependent on [Ca]free. This leads to a 3-fold slowing of CaM dissociation from CaMKIIδ (time constant slows from ~0.5 to 1.5 s) when [Ca]free is reduced with physiological kinetics. Moreover, oxidation further slows CaM dissociation from CaMKIIδ T287D (phosphomimetic) upon rapid [Ca]free chelation and increases FRET between CaM and CaMKIIδ T287A (phosphoresistant). The CaM dissociation kinetics-measured here in myocytes-are similar to the interval between heartbeats, and integrative memory would be expected as a function of heart rate. Furthermore, the PTM-induced slowing of dissociation between beats would greatly promote persistent CaMKIIδ activity in the heart. Together, these findings suggest a significant role of PTM-induced changes in CaMKIIδ affinity for CaM and memory under physiological and pathophysiological processes in the heart.

Three new patients with Steel syndrome and a Puerto Rican specific COL27A1 mutation.

Steel syndrome was initially described by H. H. Steel in 1993 in Puerto Rico, at which time he described the clinical findings required for diagnosis. The responsible gene, COL27A1, was identified in 2015 (Gonzaga-Jauregui et al., European Journal of Human Genetics, 2015;23:342-346). Eleven patients have previously been described with Steel syndrome and homozygous COL27A1 mutations, with eight having an apparent founder mutation, p.Gly697Arg. We describe three more patients identified at Einstein Medical Center Philadelphia and St. Christopher's Hospital for Children (Philadelphia, PA) diagnosed with Steel syndrome. All three are of Puerto Rican ancestry with the previously described founder mutation and had either hip dislocations or hip dysplasia. Radial head dislocation was only identified in one patient while short stature and scoliosis were noted in two of these patients. There are now 51 patients in the literature with Steel syndrome, including the 3 patients in this article, and 14 patients with a genetically confirmed Steel syndrome diagnosis.

Cardiac CaMKII activation promotes rapid translocation to its extra-dyadic targets.

Calcium-calmodulin dependent protein kinase IIδ (CaMKIIδ) is an important regulator of cardiac electrophysiology, calcium (Ca) balance, contraction, transcription, arrhythmias and progression to heart failure. CaMKII is readily activated at mouths of dyadic cleft Ca channels, but because of its low Ca-calmodulin affinity and presumed immobility it is less clear how CaMKII gets activated near other known, extra-dyad targets. CaMKII is typically considered to be anchored in cardiomyocytes, but while untested, mobility of active CaMKII could provide a mechanism for broader target phosphorylation in cardiomyocytes. We therefore tested CaMKII mobility and how this is affected by kinase activation in adult rabbit cardiomyocytes. We measured translocation of both endogenous and fluorescence-tagged CaMKII using immunocytochemistry, fluorescence recovery after photobleach (FRAP) and photoactivation of fluorescence. In contrast to the prevailing view that CaMKII is anchored near its myocyte targets, we found CaMKII to be highly mobile in resting myocytes, which was slowed by Ca chelation and accelerated by pacing. At low [Ca], CaMKII was concentrated at Z-lines near the dyad but spread throughout the sarcomere upon pacing. Nuclear exchange of CaMKII was also enhanced upon pacing- and heart failure-induced chronic activation. This mobilization of active CaMKII and its intrinsic memory may allow CaMKII to be activated in high [Ca] regions and then move towards more distant myocyte target sites.

E-cigarette or vaping product use associated lung injury (EVALI) in the time of COVID-19: A clinical dilemma.

AIM: To report on the clinical, laboratory, and radiological findings of adolescents who presented during the SARS-CoV-2 surge with symptoms of Coronavirus disease 2019 (COVID-19), did not test positive for the infection, and were diagnosed with E-cigarette and vaping product use associated lung injury (EVALI). METHODS: A retrospective review of 12 cases of EVALI admitted to the Bristol Meyers Squibb Children's Hospital between February 2020 and June 2020 was conducted. RESULTS: The ages of the patients ranged from 14 to 19 years. There were six males and six females. Three patients had a past history of anxiety, depression, or other psychiatric/mental health disorder, 9 had prolonged coagulation profile (prothrombin time, partial thromboplastin time, and/or International Normalized Ratio), and 11 had elevated inflammatory markers. Eight needed respiratory support. All 12 were negative for SARS-CoV-2 PCR. Four were tested for IgG antibodies and were negative. As these cases were admitted to rule out COVID infection, initial treatment included hydroxychloroquine. Steroids were started only after SARS-CoV-2 PCR was shown to be negative. Urine tetrahydrocannabinol was positive in all cases. Chest X-ray and computed tomography findings showed ground glass opacities. CONCLUSIONS: Clinical and radiological features are similar in both EVALI and SARS-CoV-2 infection. Inflammatory markers are elevated in both conditions. A detailed social and substance use history in patients presenting with "typical" COVID pneumonia like illness is important. EVALI should be ruled in early to start the appropriate treatment. Given the ongoing pandemic, pediatricians and other health-care providers need to be aware of other conditions that can masquerade as SARS-CoV-2.

Case report of atypical Lemierre's Syndrome associated with Fusobacterium nucleatum infection without internal or external jugular venous thrombophlebitis.

Fusobacterium nucleatum is an anaerobe that is commensal to the human oral cavity. It is usually a component of periodontal plaque that is emerging as a pathogen and quickly attracting attention of the medical and research communities. It has been even discovered in bronchoalveolar lavage of some patients with lung cancer. Lemierre's syndrome (LS) is characterized as septic thrombophlebitis of the internal jugular vein, which usually begins with oropharyngeal infection that worsens and leads to inflammation of the wall of the jugular vein. This is the hallmark of the disease. However, in this case, there was no thrombophlebitis of the internal jugular vein. There is one other case presentation where it was diagnosed without the internal jugular vein involvement. Most sequelae involve infected thrombus of the vein, soft tissue inflammation, persistent bacteremia, and septic emboli, often leading to metastatic infections. Interestingly enough, in the age of SARS-COV-2, LS has also been mistaken for multisystem inflammatory syndrome in children (MIS-C). We present a previously healthy 20-year-old female college student who was transferred from her local hospital to Bristol-Myers Squibb Children's Hospital (BMSCH) at Robert Wood Johnson University Hospital for suspected LS with loculated pleural effusions and necrotizing pneumonia with lung abscess secondary to Fusobacterium nucleatum, systemic and emphysematous osteomyelitis possibly secondary to septic emboli, thrombocytopenia, and palatine tonsil and thyroid abscesses.

Left Pericardiophrenic Vein Pacing for Tachy-Brady Syndrome Due to an Obstructing Cardiac Angiosarcoma.

We describe a case of a permanent pacemaker lead placement via the left pericardiophrenic vein for the treatment of tachy-brady syndrome due to a primary cardiac angiosarcoma. (Level of Difficulty: Advanced.).

An institution-wide algorithm for direct-stick embolization of peripheral venous malformations.

OBJECTIVE: No standardized therapeutic algorithm or embolic agent of choice has yet been identified for management of congenital peripheral venous malformations (VMs). Treatment options and reported outcomes therefore vary widely. Herein, we present an institution-wide algorithm for management of symptomatic congenital peripheral VMs using a single embolotherapeutic modality. METHODS: During 36 months, patients with symptomatic congenital peripheral VMs underwent contrast-enhanced magnetic resonance imaging. Hematologic monitoring for localized intravascular coagulopathy was performed in all. Perioperative anticoagulation was administered accordingly. When applicable, venous duplex ultrasound was performed to assess for presence and patency of a deep venous system and superficial venous reflux. If superficial venous reflux was identified, radiofrequency ablation was performed per standard protocol before or at the time of initial embolization. Direct-stick embolizations (DSEs) were performed by a single operator using two concentrations (1% and 3%) of sodium tetradecyl sulfate (STS; Sotradecol; AngioDynamics, Latham, NY) without foam preparation. Patients were followed up clinically for resolution of symptoms, coagulopathic monitoring, and development of complications. All data were prospectively maintained and retrospectively reviewed. RESULTS: There were 71 DSEs performed in 40 patients (1.8 procedures per patient [range, 1-8]; 12 male patients; mean age, 22 years [range, 2-53 years]). Mean follow-up was 17.1 months (range, 0.8-31.6 months). Presenting symptoms included pain (n = 40 [100%]), swelling (n = 36 [90%]), and cosmetic disfigurement (n = 32 [80%]). Anatomic distribution was upper extremity (n = 16 [23%]), lower extremity (n = 37 [52%]), head and neck (n = 7 [10%]), trunk (n = 10 [14%]), and visceral (n = 1 [1%]). There were 33 sporadic cases, 4 (10%) Klippel-Trénaunay syndrome cases, 2 (5%) blue rubber bleb nevus syndrome cases, and 1 (2.5%) CLOVES (congenital lipomatous overgrowth, vascular malformations, epidermal nevus, and skeletal deformities) syndrome case. Four patients presented with localized intravascular coagulopathy, two of whom required perioperative enoxaparin. Twenty-six patients (65%) required a single DSE session with complete symptom relief. Fourteen patients (35%) required repeated DSE. Two patients (5%) required adjunctive surgical excision. There was one postoperative death (1.4%) secondary to massive pulmonary embolism. Complications were otherwise limited to skin necrosis (n = 2 [3%]). Mean volume of sclerosant per session was 7 mL of 1% STS (range, 3-14 mL), and 15 mL of 3% STS (range, 3-42.5 mL). CONCLUSIONS: In the absence of allergic reactions, most congenital peripheral VMs can be safely embolized with liquid STS, thereby avoiding the well-documented toxicity of ethanol. Venous thromboembolism remains a major source of morbidity and mortality in this population of patients despite close hematologic scrutiny. Prospective randomized trials are needed for embolotherapeutic standardization.

Operative bed recurrence of thyroid cancer: utility of a preoperative needle localization technique.

BACKGROUND: Surgical management of recurrent disease after total thyroidectomy and/or neck dissection for thyroid carcinoma remains a challenging clinical problem. Reoperation is associated with a significant increase in morbidity. Preoperative needle localization technique for non-palpable breast tumors has recently been extrapolated to head and neck surgery. We report on the use of preoperative ultrasound-guided needle localization for non-palpable recurrent operative bed disease as an intraoperative aid in resection. METHODS: Patients with thyroid carcinoma were identified from a retrospective database at a tertiary care center from 2011-2014. Inclusion criteria were history of thyroidectomy and/or neck dissection, non-palpable recurrent disease in the resection bed on surveillance, and ultrasound-guided needle localization of recurrent disease before resection. Perioperative data and outcomes were analyzed. RESULTS: Seventeen patients were identified using the inclusion criteria listed above. Median patient age was 46 years (53% male, 47% female). A total of 23 masses in the previous operative bed were needle-localized successfully with no major long-term sequelae from this technique. The recurrent laryngeal nerve was involved with tumor in six patients. Two patients, in whom the tumor surrounded the nerve circumferentially, experienced recurrent laryngeal nerve injuries. No patients experienced postoperative hypocalcemia. With a routine surveillance and a median follow-up of 558 days, sixteen of the patients remain with no evidence of disease. CONCLUSIONS: Preoperative ultrasound-guided needle localization of non-palpable recurrent operative bed disease after thyroidectomy and/or neck dissection is a potentially safe method to aid in resection and cure.

Bilateral Sclerosing Stromal Ovarian Tumor in an Adolescent.

Sclerosing stromal tumor of the ovary is a rare, benign, sex cord stromal tumor occurring predominantly in younger women in the 2nd and 3rd decades of life. It typically presents unilaterally with only 2 previously reported cases of bilateral presentation. Common clinical presentations include pelvic or abdominal pain, a mass, or menstrual changes. Although occasionally presenting with hormonal manifestations, virilization as a result of androgen production by the tumor is rare. Here we present an extremely rare case of a sclerosing stromal ovarian tumor in a 14-year-old patient with bilateral presentation and with clinical and biochemical evidence of hyperandrogenemia.

Decreased vascularization of retroperitoneal kaposiform hemangioendothelioma induced by treatment with sirolimus explains relief of symptoms.

Kaposiform hemangioendothelioma (KHE) is a vascular tumor with poor prognosis. We present a child with progressive disability, extreme pain, and autonomic dysfunction due to a retroperitoneal KHE where radiologic characteristics were essential for diagnosis and monitoring of response to therapy. He received sirolimus, and the symptomatology resolved completely. Repeat MRIs revealed fast marked decrease in vascularity of the tumor, although the volume was not significantly affected. We suggest that the sirolimus-induced tumor de-vascularization may explain the clinical and coagulopathy improvement.

The utility of lymph node mapping sonogram and thyroglobulin surveillance in post thyroidectomy papillary thyroid cancer patients.

BACKGROUND: The American Thyroid Association recommends lymph node mapping (LNM) ultrasonography 6-12 months after thyroidectomy for patients with papillary thyroid cancer (PTC). The yield of LNM over thyroglobulin (TG) screening is not well defined. We sought to investigate this relationship. METHODS: Post thyroidectomy LNM was performed on 163 patients with PTC. LNM was considered positive based on these criteria: Loss of fatty hilum (LOFH), microcalcifications, hypervascularity, architectural distortion, or short axis (>8 mm). Serum TG levels were compared to LNM and fine needle aspiration (FNA). RESULTS: Sixty-nine patients had suspicious LNM (42%) and 17 had PTC on FNA (25%). There were 135 suspicious lymph nodes described with malignant nodes found in 6 of 65 patients (9%) with LOFH, 13 of 18 patients (76%) with microcalcifications, 11 of 12 patients (92%) with hypervascularity, 16 of 28 patients (52%) with architectural distortion, and 4 of 7 patients (52%) with enlarged size on FNA. The positive predictive value of LNM was 0.34, increasing to 0.66 when LOFH was excluded. Among 152 patients with documented TG data, LNM identified cervical nodal metastasis in 4 patients with TG < 0.5 pg/mL (anti-TG antibody negative, thyroid-stimulating hormone suppressed). Of the 15 patients with positive anti-TG antibody, 3 with recurrence were found on LNM. CONCLUSION: LNM can detect recurrent PTC when TG level is undetectable, and LOFH is a low-yield sonographic characteristic.

Effects of diet and exercise interventions on diabetes risk factors in adults without diabetes: meta-analyses of controlled trials.

BACKGROUND AND AIMS: Fasting insulin (FI), fasting glucose (FG), systolic blood pressure (SBP), high density lipoproteins (HDL), triacylglycerides (TAG), and body mass index (BMI) are well-known risk factors for type 2 diabetes. Reliable estimates of lifestyle intervention effects on these factors allow diabetes risk to be predicted accurately. The present meta-analyses were conducted to quantitatively summarize effects of diet and exercise intervention programs on FI, FG, SBP, HDL, TAG and BMI in adults without diabetes. MATERIALS AND METHODS: MEDLINE and EMBASE were searched to find studies involving diet plus exercise interventions. Studies were required to use adults not diagnosed with type 2 diabetes, involve both dietary and exercise counseling, and include changes in diabetes risk factors as outcome measures. Data from 18, 24, 23, 30, 29 and 29 studies were used for the analyses of FI, FG, SBP, HDL, TAG and BMI, respectively. About 60% of the studies included exclusively overweight or obese adults. Mean age and BMI of participants at baseline were 48 years and 30.1 kg/m(2). Heterogeneity of intervention effects was first estimated using random-effect models and explained further with mixed-effects models. RESULTS: Adults receiving diet and exercise education for approximately one year experienced significant (P <0.001) reductions in FI (-2.56 ± 0.58 mU/L), FG (-0.18 ± 0.04 mmol/L), SBP (-2.77 ± 0.56 mm Hg), TAG (-0.258 ± 0.037 mmol/L) and BMI (-1.61 ± 0.13 kg/m(2)). These risk factor changes were related to a mean calorie intake reduction of 273 kcal/d, a mean total fat intake reduction of 6.3%, and 40 minutes of moderate intensity aerobic exercise four times a week. Lifestyle intervention did not have an impact on HDL. More than 99% of total variability in the intervention effects was due to heterogeneity. Variability in calorie and fat intake restrictions, exercise type and duration, length of the intervention period, and the presence or absence of glucose, insulin, or lipid abnormalities explained 23-63% of the heterogeneity. CONCLUSIONS: Calorie and total fat intake restrictions coupled with moderate intensity aerobic exercises significantly improved diabetes risk factors in healthy normoglycemic adults although normoglycemic adults with glucose, insulin, and lipid abnormalities appear to benefit more.

Eosinophilic Pneumonia in a Patient with Ulcerative Colitis.

We present the case of 16-year-old woman with a 2-month history of ulcerative colitis who presented with cough, fever, dyspnea on exertion, and nasal congestion. Computed tomography of the chest demonstrated peripheral alveolar opacities with relative sparing of the central portions of the lungs. The clinical and radiologic findings raised the suspicion of eosinophilic pneumonia, possibly drug-related. The patient had recently been started on a trial of Mesalamine (5-aminosalicylic acid or 5-ASA) for treatment of her ulcerative colitis 2 months ago. The patient's condition improved after discontinuation of mesalamine and treatment with prednisone. The clinical course and radiologic features supported the presumptive diagnosis of Mesalamine-induced eosinophilic pneumonia.