Search

The Global Navigation Satellite System (GNSS) radio occultation (RO) technique has proven to be an effective tool for Earth atmosphere profiling. Traditional spaceborne RO satellite constellations are expensive with relatively low sampling density for specific regions of interest. In contrast, in-atmosphere RO platforms can provide much higher spatial and temporal sampling of ROs around regional weather events. This study explores the capability of a low-cost and scalable commercial off-the-shelf (COTS) GNSS receiver on board high-altitude balloons. The refractivity retrievals from balloon-borne RO payloads obtained from two flight campaigns (World View and ZPM-1) are presented. The balloon-borne RO soundings from the World View campaign show refractivity profiles between 6 and 19 km, with overall near-zero median difference from colocated ECMWF ERA5 reanalysis data and variability comparable to spaceborne RO missions (∼ 2.3 % median absolute deviation or MAD). Soundings from the ZPM-1 campaign show a relatively large positive refractivity bias (∼ 2.5 %). In summary, low-cost COTS RO payloads on board balloon platforms are worth further engineering and study in order to provide capabilities for dense, targeted atmospheric soundings that can improve regional weather forecasts via data assimilation.

[Image: see text] Hematopoietic progenitor kinase 1 (HPK1) is implicated as a negative regulator of T-cell receptor-induced T-cell activation. Studies using HPK1 kinase-dead knock-in animals have demonstrated the loss of HPK1 kinase activity resulted in an increase in T-cell function and tumor growth inhibition in glioma models. Herein, we describe the discovery of a series of small molecule inhibitors of HPK1. Using a structure-based drug design approach, the kinase selectivity of the molecules was significantly improved by inducing and stabilizing an unusual P-loop folded binding mode. The metabolic liabilities of the initial 7-azaindole high-throughput screening hit were mitigated by addressing a key metabolic soft spot along with physicochemical property-based optimization. The resulting spiro-azaindoline HPK1 inhibitors demonstrated improved in vitro ADME properties and the ability to induce cytokine production in primary human T-cells.

The Global Navigation Satellite System (GNSS) radio occultation (RO) technique has proven to be an effective tool for Earth atmosphere profiling. Traditional spaceborne RO satellite constellations are expensive with relatively low sampling rates for individual satellites. Airborne RO platforms can provide much higher spatial and temporal sampling of ROs around regional weather events. This paper explores the capability of a low-cost and scalable Commercial-Off-The-Shelf (COTS) GNSS receiver onboard high-altitude balloons. The refractivity retrievals from balloon-borne RO payloads obtained from two flight campaigns (World View and ZPM-1) are presented. The balloon-borne RO soundings from the World View campaign show high-quality refractivity profiles in the troposphere with near-zero median difference (~2.3 % median-absolute-deviation) from the colocated ECMWF ERA5 reanalysis data. Soundings from the ZPM-1 campaign show a relatively large positive bias (~2.5 %). In summary, the low-cost COTS RO payloads onboard balloon platforms are worth further improvement for dense targeted atmospheric soundings to improve regional weather forecasts.

Background: Trimodality therapy (TMT) with neoadjuvant chemoradiotherapy (nCRT) using concurrent carboplatin plus paclitaxel (CP) followed by surgery is the standard of care for locoregional esophageal or gastroesophageal junction (GEJ) cancers. Alternatively, nCRT with cisplatin plus fluorouracil (CF) can be used. Definitive chemoradiotherapy (dCRT) with CP or CF can be used if surgery is not planned. In the absence of comparative trials, we aimed to evaluate outcomes of CP and CF in the settings of TMT and dCRT. Methods: A single-site, retrospective cohort study was conducted at the Princess Margaret Cancer Centre to identify all patients who received CRT for locoregional esophageal or GEJ cancer. Overall survival (OS) and disease-free survival (DFS) were assessed using the Kaplan-Meier method and multivariable Cox regression model. The inverse probability treatment weighting (IPTW) method was used for sensitivity analysis. Results: Between 2011 and 2015, 93 patients with esophageal (49%) and GEJ (51%) cancers underwent nCRT (n = 67; 72%) or dCRT (n = 26; 28%). Median age was 62.3 years and 74% were male. Median follow-up was 23.9 months. Comparing CP to CF in the setting of TMT, the OS and DFS rates were similar. In the setting of dCRT, CP was associated with significantly inferior 3-year OS (36 vs. 63%; p = 0.001; HR 3.1; 95% CI: 1.2–7.7) and DFS (0 vs. 41%; p = 0.004; HR 3.6; 95% CI: 1.4–8.9) on multivariable and IPTW sensitivity analyses. Conclusions: TMT with CF and CP produced comparable outcomes. However, for dCRT, CF may be a superior regimen.

BACKGROUND: A microscopically positive (R1) resection margin following resection for gastric and esophageal cancers has been documented to be a poor prognostic factor. The optimal strategy and impact of different modalities of adjuvant treatment for an R1 resection margin remain unclear. METHODS: A retrospective analysis was performed for patients with gastric and esophageal adenocarcinoma treated at the Princess Margaret Cancer Centre (PMCC) from 2006–2016. Electronic medical records of all patients with an R1 resection margin were reviewed. Kaplan-Meier and Cox proportional hazards methods were used to analyze recurrence free survival (RFS) and overall survival (OS) with stage and neoadjuvant treatment as covariates in the multivariate analysis. RESULTS: We identified 69 gastric and esophageal adenocarcinoma patients with a R1 resection. Neoadjuvant chemoradiation was used in 13% of patients, neoadjuvant chemotherapy in 12%, surgery alone in 75%. Margins involved included proximal in 30%, distal in 14%, radial in 52% and multiple margins in 3% of patients. Pathological staging showed 3% with stage I disease, 20% stage II and 74% stage III. Adjuvant therapy was given in 52% of R1 pts (28% CRT, 20% chemotherapy alone, 3% radiation alone, 1% reoperation). Median RFS was 14.1 months [95% confidence interval (CI), 11.1–17.2]. The site of first recurrence was 72% distant, 12% mixed, 16% locoregional alone. Median OS was 34.5 months (95% CI, 23.3–57.9) for all patients. There was no significant difference in RFS (adjusted P=0.26) or OS (adjusted P=0.83) comparing modality of adjuvant therapy. CONCLUSIONS: Most patients with positive margins after resection for gastric and esophageal cancer had advanced pathologic stage and prognosis was poor. Our study did not find improved RFS or OS with adjuvant treatment and only one patient had reresection. The main failure pattern was distant recurrence, suggesting that patients being considered for adjuvant radiotherapy (RT) should be carefully selected. Further studies are required to determine factors to select patients with good prognosis despite a positive margin, or those who may benefit from adjuvant treatment.

Purpose: To summarise what is currently known about the psychosocial morbidity, experiences, and needs of people with cancer and their informal caregivers, who live in rural or regional areas of developed countries. Methods: Eligible studies dating from August 2010 until May 2021 were identified through several online databases, including MEDLINE, EMBASE, PsychINFO, and RURAL (Rural and Remote Health Database). Results were reported according to the PRISMA guidelines and the protocol was registered on PROSPERO (CRD42020171764). Results: Sixty-five studies were included in this review, including 20 qualitative studies, 41 quantitative studies, and 4 mixed methods studies. Qualitative research demonstrated that many unique psychosocial needs of rural people remain unmet, particularly relating to finances, travel, and accessing care. However, most (9/19) quantitative studies that compared rural and urban groups reported no significant differences in psychosocial needs, morbidity, or quality of life (QOL). Five quantitative studies reported poorer psychosocial outcomes (social and emotional functioning) in urban cancer survivors, while three highlighted poorer outcomes (physical functioning, role functioning, and self-reported mental health outcomes) in the rural group. Conclusion: Recent research shows that rural people affected by cancer have unique unmet psychosocial needs relating to rurality. However, there was little evidence that rural cancer survivors report greater unmet needs than their urban counterparts. This contrasts to the findings from a 2011 systematic review that found rural survivors consistently reported worse psychosocial outcomes. More population-based research is needed to establish whether uniquely rural unmet needs are due to general or cancer-specific factors. Refereed/Peer-reviewed

Background The goal of surveillance testing is to enable curative salvage therapy through early disease detection, however supporting evidence in gastroesophageal adenocarcinoma is limited. We evaluated frequency of successful salvage therapy and outcomes in patients who underwent surveillance. Methods A single‐site, retrospective cohort study was conducted to identify all patients who received curative resection for gastroesophageal adenocarcinoma. Surveillance testing were those investigations not triggered by abnormal symptoms, physical examination, or blood tests. Successful salvage therapy was any potentially curative therapy for disease recurrence which resulted in postrecurrence disease‐free survival ≥2 years. Time‐to‐event data were analyzed using the Kaplan‐Meier method and log rank tests. Results Between 2011 and 2016, 210 consecutive patients were reviewed. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%) or multimodality therapy (71%). Adjuvant therapy was administered in 35%. At median follow‐up of 38.3 months, 5‐year overall survival (OS) rate was 56%. Among 97 recurrences, 53% were surveillance‐detected, and 46% were symptomatic. None was detected by surveillance endoscopy. Median time‐to‐recurrence (TTR) was 14.8 months. Recurrences included locoregional only (4%), distant (86%), and both (10%). Salvage therapy was attempted in 15 patients, 4 were successful. Compared to symptomatic recurrences, patients with surveillance‐detected recurrences had longer median OS (36.2 vs 23.7 months, P = .004) and postrecurrence survival (PRS, 16.5 vs 4.6 months, P, For resected gastroesophageal adenocarcinoma treated at our institution, routine surveillance testing rarely enabled successful salvage therapy, did not detect recurrence earlier, and did not extend duration of palliative chemotherapy. Further prospected data is warranted to establish the role of surveillance testing in gastroesophageal adenocarcinoma.

IntroductionSars-CoV-2 is a novel coronavirus responsible for COVID-19 officially declared pandemic in March 2020. Health systems worldwide responded with swift changes to increase workflow capacity while protecting the vulnerable, including those with cancer. This led to unprecedented and rapid restructuring of health service provision. Published data from the 2003 SARS pandemic focuses on medical and nursing staff, overlooking other departmental employees such as administration officers or food service workers. Our protocol aims to document directives and adjustments communicated to staff in two cancer care departments and correlate this with measures of distress and perceived preparedness across the spectrum of all staff involved in cancer care.Methods and analysisWe use a semiqualitative approach comprising weekly diarising of events and simultaneous staff surveys. Principal investigators will document changes at a metropolitan quaternary cancer centre and a regional cancer centre. Communications, directives and changes will be diarised in real time in four executional domains. Simultaneously, prospective voluntary self-administered online surveys will be conducted at regular intervals by staff. The survey assesses the perceived institutional preparedness and personal well-being, with a combination of Likert scaled and open response questions. A semiquantitative self-assessment of distress adapted from National Comprehensive Cancer Network distress thermometer is incorporated. Additionally, open-text personal reflections on themes including difficult decisions will be invited. Survey participants will be drawn from various work areas of the cancer care departments: administrative staff, health professionals, for example, allied health, ancillary workers, nursing and medical.Ethics and disseminationThe study has been reviewed and approved by the Human Research Ethics Committee (LNR/2020/QRBW/62982). Published literature on domains of distress neglects categories of healthcare worker who form an essential part of the care delivery team. Our study hopes to gather insights about psychosocial impact and adjustment which could direct responses in future emergencies.

Background The COVID‐19 pandemic has forced rapid system‐wide changes to be implemented within cancer care at an alarming pace. Clinical trials are a key element of comprehensive cancer care. Ensuring the continuing safe conduct of cancer clinical trials in the context of a pandemic is challenging. Methods We aimed to describe the COVID‐19 pandemic response of a Cancer Care Clinical Research Unit (CRU) of a tertiary hospital in Queensland, Australia. We used a mixed methods approach for this case study. Emailed directives from CRU managers to all CRU staff sharing were qualitatively analysed and mapped against our unit activities over longitudinal time points. Data from patient recruitment and protocol deviations were analysed using descriptive statistics. Results Mapping activity from 11 March to 30 September 2020 revealed rapid change during the first 2 weeks. Four key strategies to accommodate change were identified: supporting patients and families, introduction of telehealth, accessing investigational product, and social distancing. Early in the pandemic we recognised that our core key stakeholders were integral to our response. When compared to the previous 12 months, our recruitment numbers dropped markedly in early phases of the response but recovered over time, as we accommodated internal and external impacts. Conclusion Our experience of agility as a necessity, adapting to support patients, and managing both clinical research activity and sponsors during the height of the pandemic response is presented here in order to inform future disaster response planning by clinical trial organisations.

Stage III non-small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5-year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence-based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.

The COVID-19 pandemic poses daily challenges to the entire oncology workforce. Staff members must absorb multiple executive briefings, adapt to escalating scenario modelling, and seamlessly execute ever-changing operational modes in real-time. The unique threat of looming re-deployment and rationing care add to the uncertainty. We highlight the need for qualitative research to understand the psychosocial impact of these challenges. We posit that the perspective of all team members should be explored: from doctors to ancillary staff.

Learning or identifying dynamics from a sequence of high-dimensional observations is a difficult challenge in many domains, including reinforcement learning and control. The problem has recently been studied from a generative perspective through latent dynamics: high-dimensional observations are embedded into a lower-dimensional space in which the dynamics can be learned. Despite some successes, latent dynamics models have not yet been applied to real-world robotic systems where learned representations must be robust to a variety of perceptual confounds and noise sources not seen during training. In this paper, we present a method to jointly learn a latent state representation and the associated dynamics that is amenable for long-term planning and closed-loop control under perceptually difficult conditions. As our main contribution, we describe how our representation is able to capture a notion of heteroscedastic or input-specific uncertainty at test time by detecting novel or out-of-distribution (OOD) inputs. We present results from prediction and control experiments on two image-based tasks: a simulated pendulum balancing task and a real-world robotic manipulator reaching task. We demonstrate that our model produces significantly more accurate predictions and exhibits improved control performance, compared to a model that assumes homoscedastic uncertainty only, in the presence of varying degrees of input degradation., Comment: In IEEE Robotics and Automation Letters (RA-L) and presented at the IEEE International Conference on Intelligent Robots and Systems (IROS'20), Las Vegas, USA, October 25-29, 2020

12087 Background: AML is an aggressive disease with high mortality and significant impact on quality of life. Palliative care (PC) services have become integral in managing patient’s symptoms during treatment as well as at the end of life. We hypothesize that socioeconomic factors such as achieving higher levels of education, and higher incomes, increases the odds of receiving PC. Methods: This is a retrospective analysis using NCDB data of 124,988 newly diagnosed non-M3 AML patients over 18 yrs from 2004-2016. Unadjusted and multivariate adjusted logistic regression analysis (MVA) evaluated the impact of socioeconomic variables on the receipt of PC. In the MVA, we adjusted for demographic variables and facility characteristics including facility type, facility volume, age, sex, race, Hispanic origin, income, education, urban/rural residence, Charlson-Deyo score, great circle distance, Medicaid expansion status state group, and insurance status. Patients with Medicaid expansion < 39yrs were excluded due to low patient numbers. Results: For the 124,988 patients, median age was 63 years (range 18-90) with 54% males and 86% White. 25% of patients lived in regions with the highest education level defined as < 6.3% of adults over 25 without a high school diploma. 35% of patients had a household income bracket of ≥ $63,333. A total of 3% of patients received PC. MVA showed that patients within the highest income bracket of ≥ $63,333 were less likely to have used PC services (OR 0.82, p < 0.01). More educated patients residing in regions with < 6.3% of adults without a high school diploma had higher odds of receiving PC treatment compared with patients with less education (OR 1.23, p < 0.01). Residence in states with Medicaid expansion in January 2014 or later was associated with greater utilization of PC services (Jan 2014 expansion states: OR 1.33 and late expansion states/after Jan 2014: OR 1.43, p < 0.01) compared to residence in non-expansion states. No difference was seen across races; except Hispanics with decreased use of PC services(OR 0.8, p = 0.022). Conclusions: In this large cohort, a small percentage of patients received PC. Higher education was associated with higher likelihood of using PC, while, surprisingly, higher income was associated with a lower likelihood of PC. Additionally, the higher use of PC services with Medicaid expansion suggests a broad impact of public health insurance in providing increased access to PC services.

e23016 Background: Potential moral hazards from COVID-19 for patient-facing oncology staff include rationalizing treatment, but prior research into staff distress has not included ancillary/administrative staff or compared geographic settings. We sought to document measures of distress and perceived preparedness from diverse oncology staff during the COVID-19 pandemic response, and correlate these with unfolding events. Methods: We utilised a mixed-methods approach comprising weekly diarising of executive communications and events-by investigators, and prospective self-administered online surveys-by staff. Survey domains included perceived institutional preparedness, personal wellbeing, and perceived stress using a distress thermometer (0-10, no-extreme distress). Responses were Likert-scaled or free-text. Quantitative responses were aggregated by role/site and analysed using R. These were correlated with emergent qualitative themes using the Framework Method. The study was conducted at a metropolitan and a regional hospital in Queensland, Australia. Results: 12 surveys across 18 weeks commencing April 3, 2020 (encompassing 1st lockdown, lockdown easing, and 2nd lockdown) had 993 individual responses. 40% respondents were located regionally. Role categories included: nursing (50%), allied health (18%), medical (16%), administrative (15%), ancillary (e.g. cleaner, food service) (1%). Emergent themes were: S trategies for protection- at work and home. Up to 27% respondents reported being able to attend to critical personal needs only sometimes or less, although patients were perceived to be well supported most/all of the time (>90% responses). Navigating rules and keeping up-high levels of perceived institutional preparedness in >75% responders coexisted alongside fluctuating levels of self-reported distress, from median 5 (IQR 3-7) at 1st lockdown outset to 1 (IQR 1-4) after lockdown restriction easing. Tempered optimism-pride in one’s place was reported both as reflecting healthcare worker identity and as Australians in the context of low local infection rates. No significant differences in distress or preparedness perceptions were evident comparing geographic sites. Framing the new normal-although respondents longitudinally reported increasing familiarity with pandemic directives, distress levels increased concurrently with the announcement of 2nd lockdown. Conclusions: In the context of low local COVID-19 infection rates, oncology staff regardless of role and geographic setting reported high perceptions of institutional preparedness. Distress levels increased concurrently with lockdown phases and reports of distress and psychosocial workload fatigue were made by various workers including administrative and ancillary. These should be considered frontline staff for the purpose of workplace psychosocial support in pandemic responses.

44 Background: Australia has achieved a “flattening of the curve” with a sustained COVID-19 roadmap to recovery in place. We explored the emotional impact of COVID-19 on our cancer workforce, during the preparation phase of the pandemic. Methods: We developed and pilot-tested an online survey to capture the emotional impact on cancer care staff during the COVID-19 health system response. Two large cancer centres were identified for study sample, one metropolitan and one regional, in Queensland, Australia. All cancer care staff with patient-facing roles were invited via all-staff email to participate on a weekly basis, uniquely also including ancillary and administrative workers. The final survey questionnaire included qualitative domains with open text responses for reflections on difficult decisions and subsequent emotional impacts. At the same time, a prospective diary of organizational developments was independently maintained by two investigators in order to contextualize changing survey responses over time. Qualitative data analyses by four investigators included independent, multiple cross-coding, memos, dataset review and member-checking to ensure methodological rigour. Data were synthesised into key themes utilising the Framework Method (Gale, 2013). Results: 117 metropolitan and 59 regional staff were surveyed over a 6-week period. Participants were medical, nursing, allied health, administrative and ancillary staff, working across inpatient and outpatient oncology services. Four key themes were emergent across the trajectory of the COVID preparation phase; ‘Strategies for protection’ (self-isolation, using PPE, protecting patients, families and each other), ‘Navigating rules and keeping up’ (compliance, exceptions, conflict and complex decision fatigue), ‘Tempered optimism’ (this is grief, strategies for coping, pride in one’s place), and ‘Framing the new normal’ (using new technology, second wave, uncertainty). At different time points, one theme dominated more than others. Conclusions: Despite rapid adaptations to system changes, staff responses highlight that it was their sense of connectedness that had the greatest influence on their reflections during the COVID-19 pandemic, but also underpinned the humanistic aspects of their responses. Staff perceptions of feeling supported and prepared, permeated through the duration of the survey. Results from the recovery phase are awaited.

111 Background: The COVID-19 pandemic poses psychosocial challenges to the oncology workforce. We postulate that these impacts may affect the entire patient-facing workforce. Whether distress is different in varying settings (metro vs regional hospitals) is unknown. Methods: Cancer Care staff were approached via all-staff email for a weekly online survey administered at two hospital sites, Royal Brisbane and Women’s Hospital (RBWH) (metro) and Sunshine Coast Hospital and Health System (SCHHS) (regional). Surveys included Likert-scale items exploring perceptions of departmental preparation, COVID-19 related query burden and staff well-being, and distress thermometer derived from NCCN. Mean and 95% confidence interval were calculated, with non-parametric t-tests adjusted for multiple comparisons (Holm-Sidak); significance was deemed p < 0.05. Results: 117 participants at RBWH and 59 at SCHHS consented. The survey opened April 3, 2020. Data is presented for the initial 6 weeks (COVID-19 preparation phase). Highest survey response was noted in week 1 (87%) and lowest at week 6 (36%). 65% unique responses were from RBWH. 60% participants worked in an outpatient setting, while 37% had inpatient care role. The remainder worked in either community-based or mixed settings. Significant heterogeneity was detected between sites (RBWH vs SCHHS) for some occupational roles: RBWH had more representation of administrative (19% vs 8%, p < 0.001) and ancillary staff (2% vs 0%, p = 0.005) but SCHHS had more allied health (28% vs 17%, p = 0.005). Nursing and medical staff proportions at SCHHS and RBWH were similar (50% vs 45%, and 14% vs 18% respectively). Higher levels of distress were noted early; mean (95% CI) distress thermometer result (0-10) during week 1 was 4.7 (4.3-5.2) at RBWH and 4.9 (4.2-5.5) at SCHHS. Mean distress scores significantly reduced over time: correlative scores during week 6 were 3.2 (2.3-4.1) at RBWH and 2.5 (1.6-3.4) at SCHHS. Distress levels comparing RBWH with SCHHS were similar (p = 0.22-0.76). No significant difference was noted in staff perception of self-support comparing RBWH with SCHHS, and over 80% responders felt well-supported at work most, or all of the time. Concurrently, participants perceived that the Cancer Care department of their site was either “well” or “very well” prepared for COVID-19 over 85% of the time, with no difference between sites. Conclusions: High perceptions of support and preparedness were evident, with no regional difference. Distress scores reduced over time during the COVID-19 preparation phase, in the context of low COVID-19 rates.

We aimed to assess current treatment patterns and outcomes in elderly patients with localized gastric and esophageal (ge) cancers. This retrospective analysis considered patients 75 years of age or older with ge cancers treated during 2012&ndash, 2014. Patient demographics and tumour characteristics were collected. Overall survival (os) and disease-free survival were assessed by univariable and multivariable Cox proportional hazards regression, adjusting for demographics. Logistic regression analyses were used to examine factors affecting treatment choices. The 110 patients in the study cohort had a median age of 81 years (range: 75&ndash, 99 years). Primary disease sites were esophageal (55%) and gastric (45%). Treatment received included radiation therapy alone (29%), surgery alone (26%), surgery plus perioperative therapy (14%), chemoradiation alone (10%), and supportive care alone (14%). In multivariable analyses, surgery (hazard ratio: 0.48, 95% confidence interval: 0.26 to 0.90, p = 0.02) was the only independent predictor for improved os. Patients with a good Eastern Cooperative Oncology Group performance status (p = 0.008), gastric disease site (p = 0.02), and adenocarcinoma histology (p = 0.01) were more likely to undergo surgery. At our institution, few patients 75 years of age and older received multimodality therapy for localized ge cancers. Outcomes were better for patients who underwent surgery than for those who did not. To ensure optimal treatment selection, comprehensive geriatric assessment should be considered for patients 75 years of age and older with localized ge cancers.

Introduction: The multidisciplinary team meeting (MDTM) approach is accepted as standard of care to optimise treatment for patients diagnosed with cancer. This retrospective audit reviews the proportion of patients whose care is being discussed at cancer MDTMs within the Sunshine Coast Hospital and Health Service (SCHHS). Methods: Patients included were those diagnosed with cancer within the SCHHS between 2010 and 2015, and subsequently referred to a public MDTM for discussion. Data were extracted from the Queensland Cancer Control Analysis Team (QCCAT) database regarding the incidence of breast, lung, upper gastrointestinal (GI), colorectal, genitourinary and malignant haematological cancers and the number of patients referred to the corresponding MDTM. Results: Data from 2015 show referral rates to MDTMs as follows: lung 100%, upper gastrointestinal 100%, colorectal 64%, breast 60%, malignant haematology 40% and genitourinary 28%. Of the genitourinary presentations, 70% were prostate cases and 14% bladder cases. Review of genitourinary MDTM outcomes found that, of the patients with prostate cancer discussed, 30% were metastatic, 19% were poor surgical candidates and 15% had biochemical recurrence. Conclusion: This audit demonstrates variable utilisation of MDTMs between tumour streams. Our study shows a high and increasing referral rate to all tumour stream MDTMs except for genitourinary. This suggests a possible underutilisation of genitourinary MDTMs to discuss treatment options for patients with genitourinary cancer. Collaborative research is warranted to further investigate whether this is a local or widespread issue.

The discovery of disease-modifying therapies for Parkinson’s Disease (PD) represents a critical need in neurodegenerative medicine. Genetic mutations in LRRK2 are risk factors for the development of PD, and some of these mutations have been linked to increased LRRK2 kinase activity and neuronal toxicity in cellular and animal models. As such, research towards brain-permeable kinase inhibitors of LRRK2 has received much attention. In the course of a program to identify structurally diverse inhibitors of LRRK2 kinase activity, a 5-azaindazole series was optimized for potency, metabolic stability and brain penetration. A key design element involved the incorporation of an intramolecular hydrogen bond to increase permeability and potency against LRRK2. This communication will outline the structure-activity relationships of this matched pair series including the challenge of obtaining a desirable balance between metabolic stability and brain penetration.

The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor-radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia.

328 Background: Esophageal cancer arising within a previous radiation treatment field (ECRF) is rare. The patterns of disease, treatment and outcomes in these patients (pts) have not been well characterized. Methods: A retrospective analysis was performed for pts treated for esophageal cancer at the Princess Margaret Cancer Centre from 2002-2016. Electronic medical records of all pts with a histologic diagnosis of esophageal cancer occurring within the field of previous radiotherapy were reviewed. The Kaplan-Meier method was used to calculate progression free survival (PFS) and overall survival (OS). Results: Of 31 ECRF pts identified, the most common prior cancer was head and neck (45%), median radiation (RT) dose 50Gy, median time to diagnosis of esophageal cancer 12 years. Features at diagnosis of ECRF included: median age 71 years, 58% male, 87% with performance status (PS) 0-1, 77% squamous cell carcinoma, 19% stage IV. Treatment intent was curative in 16 pts, palliative in 15 (Table). Reasons for palliative treatment were: 40% metastatic, 53% comorbidities/PS, 7% anatomic factors. Of resected pts, 36% had a pT1-2 tumour, 55% pN0, 69% R0. For curative pts, median PFS was 26.2 months (95%CI 10.9-34.4) with a 3 year PFS rate of 35% (95% CI 15-81). Median OS for curative pts was 26.4 months (95%CI 17.8-105.5) with a 3 year OS rate of 43% (95% CI 22-83). Most palliative pts were unable to have chemotherapy due to comorbidities and PS. Median OS for palliative pts was 9.5 months (95% CI 3.6-15.4). Conclusions: Most ECRF pts presented with earlier stage disease; however, more than a third of these could not have aggressive curative treatment due to comorbidities and/or PS. Most curative pts had surgery alone. Few palliative pts had chemotherapy, largely due to poor clinical status. Our data suggest that outcomes in both curative and palliative ECRF pts may be limited by the ability to tolerate standard of care treatments. [Table: see text]

Activating mutations within the epidermal growth factor receptor (EGFR) kinase domain, commonly L858R or deletions within exon 19, increase EGFR-driven cell proliferation and survival and are correlated with impressive responses to the EGFR inhibitors erlotinib and gefitinib in nonsmall cell lung cancer patients. Approximately 60% of acquired resistance to these agents is driven by a single secondary mutation within the EGFR kinase domain, specifically substitution of the gatekeeper residue threonine-790 with methionine (T790M). Due to dose-limiting toxicities associated with inhibition of wild-type EGFR (wtEGFR), we sought inhibitors of T790M-containing EGFR mutants with selectivity over wtEGFR. We describe the evolution of HTS hits derived from Jak2/Tyk2 inhibitors into selective EGFR inhibitors. X-ray crystal structures revealed two distinct binding modes and enabled the design of a selective series of novel diaminopyrimidine-based inhibitors with good potency against T790M-containing mutants of EGFR, high selectivity over wtEGFR, broad kinase selectivity, and desirable physicochemical properties.

188 Background: Discussing an oncology patient’s ceiling of care in the emergency room (ER) is a high-stakes and time-pressured challenge. Discussions and consensus for ceilings are warranted when patients are acutely unwell with sepsis. We explored whether daily oral morphine equivalent (OME) was predictive of outcome and could therefore assist in ceiling of care decision making or advanced resuscitation planning (ARP). Methods: Oncology patients presenting with infection or sepsis to a quaternary hospital ER between October 2008 and April 2011 were included. Hospital electronic databases and medical records were manually reviewed to extract data on patient demographics, OME at time of presentation to ER, illness severity (SOFA scores), whether patients had a pre-existing formalised ARP vs acute ARP documented within the ER and 90-day mortality from ER presentation. Descriptive statistics were reported. Results: A total of 91 patients were identified with median age 64 years, 60% were male, 62% were undergoing palliative-intent treatment and 70% were receiving first-line chemotherapy. There were 54 patients taking no analgesia (OME 0) and 37 patients with an OME > 0. Of the 37 patients with OME > 0, 6 patients (16.2%) had an ARP documented in the ER. A further 14 patients with OME > 0 had an ARP documented at some point during their admission. The median total SOFA scores for patients with OME > 0 was 3 and OME of 0 was also 3. The 90- day mortality from ER presentation was higher for patients with an OME > 0 compared to those with an OME of 0 (Chi-square = 5.02, p = 0.03). There were 15/37 patients (40.5%) with an OME > 0 who were deceased within 90 days compared with 10/54 patients (18.5%) with an OME of 0. Conclusions: Patients with higher OME use at ER presentation had poorer outcomes and this may be useful to guide clinicians in ceilings of care decisions. Daily OME should signal a need for timely, formalised advanced care planning with patients and their treating oncologists.

164 Background: A microscopically positive (R1) resection margin following resection for gastroesophageal (GE) cancer has been documented to be a poor prognostic factor. The optimal strategy and impact of different modalities of adjuvant treatment for an R1 resection margin remain unclear. Methods: A retrospective analysis was performed for patients (pts) with GE cancer treated at the Princess Margaret Cancer Centre from 2006-2016. Electronic medical records of all pts with an R1 resection margin were reviewed. Kaplan-Meier and Cox proportional hazards methods were used to analyze recurrence free survival (RFS) and overall survival (OS) with stage and neoadjuvant treatment as covariates in the multivariate analysis. Results: We identified 78 GE cancer pts with an R1 resection. 11% had neoadjuvant chemotherapy, 14% chemoradiation (CRT), 75% surgery alone. 28% had involvement of the proximal margin, 13% distal, 56% radial, 3% had multiple positive margins. By the American Joint Committee on Cancer 7th edition classification, 88% had a pT3-4 tumour, 66% pN2-3 nodal involvement, 64% grade 3, 68% with lymphovascular invasion. 3% were pathological stage I, 21% stage II and 74% stage III. Adjuvant therapy was given in 46% of R1 pts (24% CRT, 18% chemotherapy alone, 3% radiation alone, 1% reoperation). Median RFS for all pts was 12.6 months (95% CI 10.3-17.2). Site of first recurrence was 71% distant, 16% locoregional, 13% mixed. Median OS was 29.3 months (95% CI 22.9-50) for all pts. The 5 year survival rate was 23% (95% CI 12%-43%). There was no significant difference in RFS (log-rank test p= 0.63, adjusted p= 0.14) or OS (log-rank test p= 0.68, adjusted p= 0.65) regardless of adjuvant therapy. Conclusions: Most pts with positive margins after resection for GE cancer had advanced pathologic stage and prognosis was poor. Our study did not find improved RFS or OS with adjuvant treatment and only one pt had reresection. The main failure pattern was distant recurrence, suggesting that pts being considered for adjuvant RT should be carefully selected. Further studies are required to determine factors to select pts with good prognosis despite a positive margin, or those who may benefit from adjuvant treatment.

e15579 Background: Although commonly performed, evidence supporting routine surveillance testing (SvT) in patients (pts) with resected GEAC is lacking. We evaluated patterns of relapse, frequency of salvage therapy and outcomes among pts with resected GEAC who underwent surveillance. Methods: Between 2011 and 2016, 210 consecutive pts with GEAC followed at Princess Margaret Cancer Center after resection were reviewed. SvT was any investigation performed in the absence of pt-reported symptoms, abnormal physical exam findings, or bloodwork. Relapse patterns were classified as locoregional (LRR; surgical anastomosis/gastroesophageal lumen/regional nodes) or distant (DR; beyond locoregional). Time-to-relapse (TTR) and overall survival (OS) were calculated from initial diagnosis, post recurrence survival (PRS) from initial relapse. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (40%), and gastric adenocarcinomas (45%) were treated with surgery alone (29%), surgery plus perioperative chemotherapy (26%) or surgery plus chemoradiation (45%). SvT included imaging (71%), endoscopy (19%), tumor markers (6%), and clinical visits alone (9%). After median follow-up of 38.3 months (mo) (range 5.6-122.3), 3- and 5-year OS rates were 68% (95% confidence interval (CI) 62-75%) and 56% (95% CI 49-64%) respectively. Among 97 relapses (46%), 51 were detected by SvT, 45 by symptoms. Relapse patterns included LRR alone (4%), DR alone (86%) and both (10%). The majority of relapses (93%) occurred within 3 years. Pts with SvT-detected relapse had similar median TTR (16.2 vs 13.3 mo, p = 0.40) but longer PRS (16.5 vs 4.6 mo, p < 0.001) and OS (36.2 vs 23.7 mo, p = 0.004) than pts with symptomatic relapse. Salvage therapy in 4 pts (2%) resulted in post recurrence disease-free survival ≥2 years. Duration of palliative chemotherapy was similar between 28 pts with SvT-detected relapse and 18 pts with symptomatic relapses (3.9 vs 3.3 mo, p = 0.64). Conclusions: Following curative resection, 96% of relapses were distant. Routine SvT rarely enabled successful salvage therapy and did not extend duration of palliative chemotherapy. Longer OS in SvT-detected relapses was not due to earlier disease detection. These findings do not support routine SvT in pts with resected GEAC.

In an effort to identify potent and isoform selective inhibitors of PI3Kδ, GNE-293 (34) was identified. Inhibitor 2 was found to induce micronuclei formation in both the MNT and HCA in vitro assays. Compounds testing negative for genotoxicity were successfully identified through modifications of the 2-benzimidazole substituent and the methylene moiety to disrupt planarity. A variety of heteroatom linkers were explored to examine their effect on potency and isoform selectivity by restricting torsional angles to favor ligand interactions with PI3Kδ’s Trp760. These modifications also resulted in an improved in vivo pharmacokinetic profile.

The goal of this investigation was to perform a comparative analysis on how accurately 11 routinely-used in silico programs correctly predicted the mutagenicity of test compounds that contained either bulky or electron-withdrawing substituents. To our knowledge this is the first study of its kind in the literature. Such substituents are common in many pharmaceutical agents so there is a significant need for reliable in silico programs to predict precisely whether they truly pose a risk for mutagenicity. The predictions from each program were compared to experimental data derived from the Ames II test, a rapid reverse mutagenicity assay with a high degree of agreement with the traditional Ames assay. Eleven in silico programs were evaluated and compared: Derek for Windows, Derek Nexus, Leadscope Model Applier (LSMA), LSMA featuring the in vitro microbial Escherichia coli–Salmonella typhimurium TA102 A-T Suite (LSMA+), TOPKAT, CAESAR, TEST, ChemSilico (±S9 suites), MC4PC and a novel DNA docking model. The presence of bulky or electron-withdrawing functional groups in the vicinity of a mutagenic toxicophore in the test compounds clearly affected the ability of each in silico model to predict non-mutagenicity correctly. This was because of an over reliance on the part of the programs to provide mutagenicity alerts when a particular toxicophore is present irrespective of the structural environment surrounding the toxicophore. From this investigation it can be concluded that these models provide a high degree of specificity (ranging from 71% to 100%) and are generally conservative in their predictions in terms of sensitivity (ranging from 5% t o 78%). These values are in general agreement with most other comparative studies in the literature. Interestingly, the DNA docking model was the most sensitive model evaluated, suggesting a potentially useful new mode of screening for mutagens. Another important finding was that the combination of a quantitative structure–activity relationship and an expert rules system appeared to offer little advantage in terms of sensitivity, despite of the requirement for such a screening paradigm under the ICH M7 regulatory guideline.

Inhibitors targeting the activating mutants of the epidermal growth factor receptor (EGFR) have found success in the treatment of EGFR mutant positive non-small-cell lung cancer. A secondary point mutation (T790M) in the inhibitor binding site has been linked to the acquired resistance against those first generation therapeutics. Herein, we describe the lead optimization of a series of reversible, pan-mutant (L858R, del746–750, T790M/L858R, and T790M/del746–750) EGFR inhibitors. By use of a noncovalent double mutant (T790M/L858R and T790M/del746–750) selective EGFR inhibitor (2) as a starting point, activities against the single mutants (L858R and del746–750) were introduced through a series of structure-guided modifications. The in vitro ADME-PK properties of the lead molecules were further optimized through a number of rational structural changes. The resulting inhibitor (21) exhibited excellent cellular activity against both the single and double mutants of EGFR, demonstrating target engagement in vivo...

Gastric cancer is a highly fatal malignancy, and surgery alone often does not provide a cure, even for relatively early stages of disease. Various approaches have been adopted around the world to improve surgical outcomes; however, there currently is no global consensus with regard to the extent of surgery or the timing and choice of chemotherapy and radiation. Here we review the evidence supporting current approaches to resectable gastric cancer, including discussion of the optimal extent of surgery and lymphadenectomy, adjuvant chemotherapy, postoperative chemotherapy with chemoradiation, and perioperative chemotherapy. Additionally, we discuss novel approaches, including intensified chemotherapy (in neoadjuvant, perioperative, and adjuvant settings), pre- and postoperative chemoradiation in combination with chemotherapy, and the role of biologics and targeted therapy. Finally, we examine the promise of molecular subtyping and potential biomarkers for improved patient selection. Upcoming and future trials should help answer questions regarding the optimal sequencing and choice of treatments, in order to further improve survival and move us towards ultimately curing more patients with resectable gastric cancer.

The modulation of LRRK2 kinase activity by a selective small molecule inhibitor has been proposed as a potentially viable treatment for Parkinson's disease. By using aminopyrazoles as aniline bioisosteres, we discovered a novel series of LRRK2 inhibitors. Herein, we describe our optimization effort that resulted in the identification of a highly potent, brain-penetrant aminopyrazole LRRK2 inhibitor (18) that addressed the liabilities (e.g., poor solubility and metabolic soft spots) of our previously disclosed anilino-aminopyrimidine inhibitors. In in vivo rodent PKPD studies, 18 demonstrated good brain exposure and engendered significant reduction in brain pLRRK2 levels post-ip administration. The strategies of bioisosteric substitution of aminopyrazoles for anilines and attenuation of CYP1A2 inhibition described herein have potential applications to other drug discovery programs.

A potent inhibitor of PI3Kδ that is ⩾200 fold selective for the remaining three Class I PI3K isoforms and additional kinases is described. The hypothesis for selectivity is illustrated through structure activity relationships and crystal structures of compounds bound to a K802T mutant of PI3Kγ. Pharmacokinetic data in rats and mice support the use of 3 as a useful tool compound to use for in vivo studies.

162 Background: Although commonly performed, the benefit of routine surveillance testing (SvT) following curative resection of GEAC is undefined. We aimed to determine frequency of successful salvage therapy (SST) in patients (pts) with relapsed GEAC who were surveyed post curative therapy. Methods: Between 2011 and 2016, 210 consecutive pts with locally advanced GEAC underwent curative surgery and subsequent surveillance at Princess Margaret Cancer Center. SST was defined as any potentially curative therapy for recurrence which resulted in post-recurrence survival (PRS) two years without further relapse. Time-to-event outcomes were analyzed using Kaplan-Meier and Cox regression methods. Results: Median age was 64.1 years. Esophageal (14%), gastroesophageal junction (41%), and gastric adenocarcinomas (45%) were included. Pts received surgery alone (29%), surgery with perioperative chemotherapy (26%) or perioperative chemoradiation (45%) as primary curative therapy. At median follow-up of 33.6 months (m, range 6.0-122.4), 3- and 5-year overall survival (OS) rates were 68% (95% CI 61-75%) and 59% (95% CI 51-68%) respectively. SvT modalities included imaging (69%), endoscopy (19%), tumor markers (4%), and clinical visits only (9%). Recurrences occurred in 95 (45%) pts, 51% were surveillance-detected (SvDR), and 47% were non-SvDR. Types of recurrences included locoregional only (4%), distant (87%) or both (9%). Salvage therapy was attempted in 14 pts (7%) with SvDR and 1 with non-SvDR. In four pts with SvDR (1.9%) salvage therapy was successful with chemoradiation or surgery perioperative chemotherapy, six were unsuccessful, and 5 had immature follow-up. Compared with pts with non-SvDR, pts with SvDR had longer median OS (34.8 vs. 24.0m, p=0.03) and PRS (14.4 vs. 4.8m, p < 0.001), and similar time-to-relapse (15.6 vs. 12.0m, p = 0.67). Palliative chemotherapy was administered in 25 pts with SvDR and 18 pts with non-SvDR with similar median duration (3.5m vs. 3.3m, p=0.64). Conclusions: Following curative therapy, 96% of relapses were distant. SvT enabled SST in only 1.9% of pts, and did not extend duration of palliative chemotherapy. These data do not support the use of routine SvT in resected GEAC.

171 Background: Disease related symptoms including anorexia, nausea and dysphagia lead patients with esophageal cancer to become malnourished. Malnourishment can result in systemic inflammation, reduced treatment tolerance, poorer quality of life and decreased overall survival. Currently weight loss is the main clinical measure of malnutrition, and thus we set out to evaluate the prognostic utility of alternative screening tools of malnutrition. Methods: Patients with metastatic esophageal squamous cell cancer (MESCC) attending the Princess Margaret Cancer Centre, between January 2011 and December 2016, were identified from the institutional gastroesophageal database. Nutritional Risk Score (NRS), Nutritional Risk Index (NRI) and Neutrophil Lymphocyte Ratio (NLR) were calculated and correlated with clinical-pathological variables and survival. Malnutrition was defined as NRS ≥ 3, NRI < 97.5 and NLR ≥ 3. Results: Of the 64 consecutive patients, 30 (47%) presented with de novo metastatic disease and 34 (53%) with recurrence. The median age was 62 years (range 40-85), 47 patients were ECOG PS ≤ 2 and 29 (45%) received systemic chemotherapy. 90% of patients experienced weight loss > 5% prior to diagnosis and median BMI was 20.1 (range 14.3-34.9). NRI identified 37 (58%) and NRS 45 (70%) patients as malnourished. Both were associated with poorer ECOG PS (p = 0.012 and p = 0.027 respectively). No difference was identified with sex, smoking status or albumin with univariate analysis. NRI did not associate significantly with age. Median overall survival was 5months; 8.1-9 months with normal nutrition and 2.8-3.2 months in malnourished patients. Kaplan Meier analysis revealed significant difference in overall survival (malnutrition vs. normal nutrition) using NRS (p = 0.029) and NRI (p = 0.001) but not weight (p = 0.509) or NLR (p = 0.69). Conclusions: Patients with MESCC identified as malnourished at the time of diagnosis have inferior survival outcomes. Malnutrition tools are superior to weight alone with respect to discriminating outcomes in this patient population. Further investigation is needed in larger patient cohorts; to identify those at risk, initiate early supportive interventions and improve patient outcomes.

A one-pot procedure for the conversion of aromatic and heteroaromatic 2-nitroamines into bicyclic 2H-benzimidazoles is described. The procedure employs formic acid, iron powder, and an additive such as NH 4 Cl to reduce the nitro group and effect the imidazole cyclization with high-yielding conversions generally within one to two hours. The compatibility with a wide range of functionality demonstrates the general utility of this procedure.

The rapid advancement of a series of noncovalent inhibitors of T790M mutants of EGFR is discussed. The optimization of pyridone 1, a nonselective high-throughput screening hit, to potent molecules with high levels of selectivity over wtEGFR and the broader kinome is described herein.

Because of their increased activity against activating mutants, first-generation epidermal growth factor receptor (EGFR) kinase inhibitors have had remarkable success in treating non-small-cell lung cancer (NSCLC) patients, but acquired resistance, through a secondary mutation of the gatekeeper residue, means that clinical responses only last for 8-14 months. Addressing this unmet medical need requires agents that can target both of the most common double mutants: T790M/L858R (TMLR) and T790M/del(746-750) (TMdel). Herein we describe how a noncovalent double mutant selective lead compound was optimized using a strategy focused on the structure-guided increase in potency without added lipophilicity or reduction of three-dimensional character. Following successive rounds of design and synthesis it was discovered that cis-fluoro substitution on 4-hydroxy- and 4-methoxypiperidinyl groups provided synergistic, substantial, and specific potency gain through direct interaction with the enzyme and/or effects on the proximal ligand oxygen atom. Further development of the fluorohydroxypiperidine series resulted in the identification of a pair of diastereomers that showed 50-fold enzyme and cell based selectivity for T790M mutants over wild-type EGFR (wtEGFR) in vitro and pathway knock-down in an in vivo xenograft model.

The photochemistry of diphenylbis(trimethylsilyl)germane (2a) and 1,4-dihydro-5-methyl-1,2,3,4,9,9-hexaphenyl-1,4-germanonaphthalene (11) has been studied in solution by steady-state and laser flash photolysis methods with a view to detecting the transient germylene derivative diphenylgermylene (Ph2Ge), which has previously been shown to be the major product of photolysis of 2a and a closely related derivative of 11. Steady-state trapping experiments confirm the formation of Ph2Ge as the major germanium containing primary product in both cases; with 2a, the results indicate that other transient species are also formed in minor yields, including phenyl(trimethylsilyl)germylene (Ph(TMS)Ge, ca. 6%) and diphenyl(trimethylsilyl)germyl radicals (Ph2(TMS)Ge, ≥15%). Laser flash photolysis of 2a in deoxy genated hexane solution yields a complex mixture of overlapping transient absorptions, which is shown to be comprised of Ph2Ge, tetraphenyldigermene (15) and its oligomerization products, and another species with spectral characteristics similar to the Ph2(TMS)Ge radical. The latter has been independently generated by hydrogen abstraction from diphenyl(trimethylsilyl)germane by tert-butoxyl radicals. Compound 11 extrudes Ph2Ge more cleanly and efficiently upon photolysis in solution, yet laser flash photolysis affords excited triplet and triplet-derived species as the only detectable transient products; interpretation of the results for this compound is made difficult by its slow thermal decomposition to 5-methyl-1,2,3,4-tetraphenylnaphthalene. It is concluded that in spite of the fact that both 2a and 11 afford Ph2Ge in high yield upon photolysis, they are poor precursors for study of the species in solution by time-resolved UV–vis methods, owing to the formation of other, more strongly absorbing transient products than Ph2Ge, whose lowest energy absorption is characteristically weak.Key words: germylene, germyl radical, flash photolysis, disilylgermane, photochemistry.

Reaction of anhydrous FeCl 2 with 6,6 ′ -dimethyl-2,2 ′ -bipyridyl (dmby) in non-aqueous media gives the yellow, high spin, tetrahedral complex FeCl 2 (dmby), which is characterized crystallographically, magnetically and by 1 H NMR spectroscopy. In contrast, reaction of FeCl 2 · 4H 2 O with dmby in 0.1 M hydrochloric acid, the method of choice for preparing 3:1 and 2:1 iron(II) complexes of 2,2 ′ -bipyridyl, gives [H 2 dmby][FeCl 4 ] and [Hdmby][FeCl 4 ], in which the dmby has been protonated. These complexes are also characterized crystallographically.

We describe and evaluate a novel approach for the automatic parallelization of programs that use pointer-based dynamic data structures, written in Java. The approach exploits parallelism among methods by creating an asynchronous thread of execution for each method invocation in a program. At compile time, methods are analyzed to determine the data they access, parameterized by their context. A description of these data accesses is transmitted to a run-time system during program execution. The run-time system utilizes this description to determine when a thread may execute, and to enforce dependences among threads. This run-time system is the main focus of this paper. More specifically, the paper details the representation of data accesses in a method and the framework used by the run-time system to detect and enforce dependences among threads. Experimental evaluation of an implementation of the run-time system on a four-processor Sun multiprocessor indicates that close to ideal speedup can be obtained for a number of benchmarks. This validates our approach.

145 Background: Central nervous system (CNS) metastases (mets) in gastroesophageal (GE) cancers are rare. There have only been limited studies examining the role of HER2 status in CNS mets in GE cancers. Methods: A retrospective analysis was performed for patients (pts) treated for GE cancers at the Princess Margaret Cancer Centre from 2011-2016. Quantitative and qualitative data were collected for all pts with CNS mets. Kaplan-Meier method was used to calculate overall survival (OS) and CNS progression free survival (PFS) for CNS mets pts. Results: Of 34 GE cancer pts diagnosed with CNS mets, 11 were HER2+, 11 HER2- and 12 had unknown HER2 status. Median time from initial cancer diagnosis to CNS mets was 10.3 months (13.4 in HER2+, 5.8 in HER2-, 11.7 in HER2 unknown). Characteristics at CNS mets diagnosis included: median age 63; 85% male; 74% had extracranial systemic mets; performance status ECOG 0-1 (64%), 2 (12%), 3-4 (24%). Treatment for CNS mets is shown in Table 1. Median OS from diagnosis of CNS mets was 6.1 months (95%CI 3.2-16.4) for all pts, 17.1 (95%CI 9.9-NA) in HER2+, 1.8 (95%CI 0.6-NA) in HER2-, 6.0 (95%CI 1.9-NA) in HER2 unknown, p=0.01. Median OS from initial cancer diagnosis was 18.5 months (95%CI 13.6-33.7) for all pts, 28.9 (95%CI 21.32-NA) in HER2+, 10.8 (95%CI 6.37-NA) in HER2-, 18.6 (95%CI 10-NA) in HER2 unknown, p=0.015. The 1 year CNS PFS rate was 35% (95%CI 22.1 – 55.5%) for all pts, 53% (95%CI 29.9 – 94%) in HER2+, 18.2% (95%CI 5.3 – 63.7%) in HER2-, 33% (95%CI 15 – 74.2%) in HER2 unknown, p=0.053. Conclusions: HER2+ pts tended to develop CNS mets later than HER2-. HER2+ pts were more likely to receive CNS-directed interventions, with more HER2+ pts having surgery for CNS mets while more HER2- had supportive care. This analysis is the first to suggest that in pts with CNS mets, HER2+ pts had longer survival than HER2-, both from initial diagnosis and after developing CNS metastases.[Table: see text]

147 Background: Literature on recurrence and outcomes of HPGEC is scarce. The aim of this study was to determine pattern of recurrence and outcomes after curative intent surgery for locally advanced HPGEC. Methods: A retrospective database was used to identify consecutive patients with gastroesophageal adenocarcinomas undergoing curative intent resection between 2011 and 2016 at the Princess Margaret Cancer Centre. Clinico-demographic data were extracted from the electronic health record. Patterns of relapse are classified as nonvisceral (defined as recurrences in the bone, peritoneal or both), visceral (not nonvisceral, including the brain), or both. Time to relapse (TTR) and overall survival (OS) were calculated from date of histologic diagnosis. Results: Of 45 patients with HPGEC, 78% were male, and 91% were non-Asian. Median age was 64.4 years (interquartile range [IQR] 53, 70); 60% were gastroesophageal junction, 24% were gastric, and 16% were esophageal adenocarcinomas; 31% were poorly differentiated tumors while 68% had clinical or pathological node positive disease. Complete R0 resection occurred in 93%, and 84% had received perioperative therapy (31% with perioperative chemotherapy; 40% with pre-operative chemoradiation; 9% with post-operative chemoradiation). With a median follow-up time of 26.0 months. relapse rate of HPGEC at last follow-up was 78%. Among first relapses, 94% were distant, while 6% were local recurrences. Among distant relapses, visceral recurrences occurred in 85%, nonvisceral in 3%, and 12% patients had both visceral and nonvisceral recurrences. None had peritoneal only recurrence. Median TTR was 12.2 months (IQR 8.8, 23.5), while median post-recurrence survival was 9.7 months (IQR 4.7, 16.3). Of the entire cohort, 2-year OS was 53% and 3-year OS was 26%. Conclusions: More than three-quarters of patients with HPGEC experienced recurrence after curative intent multimodality therapy. Our results suggest that HPGEC rarely relapse with peritoneal only disease or local recurrence, thereby calling into question the utility for aggressive surveillance, pending verification from larger cohorts.

163 Background: Older adults are under-represented or excluded from pivotal trials of palliative chemotherapy for metastatic gastric and esophageal (GE) cancers. Little is known about how older patients are treated in the real world. The objective of this study was to examine the impact of age on treatment and survival. Methods: Patients aged ≥65 years were identified from a retrospective database of patients with metastatic GE cancer (Princess Margaret Cancer Centre; 2011-2016). The impact of age ≥75 years (old-old) versus (vs.) 65-74 years (young-old) on treatment and survival was assessed using multivariable logistic and Cox proportional hazard regression models, respectively, adjusted for known prognostic factors including sex, comorbidity, primary site, histology, grade, stage at initial diagnosis, metastatic sites, and chemotherapy use. Results: Of 183 patients, median age was 72 (range 65-92) years; 31% were old-old. Old-old patients were less likely to be treated with any chemotherapy (12.3% vs. 45.2% young-old; adjusted odds ratio = 0.12 (95% confidence interval (CI) 0.05-0.31)). With a median follow-up of 5.7 months, 135 (74%) had died during follow-up; median overall survival (OS) was 5.2 months (mo) for the old-old vs. 8.4 mo (young-old). There was no significant difference in survival between the two groups after adjustment for known prognostic factors (old-old vs. young-old: univariable hazard ratio (HR) 1.75 (95% CI 1.2-2.5); adjusted HR 1.1 (95% CI 0.7-1.7). Treatment with any chemotherapy was associated with an improvement in survival: adjusted HR 0.34 (95%CI 0.22-0.52). Conclusions: In this single-centre study of older adults with metastatic GE cancer, there was an overall low rate of treatment with chemotherapy; those ≥75 were rarely treated. After accounting for known prognostic factors, there was no observed difference in survival between patients ≥75 and those 65 to 74. Comprehensive geriatric assessment may improve treatment selection in the older population. [Table: see text]

148 Background: In gastric/GEJ cancer, 40% of patients (pts) are metastatic at diagnosis ( de novo stage IV) and up to 70% with locoregional disease recur (relapsed stage IV). We compared survival outcomes between de novo vs relapsed stage IV. Methods: A retrospective observational study of stage IV gastric/GEJ pts was conducted (2012-2015). Overall survival (OS) was from date of stage IV diagnosis. PFS1 defined the period from stage IV diagnosis to first progression. PFS2 was from first to second progression. For relapsed stage IV pts, disease-free interval (DFI) was the period from initial diagnosis to metastatic relapse. Cox proportional hazards models compared OS, PFS1 and PFS2 between de novo vs relapsed stage IV pts, stratified by DFI [ < 6, 6-12 and > 12 months (mo)] and controlled for baseline patient characteristics. Results: Of 198 pts, 62% were male and median age was 64 years (26-93), with 64% gastric and 36% GEJ adenocarcinomas. Primary therapy for locoregional pts included surgery (75%), perioperative chemotherapy (42%) and radiotherapy (42%). De novo and relapsed stage IV pts represented 68% and 32% of the cohort respectively. Median follow-up was 13 mo. Controlled for age, performance status and Charlson comorbidity index, there were no significant differences in OS (median OS 12.5 ( de novo) vs 12.2 mo (relapsed); HR 1.22, 95% CI 0.83-1.77, p = 0.31), PFS1 (6.8 vs 7.4 mo; HR 1.00, 95% CI 0.65-1.56, p = 0.98) or PFS2 (3.8 vs 3.0 mo; HR 1.03, 95% CI 0.44-2.41, p = 0.95). Median OS for relapsed stage IV patients were different by DFI groups (log-rank p = 0.02): 22.9 mo (for DFI > 12mo; n = 31), 11.2 mo (DFI 6-12; n = 19) and 7.5 mo (DFI < 6; n = 14). Additionally, OS was significantly better if the DFI was greater than 12 mo, compared with de novo stage IV (HR 0.50, 95% CI 0.28-0.88, p = 0.02). Conclusions: There was no observed difference in the natural history of de novo vs relapsed stage IV gastric/GEJ pts. DFI was strongly prognostic with median OS (from date of relapse) approaching 2 years for relapsed pts with DFI > 12 mo. In addition to implications for treatment strategy, tumor biology within subgroups should be examined to identify novel biomarkers and potential therapeutic targets.

131 Background: The landmark ToGA trial established trastuzumab (T) based therapy as the standard of care for advanced HER2+ gastric and gastroesophageal junction cancer. However, outcomes for T based therapy for HER2+ esophageal cancer have not been well characterized. Methods: We conducted a retrospective analysis of patients (pts) with HER2+ gastroesophageal cancer receiving T based therapy at our institution from 2011-2016. Distal esophagus ( < 35 cm) and Siewert type I/II tumours were defined as esophageal (E). Siewert type III and stomach tumours were defined as gastric (G). Trained abstractors collected pt demographics and treatment details. Overall survival (OS) and progression-free survival (PFS) were calculated from the date of first T treatment. Chi-square tests, t-tests and Cox proportional hazards models were applied where appropriate. Results: We identified 87 pts with advanced HER2+ disease. 62% (n = 54) had de novo metastatic (M1) disease. 57 patients were treated with T based therapy, with median age 57 years (IQR 48-67), 91% baseline performance status 0-1, 19% female, and 7% Asian. 63% (n = 36) had E and 37% (n = 21) had G primary tumours. 67% (n = 38) presented with M1 disease. 33% (n = 19) underwent surgery with curative intent and received T based therapy at recurrence. Baseline characteristics were balanced between the E and G groups. Survival data were available for 51 patients. The E and G groups did not have significant differences in PFS (median 9.5 vs. 9.1 months, HR 0.89 (95% CI 0.44-1.80), p = 0.74) or in OS (median 15.8 vs. 14.2 months, HR 0.88 (95% CI 0.42-1.82), p = 0.73). 63% (n = 36) were treated with subsequent systemic therapy after progression on T, with 23 receiving one line, 9 receiving two lines and 4 receiving three additional lines of treatment. The number subsequent therapies received was similar between E and G groups. Conclusions: Although patients with distal esophagus tumours were not included in the ToGA trial, our analysis suggests that patients with E and G tumours had similar outcomes. Our contemporary cohort had comparable survival outcomes relative to patients receiving T in the ToGA trial (median PFS = 6.7 months, median OS = 13.8 months).

122 Background: There are no phase 3 trials comparing definitive chemoradiation (bimodality) versus. perioperative chemoradiation (trimodality) for locoregional esophageal/GEJ cancer. Methods: A retrospective analysis (2011-2015) compared bimodality and trimodality therapy in patients (pts) with locoregional esophageal/GEJ cancer treated with curative intent. Overall survival (OS) and disease-free survival (DFS) were calculated from the date of diagnosis. Uni- and multivariable Cox proportional hazards regression adjusted for patient and disease factors. Results: Of 108 patients, 82 (76%) were male. Mean ages were 69.5 ± 11.0 years (bimodality; N = 41) and 60.5 ± 11.1 years (trimodality; N = 67). For bimodality pts, 37% had adenocarcinoma and 63% had squamous cell carcinoma (SCC). For trimodality pts, 79% had adenocarcinoma and 21% had SCC (p < 0.0001). Bimodality pts received a higher radiation dose compared to trimodality pts (50.1 ± 6.7 vs. 45.2 ± 6.4 Gy). Median follow-up was 49.3 months. We found no significant OS difference between bimodality (27.0 months) and trimodality therapy (29.8 months) in the overall cohort (p = 0.57) (4 year OS rate: 42% vs. 38%). In the subgroup with adenocarcinoma histology, trimodality therapy significantly improved OS and DFS compared to bimodality (OS: 31.8 vs. 10.4 months, hazard ratio (HR) 0.34, 95% confidence interval (CI) 0.18-0.66, p = 0.001; DFS: 15.0 vs. 6.7 months; HR 0.39, 95%CI 0.21-0.73, p = 0.003). In the SCC subgroup, median OS and DFS were similar (OS: not reached vs. 29.2 months, p = 0.48; DFS: 27.0 vs. 24.0, p = 0.96). Using multivariable regression with AIC backward selection, the only retained prognostic factors were treatment modality (p = 0.06) and histology (p = 0.01). Conclusions: Our findings support preferential use of trimodality therapy for pts with adenocarcinoma histology given superior OS and DFS, whereas bimodality and trimodality therapy appeared comparable in pts with SCC histology. Pending confirmation in a larger series with longer follow-up, these findings suggest differential treatment algorithms for locoregional esophageal and GEJ cancer based on tumor histology.