Effect of Positioning of the Region of Interest on Bone Density of the Hip.

BACKGROUND: Large changes in positioning of the global region of interest (ROI) influence the measurement of bone mineral density (BMD) in the hip and forearm regions. However, it is unknown whether minor shifts in the positioning of the bottom of the global hip ROI affect the measurement of total hip BMD. METHODS: The hip BMDs of 40 clinical densitometry patients were analyzed at baseline with the bottom of the global hip ROI positioned as usual, 10 mm distal to the base of the lesser trochanter (position 0). Then the hip was reanalyzed by shifting the bottom of the global hip ROI 1 mm proximally 10 times (positions +1 through +10) and then by shifting the bottom of the global hip ROI 1 mm distally 10 times (positions -1 through -10). The significance of the differences between mean values at the various distances from baseline was assessed using a Wilcoxon signed-rank test. RESULTS: The mean total hip area, bone mineral content and BMD decreased as the bottom of the global hip ROI was shifted proximally; the decrease was significant when shifted by even 1 mm (p < 0.001). The mean total hip area, bone mineral content and BMD increased as the bottom of the global hip ROI was shifted distally; the increase was significant when shifted by even 1 mm (p < 0.001). The change in BMD with each 1 mm shift was uniform across the range studied from positions +10 through -10, and was approx 0.54%/mm. When the least significant change was based on 40 pairs of measurements, where each pair was comprised of the baseline scan and the same scan at -1 position, the least significant change was 0.01 g/cm2. CONCLUSIONS: The BMD of the total hip is sensitive to even minor changes in the positioning of the bottom of the global hip ROI. Although a 1 mm change in the bottom of the global hip ROI positioning would make little difference in the reported T-score, it could easily affect the determination of significance in changes in BMD over time.

Loss of Gsα in the Postnatal Skeleton Leads to Low Bone Mass and a Blunted Response to Anabolic Parathyroid Hormone Therapy.

Parathyroid hormone (PTH) is an important regulator of osteoblast function and is the only anabolic therapy currently approved for treatment of osteoporosis. The PTH receptor (PTH1R) is a G protein-coupled receptor that signals via multiple G proteins including Gsα. Mice expressing a constitutively active mutant PTH1R exhibited a dramatic increase in trabecular bone that was dependent upon expression of Gsα in the osteoblast lineage. Postnatal removal of Gsα in the osteoblast lineage (P-Gsα(OsxKO) mice) yielded markedly reduced trabecular and cortical bone mass. Treatment with anabolic PTH(1-34) (80 µg/kg/day) for 4 weeks failed to increase trabecular bone volume or cortical thickness in male and female P-Gsα(OsxKO) mice. Surprisingly, in both male and female mice, PTH administration significantly increased osteoblast numbers and bone formation rate in both control and P-Gsα(OsxKO) mice. In mice that express a mutated PTH1R that activates adenylyl cyclase and protein kinase A (PKA) via Gsα but not phospholipase C via Gq/11 (D/D mice), PTH significantly enhanced bone formation, indicating that phospholipase C activation is not required for increased bone turnover in response to PTH. Therefore, although the anabolic effect of intermittent PTH treatment on trabecular bone volume is blunted by deletion of Gsα in osteoblasts, PTH can stimulate osteoblast differentiation and bone formation. Together these findings suggest that alternative signaling pathways beyond Gsα and Gq/11 act downstream of PTH on osteoblast differentiation.

Pilot study of propranolol premedication to reduce FDG uptake in brown adipose tissue on PET scans of adolescent and young adult oncology patients.

OBJECTIVE: Physiologic uptake of 18F-fluorodeoxyglucose (FDG) in brown adipose tissue (adipose tissue) of cancer patients may confound interpretation of positron emission tomography (PET) scans. Uptake in adipose tissue occurs in up to half of pediatric oncology patients undergoing PET scans, and is especially common in adolescents. adipose tissue is innervated by the sympathetic nervous system, and beta blockers such as propranolol have shown efficacy in reducing adipose tissue uptake on PET scans done in older adult oncology patients. PARTICIPANTS: Because propranolol may cause hypoglycemia or other side effects in fasting patients, we prospectively assessed the safety of a single dose of 20 mg propranolol in adolescent and young adult oncology patients undergoing FDG-PET imaging. METHODS: Ten patients (median age 18 years, range 14-24) received propranolol premedication prior to FDG-PET. RESULTS: No adverse effects or clinically significant changes in serum glucose, heart rate, or blood pressure were observed. Five of the 10 patients had adipose tissue identified on previous PET scans. However, following propranolol administration only, one patient had persistent uptake in adipose tissue. CONCLUSIONS: Propranolol was convenient and safe in fasting adolescent and young adult oncology patients undergoing PET scans. Larger studies are warranted to better define the effectiveness of this approach.

To repeat or not to repeat? Measuring bone mineral density during anti-resorptive therapy or a drug holiday.

An initial bone mineral density (BMD) measurement is used to diagnose osteoporosis and decide whether patients need treatment, but the utility of repeating this test in those on treatment or on a drug holiday (ie, during a pause in bisphosphonate treatment) is controversial. Here, we present evidence for and against the use of BMD monitoring in patients receiving antiresorptive therapy or on a drug holiday, and give our recommendations, arguing against a one-size-fits-all approach.

COVID-19: Incidental Diagnosis by 18F-FDG PET/CT.

A 73-year-old man with chronic obstructive pulmonary disease and no known malignancies was evaluated for back pain. MR examination showed lumbar spine compression fractures, and an F-FDG PET/CT scan was requested to assess for skeletal metastatic disease and potential detection of a primary neoplasm. The PET/CT examination revealed scattered FDG-avid pulmonary opacities with upper lobe preponderance highly suspicious for COVID-19. Real-time polymerase chain reaction testing of nasopharyngeal swabs confirmed the diagnosis.

Correlation of Positron Emission Tomography/Computed Tomography Scan with Smoking, Tumor Size, Stage and Differentiation in Head and Neck Cancer Patients.

The goal of this study was to identify associations between positron emission tomography/computed tomography (PET/CT) maximum standardized uptake value (SUVmax) in patients presenting with head and neck squamous cell carcinoma (SCC) with tumor site, size, histologic differentiation, smoking, and diabetes. Charts of patients with oropharyngeal and laryngeal SCC who underwent 18F-fluorodeoxyglucose PET/CT scans were reviewed between May 2007 and August 2013. Statistical analyses included modeling log-transformed SUVmax values by tumor site, size, histologic differentiation, smoking status, and diabetes using unadjusted linear regressions. Differences were considered statistically significant for P< 0.05. A total of 111 patients (54 with oropharynx and 57 with larynx cancers) were included, 83 men and 28 women with an average age of 57.5 years old. There was a significantly higher pack-year smoking history (P = 0.005) in the larynx cancer group. While tumor T-stage was found to be significantly different (P < 0.0001), there was no difference in tumor size between the two groups: 3.16 cm and 3.58 cm in the oropharynx and larynx, respectively (P = 0.55). In the oropharynx cohort, SUVmax was associated with both tumor size (P = 0.0001) and stage (P < 0.0002). Interestingly, SUVmax differed by tumor differentiation in the larynx (P = 0.04) but not the oropharynx (P = 0.71). Finally, there was no significant difference in SUVmax relative to diabetes and smoking status. PET/CT SUVmax correlated with both tumor size and stage in oropharyngeal cancer patients, and it correlated only with tumor differentiation but not the size or stage in the larynx. There were no significant differences in SUVmax by diabetes or smoking status.

Visualization of bullet track and bullet by radionuclide brain scintigraphy.

Radionuclide brain scintigraphy is a commonly performed examination for the confirmation of brain death. Although the absence of scintigraphically detectable flow of lipophilic tracers to the brain combined with the lack of uptake in the brain is considered consistent with brain death in the appropriate clinical scenario, the cause of death itself is usually not apparent on the scan. A case of bullet track and bullet visualization during a radionuclide brain death study with Tc-99m hexamethylpropyleneamine oxime (HMPAO) is described.

Scintigraphy as a confirmatory test of brain death.

The concept of "brain death" was introduced to medicine in the second half of the 20th century, when technological advancements began to allow sustaining cardiorespiratory functioning of the body in the absence of brain function. Although physicians generally agree that a patient can be declared brain dead when the loss of brain function is total and irreversible, different approaches have been taken to define what constitutes brain death. A thorough clinical examination is essential to the diagnosis. The role of confirmatory tests differ among countries in the world but generally are indicated when a specific part of the clinical examination cannot be performed or is deemed unreliable. Under certain circumstances, confirmatory tests can be used to shorten the clinical observation. Of the confirmatory tests recommended by the American Academy of Neurology and the American Academy of Pediatrics, cerebral scintigraphy is a safe, reliable, and widely available alternative. Once the radiopharmaceutical is properly compounded, cerebral scintigraphy can be performed rapidly and can be interpreted in a straightforward manner. It is tolerant of metabolic aberrations and pharmacologic intoxicants. It is not affected by electrical interference, and the presence of skull defects or scalp trauma do not preclude its performance. The radiopharmaceuticals used in scintigraphy have no deleterious effects on potential donor organs. Cerebral radionuclide angiography has been highly sensitive. Either cerebral planar scintigraphy or cerebral scintitomography with Tc-99m hexamethylpropyleneamineoxime also are highly sensitive, but, in addition, appear to be 100% specific.

The central melanocortin system and fever.

Fever is a phylogenetically ancient response that is mounted upon exposure of the host to pathogens or inflammatory agents. Melanocortin agonists act centrally to inhibit fever by acting at receptors, including the melanocortin-4 receptor, which is prominently expressed in key hypothalamic thermoregulatory centers. Furthermore, endogenous melanocortins act centrally as physiological modulators of fever, recruited during the febrile response to restrain its intensity. Functionally, these actions lie at the interface between the anti-inflammatory effects of melanocortins, which involve suppression of the synthesis and actions of proinflammatory cytokines, and the central control of thermoregulation. Considering the extensive neuroanatomic and functional overlaps between central pathways and peripheral effectors involved in thermoregulation and energy balance, it is not surprising that melanocortins have been found to influence the metabolic economy profoundly in pathological as well as normal states. For example, despite suppressing endotoxin-induced fever, endogenous melanocortins appear to mediate the associated anorexia, a classic component of the "illness syndrome" accompanying acute infections, and promote a negative energy balance. The thermoregulatory actions of melanocortins are in several respects functionally opposed, and are remarkably dependent on physiological state, indicating that responsiveness to melanocortins is a physiologically modulated variable. Elucidating the anti-inflammatory and thermoregulatory roles of central melanocortin receptors during inflammatory states may lead to novel pharmacotherapeutic targets based on selective targeting of melanocortin receptor subtypes, for clinical benefit in human disease states involving neuroinflammatory components and metabolic wasting.

Roles of the melanocortin-4 receptor in antipyretic and hyperthermic actions of centrally administered alpha-MSH.

Activation of central melanocortin receptors (MCR) inhibits fever but can also stimulate thermogenesis, and the mechanisms involved are unknown. To determine whether the long-recognized antipyretic effect of exogenous alpha-MSH is mediated by the melanocortin-4 receptor (MC4R), and what thermoeffector systems are involved, we tested the effects of intracerebroventricular (i.c.v.) injection of alpha-MSH on lipopolysaccharide (LPS, 30 microg/kg i.p.)-induced fever in rats, in the presence and absence of the selective MC4R antagonist HS014. Treatment with alpha-MSH (1 microg, i.c.v.) suppressed LPS-induced increases in core body temperature (Tc), whereas a lower dose (300 ng) was ineffective. Nevertheless, both alpha-MSH doses effectively inhibited LPS-induced peripheral vasoconstriction, the principal heat-conserving thermoeffector, as determined by changes in tail skin temperature (Tsk). This implies that the net antipyretic effect of alpha-MSH cannot be accounted for solely by modulation of heat loss effectors, but also involves other mechanisms. Surprisingly, central MC4-R blockade by coinjected HS014 (1 microg) not only prevented, but reversed the effect of alpha-MSH (1 microg) on Tc, thus resulting in augmented LPS-induced fever. In afebrile rats, alpha-MSH infusion caused a modest transient increase in Tc that was blocked by coinjected HS014, but was not accompanied by altered Tsk. Overall, the results support the hypothesis that the MC4R mediates the antipyretic effects of alpha-MSH. Paradoxically, in the presence of pharmacological MC4-R blockade during fever, exogenous alpha-MSH can exacerbate fever, probably by acting via other central MCR subtype(s). In normal animals, centrally injected alpha-MSH exerts a hyperthermic effect that is mediated by the MC4R, consistent with recent evidence that MC4R activation promotes energy expenditure in normal states through stimulation of thermogenesis.

Loss of Gsα early in the osteoblast lineage favors adipogenic differentiation of mesenchymal progenitors and committed osteoblast precursors.

In humans, aging and glucocorticoid treatment are associated with reduced bone mass and increased marrow adiposity, suggesting that the differentiation of osteoblasts and adipocytes may be coordinately regulated. Within the bone marrow, both osteoblasts and adipocytes are derived from mesenchymal progenitor cells, but the mechanisms guiding the commitment of mesenchymal progenitors into osteoblast versus adipocyte lineages are not fully defined. The heterotrimeric G protein subunit Gs α activates protein kinase A signaling downstream of several G protein-coupled receptors including the parathyroid hormone receptor, and plays a crucial role in regulating bone mass. Here, we show that targeted ablation of Gs α in early osteoblast precursors, but not in differentiated osteocytes, results in a dramatic increase in bone marrow adipocytes. Mutant mice have reduced numbers of mesenchymal progenitors overall, with an increase in the proportion of progenitors committed to the adipocyte lineage. Furthermore, cells committed to the osteoblast lineage retain adipogenic potential both in vitro and in vivo. These findings have clinical implications for developing therapeutic approaches to direct the commitment of mesenchymal progenitors into the osteoblast lineage.

Risk for fatal pulmonary hemorrhage does not appear to be increased following dose escalation using stereotactic body radiotherapy (SBRT) in locally advanced non-small cell lung cancer (NSCLC).

PURPOSE: A prospective single institution study evaluating the feasibility of conventional chemoradiation (CRT) followed by SBRT as a means of dose escalation for patients with stage II-III NSCLC with residual disease recently completed accrual. Two patients enrolled developed unexpected fatal pulmonary hemorrhages. A post-hoc analysis was performed to evaluate for an association between protocol therapy and this grade 5 toxicity. METHODS AND MATERIALS: 17 patients enrolled on the protocol with medial tumors according to the RTOG 0813 definitions, were selected for analysis. Protocol therapy consisted of SBRT boost consisting of 10Gy times two or 6.5Gy times three fractions, after completing initial CRT. Chi-square and ANOVA associations were performed using patient-specific and dosimetric characteristics, particularly volume and point doses to mediastinal structures. RESULTS: After a median follow-up of 13 months, 2 patients developed a grade V pulmonary hemorrhage, in the setting of recurrent disease. Cumulative biological effective doses (BED3) were calculated using an α/ß 3.0 for the pulmonary vasculature and bronchial wall. No volumetric or point doses administered seemed to correlate with the risk for pulmonary hemorrhage, despite an average maximum pulmonary artery dose of 175 Gy BED3. The only significant association with fatal hemorrhage was local recurrence (p = 0.0441). CONCLUSION: SBRT boost does not appear to increase the risk for fatal pulmonary hemorrhage. A cumulative maximum BED3 to the pulmonary artery less than 175 Gy appears to be safe.

Early PET/CT scans for assessing treatment responses of non-small cell lung cancer for SBRT boost: what to do with scans from multiple scanners.

Chemoradiation remains the standard of care for the nonsurgical treatment of advanced non-small cell lung cancer (NSCLC) but local recurrence rates of 30-40% are documented. We examined the early PET/CT responses of NSCLC treated with standard chemoradiation in a prospective single institutional trial of early 18F-2-deoxy-D-glucose-PET/CT scans to help define patients appropriate for dose escalation with SBRT. 48 patients with stage IIA, IIB or IIIA-B NSCLC with no or non-bulky (

Stereotactic body radiation therapy can be used safely to boost residual disease in locally advanced non-small cell lung cancer: a prospective study.

PURPOSE: To report the results of a prospective, single-institution study evaluating the feasibility of conventional chemoradiation (CRT) followed by stereotactic body radiation therapy (SBRT) as a means of dose escalation for patients with stage II-III non-small cell lung cancer (NSCLC) with residual disease. METHODS AND MATERIALS: Patients without metastatic disease and with radiologic evidence of limited residual disease (≤5 cm) within the site of the primary tumor and good or complete nodal responses after standard CRT to a target dose of 60 Gy were considered eligible. The SBRT boost was done to achieve a total combined dose biological equivalent dose >100 Gy to the residual primary tumor, consisting of 10 Gy × 2 fractions (20 Gy total) for peripheral tumors, and 6.5 Gy × 3 fractions (19.5 Gy total) for medial tumors using the Radiation Therapy Oncology Group protocol 0813 definitions. The primary endpoint was the development of grade ≥3 radiation pneumonitis (RP). RESULTS: After a median follow-up of 13 months, 4 patients developed acute grade 3 RP, and 1 (2.9%) developed late and persistent grade 3 RP. No patients developed grade 4 or 5 RP. Mean lung dose, V2.5, V5, V10, and V20 values were calculated for the SBRT boost, and none were found to significantly predict for RP. Only advancing age (P=.0147), previous smoking status (P=.0505), and high CRT mean lung dose (P=.0295) were significantly associated with RP development. At the time of analysis, the actuarial local control rate at the primary tumor site was 82.9%, with only 6 patients demonstrating recurrence. CONCLUSIONS: Linear accelerator-based SBRT for dose escalation of limited residual NSCLC after definitive CRT was feasible and did not increase the risk for toxicity above that for standard radiation therapy.

Scintigraphic confirmation of brain death.

The concept of brain death has gained importance in the past few decades to prevent futile attempts to sustain ventilation and blood circulation when the brain has lost all function and to procure beneficial tissues or life-saving organs for transplantation. However, differences remain among professional societies and various study group recommendations, as well as among individual legal statutes, in how brain death is defined and the methodology for which the diagnosis is attained. Furthermore, reports have appeared both in the medical literature and the lay press concerning quality assurance measures in brain death documentation. Scintigraphy is a commonly used technique in the evaluation of brain death and can be performed with the use of either nonspecific tracers, such as Tc99m diethylene triamine pentaacetic acid, or brain-specific tracers, such as Tc99m hexamethylpropyleneamineoxime (HMPAO). Planar imaging, with or without radionuclide angiography, continues to be the mainstay for the scintigraphic confirmation of brain death. Flow with multiprojection static planar imaging with the use of Tc99m HMPAO can be used to evaluate the cerebral hemispheres, basal ganglia, thalamus, and cerebellum. Single-photon emission computed tomography (SPECT) can provide cross-sectional information but can be difficult to perform in the context of brain death. The current use of SPECT primarily is supplemental to help differentiate overlying scalp from intracerebral activity. The reliability of SPECT to exclude flow and metabolism in the brainstem remains to be scientifically validated.

Response of thyroglobulin to radioiodine therapy in thyroglobulin-elevated negative iodine scintigraphy (TENIS) syndrome.

BACKGROUND: While radioiodine (131-I) is widely used in the treatment of differentiated thyroid cancer, its role remains less certain when abnormal 131-I uptake cannot be demonstrated in a pre-therapy diagnostic scan. Documentation of abnormal 131-I uptake in a post-therapy scan in such cases helps to justify the radioiodine therapy, but the post-therapy scan can remain persistently negative. AIM: To evaluate (i) whether 131-I therapy had any measurable effect on thyroglobulin (Tg) levels in patients who were scan negative prior to radioiodine therapy and remained scan negative after therapy, and (ii) whether the magnitude of the effect on Tg depended on the pre-therapy Tg level. PATIENTS AND METHODS: Retrospective analysis of 78 patients. All patients had pre-therapy and post-therapy Tg levels measured under stimulation with thyroid stimulating hormone. Hospital data until date of last contact were analyzed to assess for recurrent disease. RESULTS: Tg levels decreased by 55% in those having Tg 10 µg/l or higher; and by 41% in those with less than 10 µg/l. In patients with detectable Tg antibodies, there were no statistically significant decreases demonstrated for either Tg or Tg antibody levels. CONCLUSION: Radioiodine therapy can reduce Tg levels, independently of the pre-therapy level, even when the pre-therapy level is low and the pre-therapy, as well as the post-therapy, radioiodine scan remains negative.

FDG PET/CT findings of a glomangiopericytoma.

Glomangiopericytoma (GPC) is a rare vascular neoplasm that arises almost exclusively from the nasal cavity or paranasal sinuses. GPC is also called sinonasal-type hemangiopericytoma, although current nomenclature, as well as classification in a group with myopericytomas, better emphasizes the relatively indolent behavior of this tumor. The authors present the FDG PET/CT findings of GPC in a 53-year-old with symptoms of nasal congestion and facial pressure. CT and MRI showed a nasal mass to extend along the sphenoid ridge from the posterior nasal cavity into the posterior nasopharynx. PET showed the mass to have uniformly low-grade FDG hypermetabolism. Pathologic examination of the surgical specimen showed classic features of GPC.