Faculty Bibliography

Introduction No evidence-based guidelines exist for preventive dental care before ra-diation therapy (RT) in head and neck cancer (HNC) patients. An ongoing multi-center, prospective cohort study, Clinical Registry of Dental Outcomes in HNC patients (OraRad) (1U01DE022939-01), is addressing this knowledge gap. Objectives Evaluate dental disease and associated factors pre-RT. Methods OraRad enrolls patients at six U.S. clinical centers pre-RT; follows them every 6 months for 2 years post-RT with primary outcome of tooth loss. Calibrated examiners assess caries and periodontal disease using validated scales and standardized procedures. Results Baseline measures were reported for 356 participants with mean (SD) age 59.9 (11.0) years; 77% male. Pre-RT dental disease parameters (means) include: number of teeth 22.9; decayed, missing, filled surfaces (DMFS) 33.3 with 1.6 decayed surfaces; clinical attachment level 1.8mm; and probing depth 2.4 mm with 13.5% of tooth sites >=4mm. Participants with at least a high school diploma had more teeth and fewer tooth sites with PD >=4mm compared to those with less education. Patients who received routine dental care had more total teeth pre-RT vs. those without (24.0 vs. 19.8, respectively). We found 37.2% of patients had at least 1 decayed surface and 47.4% had a least one tooth with a probing depth >4mm. Conclusions A high proportion of patients have dental disease at the start of RT for HNC. Observing dental outcomes post-RT, OraRad has the potential to determine the risk of dental disease at the start of RT and determine the best treatment recommendations for HNC patients pre-and post-RT

Introduction Radiation Therapy (RT) for Head and Neck Cancer (HNC) can cause significant oral complications. However, modern techniques such as Intensity Modulated RT (IMRT) may reduce their incidence/severity. Objectives To assess severity of oral complications 6 months after modern RT for HNC. Methods OraRad is an ongoing 6-center prospective cohort study. Oral outcomes are evaluated before start of RT (baseline), and 6, 12, 18, 24 months after RT. For this analysis, we compared baseline vs. 6 month data using mixed linear models for continuous measures and generalized estimating equations for categorical measures. Data are presented as outcome mean (SD, number of subjects), unless otherwise stated. Results Stimulated whole salivary flow declined from 1.09 ml/min (0.67, 354) at baseline to 0.47 (0.47, 216) at 6 months (p < 0.0001). Maximal mouth opening reduced from 45.58 mm (10.40, 371) to 42.53 (9.52, 208) (p < 0.0001). 17 of 203 subjects (8.4%) had persistent oral mucositis at 6 months. Overall oral health-related quality of life score (1-4 scale) worsened from 1.48 (0.42, 371) to 1.86 (0.47, 211) (p < 0.0001). Contributing to this decline were subject-reported negative changes related to swallowing solid food, choking when swallowing, opening the mouth wide, dry mouth, sticky saliva, smell, and taste (p < 0.0001). At 6 months, there was greater frequency of using dental floss, and greater proportion using supplemental fluoride (p < 0.0001). Conclusions Despite use of IMRT, HNC patients continue to suffer significant oral complications of cancer therapy, with negative impact on oral health, function, and quality of life

Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the noradrenaline transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients

OBJECTIVE: To examine the prognostic capabilities of intravoxel incoherent motion (IVIM) metrics and their ability to predict response to neoadjuvant treatment (NAT). Additionally, to observe changes in IVIM metrics between pre- and post-treatment MRI. METHODS: This IRB-approved, HIPAA-compliant retrospective study observed 31 breast cancer patients (32 lesions). Patients underwent standard bilateral breast MRI along with diffusion-weighted imaging before and after NAT. Six patients underwent an additional IVIM-MRI scan 12-14 weeks after initial scan and 2 cycles of treatment. In addition to apparent diffusion coefficients (ADC) from monoexponential decay, IVIM mean values (tissue diffusivity Dt, perfusion fraction fp, and pseudodiffusivity Dp) and histogram metrics were derived using a biexponential model. An additional filter identified voxels of highly vascular tumor tissue (VTT), excluding necrotic or normal tissue. Clinical data include histology of biopsy and clinical response to treatment through RECIST assessment. Comparisons of treatment response were made using Wilcoxon rank-sum tests. RESULTS: Average, kurtosis, and skewness of pseudodiffusion Dp significantly differentiated RECIST responders from nonresponders. ADC and Dt values generally increased ( approximately 70%) and VTT% values generally decreased ( approximately 20%) post-treatment. CONCLUSION: Dp metrics showed prognostic capabilities; slow and heterogeneous pseudodiffusion offer poor prognosis. Baseline ADC/Dt parameters were not significant predictors of response. This work suggests that IVIM mean values and heterogeneity metrics may have prognostic value in the setting of breast cancer NAT.

BACKGROUND: Multiple system atrophy (MSA) is a rare, adult-onset, rapidly progressive fatal synucleinopathy that primarily affects oligodendroglial cells in the brain. Patients with MSA only rarely have visual complaints, but recent studies of the retina using optical coherence tomography (OCT) showed atrophy of the peripapillary retinal nerve fiber layer (RNFL) and to a lesser extent the macular ganglion cell layer (GCL) complex. METHODS: We performed a literature review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines for studies published before January 2017, identified through PubMed and Google Scholar databases, which reported OCT-related outcomes in patients with MSA and controls. A random-effects model was constructed. RESULTS: The meta-analysis search strategy yielded 15 articles of which 7 met the inclusion criteria. The pooled difference in the average thickness of the RNFL was -5.48 mum (95% CI, -6.23 to -4.73; p < 0.0001), indicating significant thinning in patients with MSA. The pooled results showed significant thinning in all the specific RNFL quadrants, except in the temporal RNFL quadrant, where the thickness in MSA and controls was similar [pooled difference of 1.11 microm (95% CI, -4.03 to 6.26; p = 0.67)]. This pattern of retinal damage suggests that MSA patients have preferential loss of retinal ganglion cells projecting to the magnocellular pathway (M-cells), which are mainly located in the peripheral retina and are not essential for visual acuity. Visual acuity, on the other hand, relies mostly on macular ganglion cells projecting to the parvocellular pathway (P-cells) through the temporal portion of the RNFL, which are relatively spared in MSA patients. CONCLUSION: The retinal damage in patients with MSA differs from that observed in patients with Parkinson disease (PD). Patients with MSA have more relative preservation of temporal sector of the RNFL and less severe atrophy of the macular GCL complex. We hypothesize that in patients with MSA there is predominant damage of large myelinated optic nerve axons like those originating from the M-cells. These large axons may require higher support from oligodendrocytes. Conversely, in patients with PD, P-cells might be more affected.

Weather, in particular the intensity and duration of sunshine (luminance), has been shown to significantly affect financial markets. Yet, because of the complexity of market interactions we do not know how human behavior is affected by luminance in a way that could inform theoretical choice models. In this paper, we use data from a field study using an incentive-compatible, decision task conducted daily over a period of two years and from the US Earth System Research Laboratory luminance sensor to investigate the impact of luminance on risk preferences, ambiguity preferences, choice consistency and dominance violations. We find that luminance levels affect all of these. Age and gender influence the strength of some of these effects.

Anti-PD-1 and anti-PD-L1 immunotherapy has provided a new therapeutic opportunity for treatment of advanced-stage non-small cell lung cancer (NSCLC). However, overall objective response rates are approximately 15%-25% in all NSCLC patients who receive anti-PD therapy. Therefore, strategies to overcome primary resistance to anti-PD immunotherapy are urgently needed. We hypothesized that the barrier to the success of anti-PD therapy in most NSCLC patients can be overcome by stimulating the lymphocyte infiltration at cancer sites through locoregional virotherapy. To this end, in this study, we determined combination effects of anti-PD immunotherapy and oncolytic adenoviral vector-mediated tumor necrosis factor-α-related apoptosis-inducing ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene therapy in syngeneic mice bearing subcutaneous tumors derived from M109 lung cancer cells. Both anti-PD-1 and anti-PD-L1 antibodies failed to elicit obvious therapeutic effects in the M109 tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed tumor growth in animals preexposed to an adenovector and bearing subcutaneous tumors derived from M109 cells. However, combining either anti-PD-1 or anti-PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice with existing immunity to adenoviral vectors. Dramatically enhanced intratumoral immune response was detected in this group of combination therapy based on infiltrations of CD4+ and CD8+ lymphocytes and macrophages in tumors. Our results demonstrate that resistance to anti-PD-1 immunotherapy in syngeneic mouse lung cancer can be overcome by locoregional virotherapy.

The mechanisms for acute pain regulation in the brain are not well understood. The prefrontal cortex (PFC) provides top-down control of emotional processes, and it projects to the nucleus accumbens (NAc). This corticostriatal projection forms an important regulatory pathway within the brain's reward system. Recently, this projection has been suggested to control both sensory and affective phenotypes specifically associated with chronic pain. As this projection is also known to play a role in the transition from acute to chronic pain, we hypothesized that this corticostriatal circuit can also exert a modulatory function in the acute pain state. Here, we used optogenetics to specifically target the projection from the PFC to the NAc. We tested sensory pain behaviors with Hargreaves' test and mechanical allodynia, and aversive pain behaviors with conditioned place preference (CPP) test. We found that the activation of this corticostriatal circuit gave rise to bilateral relief from peripheral nociceptive inputs. Activation of this circuit also provided important control for the aversive response to transient noxious stimulations. Hence, our results support a novel role for corticostriatal circuitry in acute pain regulation.