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Background Curative-intent treatment of acute myeloid leukaemia (AML) can lead to multiple chronic medical conditions (‘late effects’). Little is known about the burden of late effects in adolescent and young adult (AYA, 15–39 years) survivors of AML. We aimed to estimate the cumulative incidence and investigate the main predictors of late effects among these patients. Methods During 1996–2012, 1168 eligible AYAs with AML who survived ≥2 years after diagnosis were identified in the California Cancer Registry. Late effects were reported from State hospital discharge data, and patients were followed through 2014. Hazard ratios and 95% confidence intervals of late effects occurrence were estimated using Cox proportional hazard models, adjusted for sociodemographic and clinical factors. Results The most common late effects at 10 years after diagnosis were: endocrine (26.1%), cardiovascular (18.6%) and respiratory (6.6%), followed by neurologic (4.9%), liver/pancreatic (4.3%), renal (3.1%), avascular necrosis (2.7%) and second primary malignancies (2.4%). Of 1168 survivors, 547 (46.8%) received a haematopoietic stem cell transplant (HSCT). After multivariable adjustments, AYAs who underwent HSCT or had a non-favourable risk AML experienced ∼2-fold or higher increased likelihood of all late effects. Additionally, AYAs of Hispanic, Black or Asian/Pacific Islander (vs non-Hispanic White) race/ethnicity and those who resided in lower socio-economic neighbourhoods were at higher risk of numerous late effects. Conclusions Our findings underscore the need for long-term surveillance for the prevention, early detection and treatment of late effects, and can inform the development of AYA-focused consensus-based guidelines that will ultimately improve the quality of life and survival of these young vulnerable patients.

Purpose Aurora Kinase A (AKA) inhibition with gemcitabine represents a potentially synergistic cancer treatment strategy via mitotic catastrophe. The feasibility, safety, and preliminary efficacy of alisertib (MLN8237), an oral AKA inhibitor, with gemcitabine was evaluated in this open-label phase I trial with dose escalation and expansion. Methods Key inclusion criteria included advanced solid tumor with any number of prior chemotherapy regimens in the dose escalation phase, and advanced pancreatic adenocarcinoma with up to two prior chemotherapy regimens. Four dose levels (DLs 1–4) of alisertib (20, 30, 40, or 50 mg) were evaluated in 3 + 3 design with gemcitabine 1000 mg/m2 on days 1, 8, and 15 in 28-day cycles. Results In total, 21 subjects were treated in dose escalation and 5 subjects were treated in dose expansion at DL4. Dose-limiting toxicities were observed in 1 of 6 subjects each in DL3 and DL4. All subjects experienced treatment-related adverse events. Grade ≥ 3 treatment-related adverse events were observed in 73% of subjects, with neutropenia observed in 54%. Out of 22 subjects evaluable for response, 2 subjects (9%) had partial response and 14 subjects (64%) had stable disease. Median PFS was 4.1 months (95% CI 2.1–4.5). No significant changes in pharmacokinetic parameters for gemcitabine or its metabolite dFdU were observed with alisertib co-administration. Conclusions This trial established the recommended phase 2 dose of alisertib 50 mg to be combined with gemcitabine. Gemcitabine and alisertib are a feasible strategy with potential for disease control in multiple heavily pre-treated tumors, though gastrointestinal and hematologic toxicity was apparent.

Author(s): Parikh, M; Huynh, JC; Brunson, A; Keegan, T; Lara, PN | Abstract: Background: While most renal cell carcinomas (RCC) are of the clear cell subtype, other histologic subtypes are well described and have distinct clinical behavior. This study seeks to evaluate survival of clear and non-clear cell RCC retrospectively from a large, population-based cancer registry. Objectives: The key objectives of this study were to determine cancer-specific survival (CSS) and overall survival (OS) of RCC by histologic subtype and to examine survival by histologic subtype since the advent of anti-angiogenesis therapy in 2006. Methods: Within the California Cancer Registry (CCR), we used multivariable Cox proportional hazards models to assess the association of histologic subtype with CSS and OS, adjusted for sociodemographic and clinical factors. Results: In the CCR, 33,539 RCC patients were diagnosed between 2004 and 2014. The most common subtype, clear cell RCC, comprised 82.6% (n=27,717) of cases. The next most common subtypes were papillary (8.8%, 2,948) and chromophobe (5.2%, 1,759). RCC was more common in men (62.9%, 21,097) compared to women (37.1%, 12,442). Across histologic subtypes, patients with low neighborhood socioeconomic status had lower CSS (HR=1.07, 95% CI 1.02-1.13, p=0.011) and OS (HR=1.14, 95% CI: 1.10-1.19, pl0.001). On multivariate analysis, we observed an interaction between histologic subtype and CSS, finding that patients in the anti-angiogenesis treatment era with clear cell had a significant improvement in CSS (HR: 0.87, 95% CI: 0.82-0.92, pl0.001) as did patients with collecting duct subtype (HR: 0.25, 95% CI: 0.12-0.51, pl0.001), while there were no differences in outcomes over time among patients with chromophobe or papillary subtypes. After 2006, compared to clear cell subtype, patients with chromophobe subtype had a better CSS (HR=0.40, 95% CI: 0.30-0.53, pl0.001), while those with collecting duct carcinomas had a poorer CSS (HR=1.83, 95% CI: 1.29-2.59, p=0.001). Conclusions: In the era following anti-angiogenesis therapy development, patients with chromophobe subtype RCC continue to have a better prognosis compared with clear cell RCC, and patients with collecting duct subtype continue to have a significantly worse prognosis, with more advanced disease at diagnosis. There have been improvements in CSS in patients with clear cell and collecting duct subtypes since the advent of anti-angiogenesis therapy.

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.

Inhibition of mitosis is an established therapeutic approach in the treatment of cancer. However, existing drugs that use this mechanism including taxanes cause off-target effects leading to dose-limiting toxicity such as sensory neuropathy. Development of inhibitors of mitosis-specific targets has created the next generation of mitosis inhibitors with the goal of achieving similar anti-tumor efficacy but with less toxicity. Aurora Kinase A is one example of a mitosis-specific target for which multiple drugs have been developed as anti-cancer therapy. Although early preclinical studies have showed on-target effects, clinical development has been slowed by minimal efficacy as monotherapy. However, strategic combinations of Aurora Kinase A inhibition with various targeted drugs has shown promise and led to renewed interest in the potential of inhibiting this mitosis-specific target.

Simple Summary Advanced hepatocellular carcinoma (HCC) carries a grim prognosis, which has historically been compounded by a lack of available systemic therapies. Sorafenib monotherapy was the standard of care for front-line treatment of advanced HCC for many years, despite both poor tolerability and lack of durable responses. In the past few years, there have been several clinical trials evaluating the efficacy of immune checkpoint inhibitors for advanced HCC. Use of immune checkpoint inhibitors alone, and in combination with targeted therapies, has led to improved outcomes in both treatment-naïve and subsequent line treatment of advanced HCC. Here we review the role of immunotherapy in the treatment of HCC, describe the mechanistic basis for combination with targeted therapy, and summarize the recent published data as well as ongoing clinical trials for the use of immunotherapy in the treatment of advanced HCC. Abstract Hepatocellular carcinoma (HCC) is the second most common cause of cancer death worldwide. HCC tumor development and treatment resistance are impacted by changes in the microenvironment of the hepatic immune system. Immunotherapy has the potential to improve response rates by overcoming immune tolerance mechanisms and strengthening anti-tumor activity in the tumor microenvironment. In this review, we characterize the impact of immunotherapy on outcomes of advanced HCC, as well as the active clinical trials evaluating novel combination immunotherapy strategies. In particular, we discuss the efficacy of atezolizumab and bevacizumab as demonstrated in the IMbrave150 study, which created a new standard of care for the front-line treatment of advanced HCC. However, there are multiple ongoing trials that may present additional front-line treatment options depending on their efficacy/toxicity results. Furthermore, the preliminary data on the application of chimeric antigen receptor (CAR-T) cell therapy for treatment of HCC suggests this may be a promising option for the future of advanced HCC treatment.

Introduction: Patients (pts) with borderline resectable (BR) pancreatic cancer (PC) derive a clear survival benefit when margin-negative resection can be achieved after neoadjuvant treatment (tx). As such, reliable imaging is desperately needed to identify those patients with the best chance of surgical benefit. Current imaging with CT/MRI and standard 18F-fludeoxyglucose (FDG) PET lacks sensitivity and specificity to resolve residual tumor contact with the large blood vessels of the vascular groove. Dynamic PET with kernel-based image reconstruction developed by our group has potential to overcome limits of standard static PET by robust parametric imaging of radiotracer kinetics. KBD FDG-PET provides the FDG kinetic parameter K1 for tumor perfusion and Ki for tumor glucose utilization. A lower Ki/K1 ratio indicates a better perfused, less metabolically active tumor and is derived by our method without need for separate perfusion CT/MRI. Methods: Pts with PC staged as BR as defined by consensus guidelines were eligible. Pts were assessed by CA 19-9 and CT/MRI along with KBD FDG-PET both pre-tx and post-tx. KBD FDG PET was performed by IV bolus of 10 mCi of FDG followed by 60-min PET data acquisition. A 3-compartment model with 5 micro kinetic parameters K1, k2, k3, k4, and fv was used where K1 (mL/min/mL) denotes the rate constant of FDG transport from plasma to tissue, k2 (1/min) the transport rate from tissue to plasma, k3 (1/min) the rate of FDG conversion to FDG 6-phosphate, k4 (1/min) the rate of dephosphorylation, and fv the fractional blood volume. Ki was calculated from micro parameters by the formula K1*k3/(k2+k3). Parametric images of these kinetic parameters were obtained by voxel-wise implementation of kinetic modeling. Results: 4 pts were enrolled, 3 pts had pre- and post-tx KBD FDG-PET, and 2 pts were resected. In the 3 evaluable pts, an overall 62% decrease in tumor glucose utilization was observed (mean pre-tx Ki=.03, [range .013-.045]; mean post-tx Ki=.011 [range .004-.016]. Mean pre-tx K1=.37 (range .26-.50) and mean post-tx K1=.38 (range .31-.46). Delta Ki was -17%, -47%, and -91% and delta Ki/K1 was -9%, -28%, and -95% in pts 1, 2, 3 respectively. Pt 3 had the highest pre-tx Ki and the lowest pre-tx K1, but had a >90% decrease in Ki and Ki/K1 post-tx, indicating a significant decrease in metabolic activity and concomitant increase in perfusion. Despite persistent superior mesenteric vein (SMV) abutment on standard post-tx imaging, margin-negative resection was achieved. In contrast, pt 1 had the lowest pre-tx Ki and highest pre-tx K1, but had a Citation Format: John P. Schwerkoske, Guobao Wang, Kit W. Tam, Jasmine C. Huynh, Heather H. Hunt, Michael L. Rusnak, Cameron C. Foster, Michael T. Corwin, Karen E. Matsukuma, Dorina Gui, May T. Cho, Richard J. Bold, Ramsey D. Badawi, Edward J. Kim. Pilot study of kernel-based dynamic (KBD) FDG-PET in patients with borderline resectable pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3045.