A single-center retrospective analysis of outcome measures and consolidation strategies for relapsed and refractory primary CNS lymphoma.

BACKGROUND: Relapsed or refractory primary CNS lymphoma (rrPCNSL) is a rare and challenging malignancy for which better evidence is needed to guide management. METHODS: We present a retrospective cohort of 66 consecutive patients with rrPCNSL treated at the University of Washington between 2000 and 2020. Immunosuppressed and secondary CNS lymphoma patients were excluded. RESULTS: During a median follow-up of 40.5 months from initial diagnosis, median OS for relapsed disease was 14.1 (0.2-88.5) months and median PFS was 11.0 (0.2-73.9) months. At diagnosis (r2 = 0.85, p < 0.001), first relapse (r2 = 0.69, p < 0.001), multiple relapses (r2 = 0.97, p < 0.001) PFS was highly correlated with OS. In contrast, there was no correlation between the duration of subsequent progression-free intervals. No difference in PFS or OS was seen between CSF or intraocular relapse and parenchymal relapse. Patients reinduced with high-dose methotrexate-based (HD-MTX) regimens had an overall response rate (ORR) of 86.7%. Consolidation with autologous stem cell transplant (ASCT) was associated with longer PFS compared to either no consolidation (p = 0.01) and trended to longer PFS when compared to other consolidation strategies (p = 0.06). OS was similarly improved in patients consolidated with ASCT compared with no consolidation (p = 0.04), but not compared with other consolidation (p = 0.22). Although patients receiving ASCT were younger, KPS, sex, and number of recurrences were similar between consolidation groups. A multivariate analysis confirmed an independent effect of consolidation group on PFS (p = 0.01), but not OS. CONCLUSIONS: PFS may be a useful surrogate endpoint which predicts OS in PCNSL. Consolidation with ASCT was associated with improved PFS in rrPCNSL.

Cellular allograft for multilevel stand-alone anterior cervical discectomy and fusion.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is the most common treatment for degenerative disease of the cervical spine. Given the high rate of pseudarthrosis in multilevel stand-alone ACDF, there is a need to explore the utility of novel grafting materials. In this study, the authors present a single-institution retrospective study of patients with multilevel degenerative spine disease who underwent multilevel stand-alone ACDF surgery with or without cellular allograft supplementation. METHODS: In a prospectively collected database, 28 patients who underwent multilevel ACDF supplemented with cellular allograft (ViviGen) and 25 patients who underwent multilevel ACDF with decellularized allograft between 2014 and 2020 were identified. The primary outcome was radiographic fusion determined by a 1-year follow-up CT scan. Secondary outcomes included change in Neck Disability Index (NDI) scores and change in visual analog scale scores for neck and arm pain. RESULTS: The study included 53 patients with a mean age of 53 ± 0.7 years who underwent multilevel stand-alone ACDF encompassing 2.6 ± 0.7 levels on average. Patient demographics were similar between the two cohorts. In the cellular allograft cohort, 2 patients experienced postoperative dysphagia that resolved by the 3-month follow-up. One patient developed cervical radiculopathy due to graft subsidence and required a posterior foraminotomy. At the 1-year CT, successful fusion was achieved in 92.9% (26/28) of patients who underwent ACDF supplemented with cellular allograft, compared with 84.0% (21/25) of patients who underwent ACDF without cellular allograft. The cellular allograft cohort experienced a significantly greater improvement in the mean postoperative NDI score (p < 0.05) compared with the other cohort. CONCLUSIONS: Cellular allograft is a low-morbidity bone allograft option for ACDF. In this study, the authors determined favorable arthrodesis rates and functional outcomes in a complex patient cohort following multilevel stand-alone ACDF supplemented with cellular allograft.

Cancer care in lesbian, gay, bisexual, transgender and queer populations.

Lesbian, gay, bisexual, transgender and queer (LGBTQ) populations experience health and healthcare disparities that may place them at higher risk for developing cancer. In addition, LGBTQ communities have psychosocial factors, such as fear of discrimination, that have substantial impacts on their medical care. As a result, these populations have specific needs with regard to cancer screening, treatment and support that must be addressed by cancer care providers. Although much has been done to address cancer care in the general population, more improvement is needed in the care of LGBTQ patients. We aim to present an overview of the current state of LGBTQ cancer care, opportunities for improvement and how cancer centers and providers can create a better future for the care of LGBTQ cancer patients.

Acute Postoperative Seizures and Engel Class Outcome at 1 Year Postselective Laser Amygdalohippocampal Ablation for Mesial Temporal Lobe Epilepsy.

BACKGROUND: MRI-guided laser interstitial thermal therapy (MRgLITT) for mesial temporal lobe epilepsy is a safe, minimally invasive alternative to traditional surgical approaches. Prognostic factors associated with efficacy are debated; preoperative epilepsy duration and semiology seem to be important variables. OBJECTIVE: To determine whether acute postoperative seizure (APOS) after MRgLITT for mesial temporal lobe epilepsy is associated with seizure freedom/Engel class outcome at 1 year. METHODS: A single-institution retrospective study including adults undergoing first time MRgLITT for mesial temporal lobe epilepsy (2010-2019) with ≥1-year follow-up. Preoperative data included sex, epilepsy duration, number of antiepileptics attempted, weekly seizure frequency, seizure semiology, and radiographically verified anatomic lesion at seizure focus. Postoperative data included clinical detection of APOS within 7 days postoperatively, and immediate amygdala, hippocampal, entorhinal, and parahippocampal residual volumes determined using quantitative imaging postprocessing. Primary outcome was seizure freedom/Engel classification 1 year postoperatively. RESULTS: Of 116 patients, 53% (n = 61) were female, with an average epilepsy duration of 21 (±14) years, average 6 failed antiepileptics (±3), and weekly seizure frequency of 5. APOS was associated with worse Engel class ( P = .010), conferring 6.3 times greater odds of having no improvement vs achieving seizure freedom at 1 year. Residual amygdala, hippocampal, entorhinal, and parahippocampal volumes were not statistically significant prognostic factors. CONCLUSION: APOS was associated with a lower chance of seizure freedom at 1 year post-MRgLITT for mesial temporal lobe epilepsy. Amygdala, hippocampal, entorhinal, and parahippocampal residual volumes after ablation were not significant prognostic factors.

Distinguishing and treating depression, anxiety, adjustment, and post-traumatic stress disorders in brain tumor patients.

Cancer patients often suffer from psychiatric disorders as a result of their disease and its treatment. Rates of depression, anxiety, adjustment, and post-traumatic stress disorders are particularly high for individuals with cancer and differentiating between these conditions is important for providing both appropriate and high-quality care. Patients with primary and metastatic brain tumors are particularly susceptible to psychiatric morbidities as a result of direct neuropsychiatric effects from the tumor itself, as well as psychological distress stemming from their diagnosis, prognosis, or treatment. However, these morbidities are often underdiagnosed, misdiagnosed, and undertreated. Many tools exist for screening, diagnosing, and treating psychiatric disorders in brain tumor patients, and palliative care settings are well suited to both identify and treat psychiatric disorders in brain tumor patients. This review summarizes our current knowledge of psychiatric disorders in patients in patients with brain tumors, highlights the susceptibility of brain tumor patients to psychiatric conditions, provides recommendations for differentiating and treating these conditions, and emphasizes the need for further research. The goal of this review is to inform healthcare providers of the opportunities to address psychiatric morbidities in patients with primary and metastatic brain tumors, particularly in palliative care settings, and identify areas in need of additional research.

A Guide to Creating a Gender-Affirming Environment Through a Community Lens Approach.

Lesbian, gay, bisexual, transgender, queer, and intersex (LGBTQI+) communities continue to experience health care disparities and inequities due to a shortage of trained health care providers, despite increased attention to LGBTQI+ health care. Many settings are starting to integrate gender-affirming health care and focus training on the provision of hormonal therapy, medications to decrease the risk of human immunodeficiency acquisition, and referrals to surgeons for affirming surgical procedures. A vital component to providing inclusive and comprehensive care involves community input, engagement, and buy-in. This article provides a framework for comprehensive gender-affirming health care through the lens of community involvement and outreach.

Seasonal variation in the incidence of primary CNS lymphoma.

BACKGROUND: Primary CNS lymphoma is a rare and aggressive cancer that can develop in immunocompetent individuals, but little is known about risk factors and causes of disease. Previous studies have demonstrated seasonal patterns for lymphomas and brain tumors. This study examined the seasonal incidence pattern for primary CNSlymphoma. METHODS: A retrospective review was performed for patients diagnosed with primary CNS lymphoma from 2000 through 2018 at our tertiary referral center. A total of 156 patients were categorized based on month of symptom onset, month of diagnosis, and month of recurrence if they experienced a relapse of their disease. The distributions were then analyzed for seasonal patterns. RESULTS: There was a significant, bimodal seasonal incidence pattern based on month of symptom onset (P < .001), with peaks in July (n = 19) and December (n = 23) and troughs in March (n = 4) and September (n = 5). There were no significant differences in patients' sex, age at presentation, length of follow-up, and progression-free survival across months. There were no seasonal patterns based on month of diagnosis (P = .450) or month of disease recurrence (P = .572). CONCLUSION: The incidence of primary CNS lymphoma has bimodal peaks in midsummer and early winter, which could provide insight into causative agents and mechanisms of disease.

A comparison of endolymphatic shunt surgery and intratympanic gentamicin for meniere's disease.

OBJECTIVE: To report audiovestibular outcomes following endolymphatic shunt surgery (ELS) and intratympanic gentamicin injections (ITG) in patients with Meniere's disease (MD). STUDY DESIGN: Retrospective matched cohort study METHODS: Patients with MD refractory to medical management between 2004 and 2017 were reviewed: 44 patients underwent ELS and had outcomes available, while 27 patients underwent ITG and had outcomes available. Mean follow-up durations for the ELS and ITG groups were 39.1 and 43.3 months, respectively. Twenty-six patients from the ELS group and 24 patients from the ITG group were then included in a pretreatment hearing- and age-matched analysis. Main outcome measures were successful control of vertigo, pure-tone average (PTA; 0.5, 1, 2 and 4 kHz), word recognition score (WRS), and treatment complications. RESULTS: A matched analysis showed vertigo control rates of 73.1% in the ELS group and 66.8% in the ITG group, which were not significantly different (P = .760). The change in PTA following treatment was statistically similar between the ELS group (6.2 dB) and ITG group (4.6 dB) (P = .521), while the change in WRS for the ELS group (+3.9 %) was significantly more favorable than the ITG group (-13.6 %) (P = .046). Chronic post-treatment unsteadiness was reported in 25.0% of the ITG group and was not encountered in the ELS group (P = .009). CONCLUSION: ELS provided successful vertigo control at least as well as ITG with a lower incidence of audiovestibular complications. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:2455-2460, 2020.

Case of Esophageal Perforation and Repair with a Supraclavicular Artery Island Fascial Flap 15 Years After Anterior Spine Surgery.

BACKGROUND: Esophageal perforation represents a rare but potentially life-threatening complication of an anterior cervical diskectomy and fusion (ACDF). Delayed presentations of esophageal perforation more than 10 years following surgery are exceedingly rare and difficult to diagnose. Here, we discuss the case of an 80-year-old man who presented to the emergency department with progressive dysphagia 15 years after his ACDF. CASE DESCRIPTION: While prior outpatient workup was suggestive of a diverticulum, there was no evidence of esophageal perforation. Progressive symptoms and repeat imaging on admission were suggestive of retropharyngeal phlegmon. Operative esophagoscopy revealed that the spinal hardware had eroded through the posterior wall of the esophagus, creating a traction diverticulum. The hardware was removed, and the esophageal perforation was closed primarily and buttressed with vascularized tissue from a supraclavicular artery island fascial flap. CONCLUSIONS: This case emphasizes the importance of considering an esophageal perforation in patients who present with dysphagia at any interval following an ACDF, even in the extremely delayed setting. Furthermore, this is the first report, to the best of our knowledge, using a supraclavicular artery island fascial flap to reconstruct an esophageal perforation following an ACDF, and we introduce a novel strategy for managing these complicated injuries.

Stereotactic Brain Biopsy Hemorrhage Risk Factors and Implications for Postoperative Care at a Single Institution: An Argument For Postoperative Imaging.

OBJECTIVE: To determine preoperative factors contributing to postoperative hemorrhage after stereotactic brain biopsy (STB), clinical implications of postoperative hemorrhage, and the role of postoperative imaging in clinical management. METHODS: Retrospective review of STB (2005-2018) across 2 institutions including patients aged >18 years undergoing first STB. Patients with prior craniotomy, open biopsy, or prior STB were excluded. Preoperative variables included age, sex, neurosurgeon seniority, STB method. Postoperative variables included pathology, postoperative hemorrhage on computed tomography, immediate and 30-day postoperative seizure, infection, postoperative hospital stay duration, and 30-day return to operating room (OR). Analysis used the Fisher exact tests for categorical variables. RESULTS: Overall, 410 patients were included. Average age was 56.5 (±16.5) years; 60% (n = 248) were men. The majority of biopsies were performed by senior neurosurgeons (66%, n = 270); frontal lobe (42%, n = 182) and glioblastoma (45%, n = 186) were the most common location and pathology. Postoperative hemorrhage occurred in 28% (114) of patients with 20% <0.05 cm3 and 8% >0.05 cm3. Postoperative hemorrhage of any size was associated with increased rate of postoperative deficit within both 24 hours and 30 days, postoperative seizure, and length of hospital stay when controlling for pathology. Hemorrhages >0.05 cm3 had a 16% higher rate of return to the OR for evacuation, due to clinical deterioration as opposed to radiographic progression. CONCLUSIONS: Postbiopsy hemorrhage was associated with higher risk of immediate and delayed postoperative deficit and seizure. Postoperative computed tomography should be used to determine whether STB patients can be discharged same day or admitted for observation; clinical evaluation should determine return to OR for evacuation.

A Novel Curriculum for Medical Student Training in LGBTQ Healthcare: A Regional Pathway Experience.

BACKGROUND: Lesbian, gay, bisexual, transgender, and queer (LGBTQ) individuals face considerable health disparities, often due to a lack of LGBTQ-competent care. Such disparities and lack of access to informed care are even more staggering in rural settings. As the state medical school for the Washington, Wyoming, Alaska, Montana, and Idaho (WWAMI) region, the University of Washington School of Medicine (UWSOM) is in a unique position to train future physicians to provide healthcare that meets the needs of LGBTQ patients both regionally and nationally. OBJECTIVE: To describe our methodology of developing a student-driven longitudinal, region-wide curriculum to train medical students to provide high-quality care to LGBTQ patients. METHODS: A 4-year LGBTQ Health Pathway was developed and implemented as a student-led initiative at the UWSOM. First- and second-year medical students at sites across the WWAMI region are eligible to apply. Accepted Pathway students complete a diverse set of pre-clinical and clinical components: online modules, didactic courses, longitudinal community service/advocacy work, a scholarly project, and a novel clinical clerkship in LGBTQ health developed specifically for this Pathway experience. Students who complete all requirements receive a certification of Pathway completion. This is incorporated into the Medical Student Performance Evaluation as part of residency applications. RESULTS: The LGBTQ Health Pathway is currently in its fourth year. A total of 43 total students have enrolled, of whom 37.3% are based in the WWAMI region outside of Seattle. Pathway students have completed a variety of scholarly projects on LGBTQ topics, and over 1000 hours of community service/advocacy. The first cohort of 8 students graduated with a certificate of Pathway completion in spring 2020. CONCLUSIONS: The LGBTQ Health Pathway at UWSOM is a novel education program for motivated medical students across the 5-state WWAMI region. The diverse milestones, longitudinal nature of the program, focus on rural communities, and opportunities for student leadership are all strengths and unique aspects of this program. The Pathway curriculum and methodology described here serve as a model for student involvement and leadership in medical education. This program enables medical students to enhance their training in the care of LGBTQ patients and provides a unique educational opportunity for future physicians who strive to better serve LGBTQ populations.

5-HT1B Receptor-Mediated Activation of ERK1/2 Requires Both Gαi/o and ß-Arrestin Proteins.

5-HT1B receptors modulate synaptic serotonin (5-HT) levels and play a significant role in the regulation of emotional behaviors. These receptors are Gαi/o-coupled and inhibit adenylyl cyclase but have also been reported to activate MAP kinases; however, the details of signaling cascades downstream of 5-HT1B receptor activation remain unclear, particularly in neuronal cells. We generated a stable 5-HT1B receptor-expressing Neuro2A (N2A-1B) neuronal cell line and demonstrate that activation of these receptors by the selective 5-HT1B agonist CP-94253 results in activation of ERK1/2 but not of other closely related MAP kinases. Phosphoproteomics revealed four novel phosphorylation sites on the third intracellular loop of the 5-HT1B receptor, and mutations of serine-256 and serine-291 to alanine led to reduced levels of ERK1/2 phosphorylation following receptor activation. Inhibition of Gαi/o signaling with pertussis toxin, as well as MEK1/2 inhibition with U0126, also reduced 5-HT1B-mediated ERK1/2 phosphorylation. Finally, we found that knockout of either ß-arrestin 1 or ß-arrestin 2 prevented 5-HT1B-mediated phosphorylation of ERK1/2. Taken together, these results show that 5-HT1B receptor activation selectively induces ERK1/2 activation through both the Gαi subunit and ß-arrestin proteins. This work elucidates the signal transduction pathway of 5-HT1B receptors, as well as key phosphorylation sites within the receptor that modulate ERK1/2 activation, and further characterizes the intracellular mechanisms that underlie 5-HT1B receptor function.

Loss of glutamate signaling from the thalamus to dorsal striatum impairs motor function and slows the execution of learned behaviors.

Parkinson's disease (PD) is primarily associated with the degeneration of midbrain dopamine neurons, but it is now appreciated that pathological processes like Lewy-body inclusions and cell loss affect several other brain regions, including the central lateral (CL) and centromedian/parafascicular (CM/PF) thalamic regions. These thalamic glutamatergic neurons provide a non-cortical excitatory input to the dorsal striatum, a major projection field of dopamine neurons. To determine how thalamostriatal signaling may contribute to cognitive and motor abnormalities found in PD, we used a viral vector approach to generate mice with loss of thalamostriatal glutamate signaling specifically restricted to the dorsal striatum (CAV2Cre-Slc17a6lox/lox mice). We measured motor function and behaviors corresponding to cognitive domains (visuospatial function, attention, executive function, and working memory) affected in PD. CAV2Cre-Slc17a6lox/lox mice were impaired in motor coordination tasks such as the rotarod and beam-walk tests compared with controls (CAV2Cre-Slc17a6+/+ mice). They did not demonstrate much cognitive impairment in the Morris water maze or a water U-maze, but had slower processing reaction times in those tests and in a two-way active avoidance task. These mice could model an aspect of bradyphrenia, the slowness of thought that is often seen in patients with PD and other neurological disorders.

Striatal 5-HT6 Receptors Regulate Cocaine Reinforcement in a Pathway-Selective Manner.

The nucleus accumbens (NAc) in the ventral striatum integrates many neurochemical inputs including dopamine and serotonin projections from midbrain nuclei to modulate drug reward. Although D1 and D2 dopamine receptors are differentially expressed in the direct and indirect pathway medium spiny neurons (dMSNs and iMSNs, respectively), 5-HT6 receptors are expressed in both pathways, more strongly than anywhere else in the brain, and are an intriguing target for neuropsychiatric disorders. In the present study, we used viral vectors utilizing dynorphin or enkephalin promoters to drive expression of 5-HT6 receptors or green fluorescent protein (GFP) selectively in the dMSNs or iMSNs of the NAc shell. Rats were then trained to self-administer cocaine. Increased 5-HT6 receptor expression in dMSNs did not change any parameter of cocaine self-administration measured. However, increasing 5-HT6 receptors in iMSNs reduced the amount of cocaine self-administered under fixed-ratio schedules, especially at low doses, increased the time to the first response and the length of the inter-infusion interval, but did not alter motivation as measured by progressive ratio 'break point' analysis. Modeling of cocaine pharmacokinetics in NAc showed that increased 5-HT6 receptors in iMSNs reduced the rat's preferred tissue cocaine concentration at each dose. Finally, increased 5-HT6 receptors in iMSNs facilitated conditioned place preference for a low dose of cocaine. We conclude that 5-HT6 receptors in iMSNs of NAcSh increase the sensitivity to the reinforcing properties of cocaine, particularly at low doses, suggesting that these receptors may be a therapeutic target for the treatment of cocaine addiction.

Embryonic arsenic exposure reduces the number of muscle fibers in killifish (Fundulus heteroclitus).

Arsenic is a contaminant of drinking water and has been correlated with adverse developmental outcomes such as low birth weight, reduced weight gain, and altered locomotor activity. Previous research has shown that killifish (Fundulus heteroclitus) exposed to high arsenic levels during embryogenesis had smaller muscle fiber diameters. The current study was designed to determine whether changes in muscle fibers persisted, were exacerbated, or resolved over time. Killifish embryos were exposed to 0-5 ppm arsenite and, upon hatching, were transferred into either clean water or continued receiving the same exposure to arsenic for up to 16 weeks. Arsenic significantly decreased the weight of both embryonic-only exposed juveniles and continuously exposed juveniles between 4 and 16 weeks of development at concentrations as low as 0.8 ppm. Although arsenite exposure increased the percentage of small diameter fibers during the early weeks, fiber diameters returned to control levels in the embryonic-only exposed fish. However, muscle fiber density was still reduced to 85.7%, 80.3%, and 73.8% of control for the 0.8, 2, and 5 ppm embryonic-only exposure groups, respectively, even after 16 weeks of development. These results indicate that while continuous exposure to arsenic may alter the size of muscle fibers, embryonic-only exposure to arsenic has lasting effects on the number of muscle fibers formed.