Citations

AbstractThe care of primary pulmonary coccidioidomycosis remains challenging. Such infections produce a variety of signs, symptoms, and serologic responses that cause morbidity in patients and concern in treating clinicians for the possibility of extrapulmonary dissemination. Illness may be due to ongoing fungal growth that produces acute inflammatory responses, resulting in tissue damage and necrosis, and for this, administering an antifungal drug may be of benefit. In contrast, convalescence may be prolonged by other immunologic reactions to infection, even after fungal replication has been arrested, and in those situations, antifungal therapy is unlikely to yield clinical improvement. In this presentation, we discuss what findings are clinical indicators of fungal growth and what other sequelae are not. Understanding these differences provides a rational management strategy for deciding when to continue, discontinue, or reinstitute antifungal treatments.

Abstract BACKGROUND The impact of treatment on both the quality and the quantity of life, i.e. the ‘net clinical benefit’, should be considered to inform glioma patients and facilitate shared decision making. We applied two methods (i.e. Quality Adjusted Effect Sizes (QASES) and Joint Modelling (JM)) that combine survival and health-related quality of life (HRQoL) data into one outcome, to gain insight in the net clinical benefit of a treatment strategy. In addition, we assessed if both methods result in similar interpretations. MATERIAL AND METHODS We calculated the net clinical benefit in one randomized controlled trial, EORTC 26951 comparing radiotherapy (RT) + PCV chemotherapy versus RT alone, as a proof of concept for other trials. With the QASES method, effect sizes for differences in survival and HRQoL between treatment arms were calculated. Next, the combined effect size can be determined by weighing the emphasis put on survival or HRQoL (e.g. survival more important). JM allows simultaneous modeling of a longitudinal outcome (HRQoL), and a time-to event outcome (survival). HRQoL scales/items that were selected for primary analysis in the main study were also selected for this analysis: fatigue, global health, social functioning, communication deficit, seizures, physical functioning, and nausea/vomiting. RESULTS 288/386 patients completed baseline HRQoL forms and were included in the analysis. Overall survival (OS) was significantly longer with combined treatment (difference of 10.8 months). In contrast, the percentage of patients who experienced a clinically relevant deterioration (≥10 points) in nausea/vomiting, fatigue, social functioning and global health up to one year after treatment compared to baseline was larger in the RT+PCV arm. The QASES corresponded to a reduction in the median OS difference from 10.8 months to 6.8 months when adjusted for the HRQoL scales/items, when given equal weights to OS and HRQoL. JM analyses resulted in a theoretical loss of treatment effect in OS of 2–6% when adjusting for HRQoL. CONCLUSION Both methods showed that adjusting for the impact of treatment on a relevant HRQoL parameter reduced the survival benefit in the experimental treatment arm compared to standard treatment arm. Applying these methods may facilitate communicating the impact of treatment to patients in clinical practice.

Objective: The etiology of sensorineural hearing loss (SNHL) in patients with jugular paraganglioma (JP) whose tumors lack inner ear fistulae or vestibulocochlear nerve involvement is unknown. Recent literature has proposed that occlusion of the inferior cochlear vein may be causative. Herein, we assess the association between radiologic involvement of the cochlear aqueduct (CA) and the development of SNHL. Study Design: Blinded, retrospective review of imaging and audiometry. Setting: Tertiary center. Patients: Adults with JP. Intervention(s): None. Main Outcome Measures: Asymmetric SNHL was assessed continuously as the difference in bone conduction pure-tone average (BCPTA) between ears and as a categorical variable (≥15 dB difference at two consecutive frequencies, or a difference in speech discrimination score of ≥15%). Involvement of the CA was considered present if there was evidence of medial T2 fluid signal loss, contrast enhancement, or bony erosion/expansion. Results: Of 30 patients meeting inclusion criteria, 15 (50%) had asymmetric SNHL. CA involvement was observed in 87% of patients with asymmetric SNHL compared with 13% in those with symmetric hearing (p = 0.0001). Univariate analysis demonstrated that age, sex, and tumor volume were not associated with asymmetric SNHL. The median difference in BCPTA between ears in patients with CA involvement was 21.3 dB HL compared to 1.2 dB HL in those without CA involvement (p < 0.0001). Regression analysis demonstrates that enhancement within the CA is associated with a BCPTA difference of 19.4 dB HL (p = 0.0006). Conclusions: Cochlear aqueduct involvement by JP is associated with SNHL in the absence of inner ear fistula, vestibulocochlear nerve involvement, or brainstem compression. Correlation with operative findings or histopathologic evidence of tumor involvement may validate this intriguing imaging finding.

Objective: Previous research has shown that tumor growth during observation of small-to-medium sized sporadic vestibular schwannomas (VSs) occurs almost exclusively within 3 to 5 years following diagnosis. This has led some to consider ending surveillance after this interval. This study seeks to characterize a cohort of patients with tumors that exhibited late growth. Study Design: Retrospective cohort study. Setting: Tertiary referral center. Patients: Adults with sporadic VSs who initially elected observation with serial magnetic resonance imaging (MRI) surveillance. Intervention(s): None. Main Outcome Measure(s): Linear tumor growth was measured in accordance with AAO-HNS reporting guidelines. Delayed growth was defined as growth ≥2 mm in linear diameter that was first detected 5 years or more from the initial MRI. Results: From a total of 361 patients, 172 experienced tumor growth during the interval of observation. Fourteen of these 172 patients (8.1%) experienced late growth occurring at 5 years or beyond. Among patients with delayed growth, the fastest growth rate after extended quiescence was 1.33 mm/yr, and the longest delay before tumor growth detection was 11.1 years. Additional treatment was recommended for six (42.9%) of the patients with delayed growth. Of 68 tumors that remained in the IAC, 11 (16.2%) demonstrated delayed growth. Of 66 tumors that presented in the CPA, 2 (3.0%) demonstrated delayed growth. Initial size was larger for tumors demonstrating early growth compared with those with delayed growth. For tumors within the IAC, those with early growth had a significantly higher median growth rate than those with delayed growth (1.40 vs. 0.45 mm/yr, p < 0.001). Conclusions: Delayed growth encompassed 8.1% of growing VSs and 3.9% of all observed tumors. Patients with delayed growth exhibited slower growth rates compared with those who were diagnosed with growth early in their observation course. These findings support the need for lifelong surveillance of untreated VSs given the possibility of clinically significant delayed growth. Increasing the time interval between MRI studies after 5 years is a reasonable concession to balance practicalities of cost and convenience with risk of delayed of tumor growth.

Abstract Background Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterized by neuronal loss in the extrapyramidal system with pathologic accumulation of tau in neurons and glia. The most common clinical presentation of PSP, referred to as Richardson syndrome, is that of atypical parkinsonism with vertical gaze palsy, axial rigidity, and frequent falls. Although cognitive deficits in PSP are often ascribed to subcortical dysfunction, a subset of patients has dementia with behavioral features similar to the behavioral variant of frontotemporal dementia. In this study we aimed to identify the clinical and pathological characteristics of PSP presenting with frontotemporal dementia. Methods In this study, we compared clinical and pathologic characteristics of 31 patients with PSP with Richardson syndrome with 15 patients with PSP with frontotemporal dementia. For pathological analysis, we used semiquantitative methods to assess neuronal and glial lesions with tau immunohistochemistry, as well image analysis of tau burden using digital microscopic methods. Results We found greater frontal and temporal neocortical neuronal tau pathology in PSP with frontotemporal dementia compared with PSP with Richardson syndrome. White matter tau pathology was also greater in PSP with frontotemporal dementia than PSP with Richardson syndrome. Genetic and demographic factors were not associated with atypical distribution of tau pathology in PSP with frontotemporal dementia. Conclusions The results confirm the subset of cognitive‐predominant PSP mimicking frontotemporal dementia in PSP. PSP with frontotemporal dementia has distinct clinical features that differ from PSP with Richardson syndrome, as well as differences in distribution and density of tau pathology. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Prior research explored reasons for tobacco use among pregnant Alaska Native (AN) women but did not address the postpartum period. This study followed up with AN women one to three years postpartum who had participated in a prenatal smoking cessation intervention study (Motivate Alaska Women (MAW) Phase 3) and had consented to be re-contacted for future studies. Of 47 eligible women, 32 (68%) participated. A semi-structured phone interview was conducted a mean of 2.0 years after delivery (range 1.6–2.8). Measures assessed self-reported tobacco use status in the 12 months after delivery, at 12 months postpartum, and at the time of the interview; reasons for maintaining abstinence, continued use, or relapse; and included the Perceived Stress Scale (PSS) and Negative Affect (NA) scale. Content analysis was used to generate themes from open-ended response items. Tobacco use was reported by 23 women (72%) at delivery, 30 (94%) within the 12 months after delivery, 27 (84%) at 12 months postpartum, and 29 (91%) at the time of the interview. Among nine women not using tobacco at delivery, seven (78%) relapsed during the 12 months after delivery. Of the 29 current tobacco users, 28 (97%) smoked cigarettes. Twenty-seven participants (84%) reported stress and 15 (52%) indicated addiction as reasons for continuing, starting, or resuming tobacco use. Types of stressors were related to parenting and traumatic experiences. Among current tobacco users, mean NA score (18.7) was significantly higher (p = 0.01) than the normative mean (14.8), but no differences were detected for PSS score. In this sample of AN women, postpartum tobacco use was highly prevalent, and stress was a primary reason that women endorsed for using tobacco. These preliminary results have several practice and research implications for exploring ways to support non-tobacco use among postpartum AN women.

PURPOSERegular physical activity is associated with reduced risk of recurrence and mortality in patients with nonmetastatic colorectal cancer. Its influence on patients with advanced/metastatic colorectal cancer (mCRC) has been largely unexplored.PATIENTS AND METHODSWe conducted a prospective cohort study nested in Cancer and Leukemia Group B (Alliance)/SWOG 80405 (ClinicalTrials.gov identifier: NCT00265850 ), a National Cancer Institute–sponsored phase III trial of systemic therapy for mCRC. Within 1 month after therapy initiation, patients were invited to complete a validated questionnaire that reported average physical activity over the previous 2 months. On the basis of responses, we calculated metabolic equivalent task (MET) hours per week to quantify physical activity. The primary end point of the clinical trial and this companion study was overall survival (OS). Secondary end points included progression-free survival (PFS) and first grade 3 or greater treatment-related adverse events. To minimize confounding by poor and declining health, we excluded patients who experienced progression or died within 60 days of activity assessment and used Cox proportional hazards regression analysis to adjust for known prognostic factors, comorbidities, and weight loss.RESULTSThe final cohort included 1,218 patients. Compared with patients engaged in less than 3 MET hours per week of physical activity, patients engaged in 18 or more MET hours per week experienced an adjusted hazard ratio for OS of 0.85 (95% CI, 0.71 to 1.02; PTrend= .06) and for PFS of 0.83 (95% CI, 0.70 to 0.99; PTrend= .01). Compared with patients engaging in less than 9 MET hours per week, patients engaging in 9 or more MET hours per week experienced an adjusted hazard ratio for grade 3 or greater treatment-related adverse events of 0.73 (95% CI, 0.62 to 0.86; PTrend< .001).CONCLUSIONAmong patients with mCRC in Cancer and Leukemia Group B (Alliance)/SWOG 80405, association of physical activity with OS was not statistically significant. Greater physical activity was associated with longer PFS and lower adjusted risk for first grade 3 or greater treatment-related adverse events.

Abstract Dysregulation of ErbB-mediated signaling is observed in up to 90% of solid tumors. ErbB family cross-talk is implicated in the development of resistance and metastasis, including CNS metastases. Inhibition of multiple ErbB receptors may result in improved patient outcomes. EO1001 is a novel, patented, oral, brain-penetrating, irreversible pan-ErbB inhibitor targeting EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4). METHODS: (1) In vitro testing. EO1001 demonstrates high specificity for the ErbB family of receptors with excellent, balanced equipotent activity against EGFR, HER2 and HER4 (0.4 to 7.4 nM). EO1001 inhibits signaling downstream of wild type EGFR, mutant EGFR (T790M, L858R and d746-750) and HER2. (2) PK and toxicity. In rodent studies in vivo, EO1001 exhibited a half-life of 16–20 hours. EO1001 rapidly enters the CNS and penetrates tumor tissue at higher concentrations relative to plasma. Safety of EO1001 was evaluated by repeat-dosing studies in SD rats and beagle dogs. Toxicities typical of the ErbB inhibitor class, including gastro-intestinal effects, weight loss and decreased activity were observed at higher dose groups in both species. Mortality was observed in SD rats at higher dose groups. (3) In vivo efficacy studies. EO1001 was studied following oral administration in several erbB-positive mouse xenograft models including N87 (Her2+), H1975 (EGFR/T790M), GBM12 (EGFR+), GBM39 (EGVRvIII+). Following oral administration, treatment with EO1001 resulted in a statistically significant improvement in outcomes compared to positive and negative controls in both CNS and systemic tumor models. EO1001 was well-tolerated with no gastrointestinal side effects observed at efficacious doses in these models. CONCLUSION: Based on research to date, EO1001 has the potential to be a best-in-class CNS-penetrating pan-ErbB inhibitor with a safety and pharmacokinetic profile amenable for use as a single agent and in combination with other agents. EO1001 is poised to enter phase 1-2a clinical testing in the second-half of 2019.

Abstract CLL is a clinically heterogeneous disease with wide ranging disease course. A novel CLL-IPI based on Rai/Binet stage, IGHV-mutation status, TP53 mutation/deletion, B2M level, and age was developed to stratify patients into 4 risk groups, with a c-statistic of 0.75. Next-generation sequencing has identified ~60 genes recurrently mutated in CLL, some of which are associated with poor overall survival, whereas the clinical effect of most genes is still unknown. Herein, we examine whether somatic mutations in these putative driver genes are associated with time to first treatment (TTT), and whether they add prognostic value beyond CLL-IPI. Based on the 2008 International Workshop CLL criteria, we identified 100 CLL and 96 high-count monoclonal B-cell lymphocytosis (MBL) newly diagnosed from the Mayo Clinic CLL biobank. Pre-treatment peripheral blood mononuclear cells were collected &lt;2 years of diagnosis and tumor DNA was extracted from sorted CD5+/CD19+. We sequenced the coding regions of 61 recurrently mutated CLL driver genes using a custom SureSelect panel, with 24 samples per flow cell in Illumina HiSeq 4000. The average coverage depth was &gt;1000X. Somatic mutations were called using MuTect2 in tumor-only mode. To remove germline variants, variants were eliminated based on minor allele frequencies &gt;0.01%, identified in 1000 Genomes Project, ExAC and/or ESP6500 databases, unless present in known mutation hotspots or COSMIC. After filtering, high/moderate impact mutations were analyzed using Cox regression, to estimate hazard ratios (HR) and 95% confidence intervals (CI) to test for associations with TTT. Among 196 patients the most commonly mutated genes were TP53 (11%), ATM (10%), SF3B1 (10%), NOTCH1 (9%), CHD2 (8%), and BIRC3 (7%). The median follow-up was 8.7 years, and 73 patients were subsequently treated. ATM (HR=3.27, CI:1.8-6.1, P=0.0002) and NOTCH1 (HR=2.41, CI:1.3-4.6, P=0.008) were associated with TTT. When evaluating the total number of mutated genes, we found 32%, 29%, and 39% patients had ≥2, 1, or 0 genes mutated, respectively, and this was associated with shorter TTT (HR=1.74, CI:1.3-2.4, P=0.0005) adjusting for sex and CLL-IPI with a c-statistic=0.8 (CI: 0.75-0.84). When stratified by CLL-IPI, the association held for low (N=99, HR=1.88, CI:1.1-3.4, P=0.03) and intermediate risk (N=54, HR=1.87, CI:1.1-3.2, P=0.03) but not high/very high risk (N=35, HR=1.07, CI:0.6-1.9, P=0.83). We demonstrated that the total number of CLL putative driver genes with high or moderate impact mutations provided prognostic information in newly diagnosed CLL/MBL beyond CLL-IPI. Moreover, even among those with low or intermediate CLL-IPI risk, the total number of somatic mutations separated those patients who progressed. Sequencing the CLL driver genes at time of diagnosis could be a potential biomarker for outcome prediction. Citation Format: Geffen Kleinstern, Daniel R. O’Brien, Brian F. Kabat, Kari G. Chaffee, Aaron D. Norman, Timothy G. Call, Sameer A. Parikh, Jose F. Leis, Wei Ding, James R. Cerhan, Neil E. Kay, Susan L. Slager, Esteban Braggio. Somatic mutations within chronic lymphocytic leukemia (CLL) putative driver genes are associated with outcomes beyond the CLL international prognostic index (CLL-IPI) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4466.

Abstract Background: In non-metastatic colorectal cancer, a body mass index (BMI) paradox is observed where overweight and early obese patients experience improved outcomes compared to patients with normal, low, or morbidly obese BMI. The influence of obesity on patients with advanced or metastatic colorectal cancer (mCRC) is relatively unexplored. Methods: We conducted a prospective BMI companion study in CALGB (now Alliance for Clinical Trials in Oncology)/SWOG 80405, a phase III mCRC treatment trial. BMI was measured at trial registration. Primary and secondary endpoints were overall and progression-free survival, respectively. To minimize confounding by poor and rapidly declining health, we used Cox proportional hazards regression to adjust for known prognostic factors, comorbidities, physical activity, and weight loss, and excluded individuals with low BMI &lt;21 from statistical tests for trend. We also examined self-reported weight loss over the six months prior to trial enrollment as an independent predictor of patient outcome. Results: In this sub-study of a phase III mCRC trial, BMI was recorded for all 2,323 patients enrolled. Following adjustment for confounders, there were no significant associations between BMI and overall or progression-free survival (excluding BMI &lt;21, Ptrend with increasing BMI = 0.12 and 0.42, respectively). Conversely, weight loss prior to treatment was associated with shorter overall and progression-free survival; compared to individuals with weight change &lt;5%, individuals with weight loss &gt;20% experienced an adjusted hazard ratio of 1.46 for all-cause mortality (95% confidence interval 1.15 to 1.85, Ptrend &lt;.0001) and of 1.27 for disease progression or death (95% confidence interval 1.04 to 1.56, Ptrend = .009). Conclusion: In this prospective study of patients with mCRC, BMI at time of first-line chemotherapy initiation was not associated with patient outcome. Weight loss prior to study entry was associated with increased risk of patient mortality and disease progression. Citation Format: Brendan Guercio, Sui Zhang, Alan P. Venook, Fang-Shu Ou, Donna Niedzwiecki, Heinz-Josef Lenz, Federico Innocenti, Hanna Sanoff, Michelle R. Mahoney, Bert H. O'Neil, James E. Shaw, Blase N. Polite, Howard S. Hochster, James N. Atkins, Richard M. Goldberg, Robert J. Mayer, Charles D. Blanke, Charles S. Fuchs, Jeffrey A. Meyerhardt. Body mass index, weight loss, and progression and mortality in metastatic colorectal cancer: Results from CALGB/SWOG 80405 (Alliance) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3285.