Citations

131 Background: Gynecologic oncologists report a lack of knowledge and comfort with palliative care topics including opioid management, despite their clinical importance. The objective of this study is to evaluate the impact of an online opioid educational module among gynecologic oncologists. Methods: A 25-minute video module was developed to provide an overview and example cases for opioid initiation, titration, and conversion. Fellows and early career gynecologic oncologists were invited to participate in a 24-question online survey addressing demographics, palliative care education in training, and preparedness and opioid-related knowledge. After viewing the module, participants completed a post-intervention survey, which was comprised of the same six knowledge-based questions and an assessment of the module. Responses were anonymous. A 3 month follow up survey will be sent to assess knowledge retention. Results: A total of 38 participants completed the initial and post-module survey, including 14 residents, 12 fellows, and 12 candidate members. Nineteen (50%) respondents had been previously taught to calculate a 24-hour oral morphine equivalent (OME) and to titrate opioids, but only 7 (18%) had received formal teaching on opioid rotation. Twenty four (63%) participants rated the quality of teaching overall in their fellowship as good, very good, or excellent, but only 15 (39%) rated palliative care education as at least good. Eleven (30%) respondents had a palliative care rotation in fellowship. Knowledge scores improved from pre-module to post-module, 49.5% correct answers compared to 74.6% (p<0.001). Thirty five (92%) of respondents were satisfied or very satisfied with this module and are interested in additional palliative care modules. Conclusions: A single online palliative care education module was associated with significantly improved participant knowledge on opioid management. Over 90% of respondents were satisfied with the module demonstrating an opportunity for improvement in palliative care education in gynecologic oncology via online education.

Abstract Chimeric antigen receptor T (CAR-T) cell therapy is a new pillar in cancer therapeutics; however, its application is limited by the associated toxicities. These include cytokine release syndrome (CRS) and neurotoxicity. Although the IL-6R antagonist tocilizumab is approved for treatment of CRS, there is no approved treatment of neurotoxicity associated with CD19-targeted CAR-T (CART19) cell therapy. Recent data suggest that monocytes and macrophages contribute to the development of CRS and neurotoxicity after CAR-T cell therapy. Therefore, we investigated neutralizing granulocyte-macrophage colony-stimulating factor (GM-CSF) as a potential strategy to manage CART19 cell–associated toxicities. In this study, we show that GM-CSF neutralization with lenzilumab does not inhibit CART19 cell function in vitro or in vivo. Moreover, CART19 cell proliferation was enhanced and durable control of leukemic disease was maintained better in patient-derived xenografts after GM-CSF neutralization with lenzilumab. In a patient acute lymphoblastic leukemia xenograft model of CRS and neuroinflammation (NI), GM-CSF neutralization resulted in a reduction of myeloid and T cell infiltration in the central nervous system and a significant reduction in NI and prevention of CRS. Finally, we generated GM-CSF–deficient CART19 cells through CRISPR/Cas9 disruption of GM-CSF during CAR-T cell manufacturing. These GM-CSFk/o CAR-T cells maintained normal functions and had enhanced antitumor activity in vivo, as well as improved overall survival, compared with CART19 cells. Together, these studies illuminate a novel approach to abrogate NI and CRS through GM-CSF neutralization, which may potentially enhance CAR-T cell function. Phase 2 studies with lenzilumab in combination with CART19 cell therapy are planned.

Introduction Optimal management of vestibular schwannoma (VS) demands involvement of an experienced multidisciplinary team. As the number of training programs in neurotology and skull base neurosurgery continues to rise, ensuring that trainees are capable of evidence-based decision-making and treatment, whether microsurgical or radiosurgical, is of paramount importance. The purpose of this study is to characterize the landscape of neurotologic and neurosurgical fellowship training programs in North America, with special reference to VS management. Methods A 64-item web-based survey assessing VS practice trends was devised by members of the North American Skull Base Society (NASBS) Research Task Force and distributed electronically to NASBS membership via SurveyMonkey as a cross-sectional study. Participation was entirely voluntary and there was no remuneration for survey completion. The survey link was active from November 29 to December 14, 2016. Results Of 719 members of the NASBS who were emailed a survey link, a total of 57 were returned (8%) completed surveys. Of all respondents, 51 (89%) claimed to have formal training in skull base neurosurgery or neurotology. Thirty-three respondents (65%) were skull base neurosurgeons while the remainder were neurotologists (n = 18; 35%). Institutions with fellowship programs tended to have a higher surgical, radiosurgical, and overall case volume than those with a residency program alone. However, 20% of respondents at institutions with fellowship programs reported evaluating less than 50 new diagnoses of VS per year and 12% reported a surgical case volume of less than 10 cases per year. Conclusion As the number of skull base training programs expands, it is our duty to ensure that trainees gain sufficient experience to enter independent practice with the ability to exercise informed decision-making and safely perform VS surgery and radiosurgery. In the current training climate, implementing multidisciplinary care models, formalized training requirements, and emerging surgical simulators will support the development of minimum proficiencies in VS care.

The expansion and accumulation of HIV-infected BCL6 + Tfh CD4 + T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4 + T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8 + T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4 + T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation.

Abstract Introduction We sought to establish the relationships between standard postmortem measures of AD neuropathology and antemortem [ 11 C]PIB–positron emission tomography ([ 11 C]PIB‐PET) analyzed with the Centiloid (CL) method, a standardized scale for Aβ‐PET quantification. Methods Four centers contributed 179 participants encompassing a broad range of clinical diagnoses, PET data, and autopsy findings. Results CL values increased with each CERAD neuritic plaque score increment (median −3 CL for no plaques and 92 CL for frequent plaques) and nonlinearly with Thal Aβ phases (increases were detected starting at phase 2) with overlap between scores/phases. PET‐pathology associations were comparable across sites and unchanged when restricting the analyses to the 56 patients who died within 2 years of PET. A threshold of 12.2 CL detected CERAD moderate‐to‐frequent neuritic plaques (area under the curve = 0.910, sensitivity = 89.2%, specificity = 86.4%), whereas 24.4 CL identified intermediate‐to‐high AD neuropathological changes (area under the curve = 0.894, sensitivity = 84.1%, specificity = 87.9%). Discussion Our study demonstrated the robustness of a multisite Centiloid [ 11 C]PIB‐PET study and established a range of pathology‐based CL thresholds.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

With recent changes in United Network for Organ Sharing policy, patients in the United States with hepatocellular carcinoma (HCC) are likely to spend more time on the liver transplantation (LT) waiting list. The increasing wait time will allow for an opportunity to assess tumor biology prior to LT. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) paradigm provides such a framework for this assessment, and yet little is understood of its utility as it would apply for patients listed for LT in the United States. Through a collaboration between the University of California, San Francisco, and the Mayo Clinic, Jacksonville, Florida, the experience of 772 patients listed for LT were retrospectively reviewed to study the impact of immediate mRECIST classification following locoregional therapy (LRT) on pre‐ and post‐LT outcomes. Patients who had progression of disease (PD; n = 72), failed to respond to LRT (n = 89) at any time point, or did not achieve radiologic complete response (CR; n = 224) were all at significant risk for wait‐list dropout (odds ratio [OR] = 12.11, 4.81, and 2.48; respectively). CR identified a cohort of patients who were at a reduced risk for wait‐list dropout. However, 24.9% eventually required further intervention while waiting for transplant, and as many as 82.4% were found to have residual HCC on explant pathology. Failure to respond to LRT was associated with increased risk for recurrence (OR = 3.00) more so than PD (OR = 1.36), suggesting that despite PD, patients who eventually can respond to LRT may represent favorable candidates for LT. In conclusion, for patients awaiting LT, the mRECIST assessment provides critical guidance for patient management. Although PD portends a poor prognosis, our findings suggest that further aggressive LRT should be pursued because a response to LRT may yield acceptable results for patients awaiting LT as well as after LT.

Objectives: To highlight superior semicircular canal dehiscence (SSCD) involving the superior petrosal sinus (SPS), and to propose a novel classification system for SPS associated SSCD with potential surgical implications. Study Design: Multicenter retrospective review. Setting: Three tertiary referral centers. Patients: All patients diagnosed with SPS associated SSCD (1/2000 to 8/2016). Radiographic findings and clinical symptoms were analyzed. Intervention: Surgical repair or observation. Main Outcome Measure: Radiographic findings and clinical symptoms were analyzed. Results: Thirty-three dehiscences (30 patients) involving the SPS were identified. The average age at the time of presentation was 52.5 years (median, 56.9; range, 4.9–75.3 yr), and 53.3% of patients were men. Three patients had bilateral SPS associated SSCD. The most common associated symptoms at presentation were episodic vertigo (63.6%), subjective hearing loss (60.6%), and aural fullness (57.6%). Four distinct types of dehiscence were identified: class Ia. SSCD involving a single dehiscence into an otherwise normal appearing SPS; class Ib. SSCD involving a single dehiscence into an apparent venous anomaly of the SPS; class IIa. SSCD involving two distinct dehiscences into the middle cranial fossa and the SPS; class IIb. SSCD involving a single confluent dehiscence into the middle cranial fossa and the SPS. Conclusions: SSCD involving the SPS represents a small but distinct subset of SSCD cases. This scenario can create a unique set of symptoms and surgical challenges when intervention is sought. Clinical findings and considerations for surgical intervention are provided to facilitate effective diagnosis and management.