Diagnosis and Treatment of Patients with Thyroid Cancer

Background

Thyroid cancer is the most common malignancy of the endocrine system, representing 3.8% of all new cancer cases in the United States and is the ninth most common cancer overall. The American Cancer Society estimates that 62,450 people in the United States will be diagnosed with thyroid cancer in 2015, and 1950 deaths will result from the disease.

Objective

To review the current approach to the diagnosis and treatment of patients with thyroid cancer.

Discussion

Over the past 3 decades, there has been a dramatic increase in the number of people diagnosed with thyroid cancer, which may be attributable to the wide use of imaging studies, including ultrasounds, computed tomography, magnetic resonance imaging, and positron emission tomography scans that incidentally detect thyroid nodules. Thyroid cancer is divided into several main types, with papillary thyroid cancer being the most common. The treatment options for patients with thyroid cancer include the surgical removal of the entire thyroid gland (total thyroidectomy), radioactive iodine therapy, and molecular-targeted therapies with tyrosine kinase inhibitors. This article summarizes the diagnosis and treatment of thyroid cancer, with recommendations from the American Thyroid Association regarding thyroid nodules and differentiated thyroid cancer. Recently approved drugs and treatment trends are also explored.

Conclusion

The prognosis and treatment of thyroid cancer depend on the tumor type and its stage at the time of diagnosis. Many thyroid cancers remain stable, microscopic, and indolent. The increasing treatment options for patients with thyroid cancer, including therapies that were recently approved by the US Food and Drug Administration, have kept the mortality rate from this malignancy low, despite the increase in its incidence. Early diagnosis and appropriate treatment can improve prognosis and reduce mortality.     

Simple device to determine the pressure applied by pressure clips for the treatment of earlobe keloids

Background:Keloids of the ear are common problems. Various treatment modalities are available for the treatment of ear keloids. Surgical excision with intralesional steroid injection along with compression therapy has the least recurrence rate. Various types of devices are available for pressure therapy. Pressure applied by these devices is uncontrolled and is associated with the risk of pressure necrosis. We describe here a simple and easy to use device to measure pressure applied by these clips for better outcome.Objectives:To devise a simple method to measure the pressure applied by various pressure clips used in ear keloid pressure therapy.Results:The pressure applied by different clips was variable. The spring clips were adjustable by slight variation in the design whereas the pressure applied by binder clips and magnet discs was not adjustable.Conclusion:The uncontrolled/suboptimal pressure applied by certain pressure clips can be monitored to provide optimal pressure therapy in ear keloid for better outcome.KEY WORDS: Clips, device, earlobe, magnetic discs, measure, pressure therapy, splint     

Addressing Cardiovascular Disease Burden in low and Middle Income Countries (LMICs)

The global epidemic of cardiovascular diseases (CVDs) is spiraling upwards primarily due to a sharp rise in the low and middle income countries (LMICs) which are experiencing rapid health transition driven by socioeconomic, technological and lifestyle changes. LMICs currently face a double burden of communicable and non-communicable diseases, leading to competing claims of health conditions that vie for policy makers’ attention as public health priorities in a setting of limited resources, substantially high out-of-pocket expenditure and weak systems of healthcare delivery. Evidence from high income countries suggests that most CVDs are largely preventable as the major CVD risk behaviours including tobacco use, physical inactivity, unhealthy diet, harmful use of alcohol, are avoidable and modifiable. Effective and sustainable behaviour change strategies for LMICs would require low cost, affordable and scalable interventions. There is limited evidence from LMICs on effective interventions to prevent, control and manage CVDs in LMICs. The global guidelines and framework for addressing CVD calls for an urgent need to identify and assess contextually relevant and resource sensitive health care interventions augmented by policy actions. A combination of population based and high risk individual based strategies which are evidence based, cost-effective, feasible as well as scalable would reduce CVD mortality and its devastating impact in LMICs.     

Tim-3 marks human natural killer cell maturation and suppresses cell-mediated cytotoxicity

Natural killer (NK) cells are innate lymphocytes that play an important role against viral infections and cancer. This effect is achieved through a complex mosaic of inhibitory and activating receptors expressed by NK cells that ultimately determine the magnitude of the NK-cell response. The T-cell immunoglobulin- and mucin domain-containing (Tim)-3 receptor was initially identified as a T-helper 1-specific type I membrane protein involved in regulating T-cell responses. Human NK cells transcribe the highest amounts of Tim-3 among lymphocytes. Tim-3 protein is expressed on essentially all mature CD56(dim)CD16(+) NK cells and is expressed heterogeneously in the immature CD56(bright)CD16(-) NK-cell subset in blood from healthy adults and in cord blood. Tim-3 expression was induced on CD56(bright)CD16(-) NK cells after stimulation with IL-15 or IL-12 and IL-18 in vitro, suggesting that Tim-3 is a maturation marker on NK cells. Whereas Tim-3 has been used to identify dysfunctional T cells, NK cells expressing high amounts of Tim-3 are fully responsive with respect to cytokine production and cytotoxicity. However, when Tim-3 was cross-linked with antibodies it suppressed NK cell-mediated cytotoxicity. These findings suggest that NK-cell responses may be negatively regulated when NK cells encounter target cells expressing cognate ligands of Tim-3.     

Covalent agonists for studying G protein-coupled receptor activation

Structural studies on G protein-coupled receptors (GPCRs) provide important insights into the architecture and function of these important drug targets. However, the crystallization of GPCRs in active states is particularly challenging, requiring the formation of stable and conformationally homogeneous ligand-receptor complexes. Native hormones, neurotransmitters, and synthetic agonists that bind with low affinity are ineffective at stabilizing an active state for crystallogenesis. To promote structural studies on the pharmacologically highly relevant class of aminergic GPCRs, we here present the development of covalently binding molecular tools activating G_s-, G_i-, and G_q-coupled receptors. The covalent agonists are derived from the monoamine neurotransmitters noradrenaline, dopamine, serotonin, and histamine, and they were accessed using a general and versatile synthetic strategy. We demonstrate that the tool compounds presented herein display an efficient covalent binding mode and that the respective covalent ligand-receptor complexes activate G proteins comparable to the natural neurotransmitters. A crystal structure of the β₂-adrenoreceptor in complex with a covalent noradrenaline analog and a conformationally selective antibody (nanobody) verified that these agonists can be used to facilitate crystallogenesis.One of the major obstacles to the investigation of the structural basis of G protein-coupled receptor (GPCR) activation is the flexibility of their seven-transmembrane core, particularly in the active state (1), and the resulting biochemical instability of the solubilized protein (2, 3). Protein crystallography, the most powerful tool for the study of GPCR structure, requires the formation of stable and conformationally homogeneous ligand-receptor complexes (4). High-affinity agonists with dissociation constants in the low to subnanomolar range and low off-rates facilitate stabilization of the protein throughout the process of expression, purification, and crystallogenesis (2); however, endogenous neurotransmitters usually show poor binding affinity. Low binding affinity with rapid association and dissociation rates leads to conformational heterogeneity that prevents the formation of diffraction-quality crystals. The rapid dissociation rate of agonists also makes it difficult to generate active-state stabilizing proteins, such as the camelid antibodies (nanobodies) that have been used to obtain active-state structures of the β₂-adrenergic receptor (β₂AR) (5) and M2 muscarinic receptor (6).To prevent ligand dissociation, irreversible ligation of electrophilic moieties like halomethylketones, isothiocyanates, Michael acceptors, or aziridinium groups of small-molecule ligands with a suitably positioned nucleophilic residue in the receptor has been used (7–16). However, irreversible ligands often suffer from incomplete cross-linking (15) and reduced receptor activation when covalent binding leads to loss of agonist efficacy (10, 16). Furthermore, their highly electrophilic nature and the abundance of nucleophilic groups in biological systems may lead to a low coupling selectivity (7, 8).Disulfide-based cross-linking approaches (17, 18) offer the advantage that the covalent binding of disulfide-containing compounds is chemoselective for cysteine and enforced by the affinity of the ligand-pharmacophore rather than by the electrophilicity of the cross-linking function (19). We refer to the described ligands as covalent rather than irreversible agonists because cleavage may be promoted by reducing agents and the disulfide transfer process is a reversible chemical reaction in general.Structural information on the target protein facilitates the development of covalent ligand-receptor pairs. Mutation of H93^2.64 in the β₂AR to cysteine introduced an anchor for the disulfide-based covalent agonist FAUC50, which does not perturb ligand binding or the activation of the receptor, and thus enabled, to our knowledge, the first agonist-bound GPCR structure (20). Taking advantage of the high structural homology among aminergic GPCRs, we reasoned that the introduction of cysteine into position X^2.64 should also result in a covalently binding receptor mutant for other aminergic GPCRs.We here report a methodology to generate disulfide-based covalent ligand-receptor pairs to promote structural and functional studies on GPCRs. We demonstrate that even the low-affinity endogenous agonists noradrenaline, dopamine, and serotonin can be converted into efficient covalently binding molecular tools for the β₂AR, the dopamine D₂ receptor (D₂R), and the 5-hydroxytryptamine 2A (5-HT_2A) serotonergic subtype representing G_s-, G_i-, and G_q-coupled GPCRs, respectively. Analogous studies were conducted starting from histamine and the receptor subtype H₁. We applied this strategy to obtain an active-state crystal structure of the β₂AR^H93C and a covalent (nor)adrenaline analog.     

Planting the seeds of success: CT‐guided gold seed fiducial marker placement to guide robotic radiosurgery

Fiducial marker (FM)‐guided stereotactic body radiation therapy (SBRT) allows for precise targeting and delivery of radiation to a tumor site. In this article, we briefly discuss SBRT, provide examples to describe CT‐guided FM placement to guide SBRT, and discuss some of the associated risks and benefits. This article serves as a pictorial review for body imagers and interventional radiologists who perform CT‐guided procedures and interpret diagnostic studies for oncology patients. CT‐guided FMs were placed in patients who were appropriate candidates for SBRT. One week following placement, patients underwent diagnostic CT and/or MR examinations in order to include the FM data in the development of a treatment plan. From October 2007–November 2009, a total of 89 patients were implanted with FMs. Sites of implantation included lung, liver, bone, chest and abdominal wall, and peritoneum/retroperitoneum. Complications included pneumothorax and FM migration. Twenty‐one patients (33%) with lung FM placement experienced at least a small pneumothorax and 6 patients (9%) required thoracostomy tubes. FM migration occurred in 5 patients (8%) with lung placement. SBRT provides a safer and more effective alternative to conventional radiotherapy, and CT‐guided FM implantation of tumor sites increases the precision of SBRT. Technical improvements in FM placement can limit the complications associated with the procedure and further enable highly localized tumor therapy.     

Reversible renal medullary hyperechogenicity in neonatal hypernatremic dehydration

Three exclusively breastfed term neonates were admitted with lethargy, poor feeding, and oligoanuria. All three babies were severely dehydrated and had a weight loss ranging from 18% to 40%. Serum sodium of more than 180 mEq/l and renal failure were observed in all three. Two had very high creatinine levels of 9.5 mg/dl and 6.7 mg/dl. Both these babies also had multiple seizures. One baby required mechanical ventilation. All three babies showed markedly hyperechoic renal medullary pyramids with speckled foci suggestive of crystal deposition that reversed completely on therapy. Urine showed abundant urate crystals in two and an elevated calcium/creatinine ratio of 1.6 in one. There was no evidence of distal renal tubular acidosis, Bartter syndrome, or high serum calcium. Supersaturation of the ions in a markedly hypertonic renal medulla may have led to crystallization, with resolubilization with hydration and restoration of good urine output. The hypernatremic dehydration was primarily due to lactation failure leading to inadequate fluid intake in the face of ongoing insensible losses. High breast milk sodium may have been a contributory factor in one patient.