Outcomes Following Hypofractionated Stereotactic Radiotherapy to the Cavity After Surgery for Melanoma Brain Metastases.

AIMS: Hypofractionated stereotactic radiotherapy (HSRT) to the cavity after surgical resection of brain metastases improves local control. Most reported cohorts include few patients with melanoma, a population known to have high rates of recurrence and neurological death. We aimed to assess outcomes in patients with melanoma brain metastases who received HSRT after surgery at two Australian institutions. MATERIALS AND METHODS: A retrospective analysis was carried out including patients treated between January 2012 and May 2020. HSRT was recommended for patients with melanoma brain metastases at high risk of local recurrence after surgery. Treatment was delivered using appropriately commissioned linear accelerators. Routine follow-up included surveillance magnetic resonance imaging brain every 3 months for at least 2 years. Primary outcomes were overall survival, local control, incidence of radiological radionecrosis and symptomatic radionecrosis. RESULTS: There were 63 cavities identified in 57 patients. The most common HSRT dose prescriptions were 24 Gy in three fractions and 27.5 Gy in five fractions. The median follow-up was 32 months in survivors. Local control was 90% at 1 year, 83% at 2 years and 76% at 3 years. Subtotal brain metastases resection (hazard ratio 12.5; 95% confidence interval 1.4-111; P = 0.0238) was associated with more local recurrence. Overall survival was 64% at 1 year, 45% at 2 years and 40% at 3 years. There were 10 radiological radionecrosis events (16% of cavities) during the study period, with 5% at 1 year and 8% at 2 years after HSRT. The median time to onset of radiological radionecrosis was 21 months (range 6-56). Of these events, three became symptomatic (5%) during the study period at a median time to onset of 26 months (range 21-32). CONCLUSION: Cavity HSRT is associated with high rates of local control in patients with melanoma brain metastases. Subtotal resection strongly predicts for local recurrence after HSRT. Symptomatic radionecrosis occurred in 5% of cavities but increased to 8% of longer-term survivors.

Dual-Layer Spectral CT Imaging of Upper Aerodigestive Tract Cancer: Analysis of Spectral Imaging Parameters and Impact on Tumor Staging.

BACKGROUND AND PURPOSE: Dual-layer spectral CT is a novel technology that utilized conventional single-tube CT acquisition with a dual-layer detector for the separation of high and low-energy photons to create spectral data for material decomposition. We evaluated the spectral parameters of iodine density and Z-effective values in primary head and neck squamous cell carcinoma and determined its impact on local tumor staging. MATERIALS AND METHODS: Twenty-one patients with primary head and neck squamous cell carcinoma and 15 healthy controls were retrospectively evaluated. Iodine density (milligram/milliliter) and Z-effective values were compared quantitatively between head and neck squamous cell carcinoma and normal neck mucosa. The receiver operating characteristic area under the curve determined the diagnostic performance of the spectral data for local staging. We compared conventional CT images without and with iodine density and Z-effective images to determine its impact on local tumor staging. RESULTS: Primary head and neck squamous cell carcinoma showed higher mean iodine density (2.01 [SD, 0.26] mg/mL, P < .001) and Z-effective values (8.21 [SD, 0.36], P < .001). A high interobserver correlation was demonstrated for ROI measurements for both the control group (iodine density, κ = 0.71, and Z-effective values, κ = 0.78) and head and neck squamous cell carcinoma (iodine density, κ = 0.84, and Z-effective values, κ = 0.75) group. The area under the curve for iodine density and Z-effective values was 0.98 and 0.93, respectively. Optimal thresholds were identified as 1.58 mg/mL (95% CI, 1.45-1.71 mg/mL; P < .001; sensitivity = 1.0; specificity = .0.93) for iodine density and 8.08 (95% CI, 7.96-8.19; P < .001; sensitivity = 0.86; specificity = 0.93) for Z-effective values. Conventional CT with the addition of dual-layer spectral data (iodine density and Z-effective values) improved the accuracy of local tumor staging in 3 of 21 patients (14%) with head and neck squamous cell carcinoma compared with the criterion standard surgical staging/histopathology. CONCLUSIONS: Dual-layer spectral iodine density and Z-effective values provided increased quantitative and qualitative differentiation between upper aerodigestive head and neck squamous cell carcinoma and normal mucosa. Increased tissue differentiation improved the local tumor staging accuracy.

2,4-Dinitrophenol overdose - Everything old is new again.

A complete case example of a fatal 2,4-dinitrophenol (DNP) overdose involving a 23-year-old male is described. Included are details of not only the patient's presentation symptoms and treatment, but also the subsequent findings of the coronial investigation process including the autopsy, post-mortem computed tomography (PMCT) scanning and toxicological analysis and results. The patient presented with elevated temperature, heart rate and blood pressure. Multiple treatments were conducted to counteract these symptoms, however the patient died approximately 1.5 hours after hospital admission and some 4.5 hours after the DNP was initially consumed. Autopsy revealed the presence of cardiovascular disease that was contributory to death and post-mortem computed tomography showed evidence of decompositional intravascular gas in the neck, head, face, lower abdomen, heart and hepatic systems. Toxicological analysis was completed by protein precipitation with methanol and subsequent instrumental analysis by LC/MS/MS in negative ion mode. The antemortem blood specimen showed the presence of tadalafil, two anabolic steroids and a DNP concentration of 110 mg/kg which is consistent with other reported DNP fatalities. Despite the small amount of time between the antemortem specimen collection and death, the DNP concentration identified in the femoral blood post-mortem specimen was comparably low (5.5 mg/kg). DNP concentrations also reduced during an extended period of specimen storage prior to analysis indicating some instability in biological specimens even when refrigerated or frozen. DNP was found to be distributed primarily in the aqueous tissues (blood, vitreous, bile) rather than solid matrices (liver, kidney, muscle).

Radiological Kinetics of Brain Metastases and Clinical Implications for Patients Treated With Stereotactic Radiosurgery.

AIMS: Select patients with brain metastases receive stereotactic radiosurgery (SRS) with the objective of improving survival and intracranial disease control. Brain metastases number and volume are prognostic factors used to inform patient selection. The aim of this study was to assess the rate of change of brain metastases size and number (growth kinetics) between the diagnostic and day of SRS magnetic resonance imaging (MRI) scans. MATERIALS AND METHODS: All patients treated with Gamma Knife SRS between October 2015 and April 2017 were included in this single-centre retrospective analysis. Brain metastases number and diameter were recorded at diagnosis and treatment. For patients with multiple brain metastases, the largest lesion was the index lesion. Distant intracranial control and overall survival were reported from the date of SRS. RESULTS: In total, 146 patients received 156 episodes of SRS. The median interval between diagnostic and SRS MRI was 20 days (range 1-68). Interval growth in the index lesion of at least 3 mm or the development of a new brain metastasis was noted in 60.2% of patients. This was associated with age less than 60 years (P = 0.001), Eastern Cooperative Oncology Group (ECOG) performance status 2 or above (P = 0.04), non-small cell lung carcinoma (NSCLC) (P = 0.03) or melanoma histologies (P = 0.05) and uncontrolled extracranial disease (P = 0.05). These patients were also more likely to develop distant intracranial recurrence (P = 0.046). Clinically significant growth was not associated with scan interval or differences in overall survival. The Kaplan-Meier estimate of probability of survival at 12 months was 59.3% (95% confidence interval 46.7-75.2%) for all patients. CONCLUSION: Intracranial progression between diagnosis and day of SRS is common. Risk factors are uncontrolled extracranial disease, poorer performance status, NSCLC or melanoma histologies and age less than 60 years. These patients would benefit from an MRI closer to treatment to inform patient selection and target delineation for SRS planning.

Multinodular and Vacuolating Neuronal Tumor of the Cerebrum: A New "Leave Me Alone" Lesion with a Characteristic Imaging Pattern.

Multinodular and vacuolating neuronal tumor of the cerebrum is a recently reported benign, mixed glial neuronal lesion that is included in the 2016 updated World Health Organization classification of brain neoplasms as a unique cytoarchitectural pattern of gangliocytoma. We report 33 cases of presumed multinodular and vacuolating neuronal tumor of the cerebrum that exhibit a remarkably similar pattern of imaging findings consisting of a subcortical cluster of nodular lesions located on the inner surface of an otherwise normal-appearing cortex, principally within the deep cortical ribbon and superficial subcortical white matter, which is hyperintense on FLAIR. Only 4 of our cases are biopsy-proven because most were asymptomatic and incidentally discovered. The remaining were followed for a minimum of 24 months (mean, 3 years) without interval change. We demonstrate that these are benign, nonaggressive lesions that do not require biopsy in asymptomatic patients and behave more like a malformative process than a true neoplasm.

Cebranopadol: novel dual opioid/NOP receptor agonist analgesic.

WHAT IS KNOWN AND OBJECTIVE: Chronic pain presents a difficult clinical challenge because of the limited efficacy, the limiting adverse-effect profile or the abuse potential of current analgesic options. Cebranopadol is a novel new agent in clinical trials that combines dual agonist action at opioid and nociceptin/orphanin FQ peptide (NOP) receptors. It is the first truly unique, centrally acting analgesic in several years. We here review the basic and clinical pharmacology of cebranopadol. METHODS: Published literature and Internet sources were searched to identify information related to the basic science (pharmacology and medicinal chemistry) and development (clinical trial) information on the mechanism of dual opioid and NOP receptor pharmacologic action in general, and for cebranopadol in particular. The identified sources were reviewed and the information synthesized. RESULTS: The preclinical testing of cebranopadol has characterized it as a dual opioid and NOP receptor agonist that displays antinociceptive and antihyperalgesic action in a variety of acute and chronic pain models in animals. Unlike most current traditional opioids, it is generally more potent against neuropathic than nociceptive pain. Several phase 2 clinical trials have been completed. WHAT IS NEW AND CONCLUSION: Despite the medical need, a truly novel centrally acting analgesic has not been developed in many years. Cebranopadol represents a truly novel mechanistic approach. Its actual place in pain pharmacotherapy awaits the results of phase 3 clinical trials.

Reversible brainstem dysfunction from spinal arterio-venous fistula.

A 45-year-old man presented with subacute onset of ataxia, diplopia, urinary retention and paraparesis. MR scan of brain showed abnormal T2 hyperintense signal within the cervical cord, medulla and lower pons and vascular appearances suggesting an arterio-venous fistula. The fistula was surgically explored and successfully disconnected with good clinical outcome. Brainstem or cervical dural arterio-venous fistulae more typically present as a myelopathy; only a handful of cases have presented with brainstem dysfunction. This is a rare but reversible cause of subacute brainstem dysfunction.

Maternal obesity and venous thromboembolism.

The incidence of obesity in pregnancy has increased rapidly in the last decade. Obesity is a risk factor for venous thromboembolism outside of pregnancy and previous studies of maternal death in the UK have identified obesity as a risk factor in pregnancy. As a result the Royal College of Obstetricians and Gynaecologists have targeted obesity as a risk factor in evaluation of the need for thromboprophylaxis in pregnancy. This article highlights the evidence that obesity increases the risk of venous thromboembolism in pregnancy and the puerperium, discusses thromboprophylaxis and appropriate dosing in obese parturients and details the anaesthetic implications of the 2009 Royal College of Obstetricians and Gynaecologists' guidelines. More clinical studies are required to clarify the appropriate dose of low-molecular-weight heparin in an obese parturient.

rPSGL-Ig for improvement of early liver allograft function: a double-blind, placebo-controlled, single-center phase II study.

The selectin antagonist known as recombinant P-selectin glycoprotein ligand IgG (rPSGL-Ig) blocks leukocyte adhesion and protects against transplantation ischemia reperfusion injury (IRI) in animal models. This randomized (1:1) single-center double-blind 47-patient phase 2 study with 6-month follow-up assessed rPSGL-Ig's safety and impact on early graft function at 1 mg/kg systemic dose with pretransplant allograft ex vivo treatment in deceased-donor liver transplant recipients. Safety was assessed in all patients, whereas efficacy was assessed in a prospectively defined per-protocol patient set (PP) by peak serum transaminase (TA) and bilirubin values, and normalization thereof. In PP patients, the incidence of poor early graft function (defined as peak TA >2500 U/L or bilirubin >10 mg/dL), average peak liver enzymes and bilirubin, normalization thereof and duration of primary and total hospitalization trended consistently lower in the rPSGL-Ig group compared to placebo. In patients with donor risk index above study-average, normalization of aspartate aminotransferase was significantly improved in the rPSGL-Ig group (p < 0.03). rPSGL-Ig treatment blunted postreperfusion induction versus placebo of IRI biomarker IP-10 (p < 0.1) and augmented cytoprotective IL-10 (p < 0.05). This is the first clinical trial of an adhesion molecule antagonist to demonstrate a beneficial effect on liver transplantation IRI and supported by therapeutic modulation of two hepatic IRI biomarkers.

Thirty-five year review of a mercury monitoring service for Scottish dental practices.

AIMS AND OBJECTIVES: To review a long-standing mercury monitoring service offered to staff in dental practices in Scotland. METHODS: During the first 20 years of the service, dentists and their staff were contacted by letter and invited to participate. Respondents were asked to collect samples of head hair, pubic hair, fingernail and toenail for analysis of mercury. After 1995, head hair samples were collected initially and further samples were only measured if head hair mercury was elevated. RESULTS: At the start of this scheme many staff, including administrative staff, had systemic exposure to mercury (defined as increased mercury in all four samples). Incidents of exposure have decreased over the 35 years and are now very rare. Male staff were found to have higher mercury concentrations than female staff and dentists tended to have higher concentrations than other staff. Staff working in dental practices more than five years old had small but discernable increases in head hair mercury concentration. In recent years the use of reusable capsules such as Dentomats has been associated with a slight but statistically significant increase in head hair mercury concentrations when compared to the use of encapsulated amalgam systems. Staff wearing open-toed footwear had significantly higher toenail mercury concentrations compared to those who wore shoes. CONCLUSIONS: Exposure of staff to mercury in Scottish dental practices is currently now very low. This is probably as a result of increased awareness to the toxicity of mercury and improved methods of preparing amalgam. It may be possible to reduce exposure further, although probably only slightly, by upgrading practices and using encapsulated mercury amalgam.

A novel mechanism whereby BRCA1/1a/1b fine tunes the dynamic complex interplay between SUMO-dependent/independent activities of Ubc9 on E2-induced ERalpha activation/repression and degradation in breast cancer cells.

BRCA1 dysfunction is associated with hormone-responsive cancers. We have identified a consensus SUMO modification site in the amino-terminal region of BRCA1/1a/1b proteins and the mutation in this potential SUMO acceptor site (K 109 to R) impaired their ability to bind and repress ligand-dependent ERalpha transcriptional activity in breast cancer cells. Furthermore, we have found SUMO E2-conjugating enzyme Ubc9 to bind BRCA1 proteins. We have mapped BRCA1 [within amino acids (aa) 1-182] as the minimum domain that is sufficient for in vitro binding to Ubc9 as well as for regulating ERalpha activity. BRCA1 Mutant #1 (K109 to R) was impaired in its ability to both bind, as well as modulate Ubc9 mediated SUMO-dependent/independent E2-induced ERalpha transcriptional activity in breast cancer cells. Similarly, BRCA1 cancer-predisposing mutation (61Cys-Gly) abrogated the ability to both bind Ubc9 as well as inhibit ERalpha activity suggesting physiological significance. Addition of BRCA1 but not Mutant #1 to E2-induced ERalpha in the presence of SUMO-1 and Ubc9 resulted in the degradation of ERalpha suggesting BRCA1 to be a putative SUMO-1 and Ubc9-dependent E3 ubiquitin ligase for ERalpha. This is the first report demonstrating the participation of Ubc9 in BRCA1 E3 ubiquitin ligase mediated degradation of ERalpha. These results suggest a novel function for BRCA1 in regulating the dynamic cycles of SUMO and ubiquitin modifications required for ERalpha turn over and deregulation of this molecular switch due to lack of BRCA1 results in ERalpha-negative/positive breast cancers. This study will help in designing novel BRCA1 function-based targeted treatment for breast cancers.

Percutaneous radiofrequency ablation of renal tumours: case series of 11 tumours and review of published work.

Detection of renal cell carcinoma (RCC) is increasing with the greater use of cross-sectional imaging and up to two-thirds of RCCs are discovered incidentally in asymptomatic patients. The traditional option of nephrectomy or partial nephrectomy may not always be appropriate. A minimally invasive treatment alternative is radiofrequency ablation (RFA). We retrospectively reviewed the RFA cases for renal tumours at our institution between January 2004 and June 2006. Thirteen RFA treatment sessions were conducted for 11 neoplasms in 11 patients. Mean patient age was 74.4 years (61-88 years). Imaging was carried out after ablation with a mean follow up of 8.0 months (2-26 months). No residual tumour was observed after the first RFA treatment in 82% of patients (nine of 11). Two patients required a second RFA treatment for residual (one) or recurrent tumour (one). RFA is emerging as a useful technique for treatment of small renal tumour. A number of short-term studies reflect this, however, long-term findings are still lacking.

A quantitative genetic test of adaptive decoupling across metamorphosis for locomotor and life-history traits in the pacific tree frog, Hyla regilla.

Metamorphosis is assumed to be beneficial because it can break developmental links between traits in the different phases of a complex life-cycle and thereby allow larval and adult phases to adapt independently. I tested the prediction that correlations between the larval and adult phases are smaller than within stages. I estimated phenotypic and additive genetic variances and correlations for tadpole swimming speed, frog jump distance, body size, and larval period in a single population of the Pacific tree frog, Hyla regilla. These traits are known or reasonably assumed to be important for survival in this and other anuran species from temporary ponds. Only the three size variables were affected by sire identity. Heritabilities for locomotor performance, larval period, and size-independent performance were low (0.00-0.23) and not significant. Body size measurements showed somewhat higher and statistically significant heritabilities (0.24-0.34). Most traits were phenotypically correlated. On average, phenotypic correlations were larger between phases than within phases (0.41 vs. 0.28). Genetic correlations involving body-size traits were positive and large, and average within- and between-phase genetic correlation coefficients were identical (0.81). These results do not support the adaptive decoupling hypothesis, and they indicate that a paucity of additive genetic variation is a likely constraint on the evolution of traits measured for this population.

Combination of gene delivery and DNA vaccination to protect from and reverse Th1 autoimmune disease via deviation to the Th2 pathway.

Using a combination of local gene delivery and tolerizing DNA vaccination, we demonstrate that codelivery of the interleukin-4 (IL-4) gene and a DNA vaccine encoding the self-peptide proteolipid protein 139-151 (PLP139-151) provides protective immunity against experimental autoimmune encephalomyelitis (EAE). We provide evidence for a mechanism whereby IL-4 expressed from the naked DNA is secreted and acts locally on autoreactive T cells via activation of STAT6 to shift their cytokine profile to T helper 2. We also show that DNA vaccines can be used to reverse established EAE by covaccination with the genes for myelin oligodendrocyte glycoprotein and IL-4. This treatment strategy combines the antigen-specific effects of DNA vaccination and the beneficial effects of local gene delivery.

A multiple-site-specific heteroduplex tracking assay as a tool for the study of viral population dynamics.

Rapidly evolving entities, such as viruses, can undergo complex genetic changes in the face of strong selective pressure. We have developed a modified heteroduplex tracking assay (HTA) capable of detecting the presence of single, specific mutations or sets of linked mutations. The initial application of this approach, termed multiple-site-specific (MSS) HTA, was directed toward the detection of mutations in the HIV-1 pro gene at positions 46, 48, 54, 82, 84, and 90, which are associated with resistance to multiple protease inhibitors. We demonstrate that MSS HTA is sensitive and largely specific to all targeted mutations. The assay allows the accurate and reproducible quantitation of viral subpopulations comprising 3% or more of the total population. Furthermore, we used MSS HTA in longitudinal studies of pro gene evolution in vitro and in vivo. In the examples shown here, populations turned over rapidly and more than one population was present frequently. To demonstrate the versatility of MSS HTA, we also constructed a probe sensitive to changes at positions 181 and 184 of the RT coding domain. Changes at these positions are involved in resistance to nevirapine and 2',3'-dideoxy-3'-thiacytidine (3TC), respectively. This assay easily detected the evolution of resistance to 3TC. MSS HTA provides a rapid and sensitive approach for detecting the presence of and quantifying complex mixtures of distinct genotypes, including genetically linked mutations, and, as one example, represents a useful tool for following the evolution of drug resistance during failure of HIV-1 antiviral therapy.

Comparing the similarity of time-series gene expression using signal processing metrics.

Many algorithms have been used to cluster genes measured by microarray across a time series. Instead of clustering, our goal was to compare all pairs of genes to determine whether there was evidence of a phase shift between them. We describe a technique where gene expression is treated as a discrete time-invariant signal, allowing the use of digital signal-processing tools, including power spectral density, coherence, and transfer gain and phase shift. We used these on a public RNA expression set of 2467 genes measured every 7 min for 119 min and found 18 putative associations. Two of these were known in the biomedical literature and may have been missed using correlation coefficients. Digital signal processing tools can be embedded and enhance existing clustering algorithms.

The effects of acute and developmental temperature on burst swimming speed and myofibrillar ATPase activity in tadpoles of the Pacific tree frog, Hyla regilla.

The effects of acute and developmental temperature on maximum burst swimming speed, body size, and myofibrillar ATPase activity were assessed in tadpoles of the Pacific tree frog, Hyla regilla. Tadpoles from field-collected egg masses were reared in the laboratory at 15 degrees (cool) and 25 degrees C (warm). Body size, maximum burst swimming speed from 5 degrees to 35 degrees C, and tail myofibrillar ATPase activity at 15 degrees and 25 degrees C were measured at a single developmental stage. Burst speed of both groups of tadpoles was strongly affected by test temperature (P<0. 001). Performance maxima spanned test temperatures of 15 degrees -25 degrees C for the cool group and 15 degrees -30 degrees C for the warm group. Burst speed also depended on developmental temperature (P<0.001), even after accounting for variation in body size. At most test temperatures, the cool-reared tadpoles swam faster than the warm-reared tadpoles. Myofibrillar ATPase activity was affected by test temperature (P<0.001). Like swimming speed, enzyme activity was greater in the cool-reared tadpoles than in the warm-reared tadpoles, a difference that was significant when assayed at 15 degrees C (P<0. 01). These results suggest a mechanism for developmental temperature effects on locomotor performance observed in other taxa.

Identification of autoantibodies associated with rippling muscles and myasthenia gravis that recognize skeletal muscle proteins: possible relationship of antigens and stretch-activated ion channels.

The role of mechanosensitive calcium channels in skeletal muscle physiology is not understood. This study takes advantage of an autoimmune neuromuscular disorder (myasthenia gravis associated with rippling muscles) to identify components in the skeletal muscle myocyte that may play a role in mechanosensitive calcium channel activity. Rippling muscles are characterized by stretch or percussion activated wave-like muscle contractions that do not require motor unit action potentials for propagation. Autoantibodies from the sera of patients with autoimmune rippling muscles (associated with myasthenia gravis) are directed against high molecular weight muscle proteins. Some of these proteins are uniquely recognized by antisera from patients with autoimmune rippling muscles. This suggests these autoantigens are distinct from those normally associated with myasthenia gravis, and may play a role in the mechanosensitive activation of muscle contraction.

Androgen-sensitive preganglionic neurons innervate the male rat pelvic ganglion.

In adult male rats many pelvic autonomic ganglion cells change in structure and function after androgen deprivation. In this study we have investigated whether preganglionic neurons in the lumbar and sacral spinal cord that innervate these ganglion cells are also androgen-sensitive. Numerous spinal neurons retrogradely labelled from the pelvic ganglion possessed androgen receptor immunoreactivity and this was diminished by castration or enhanced by additional testosterone exposure. These comprised 27-77% of all preganglionic neurons innervating the pelvic ganglion, depending on the spinal level and whether animals were administered testosterone prior to sacrifice or not. When adult animals were castrated, no change occurred in the soma size or number of primary dendrites in these lumbar or sacral preganglionic neurons. Mean dendrite length was also determined in lumbar preganglionic neurons supplying the pelvic ganglion, but was not affected by castration. However, the total volume of lumbar preganglionic terminal varicosities supplying each noradrenergic pelvic ganglion cell decreased in parallel with the volume of the target neuron. These studies show that many preganglionic autonomic neurons involved in pelvic reflexes are androgen-sensitive, but that androgens selectively influence particular neuronal compartments. The prevalence of androgen receptors in these neurons suggests that testosterone may directly influence gene expression of preganglionic neurons. Together these studies suggest that testosterone (or a metabolite) has widespread actions on pelvic reflex circuits during adulthood and that under conditions of diminished circulating androgens a variety of reflex activities may not function optimally.