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Immune checkpoint inhibitors and related molecules can achieve tumour regression, and even prolonged survival, for a subset of cancer patients with an otherwise dire prognosis. However, it remains unclear why some patients respond to immunotherapy and others do not. PET imaging has the potential to characterise the spatial and temporal heterogeneity of both immunotherapy target molecules and the tumor immune microenvironment, suggesting a tantalising vision of personally-adapted immunomodulatory treatment regimens. Personalised combinations of immunotherapy with local therapies and other systemic therapies, would be informed by immune imaging and subsequently modified in accordance with therapeutically induced immune environmental changes. An ideal PET imaging biomarker would facilitate the choice of initial therapy and would permit sequential imaging in time-frames that could provide actionable information to guide subsequent therapy. Such imaging should provide either prognostic or predictive measures of responsiveness relevant to key immunotherapy types but, most importantly, guide key decisions on initiation, continuation, change or cessation of treatment to reduce the cost and morbidity of treatment while enhancing survival outcomes. We survey the current literature, focusing on clinically relevant immune checkpoint immunotherapies, for which novel PET tracers are being developed, and discuss what steps are needed to make this vision a reality.

BACKGROUND: Aberrations in homologous recombination repair (HRR) genes are emerging as important biomarkers for personalized treatment in prostate cancer (PCa). HRR deficiency (HRD) could affect the tumor immune microenvironment (TIME), potentially contributing to differential responses to poly ADP-ribose polymerase (PARP) inhibitors and immune checkpoint inhibitors. Spatial distribution of immune cells in a range of cancers identifies novel disease subtypes and is related to prognosis. In this study we aimed to determine the differences in the TIME of PCa with and without germline (g) HRR mutations. METHODS: We performed gene expression analysis, multiplex immunohistochemistry of T and B cells and quantitative spatial analysis of PCa samples from 36 patients with gHRD and 26 patients with sporadic PCa. Samples were archival tumor tissue from radical prostatectomies with the exception of one biopsy. Results were validated in several independent cohorts. RESULTS: Although the composition of the T cell and B cells was similar in the tumor areas of gHRD-mutated and sporadic tumors, the spatial profiles differed between these cohorts. We describe two T-cell spatial profiles across primary PCa, a clustered immune spatial (CIS) profile characterized by dense clusters of CD4+ T cells closely interacting with PD-L1+ cells, and a free immune spatial (FIS) profile of CD8+ cells in close proximity to tumor cells. gHRD tumors had a more T-cell inflamed microenvironment than sporadic tumors. The CIS profile was mainly observed in sporadic tumors, whereas a FIS profile was enriched in gHRD tumors. A FIS profile was associated with lower Gleason scores, smaller tumors and longer time to biochemical recurrence and metastasis. CONCLUSIONS: gHRD-mutated tumors have a distinct immune microenvironment compared with sporadic tumors. Spatial profiling of T-cells provides additional information beyond T-cell density and is associated with time to biochemical recurrence, time to metastasis

BACKGROUND: ImmunoPET is a multicentre, single arm, phase 0-1 study that aims to establish if 89Zr-durvalumab PET/CT can be used to interrogate the expression of PD-L1 in larger, multicentre clinical trials. METHODS: The phase 0 study recruited 5 PD-L1+ patients with metastatic non-small cell lung cancer (NSCLC). Patients received 60MBq/70 kg 89Zr-durva up to a maximum of 74 MBq, with scan acquisition at days 0, 1, 3 or 5±1 day. Data on (1) Percentage of injected 89Zr-durva dose found in organs of interest (2) Absorbed organ doses (µSv/MBq of administered 89Zr-durva) and (3) whole-body dose expressed as mSv/100MBq of administered dose was collected to characterise biodistribution.The phase 1 study will recruit 20 patients undergoing concurrent chemoradiotherapy for stage III NSCLC. Patients will have 89Zr-durva and FDG-PET/CT before, during and after chemoradiation. In order to establish the feasibility of 89Zr-durva PET/CT for larger multicentre trials, we will collect both imaging and toxicity data. Feasibility will be deemed to have been met if more than 80% of patients are able complete all trial requirements with no significant toxicity. ETHICS AND DISSEMINATION: This phase 0 study has ethics approval (HREC/65450/PMCC 20/100) and is registered on the Australian Clinical Trials Network (ACTRN12621000171819). The protocol, technical and clinical data will be disseminated by conference presentations and publications. Any modifications to the protocol will be formally documented by administrative letters and must be submitted to the approving HREC for review and approval. TRIAL REGISTRATION NUMBER: Australian Clinical Trials Network ACTRN12621000171819.

Gene expression by RNA polymerase II (RNAPII) is tightly controlled by cyclin-dependent kinases (CDKs) at discrete checkpoints during the transcription cycle. The pausing checkpoint following transcription initiation is primarily controlled by CDK9. We discovered that CDK9-mediated, RNAPII-driven transcription is functionally opposed by a protein phosphatase 2A (PP2A) complex that is recruited to transcription sites by the Integrator complex subunit INTS6. PP2A dynamically antagonizes phosphorylation of key CDK9 substrates including DSIF and RNAPII-CTD. Loss of INTS6 results in resistance to tumor cell death mediated by CDK9 inhibition, decreased turnover of CDK9 phospho-substrates, and amplification of acute oncogenic transcriptional responses. Pharmacological PP2A activation synergizes with CDK9 inhibition to kill both leukemic and solid tumor cells, providing therapeutic benefit in vivo. These data demonstrate that fine control of gene expression relies on the balance between kinase and phosphatase activity throughout the transcription cycle, a process dysregulated in cancer that can be exploited therapeutically.Copyright © 2021 Elsevier Inc.

BACKGROUND: In the curative-intent treatment of locally advanced lung cancer, significant morbidity and mortality can result from thoracic radiation therapy. Symptomatic radiation pneumonitis occurs in one in three patients and can lead to radiation-induced fibrosis. Local failure occurs in one in three patients due to the lungs being a dose-limiting organ, conventionally restricting tumour doses to around 60 Gy. Functional lung imaging using positron emission tomography (PET)/CT provides a geographic map of regional lung function and preclinical studies suggest this enables personalised lung radiotherapy. This map of lung function can be integrated into Volumetric Modulated Arc Therapy (VMAT) radiotherapy planning systems, enabling conformal avoidance of highly functioning regions of lung, thereby facilitating increased doses to tumour while reducing normal tissue doses. METHODS AND ANALYSIS: This prospective interventional study will investigate the use of ventilation and perfusion PET/CT to identify highly functioning lung volumes and avoidance of these using VMAT planning. This single-arm trial will be conducted across two large public teaching hospitals in Australia. Twenty patients with stage III non-small cell lung cancer will be recruited. All patients enrolled will receive dose-escalated (69 Gy) functional avoidance radiation therapy. The primary endpoint is feasibility with this achieved if ≥15 out of 20 patients meet pre-defined feasibility criteria. Patients will be followed for 12 months post-treatment with serial imaging, biomarkers, toxicity assessment and quality of life assessment. DISCUSSION: Using advanced techniques such as VMAT functionally adapted radiation therapy may enable safe moderate dose escalation with an aim of improving local control and concurrently decreasing treatment related toxicity. If this technique is proven feasible, it will inform the design of a prospective randomised trial to assess the clinical benefits of functional lung

Surgery is the main curative therapy for patients with localized non-small-cell lung cancer while radiotherapy (RT), alone or with concurrent platinum-based chemotherapy, remains the primary curative modality for locoregionally advanced non-small-cell lung cancer. The risk of distant metastasis is high after curative-intent treatment, largely attributable to the presence of undetected micrometastases, but which could also be related to treatment-related increases in circulating tumor cells (CTCs). CTC mobilization by RT or systemic therapies might either reflect efficient tumor destruction with improved prognosis, or might promote metastasis and thus represent a potential therapeutic target. RT may induce prometastatic biological alterations in CTC at the cellular level, which are detectable by 'liquid biopsies', though their rarity represents a major challenge. Improved methods of isolation and ex vivo propagation will be essential for the future of CTC research.

A novel assessment program was implemented in an upper level mathematical modelling subject for a small group of advanced undergraduate students of applied mathematics and engineering. The students were all enrolled in undergraduate degree programs at the selective private colleges, Harvey Mudd College and Pitzer College, in California. The subject itself was labelled Mathematics and Sport and introduced the students to various techniques and strategies of mathematical modelling and related research using a number of interesting applications of mathematics to sports. The assessment program was designed to provide the students with authentic activities preparing them for their future work as graduate students and researchers. The program included a mock “conference day‿ for which students prepared papers and presented a seminar. The written paper and the seminar were scaffolded by instruction in such writing and presentation as well as activities to encourage free thinking and creative interpretation of problems throughout the semester. The assessment scheme proved to be both popular with students and effective, in that continuous components prepared the students for the requirements of terminating assessment items. The students’ papers proved to be well-written, thoughtful and to some extent, illustrated the students’ development as researchers over the course of the subject. Unfortunately, the oral presentations were not of the same high standard for a number of reasons including the level of instruction in this subject and also previous experience in presenting orally. This paper offers a description of the novel assessment program and the results of its implementation in order to provide guideposts for others confronted with similar student groups.

An occupational hygiene evaluation of the Dental Clinic - CFB Ottawa (N) was carried out to assess the existence or potential of a toxic hazard due to inorganic mercury. Atmospheric inorganic mercury levels were measured and recommendations are included regarding safe operating procedures. (Author)