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Drug-tolerance is an acute defense response prior to a fully drug-resistant state and tumor relapse, however there are few therapeutic agents targeting drug-tolerance in the clinic. Here we show that miR-147b initiates a reversible tolerant-state to the EGFR inhibitor osimertinib in non-small cell lung cancer. With miRNA-seq analysis we find that miR-147b is the most upregulated microRNA in osimertinib-tolerant and EGFR mutated lung cancer cells. Whole transcriptome analysis of single-cell derived clones reveals a link between osimertinib-tolerance and pseudohypoxia responses irrespective of oxygen levels. Further metabolomics and genetic studies demonstrate that osimertinib-tolerance is driven by miR-147b repression of VHL and succinate dehydrogenase linked to the tricarboxylic acid cycle and pseudohypoxia pathways. Finally, pretreatment with a miR-147b inhibitor delays osimertinib-associated drug tolerance in patient-derived three-dimensional (3D) structures. This link between miR-147b and tricarboxylic acid cycle may provide promising targets for preventing tumor relapse.

Tertiary lymphoid structures (TLSs) are a recently-described immune response that occurs when chronic inflammation leads to an organ-like organization of immune cells and specialized blood vessels. In humans, they have been shown to develop in and around many different types of tumors, and often lead to a more promising prognosis when found. In non-small cell lung cancer (NSCLC), they have a highly beneficial effect on patients' survival. What remains to be studied is the heterogeneity of the TLSs and the mechanisms of their development. In order to study these important aspects of the immune response to NSCLC, we developed a protocol to image a time course of TLS development in murine bronchiolo-alveolar adenomas and adenocarcinomas, and further expanded on how to quantify, and therefore characterize, these structures.

INTRODUCTION: The focus of this work is to develop new mouse models for metastatic lung cancer. Lung cancer is the leading cause of cancer deaths worldwide and greater than 90% of human cancer deaths are due to metastasis. Metastatic disease in most existing mouse models of lung cancer is typically sporadic and often requires aging mice for several months. These factors limit the usefulness of mouse models for basic and pre-clinical research aimed at effective treatment of metastatic disease. METHODS AND RESULTS: We have developed a new mouse model of lung cancer and are in the process of developing two additional models. In the first model, we added mutations in Dicer1, an RNAse III enzyme within the microRNA (miRNA) biosynthesis pathway to a mouse model of Kras-driven pulmonary adenocarcinoma. When we combined conditional expression of an oncogenic allele of Kras (KrasG12D), deletion of both alleles of Trp53 and one allele of Dicer1 in Club cells with expression of truncated Dicer1 in alveolar type II cells, we generated mice with metastatic pulmonary adenocarcinoma. In 30% of these mice, metastatic tumors were observed in the lymph nodes within 11 weeks of tumor induction. In a second mouse model, we switched the cell types expressing the various mutations to determine the effects of cell of origin on tumor progression and metastasis. Our preliminary results suggest that adenocarcinoma develops even faster when KrasG12D is expressed and Trp53 and one allele of Dicer1 are deleted in alveolar type II cells. Finally, based on an analysis of human lung cancer genomics data from TCGA, we generated a mouse model with mutations in Zfhx4 and are crossing these mice with our models that express oncogenic KrasG12D, delete expression of Trp53 and one allele of Dicer1 and truncate the second allele of Dicer1 to determine the effects of adding Zfhx4 mutations on progression and metastasis of pulmonary adenocarcinoma. CONCLUSIONS: Through cell type specific truncation/deletion of Dicer1 we have generated new mouse models that rapidly develop pulmonary adenocarcinomas and metastatic disease. These models have potential for both understanding the basic processes of metastasis and for pre-clinical studies aimed at preventing and/or treating metastatic lung cancer. Citation Format: Julie Wells, Richard S. Maser, Teresa McGee, Wendy Memishian, Rosalinda Doty, Carol J. Bult. Developing new mouse models of metastatic lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1617.

The Macmillan Values Based Standard aims to achieve a transformation in patients' and families' experience of care. Importantly, the standard provides a framework and methodology for improving both patient and staff experience. Of all health professionals, healthcare assistants (HCAs) spend the most ‘face-time’ with patients and are therefore crucial in the drive to transform patients' experience of care. HCAs have contributed to the implementation of the Values Based Standard in a number of Macmillan pilot sites and they have demonstrated how the framework can help drive improvement. Macmillan believes HCAs are key to changing the way patients and their families experience care. For this reason, Macmillan is investing in testing a new development programme, designed specifically to support HCAs, while also ensuring that the organisations they work within focus on the Values Based Standard and provide workforce support to HCAs. This article introduces the programme.

ADH-1 (Exherin™) is a pentapeptide, which competitively inhibits N-cadherin, resulting in vascular disruptive effect of tumor vasculature in preclinical models. This study was designed to assess the toxicity of ADH-1 and to determine the maximal tolerated dose (MTD). Patients and Methods: Adult patients with advanced measurable solid tumors were stratified according to their tumor N-cadherin status. ADH-1 was administered as a short infusion, every six weeks. Assessment of response was done every 6 weeks. PK parameters included: estimated volume of distribution of the central compartment, the α and β phase half-lives, area under the plasma concentration- time curve (AUC), clearance, and volume of distribution. Target lesions were assessed by dynamic contrast enhancing- magnetic resonance imaging (DCE-MRI). Results: 46 patients were enrolled, 25 (54%) had N-cadherin positive status. The doses administered ranged from 50 mg/m2 to 1000 mg/m2, and the MTD was not reached. The PK analysis of the concentration-time data displayed a biphasic profile. Most of the toxicities were grade 1 and 2 with fatigue, nausea, chest pain and dysgeusia being the most common. Eleven patients had disease control, the single patient who had partial response had N-cadherin positive tumor. Conclusion: ADH-1 is a well tolerated drug with a modest anti tumor effect in tumors which express N-cadherin.

Background Olaparib is an orally available inhibitor of PARP-1. In pre-clinical studies, olaparib was shown to potentiate anti-tumor effects of irinotecan in colon cancer cell lines. This phase I study was conducted to evaluate the safety and tolerability of olaparib in combination with irinotecan. Patients and Methods Patients with advanced colorectal cancer whose disease progressed after at least one systemic therapy regimen were enrolled. Dose escalation and de-escalation were based on toxicity assessment. Pharmacokinetic samples were collected in Cycle 1 for olaparib, irinotecan and SN-38. Results Twenty-five patients were enrolled, 11 patients on a schedule of continuous olaparib and irinotecan every 3 weeks (Part A) and 14 patients on a schedule of intermittent olaparib and irinotecan every 2 weeks (Part B). Continuous olaparib administration was associated with higher than expected toxicities and was not considered to be tolerable. Intermittent olaparib administration was better tolerated, and the recommended phase 2 doses were olaparib 50 mg p.o twice daily days 1-5 and irinotecan 125 mg/m(2) i.v. every 2 weeks. Common toxicities included fatigue, anorexia, diarrhea, nausea, vomiting, neutropenia, thrombocytopenia and abdominal pain. Nine patients had stable disease as the best response, 2 from Part A (3 and 9 months respectively), and 7 from Part B (median duration: 7.4 months; range: 4 to 13 months). There was no pharmacokinetic interaction between olaparib and irinotecan. Conclusions Olaparib can be combined with irinotecan if administered intermittently. Both olaparib and irinotecan required significant dose reductions. The lack of anti-tumor efficacy observed in this trial makes this combination of little interest for further clinical development. Trial Registration ID NCT00535353.

The National Institute for Health and Clinical Excellence (NICE) in Clinical Guideline 83: Rehabilitation after critical illness has set challenging recommendations regarding the routine evaluation for, and provision of, rehabilitation within critical care units. There is no published information regarding current practice in the UK. To establish current practice in Scotland we undertook a telephone survey of all 23 Scottish ICU lead clinicians and physiotherapists − 96% of lead clinicians and 100% of lead physiotherapists completed the survey. Routine assessment for physical (median two (IQR 1–3 [range 0–4])) and non-physical sequelae (median zero (IQR 0–2 [range 0–5])) is low. Aproximately half of ICUs (52%) provide an individualised, structured rehabilitation programme, 32% include activities of daily living and all provide low intensity rehabilitation (eg limb stretching and positioning exercises). There are significant differences (all p

A team of practitioners, university researchers, and health care policy makers has been working to develop and apply “design sciences” thinking within the challenging context of a national system aiming to bring about a “revolution in health care.” As members of that team, the authors share that thinking and early findings with those interested in the concept, theory, and practice of design as an approach to large-scale organizational change. The article builds on what to date has been a somewhat abstract debate around the design sciences, its aim being to forge stronger links between the concept and the practice of design. Using empirical data from the English National Health Service as a case study, the article seeks to demonstrate how design sciences may first, expand our thinking around organizational theory and practice and second, offer organization development some new methods, approaches, and processes around the “doing” of large-scale change.

In May 2003, a survey questionnaire was distributed to all licensed primary care physicians in Newfoundland and Labrador. The objective was to examine the attitudes, self-reported practices, and continuing medical education (CME) preferences of primary care physicians as they pertain to prostate cancer screening.Data was obtained from 485 primary care physicians using self-reports of prostate cancer screening practices, attitudes towards prostate cancer screening, and CME preferences. Respondents' characteristics were also collected (eg, gender, years of experience).A majority of respondents screen asymptomatic male patients for prostate cancer. Screening behaviour was related to high volume practice settings, fee-for-service and increased with patient age. Most common reasons for screening were family history, age of patient, and patient request. Majority of physicians agreed that prostate screening should be routinely performed on all men beginning at age 50, however half of physicians believe there is lack of evidence to support digital rectal examination (DRE) and one-third of physicians do not believe the prostate-specific antigen (PSA) nor DRE are accurate screening tests. Areas of greatest interest for CME included topics related to prostate cancer screening effectiveness, strategies for prevention, sexual dysfunction, available treatments and their side effects, and management options.Physicians are supportive of the value of screening, however the reliability of and evidence to support DRE and PSA as prostate cancer screening tests are in question. CME which addresses issues surrounding prostate screening and areas related to patient education and counselling are of greatest need.

e14637 Background: OVs display oncolytic activity and boost adaptive cell immunity. MG1MA3 is a Maraba virus modified to express tumour antigen MAGE-A3. MG1MA3, both alone and after immune priming with a MAGE-A3 modified adenovirus (AdMA3) may trigger anti-tumour T-cell responses. Methods: N = 41 patients (pts) with MAGE-A3 expressing solid tumours were evaluated in 3 groups (A) Dose escalation of MG1MA3 iv d1+4, q8w (n = 9); (B) Single fixed dose AdMA3 1e10 pfu IM d1 (n = 6); (C) AdMA3 priming d(-14) followed by dose escalated MG1MA3 (d1+4, q8w) (n = 25). Arm A and C had a 3+3 design. Pre + post treatment blood and tissue biopsies were evaluated for viral and immune markers. Endpoints included MTD/MFD, RP2DL, safety, tolerability, pharmacokinetics, viral delivery and replication. Results: Dose limiting toxicities (hypoxia/dyspnea, vomiting, headache) occurred in 4 pts (2 each Arm A +C). RP2DL for arm C was AdMA3 1e10 pfu IM d(-14) then MG1MA3 1e11 pfu iv d1+4. Common treatment related toxicities on Arm C occurring hours to a few days after MG1MA3 included diarrhea, nausea, vomiting, anorexia, chills, fatigue, fever, flu-like symptoms, hypophosphatemia, headache, and hypotension. Preliminary tumour gene expression results reveal induction of pro-inflammatory genes, including chemokines (CCL2, CCL5, CX3CL1, CXCL10), acute phase response proteins (IL-6, TNF), antigen presenting cell (APC) activation markers (CD80, HLA-A, HLA-B), markers of APC and Natural Killer cell infiltration (CD56, CD68, TLR3), as well as a co-incident decrease in the suppressive cytokine TGF-β. MG1MA3 replication was observed in some pts, inferred by detection of circulating genomes on days 4, 8 and 15 after clearance of the input dose. Induction of anti-tumour immune responses (CD8 T cells and antibodies vs MAGE-A3) was demonstrated in 3 of 6 Arm C pts evaluated to date. In one patient, over 1% of circulating CD8 T cells were directed against MAGE-A3. Conclusions: AdMA3 prime followed by MG1MA3 OV boost is feasible with a defined RP2DL, and capable of inducing potent anti-tumour immune response. Alternate schedules will be evaluated. Clinical trial information: NCT02285816.

3016 Background: Malignant transformation and invasiveness correlate with upregulation of N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. N-cad antagonism by ADH-1, a cyclic pentapeptide (CHAVC), causes rapid tumor vascular disruption and apoptosis in preclinical models. We report the final clinical and PK results from the first human study (AHX-01–001). Methods: 46 subjects with incurable solid tumors stratified according to tumor N-cad expression were enrolled. 99 doses of ADH-1 were given by IV bolus or short infusion (31 in a Special Access Program). Doses ranged from 50–1000 mg/m2, with 3–6 subjects/cohort. Blood and urine were collected for PK on Day 1, assayed by LC/MS/MS, and a 2 compartment analysis was performed. Results: ADH-1 was generally well tolerated and the maximum tolerated dose was not defined. The most commonly reported adverse events were grade 1–2 fatigue (59%), nausea (32%), dysgeusia (25%), and flushing (20%). 4 subjects in the N-cad positive group (n=28, including 3 N-cad unknown) demonstrated anti-tumor activity; a PR of 6 month duration in refractory esophageal carcinoma; a minor response in lung metastases from an unknown primary following a single dose; and >7 months SD in refractory adrenocortical and colorectal carcinoma. No anti-tumor activity was noted in the N-cad negative group (n=18). The mean initial ADH-1 half-life (t½) was 20 min and the mean terminal phase t½ was 2.2 hr. Mean systemic clearance (CL) was 6.5 L/hr/m2. Both t½ and CL were independent of dose. Cmax increased dose proportionally, ranging from 7 to148 μg/mL, and AUC0-∞ tended to increase dose proportionally. The volume of distribution at steady-state (Vss) averaged 14.3 L/m2, indicating modest tissue distribution. Approximately 30% of the dose was excreted unchanged in the urine. Conclusions: ADH-1 was generally well tolerated and demonstrated evidence of anti-tumor activity in subjects with N-cad positive tumors. The PK profile was biphasic and the t½ averaged 2.2 hr. Cmax and AUC0-∞ increased dose proportionally, and CL was independent of dose. No significant financial relationships to disclose.

3038 Background: Malignant transformation and invasive capacity is highly correlated with upregulation of N-cadherin, a cell adhesion molecule expressed on both tumor cells and vascular endothelium. ADH-1 is a cyclic pentapeptide (CHAVC) which competitively inhibits N-cadherin mediated endothelial cell, pericyte and tumor cell interaction resulting in rapid onset of tumor vascular angiolysis and apoptosis in preclinical models. We report safety and pharmacokinetics (PK) from the first human study. Methods: 33 patients with refractory solid tumors received 54 cycles of ADH-1 by bolus injection at 8 dose escalations from 50 to 840 mg/m2to define toxicities (AE) and maximum tolerated dose (MTD) stratified by cadherin status with N-cadherin positive (n=12), unknown (n=3) or negative (n=18) tumors. Dynamic MRI was performed in cohorts 3 to 8 where feasible to assess tumor perfusion changes. Results: MTD has not been reached. The most common AEs were grade 1–2 nausea (27%), fatigue (58%), hot flushes (15%) and ...