Citations

3598 Background: Drug resistance to topotecan can be the result of BCRP/ABCG2 expression. BCRP is a member of the ABC transporter family that pumps anticancer drugs out of the cell. Lapatinib is a potent and selective dual inhibitor of epidermal growth factor receptor (EGFR or ErbB1) and ErbB2 (Her2/Neu). 4-aminoquinazoline tyrosine kinase inhibitors have been shown to enhance the cytotoxicity of topotecan through inhibition of BCRP-mediated drug efflux in cancer cells. Methods: Thirty-seven patients with advanced stage cancers were enrolled at escalating dose levels of lapatinib and topotecan in cohorts IA, IB and IIB (MTD). Treatment schedule included lapatinib (750 - 1500 mg/d) daily for 21 (cohort IA) or 28 days (cohort IB) and topotecan (2.4 - 4.0 mg/ m2), days 1, 8 and 15; cycles were repeated every 28 days. Three patients were treated at each dose level, 18 on cohort IA, 9 on cohort IB and 10 at MTD (cohort IIB). Assessments of toxicity were performed with each cycle and clinical response was determined per RECIST criteria every other cycle. Results: The MTD for cohorts IA and IB was reached at a dose of 1250 mg of lapatinib and 3.2 mg/m2 of IV topotecan on days 1, 8 and 15. No DLT were seen during the dose escalation stage of cohorts IA and IB. Ten patients were enrolled at the MTD. There were no grade 4+ events. Thirteen grade 3+ events, considered to be related to treatment, were seen in 6 patients. The most common grade 3+ toxicities included dehydration (2) diarrhea (2), nausea (3), vomiting (2), neutropenia (1), thrombocytopenia (1), and fatigue (1). No abnormalities in left ventricular ejection fraction were noted. Stable disease was seen in 46% of the 37 patients. Conclusions: The combination of lapatinib and topotecan is a well-tolerated regimen. The MTD for the combination is lapatinib 1,250 mg orally once daily for 21 or 28 days and topotecan 3.2 mg/m2 on days 1, 8 and 15. Pharmacokinetic analysis for drug interaction will be available for presentation at the meeting. Supported in part by GSK and Mayo Clinic No significant financial relationships to disclose.

AbstractCIC rearranged sarcomas have significant overlap with Ewing sarcoma, are aggressive, and typically present in deep soft tissue. They most commonly have a t(4;19)(q35;q13) with CIC‐DUX4 fusion. Superficial presentation is rare. We report eight (6F, 2M; median 45‐years‐old, range 14‐65) superficial CIC‐rearranged sarcomas, involving the extremities (n = 4), vulva (n = 2), and trunk (n = 2). The tumors were composed of nodules/sheets of round cells with necrosis and hemorrhage separated by dense hyaline bands. Tumor cells had vesicular chromatin, prominent nucleoli and frequent mitotic figures. One showed pagetoid spread. Targeted next‐generation sequencing was positive for CIC‐DUX4 fusion (6/6); fluorescence in situ hybridization (FISH) was positive for CIC rearrangement (2/3). Eight of eight had evidence of CIC‐DUX4 fusion/rearrangement by molecular techniques. Immunohistochemistry was positive for CD99+ (8/8) and DUX4+ (4/4). FISH for EWSR1 rearrangement was negative (5/5). Of five patients with at least 6 months follow‐up, three of five died of disease, all within 2 years of presentation. One is alive with disease at 48 months. One is disease free at 3 months. Superficial CIC‐rearranged sarcomas should be considered in cases exhibiting features reminiscent of Ewing sarcoma, but with increased pleomorphism and/or geographic necrosis. In contrast to superficial Ewing sarcomas, superficial CIC‐rearranged sarcomas are aggressive.

ABSTRACT During bone marrow stromal cell (BMSC) differentiation, both Wnt signaling and the development of a rigid cytoskeleton promote commitment to the osteoblastic over adipogenic lineage. β-catenin plays a critical role in the Wnt signaling pathway to facilitate downstream effects on gene expression. We show that β-catenin was additive with cytoskeletal signals to prevent adipogenesis, and β-catenin knockdown promoted adipogenesis even when the actin cytoskeleton was depolymerized. β-catenin also prevented osteoblast commitment in a cytoskeletal-independent manner, with β-catenin knockdown enhancing lineage commitment. Chromatin immunoprecipitation (ChIP)-sequencing demonstrated binding of β-catenin to the promoter of enhancer of zeste homolog 2 (EZH2), a key component of the polycomb repressive complex 2 (PRC2) complex that catalyzes histone methylation. Knockdown of β-catenin reduced EZH2 protein levels and decreased methylated histone 3 (H3K27me3) at osteogenic loci. Further, when EZH2 was inhibited, β-catenin's anti-differentiation effects were lost. These results indicate that regulating EZH2 activity is key to β-catenin's effects on BMSCs to preserve multipotentiality. © 2020 American Society for Bone and Mineral Research.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

Adenoviruses (Ads) are robust vectors for therapeutic applications and vaccines, but their use can be limited by differences in their in vitro and in vivo pharmacologies. This review emphasizes that there is not just one Ad, but a whole virome of diverse viruses that can be used as therapeutics. It discusses that true vector targeting involves not only retargeting viruses, but importantly also detargeting the viruses from off‐target cells.

Abstract Background : Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods : Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients (299 males and 195 females). Results : Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than other patients (M p=0.004, F p=0.001, t-test). Conclusion : Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes.

BACKGROUND: Cross-sectional studies in ulcerative colitis (UC) have shown at best a moderate association between histologic and clinical measures of disease activity, but few longitudinal studies have evaluated this relationship. As endoscopy and histology are both independent predictors of clinical outcomes in UC, there remains a need to assess these measures in parallel to demonstrate clinical benefit. HICKORY (NCT02100696) is an ongoing Phase 3 study evaluating etrolizumab in anti-tumor necrosis factor (aTNF)–experienced patients with moderate-to-severe UC. The correlation between histologic changes and established disease activity measures at end of induction (week 14) was assessed using data from the open-label induction (OLI) cohort of HICKORY. METHODS: Study analysis is based on data from patients in the OLI cohort who received ≥1 dose of etrolizumab 105 mg subcutaneously every 4 weeks during the 14-week induction phase. Baseline and week 14 biopsies were scored by 1 of 4 central readers using the Nancy histologic index (NHI) and the Robarts histopathology index (RHI) in patients who had active baseline histology (NHI >1 and RHI >3) and complete scoring at week 14 (n = 97). Binary week 14 histologic outcomes were characterized by presence or absence of neutrophils (NHI ≤1 or RHI ≤3 and Geboes subgrades 2B.0/3.0). Mayo Clinic score (MCS) endoscopic subscore (ES) was used to assess endoscopy. Pairwise associations were quantified by Spearman correlation (ρ; for correlation between change from baseline scores) and Cohen kappa coefficients (κ; for agreement among week 14 outcomes). ΔNHI and ΔRHI were compared to determine presence of a minimum clinically important difference (MCID) in MCS (∆MCS ≥3 from baseline). RESULTS: At week 14, 22% (21/97), 23% (22/97), and 8% (8/97) of patients achieved resolution of neutrophilic inflammation based on either NHI or RHI/Geboes, endoscopic improvement (ES ≤ 1), and endoscopic remission (ES = 0), respectively. Among patients with endoscopic improvement and endoscopic remission, neutrophilic resolution was achieved in 55% (12/22) and 75% (6/8) of patients, respectively. ΔNHI and ΔRHI were highly correlated (ρ = 0.91). There was weak to no association between ΔNHI/ΔRHI/ΔES and Δfecal calprotectin (ρ = –0.02 to 0.38), ΔC-reactive protein (ρ = 0.03 to 0.07), Δalbumin (ρ = –0.19 to –0.10), Δhemoglobin (ρ = –0.22 to –0.19), and Δsegmented neutrophils in the blood (ρ = –0.06 to 0.01). Weak correlations were observed between ΔNHI/ΔRHI and ΔES (ρ = 0.26–0.27), Δrectal bleeding (ρ = 0.24–0.28), and Δstool frequency (ρ = 0.40–0.42). Correlations between NHI, RHI/Geboes, and ES with symptomatic outcomes were weak (κ = 0.28–0.45). Difference in the mean grouped by achievement of ΔMCS ≥3 suggests MCIDs in ΔNHI and ΔRHI of 1.2 and 8.6, respectively. CONCLUSION(S): The analysis showed weak to moderate agreement between changes in histologic scores and changes in endoscopic scores, and weak to no agreement between changes in histologic scores and changes in laboratory results at week 14. There was a weak correlation between histologic scores and symptoms at the end of induction. MCID results suggest that both the NHI and RHI appear to effectively evaluate neutrophilic resolution, making the changes in score more clinically interpretable.

Abstract PURPOSE Brain tumor related epilepsy (BTE) is a major co-morbidity in patients with glioma. It is difficult to determine whether the use of anti-epileptic drugs is necessary. We attempted to build a machine-learning model to predict the probability of seizure presentation (SP) with glioma. METHODS We trained a random forest classifier using the following variables: volumetric data of pre-treatment MR images (T1Gd and T2-FLAIR sequences), patient demographics (age; sex), and measurements of tumor proliferation (log(ρ)), invasiveness (log(D)) and their relative ratio (log(ρ/D)). Our cohort consisted of 221 patients total. Using an 80-20 ratio, we used 176 patients (76 SP, 100 nSP) for training and the remaining 45 patients (19 SP, 26 nSP) were used for testing. We also trained on male-only and female-only cohorts to evaluate any sex differences in prediction. For training, 108 males (53 SP, 55 nSP) were used and 28 for testing (14 SP, 14 nSP). We used 72 females (21 SP, 49 nSP) for training and 15 (7 SP, 8 nSP) for testing. We corrected for class imbalance in the female cohort before training. Using 10-fold cross-validation and a separate testing set, we measured performance by ROC curve (AUC), accuracy, sensitivity, and specificity of predictions (average of folds in cross validation). RESULTS The female model achieved the highest AUC (0.853) followed by the mixed model (0.726) and the male model (0.651). In the validation set, the accuracy/sensitivity/specificity of the three cohorts were as follows: mixed (0.726/0.696/0.750), female (0.853/0.830/0.875), and male (0.651/0.577/0.722). The performance of the testing set, in terms of accuracy/sensitivity/specificity were: mixed (0.733/0.74/0.73), female (0.8/0.57/1), and male (0.714/0.64/0.79). CONCLUSION We found a negative correlation between seizure probability and size and invasiveness of tumors. Our model shows promising performance on testing set data. Further cohort studies and training is warranted.

Abstract INTRODUCTION Glioblastoma (GBM) is the most common malignant primary brain tumor in adults with a median overall survival (OS) of 15months. Despite advancements in treatments, prognosis is dismal and the prognostic significance of tumor location is not entirely understood. METHODOLOGY: In our study, we investigated sex-specific volumetric, tumor growth kinetics, and outcome differences among GBMs in various brain locations. Primary GBM patients with pretreatment magnetic resonance imaging (MRI) data (N=289, 173 males, 116 females) were selected from our brain tumor repository. Tumor abnormality was segmented on T1-weighted post-gadolinium contrast agent (T1Gd) MRIs. We utilized the Harvard-Oxford brain atlases to determine the location of GBMs. RESULTS Overall, our study found smaller tumors in the left hemisphere. This may be expected as left-hemispheric GBM symptoms could present earlier, leading to earlier diagnosis and treatment. However, when the cohort was split by sex, we found this observation significant for females only in the parietal lobe (p < 0.0001). Further, female GBMs demonstrated smaller necrotic volume in the left hemisphere (p = 0.030). Sex-specific differences in incidence were noted in the temporal and occipital lobes (2M:1F). Comparing tumor growth kinetics in different brain locations and hemispheres, females had significantly lower tumor proliferation rates in the left hemisphere (p = 0.009) and lower tumor proliferation rates in the left frontal lobe (p = 0.031). Controlling for treatment, patients with frontal lobe tumors had significantly longer OS compared to those with GBMs in the temporal lobe (p = 0.046, 312 days). Differences in growth velocities were noted between frontal and parietal lobe with frontal GBMs having lower velocities in comparison to parietal lobe GBMs. CONCLUSION Together, our results demonstrate that tumor growth and proliferation rates may vary based on location and sex. Additional research is needed to further explore the clinical significance of tumor location.