Publications

<title>Abstract</title> Purpose To evaluate the impact of routine multidisciplinary allied health prehabilitation care in haematologic cancer patients receiving high-dose chemotherapy with autologous stem cell transplant (AuSCT). Methods In a tertiary cancer centre, 12-months of prospectively collected data was retrospectively analysed. Patients were referred to the service for individualised exercise prescription, nutrition intervention and, if indicated through screening, psychological intervention. Impact and operational success were investigated based on the RE-AIM framework: patient uptake of the service and sample representativeness (Reach); Effectiveness in terms of changes in outcomes from initial to pre-transplant assessment; Adoption of the service by key stakeholders; fidelity of the prescribed exercise program (Implementation); and the extent to which the service had become part of routine standard care (Maintenance). Results 183 patients were referred to the AuSCT service, of whom 133 (73%) were referred into the prehabilitation service, 128 (96%) were eligible and 116 (91%) participated. Significant improvements were demonstrated between initial and pre-transplant assessments particularly six-minute walk distance (n = 45); mean difference (95% CI) 39.9m (18.8 to 61.0, p = &lt; 0.005). Missing data were an issue for assessment of effectiveness. Fidelity of exercise prescription was moderate with 72% of eligible patients receiving the intended aerobic and resistance exercise interventions. Conclusion The prehabilitation service was well adopted by clinicians. Clinically relevant improvements in outcomes were demonstrated. Recommendations, including development of well-integrated discipline-specific assessment intervention and measurement protocols, are highlighted to improve the service. Prehabilitation should be routinely considered to support the care of patients undergoing AuSCT.

5063 Background: Declines in prostate specific antigen (PSA) levels at 12-weeks are currently used to evaluate treatments response in metastatic castration resistant prostate cancer (mCRPC). Early PSA fall by 30% at 4-weeks (PSA4w30) has been previously shown to be associated with better outcome in mCRPC in a small single-centre cohort. Methods: We identified mCRPC patients who had received Abiraterone Acetate (AA) between 06.01.06 and 08.09.17 in 13 cancer centres worldwide. Eligible patients had PSA levels assessed at baseline, after 4-weeks and/or 12-weeks of treatment. PSA response was defined as a ≥30% decline from baseline and PSA progression as a ≥25% increase from baseline. Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term. Results: We identified 1057 patients who had received AA (447 pre-chemotherapy, 610 post-chemotherapy), with 835 patients having PSA values available at 4 and 12 weeks. Overall, 372/835 (44.5%) had PSA4w30; this associated with longer OS (mOS 22vs15 months; HR = 0.62; 95%CI 0.53–0.72; p < 0.001). A ≥30% PSA decline at 12-weeks (PSA12w30) associated with a lower mortality (mOS 22vs14; HR = 0.57; 95%CI = 0.48–0.67; p < 0.001). Sensitivity analyses confirmed the association between PSA4w30 and OS when pre- and post-chemotherapy cohorts were analysed separately. PSA4w30 strongly correlated with PSA12w30 (ρ = 0.92; p < 0.001). In total, 320/372 (86%) patients with a PSA decline at 4-weeks had a PSA decline at 12-weeks. Conversely, 11/835 (1.3%) patients progressed at 4-weeks and then met the criteria for PSA12w30. PSA4w30 remained correlated with OS (HR = 0.56; 95%CI = 0.48–0.65; p < 0.001) in multivariate analyses including other established prognostic factors in mCRPC (baseline ALP, LDH, Hb, M status and Gleason at diagnosis). Conclusions: PSA changes in the first 4-weeks of AA therapy are strongly associated with clinical outcome in mCRPC patients and should be prospectively evaluated in early treatment switch decision trials.

Burkitt lymphoma (BL) is a germinal center B-cell-derived malignancy characterized by oncogenic MYC activation through translocation with one of the immunoglobulin loci. This highly aggressive lymp...

Recent studies indicate that astrocytes can play a much more active role in neuronal circuits than previously believed, by releasing neurotransmitters such as glutamate and ATP. Here we report that local application of glutamate or glutamine synthetase inhibitors induces astrocytic release of glutamate, which activates a slowly decaying transient inward current (SIC) in CA1 pyramidal neurons and a transient inward current in astrocytes in hippocampal slices. The occurrence of SICs was accompanied by an appearance of large vesicles around the puffing pipette. The frequency of SICs was positively correlated with [glutamate]o. EM imaging of anti-glial fibrillary acid protein-labeled astrocytes showed glutamate-induced large astrocytic vesicles. Imaging of FM 1-43 fluorescence using two-photon laser scanning microscopy detected glutamate-induced formation and fusion of large vesicles identified as FM 1-43-negative structures. Fusion of large vesicles, monitored by collapse of vesicles with a high intensity FM 1-43 stain in the vesicular membrane, coincided with SICs. Glutamate induced two types of large vesicles with high and low intravesicular [Ca2+]. The high [Ca2+] vesicle plays a major role in astrocytic release of glutamate. Vesicular fusion was blocked by infusing the Ca2+ chelator, 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, or the SNARE blocker, tetanus toxin, suggesting Ca2+- and SNARE-dependent fusion. Infusion of the vesicular glutamate transport inhibitor, Rose Bengal, reduced astrocytic glutamate release, suggesting the involvement of vesicular glutamate transports in vesicular transport of glutamate. Our results demonstrate that local [glutamate]o increases induce formation and exocytotic fusion of glutamate-containing large astrocytic vesicles. These large vesicles could play important roles in the feedback control of neuronal circuits and epileptic seizures.

&lt;p&gt;Supplementary Figure 5. Pano did not alter Her2 or H2-Db expression on Panc02-Her2 tumor cells in vivo and CARaMEL cells were detectable over 100 days in ACTIV+ Pano treated mice.&lt;/p&gt;

The MYC oncogene is frequently overexpressed in prostate cancer. Upregulation of ribosome biogenesis and function is characteristic of MYC-driven tumors. In addition, PIM kinases activate MYC signaling and mRNA translation in prostate cancer and cooperate with MYC to accelerate tumorigenesis. Here, we investigate the efficacy of a single and dual approach targeting ribosome biogenesis and function to treat prostate cancer.The inhibition of ribosomal RNA (rRNA) synthesis with CX-5461, a potent, selective, and orally bioavailable inhibitor of RNA polymerase I (Pol I) transcription, has been successfully exploited therapeutically but only in models of hematologic malignancy. CX-5461 and CX-6258, a pan-PIM kinase inhibitor, were tested alone and in combination in prostate cancer cell lines, in Hi-MYC- and PTEN-deficient mouse models and in patient-derived xenografts (PDX) of metastatic tissue obtained from a patient with castration-resistant prostate cancer.CX-5461 inhibited anchorage-independent growth and induced cell-cycle arrest in prostate cancer cell lines at nanomolar concentrations. Oral administration of 50 mg/kg CX-5461 induced TP53 expression and activity and reduced proliferation (MKI67) and invasion (loss of ductal actin) in Hi-MYC tumors, but not in PTEN-null (low MYC) tumors. While 100 mg/kg CX-6258 showed limited effect alone, its combination with CX-5461 further suppressed proliferation and dramatically reduced large invasive lesions in both models. This rational combination strategy significantly inhibited proliferation and induced cell death in PDX of prostate cancer.Our results demonstrate preclinical efficacy of targeting the ribosome at multiple levels and provide a new approach for the treatment of prostate cancer. Clin Cancer Res; 22(22); 5539-52. ©2016 AACR.

Supplementary Figure from Tumor Genomic Testing for &gt;4,000 Men with Metastatic Castration-resistant Prostate Cancer in the Phase III Trial PROfound (Olaparib)

Early detection is critical in limiting the spread of 2019 novel coronavirus (COVID-19). Although previous data revealed characteristics of GI symptoms in COVID-19, for patients with only GI symptoms onset, their diagnostic process and potential transmission risk are still unclear. We retrospectively reviewed 205 COVID-19 cases from January 16 to March 30, 2020, in Renmin Hospital of Wuhan University. All patients were confirmed by virus nuclei acid tests. The clinical features and laboratory and chest tomographic (CT) data were recorded and analyzed. A total of 171 patients with classic symptoms (group A) and 34 patients with only GI symptoms (group B) were included. In patients with classical COVID-19 symptoms, GI symptoms occurred more frequently in severe cases compared to non-severe cases (20/43 vs. 91/128, respectively, p < 0.05). In group B, 91.2% (31/34) patients were non-severe, while 73.5% (25/34) patients had obvious infiltrates in their first CT scans. Compared to group A, group B patients had a prolonged time to clinic services (5.0 days vs. 2.6 days, p < 0.01) and a longer time to a positive viral swab normalized to the time of admission (6.9 days vs. 3.3 days, respectively, p < 0.01). Two patients in group B had family clusters of SARS-CoV-2 infection. Patients with only GI symptoms of COVID-19 may take a longer time to present to healthcare services and receive a confirmed diagnosis. In areas where infection is rampant, physicians must remain vigilant of patients presenting with acute gastrointestinal symptoms and should do appropriate personal protective equipment.

In this trial involving patients with hematologic cancers, the immune responses that were elicited were similar for adjuvanted-dose and standard-dose influenza vaccines.