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Silver nanoparticle embedded POP was synthesized and used as a heterogeneous catalyst for the synthesis of α-alkylidene cyclic carbonates and acyclic carbamates via CO2 fixation under mild conditions.

Premixed turbulent flames, encountered in power generation and propulsion engines, are an archetype of a randomly advected, self-propagating surface. While such a flame is known to exhibit large-scale intermittent flapping, the possible intermittency of its small-scale fluctuations has been largely disregarded. Here, we experimentally reveal the inner intermittency of a premixed turbulent V-flame, while clearly distinguishing this small-scale feature from large-scale outer intermittency. From temporal measurements of the fluctuations of the flame, we find a frequency spectrum that has a power-law subrange with an exponent close to $-2$ , which is shown to follow from Kolmogorov phenomenology. Crucially, however, the moments of the temporal increment of the flame position are found to scale anomalously, with exponents that saturate at higher orders. This signature of small-scale inner intermittency is shown to originate from high-curvature, cusp-like structures on the flame surface, which have significance for modelling the heat release rate and other key properties of premixed turbulent flames.

Aim: Reviewing outcomes of regorafenib use in metastatic colorectal cancer using real-world data from the South Australian Metastatic Colorectal Cancer Registry. Methods: A retrospective review of the characteristics and outcomes of patients who received regorafenib in the Registry up to December 2018. The registry started in February 2006. Results: Fifty-three patients received regorafenib therapy since approved by the therapeutic goods administration in November 2013. The median age was 66 (range 34–82). 66% were male, 66% had stage IV disease at diagnosis, 53% had liver only involvement, whereas 13% had liver and lung disease and 6% had lung only involvement. 75% had left-sided primary. KRAS was available in 35/53 patients with 49% of them being WT. BRAF status was known in 8/53 with 25% of them having a mutated variant. MSI testing was known in 14 patients in whom 21% of them had MSI-High tumors. Prior lines of treatment received: one line 4%, two 9%, three 23%, four 26%, >four 37%. Prior biological use: bevacizumab 72%, anti-EGFR 100% (for RAS WT). Median survival from diagnosis was 3.3 years (95% CI, 2.8–3.8 years). Median survival from the start of regorafenib was 7.1 months (95% CI, 4.8–9.4 months) and the 12-month survival rate was 28%. Conclusion: The survival outcome for those patients from our population-based registry who access regorafenib is in keeping with reports from large, randomized trials. Thus, clinicians can quote local real world data when discussing efficacy and access to regorafenib therapy for mCRC patients. Refereed/Peer-reviewed

BACKGROUND A single state-wide upper gastrointestinal (GI) cancer video-linked multidisciplinary team (MDT) meeting guides management and evidence-based care for all newly diagnosed upper GI cancer patients in South Australia. This study determined the patterns of care and outcomes for patients diagnosed with gastric and gastro-oesophageal junction (GOJ) cancers. METHODS Patients diagnosed with gastric cancer and GOJ (Siewert III) cancer between June 2012 and June 2016 were included. Patient demographics, cancer stage, histology, diagnostic modalities and treatment data was analysed from a prospective database. Stage-specific survival outcomes were determined and analysed for each treatment modality. RESULTS The study included 218 patients and at diagnosis 132 (61%) patients had stage I-III and 86 (39%) patients had stage IV disease. One hundred and ninety-five (89%) patients had gastric cancer and 23 (11%) had GOJ cancer (Siewert III). One hundred and nine (50%) patients underwent surgery, with 92% R0 resection rate. Forty-six patients received perioperative chemotherapy and 111 (51%) patients received palliative intent treatment. Median overall survival for stage II, III and IV cancers was 57.6 (95% CI 57.6-NR), 22.8 (95% CI 20.4-43.2), and 6.0 months (95% CI 4.8-8.4) respectively (p

In turbulent premixed flames, the fractal dimension of flame iso-surface is argued to be D = 7 / 3 for Damkohler’s large-scale limit ( D a > > 1 ) and D = 8 / 3 for Damkohler’s small-scale limit ( D a ∼ O ( 1 ) ) based on heuristic scaling arguments. However, such scaling arguments do not consider the effect of the intermittent nature of turbulent kinetic energy dissipation on the flame surface. In this paper, we account for the effects of intermittent dissipation on the fractal dimension of low D a turbulent premixed flames. Intermittent dissipation leads to variability in the inner cut-off, which then affects the scalar flux and total interface area. We account for these variabilities through two approaches: coarse-grained approach based on the moments of the dissipation and fine-scale analysis by adopting the multifractal formalism. We derive two corrections to the upper-limit of fractal dimension – D = 8 / 3 + 3 / 4 ( 1 − D 1 / 4 ) and D = 8 / 3 + 2 / 3 ( 3 − D 1 / 3 ) . We further show that the second correction leads to an explicit dependence of the fractal dimension ( D ) on the scaling exponent ( ξ ) of the velocity structure function through the relation: D = 7 / 3 + ξ . Thus, we explicitly quantify the effect of the intermittent nature of turbulence upon low D a premixed combustion.

Open-loop control is known to be an effective strategy for controlling self-excited periodic oscillations, known as thermoacoustic instability, in turbulent combustors. Here, we present experimental observations and a synchronization model for the suppression of thermoacoustic instability achieved by rotating the otherwise static swirler in a lab-scale turbulent combustor. Starting with the state of thermoacoustic instability in the combustor, we find that a progressive increase in the swirler rotation rate leads to a transition from the state of limit cycle oscillations to the low-amplitude aperiodic oscillations through a state of intermittency. To model such a transition while also quantifying the underlying synchronization characteristics, we extend the model of Dutta et al. [Phys. Rev. E 99, 032215 (2019)] by introducing a feedback between the ensemble of phase oscillators and the acoustic. The coupling strength in the model is determined by considering the effect of the acoustic and swirl frequencies. The link between the model and experimental results is quantitatively established by implementing an optimization algorithm for model parameter estimation. We show that the model is capable of replicating the bifurcation characteristics, nonlinear features of time series, probability density function, and amplitude spectrum of acoustic pressure and heat release rate fluctuations at various dynamical states observed during the transition to the state of suppression. Most importantly, we discuss the flame dynamics and demonstrate that the model without any spatial inputs qualitatively captures the characteristics of the spatiotemporal synchronization between the local heat release rate fluctuations and the acoustic pressure that underpins a transition to the state of suppression. As a result, the model emerges as a powerful tool for explaining and controlling instabilities in thermoacoustic and other extended fluid dynamical systems, where spatiotemporal interactions lead to rich dynamical phenomena.

Abrupt transitions to the state of thermoacoustic instability (TAI) in gas turbine combustors are a significant challenge plaguing the development of next-generation low-emission aircraft and power generation engines. In this paper, we present the observation of abrupt transition in three disparate turbulent thermoacoustic systems: an annular combustor, a swirl-stabilized combustor, and a preheated bluff-body stabilized combustor. Using a low-order stochastic thermoacoustic model, we show that the reported abrupt transitions occur when an initially stable, supercritical limit cycle becomes unstable, leading to a secondary bifurcation to a large amplitude limit cycle solution. The states of combustion noise and intermittency observed in these turbulent combustors are well captured by the additive stochastic noise in the model. Through amplitude reduction, we analyze the underlying potential functions affecting the stability of the observed dynamical states. Finally, we make use of the Fokker-Planck equation, educing the effect of stochastic fluctuations on subcritical and secondary bifurcation. We conclude that a high enough intensity of stochastic fluctuations which transforms a subcritical bifurcation into an intermittency-facilitated continuous transition may have little effect on the abrupt nature of secondary bifurcation. Our findings imply the high likelihood of abrupt transitions in turbulent combustors possessing higher-order nonlinearities where turbulence intensities are disproportionate to the large amplitude limit cycle solution.

In this experimental study on a laboratory-scale turbulent annular combustor with sixteen swirl-stabilized burners, we study the flame-flame and flame-acoustic interactions during different dynamical states associated with the longitudinal mode of the combustor. We simultaneously measure the acoustic pressure and CH* chemiluminescence emission of the flame using a high-speed camera. Upon increasing the equivalence ratio, the combustor undergoes the following sequence of transition: combustion noise (CN) to low amplitude longitudinal thermoacoustic instability (TAI) through the state of intermittency (INT), and from low amplitude to high amplitude longitudinal TAI through a secondary bifurcation. We report the first evidence of secondary bifurcation from low amplitude TAI to high amplitude TAI for a turbulent thermoacoustic system which allows us to test the flame response at two different amplitude of perturbation in a natural setting. We find a significant difference in the dynamics of the flame interactions during the periodic part of intermittency and low and high amplitude TAI. Specifically, during the periodic part of intermittency, the phase difference between the local heat release rate (HRR) measured from various burners show significant phase slips in time. During low amplitude TAI, there are fewer phase slips among the HRR response of the burners, which result in a state of weak synchronization among the flames. During high amplitude TAI, we find that the flames are in perfect synchrony amongst themselves and with the pressure fluctuations. We then quantify the degree of temporal and spatial synchronization between different flames, and flames and pressure fluctuations using the Kuramoto order parameter and the phase-locking value. We show that synchronization theory can be conveniently used to characterize and quantify flame-acoustic interactions in an annular combustor., Comment: 24 pages, 7 figures. Submitted to Proceedings of the Combustion Institute. Article replaced to correct the author name

Cancers of the upper gastrointestinal tract are a leading cause of cancer-related death world-wide and historically have a poor prognosis. The incidence and histology of these cancers have varied temporally and geographically over the last three decades, with an emerging understanding of the differences in the molecular and genetic profiles across different subgroups. Management of oesophagogastric cancers is by a multidisciplinary team with utilisation of surgery, radiotherapy and systemic treatments in combinations where appropriate. Immune checkpoint inhibition (ICI) has drastically changed the treatment landscape of multiple solid malignancies in the last 5 years. In oesophagogastric cancer, clinical trials have only recently shown activity that is often associated with the molecular characteristics of these tumours, in particular PD-L1 scores or microsatellite instability (MSI-H). This review looks to present the pivotal trials in this space, discuss the complexities between trials that may explain the disparate results and assess the benefit ICI offers in the treatment landscape at present.

Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab or panitumumab) are today increasingly used in the first- or second-line setting for RAS wild-type metastatic colorectal cancer (CRC) patients. Following progression beyond third- or fourth-line therapy, some patients are unsuitable for further chemotherapy because of poor performance status or patient choice. However, a significant number of patients are still candidates for further therapy despite limited standard options being available. The role of rechallenge with anti-EGFR therapy, particularly in patients who had previously responded, is often considered, but there is limited evidence in the literature to support such a strategy. This retrospective study aims to review the outcome of metastatic CRC patients who had anti-EGFR rechallenge. Patients who had been rechallenged with anti-EGFR therapy were identified from the South Australian metastatic CRC database. Patient characteristics were recorded and tumor response was retrospectively assessed using Response Evaluation Criteria in Solid Tumors (RECIST). Kaplan–Meier analysis was used to assess progression free survival (PFS) for each rechallenge and overall survival (OS). Twenty-two patients were eligible for inclusion in this analysis. Disease control rate (stable disease and partial response) was 45.4% (ten patients) for patients who received rechallenge anti-EGFR. Seven patients received a second rechallenge and disease control rate was 28.6% (two patients). The median interval time between initial anti-EGFR therapy and rechallenge was 13.5 months. The median PFS after rechallenge 1 was 4.1 months and after rechallenge 2 was 3.5 months. The median OS was 7.7 months from date of rechallenge. Anti-EGFR rechallenge provides clinical benefit in patients with RAS wild-type metastatic CRC.

Introduction: Outcomes in metastatic colorectal cancer are improving, due to the tailoring of therapy enabled by better understanding of clinical behavior according to molecular subtype. Areas covered: A review of the literature and recent conference presentations was undertaken on the topic of systemic treatment of metastatic colorectal cancer. This review summarizes expert discussion of the current evidence for therapies in metastatic colorectal cancer (mCRC) based on molecular subgrouping. Expert opinion: EGFR-targeted and VEGF-targeted antibodies are now routinely incorporated into treatment strategies for mCRC. EGFR-targeted antibodies are restricted to patients with extended RAS wild-type profiles, with evidence that they should be further restricted to patients with left-sided tumors. Clinically distinct treatment pathways based on tumor RAS, BRAF, HER2 and MMR status, are now clinically applicable. Evidence suggests therapy for additional subgroups will soon be defined; the most advanced being for patients with KRAS G12 C mutation and gene TRK fusion defects.

Influenza virus infection has significant morbidity and mortality in patients with medical co-morbidities who are also immunosuppressed. The efficacy of the seasonal influenza vaccine has not been well studied in patients receiving chemotherapy. We assessed the efficacy of seasonal influenza vaccine in patients with non-haematological malignancy on active treatment (chemotherapy and targeted therapy). A prospective single arm, open label study with 53 patients with non-haematological cancers recruited during the 2011 and 2012 influenza seasons. Participants had one dose of 2011/2012 trivalent vaccine containing strains A/California/7/2009(H1N1), A/Perth/16/2009 (H3N2) and B/Brisbane/60/2008 (Fluvax) prior to or in-between treatment cycles. Haemagglutination inhibition antibody (HIA) titres in serum were measured at baseline 3, 6 and 24 weeks. Primary endpoint: seroconversion rate (SCR) at 3 weeks. Secondary endpoints: Seroconversion was defined as postvaccination ≥ 4-fold increase in HIA titre and sero-protection defined as a HIA ≥ 1:40. The SCR at 3 weeks were 35%, 30% and 22.5% to the H1N1, H3N2 and B/Bris strains, respectively. There were no new cases of late SC at 6 weeks or 24 weeks. The SPR at 3 weeks were 72.5%, 65% and 40%, respectively, to H1N1, H3N2 and B/Bris. The SPR at 24 weeks to H1N1, H3N2 and B/Bris were 40%, 52.5% and 17.5%, respectively. Patients on various solid tumour treatments achieve sero-protection rate congruent with the general population. The sero-protection HIA titres were not sustained at 24 weeks postvaccination.

Background The sensitive detection of recurrent colorectal cancer (CRC) by the measurement of circulating tumor DNA (ctDNA) might improve the chance of a cure. This study compared a quantitative methylated ctDNA test with carcinoembryonic antigen (CEA) in the setting of surveillance for recurrence. Methods Blood samples collected either during surveillance or within 12 months of the confirmation of recurrence were assayed for ctDNA (methylated branched‐chain amino acid transaminase 1 [BCAT1]/Ikaros family zinc‐finger 1 protein [IKZF1]) and CEA. The optimal ctDNA threshold was determined by receiver operating characteristic analysis, and the test performance for the detection of recurrence was compared with CEA (5 ng/mL threshold). Results The study cohort comprised 144 eligible patients and included 50 recurrence events. The sensitivity of the methylated ctDNA test for recurrence was 66.0% (95% confidence interval [CI], 57.1%‐69.3%), which was significantly higher than the sensitivity of CEA (31.9%; 95% CI, 22.8%‐36.6%; P, An optimal positivity threshold has been determined for an epigenetic circulating tumor DNA panel of biomarkers (methylated BCAT1 and IKZF1), and it has been applied to investigating the panel's utility in the detection of colorectal cancer recurrence. The sensitivity of the circulating tumor DNA test is superior to that of the clinically used carcinoembryonic antigen test for all recurrences (66% vs 32%) and those considered curable (60% vs 20%), with both tests having a very high specificity (98% vs 96%).

42 Background: The anti-EGFR monoclonal antibodies panitumumab (Pmab) and cetuximab (Cmab) and the anti-VEGF antibody bevacizumab (bev) have demonstrated clinical efficacy in mCRC in combination with first-line chemotherapy. Clinical and molecular characteristics, such as primary tumour sidedness, RAS, BRAF and MMR status are prognostic and predictive biomarkers for response to treatment. Our aim was to compare the survival and tumour characteristics of patients receiving first-line chemotherapy and antibody combinations using the SA mCRC Registry. Methods: This real-world registry has collected data from all patients diagnosed with mCRC in SA prospectively since 2006. We identified patients who had received first-line Pmab, Cmab or bev. Survival was analysed using the Kaplan-Meier method and log-rank test to compare outcomes based on primary tumour location. Results: Of the 5537 patients currently entered onto the registry, 1313 with RAS results available had received first-line anti-EGFR/VEGF antibodies and had colon tumour side recorded. The table summarises median overall survival (mOS) and patient characteristics. Survival was significantly shorter for those with right colon cancers (P < 0.001). There were more high-grade (P < 0.001), KRAS mutant (P = 0.004) and BRAF mutant (P = 0.036) tumours in those with right colon cancers, and a trend towards fewer curative liver resections (P = 0.059). There was no significant difference in mOS seen between Pmab, Cmab or bev for both left (P = 0.14) and right-sided (P = 0.88) primary tumours. Conclusions: There were more high-grade, BRAF and KRAS mutant patients with right colon tumours, and lower rates of liver resection, which may explain the significantly shorter mOS. The survival seen for Pmab and Cmab was almost identical for both right and left primary tumours. When comparing Pmab, Cmab and bev as first-line therapy, there was no significant difference in mOS for both left- and right-sided CRC. [Table: see text]

Introduction Pancreatic cancer remains a challenging malignancy due to the high proportion of patients diagnosed at advanced stages and the limited treatment options. This article discusses recent evidence in the management of both localised and advanced pancreatic cancer and offers an expert opinion on current best practice. Areas covered For patients with localised disease, the evidence for adjuvant chemotherapy is discussed as well as emerging neoadjuvant approaches for resectable, borderline resectable and locally advanced disease. Advances in metastatic disease are discussed including cytotoxic chemotherapy, targeted therapies and the role of genomic testing to identify patients with molecular alterations. Reviewed literature included; journal publications, abstracts presented at major international oncology meetings and ongoing clinical trials databases. Expert opinion Pancreatic cancer is a devastating diagnosis and despite recent advances has a very poor prognosis. Only a minority of patients, 20%, are diagnosed with potentially curable disease. The shifting paradigm towards neoadjuvant therapy may improve resectability and survival rates however robust evidence is required. Thus far, there has only been limited progress in advanced stage disease. Genomic testing may potentially identify more treatment targets although limited to small subgroups.

Aims Gastric cancer with peritoneal involvement has a poor prognosis. Intraperitoneal (IP) paclitaxel has shown promising results in these patients. However, this approach has only been studied in the Asian population, and in combination with S-1. We investigated the maximum tolerated dose of IP paclitaxel, with a standard chemotherapy combination, in the Australian population. Methods The study of the population included metastatic human epidermal growth factor receptor 2 (HER2) negative gastric adenocarcinoma with peritoneal involvement. Treatment included six 21-day cycles of cisplatin (80 mg/m2 IV, day 1) plus capecitabine (1000 mg/m2 PO BD, days 1-14) plus IP paclitaxel (days 1 and 8). IP paclitaxel doses for cohort 1-3 were 10, 20, and 30 mg/m2 , respectively, in a 3 + 3 standard dose-escalation design. Results Fifteen patients were enrolled of which 6 were female and the median age was 63. Two patients developed dose-limiting toxicities. No grade 4/5 toxicities were recorded. The maximum tolerated dose was not reached. Therefore, as defined by the study protocol, the recommended phase-2 dose for IP paclitaxel was determined to be 30 mg/m2 . The 12-month survival rate was 46.7%, and the median survival was 11.5 months (interquartile range [IQR]: 15.3-6.9). Conclusions IP paclitaxel is safe in combination with cisplatin and capecitabine and the recommended phase-2 dose is 30 mg/m2 .

Background Nivolumab improves disease control and survival in advanced NSCLC in patients with good performance status (PS), but there is limited data on its efficacy in patients with poor PS. Aim Primary objective of the study was to evaluate the efficacy and safety of nivolumab and examine the influence of PS on outcomes. Methods and results Retrospective analysis of patients treated with single-agent nivolumab for advanced NSCLC at a single institution was performed. Sixty-six patients treated with nivolumab were identified (33 male) with a median age of 68.5 years. Fifty-six (85%) patients were current or former smokers and 17 (26%) had brain metastasis. All patients had received prior chemotherapy, 39 (59%) patients received one and 27 (41%) had ≥2 prior lines of therapy. Median overall survival (OS) was 7.1 months (95%CI 3.61-11.3) in the overall study population. OS of patients with PS ≥2 at the start of treatment was 3.04 months (95%CI 1.64-7.36) as compared to 10.23 months (95%CI 7.06-18.9) with PS ≤1. The overall response rate was 7% (four patients had a partial response), 23 (40%) patients had stable disease; the overall disease control rate (partial response and stable disease) was 47%. Twenty-six (40%) patients had PS ≥2 at the start of treatment and 2 (8%) of these patients developed a partial response, 4 (15%) had stable disease; the overall disease control rate was 23%. Fourteen (58%) patients with PS ≥2 had disease progression at the time of first disease response evaluation. In the overall population, 20% of patients experienced grade ≥3 treatment-related adverse events (TRAEs), most commonly pneumonitis, hepatitis, and colitis. Fourteen TRAEs led to treatment discontinuation, 9 (23%) adverse events (AEs) in patients with PS ≤1 and 5 (19%) with PS ≥2. Fourteen (21%) patients died within 30 days of the last nivolumab treatment. Conclusion There was no significant difference in toxicity leading to treatment discontinuation between the poor and good PS groups, but survival was shorter with poorer PS. PS appears to be an important prognostic factor and remains a relevant discriminator in the selection of treatment with immunotherapy for lung cancer.

We study the dependence of the flame sheet response of an open V-flame when subjected to simultaneous but independently controlled – (1) narrowband, coherent disturbances, (2) mean flow velocity, and (3) turbulent broadband disturbances. We re-examine the data presented in Humphrey et al. (2018). Flame edge and flow field were obtained from Mie scattering images and PIV vector fields, respectively. We determine the flame sheet response, which allows us to understand the effects of kinematic restoration on the local and global flame dynamics. We find some highly nonlinear behaviors in the flame sheet response, which have not been reported previously. In particular, we observe (1) oscillations in the rise and peak region of the flame response, and (2) early onset of the nonlinear coupling between narrowband and broadband disturbances, resulting in oscillatory decay immediately downstream of the flame holder region. The spatial oscillations seen in the flame response arise only when unalike disturbances such as vortical and flame wrinkle disturbances have a comparable wavelength and, thus, interfere. We then find that higher nominal velocity and turbulent intensities increase asymmetry in the flame response, and subsequently affect the local and global heat release response (HRR). We analytically calculate HRR from flame sheet response. We find that there is a monotonic increase in the response with increasing flame length for lower nominal velocities, possibly due to higher flame symmetry. Moreover, the HRR calculated from flame sheet response captures the effect of kinematic restoration very well. Notably, there is a decrease in HRR with increasing turbulence intensity due to enhanced smoothing from kinematic restoration at higher turbulence levels. We further find that the flame response dependence on harmonic forcing manifest in the low-pass filter characteristics of the global HRR response.

We experimentally study thermoacoustic transitions in an annular combustor consisting of sixteen premixed, swirl-stabilized turbulent flames. We show the changes in the characteristics of bifurcations leading to the state of longitudinal thermoacoustic instability (TAI) when equivalence ratio and bulk velocity are systematically varied. Depending upon the bulk velocity, we observe different states of combustor operation when the equivalence ratio is varied. These states include combustion noise, intermittency, low-amplitude TAI, mixed-mode oscillations (MMO), and high-amplitude TAI. We closely examine the special case of MMO that is encountered during the transition from low-amplitude TAI to high-amplitude TAI. We also discuss the global and local flame dynamics observed during the state of MMO. We find that during epochs of low-amplitude oscillations of MMO, all the flames are partially synchronized, while during epochs of high-amplitude oscillations, all the flames are perfectly synchronized. Finally, we replicate the criticalities of bifurcation of the annular combustor in a phenomenological model containing sixth-order nonlinearities.

Background Chemotherapy can cause premature menopause which may result in adverse effects such as fertility loss, osteoporosis, cardiovascular disease and menopausal symptoms. It is thus very important that women are provided with accurate information regarding their risk of premature menopause as a consequence of proposed chemotherapy. Unfortunately, at present there are no reliable tools which can be applied in clinical practice to estimate the risk of premature menopause in women undergoing chemotherapy, beyond age of the patient and form of chemotherapy utilized. Aim This was a pilot study to determine whether AMH levels pre and during chemotherapy are able to predict for chemotherapy induced menopause, and to assess quality of life and menopausal symptoms. Methods and results Premenopausal women between 18 to 45 who were planned to undergo gonadotoxic chemotherapy with curative intent for either breast cancer or haematologic malignancy were recruited from a single centre. AMH, FSH, LH and oestradiol levels were recorded prior to commencement of therapy, during and following completion of chemotherapy. Menstrual status, menopausal symptoms and quality of life data were collected at baseline and during follow‐up. Twenty two women were recruited. The baseline AMH was higher in women who regained menses post‐chemotherapy (median 23.1 vs 9.9 pM (P = .06). Menopausal symptoms were significantly higher at 1 year post diagnosis than at baseline however quality of life was similar. Conclusion AMH may be useful for predicting chemotherapy induced menopause. Further research is still required to determine the place of such testing for patient counselling and management.

Introduction: A comprehensive trimodality approach has become the standard of care for patients with locally advanced rectal cancer. However, the sequencing and duration of chemotherapy and chemoradiotherapy around surgery varies between clinical studies and geographical regions. Growing evidence is also mounting for strategies such as total neoadjuvant therapy and non-operative management for carefully selected patients.Areas covered: We provide a perspective review of the current evidence and controversies in the treatment of locally advanced rectal cancer including the recent updates from the 2020 ASCO annual conference.Expert opinion: With ongoing advances in the management of locally advanced rectal cancer, a multidisciplinary team approach is necessary as treatments could involve multiple approaches. Chemoradiotherapy whether short or long course followed by at least 3 months of systemic chemotherapy may be the preferred option to balance local and distant disease control. Albeit the choice of doublet or triplet chemotherapy is still controversial. As total neoadjuvant treatment becomes part of the standard of care in rectal cancer, modification of the surveillance schedule is needed to detect early recurrences which may be limited by resources and availability of services.

We develop a passive control strategy for suppressing thermoacoustic instability in a bluff-body stabilized premixed turbulent combustor. When the equivalence ratio is varied, there is a transition from combustion noise to thermoacoustic instability via intermittency in the combustor. We perform simultaneous acoustic pressure, 2D-PIV, and CH$^*$ chemiluminescence measurements to capture the pressure fluctuations, the velocity field, and the heat release rate (HRR) field during the transition. We measure the spatial distribution of the amplitude of turbulent velocity at the acoustic frequency, time-averaged vorticity, time-averaged HRR, and Rayleigh index and identify various regions of significance. We implement a passive control strategy by targeting these regions with a steady injection of secondary micro-jet of air to optimize the injection location and determine the critical region. Targeting the critical region with secondary air leads to greater than 20 dB suppression of the dominant thermoacoustic mode. We observe that the coherent structure forming from the shear layer following the dump plane gets suppressed, leading to an incoherent spatial distribution of HRR fluctuations. We find that the turbulent velocity amplitude correctly identifies the critical region for optimized passive control during thermoacoustic instability. In contrast, the Rayleigh index identifies the region of the most significant acoustic driving; however, it does not identify the region most sensitive to control. Finally, we extend our analysis by determining the spatial distribution of the Hurst exponent measured from the turbulent velocity field. We show that the Hurst exponent identifies the critical region during thermoacoustic instability and intermittency, unlike the other physical measures., 12 pages, 10 figures; Preprint under review in Combustion and Flame

PURPOSE To compare cisplatin plus fluorouracil (FU) versus carboplatin plus paclitaxel in chemotherapy-naïve advanced anal cancer to establish the optimal regimen. PATIENTS AND METHODS Patients who had not received systemic therapy for advanced anal cancer were randomly assigned 1:1 to intravenous cisplatin 60 mg/m2 (day 1) plus FU 1,000 mg/m2 (days 1-4) every 21 days or carboplatin (area under the curve, 5; day 1) plus paclitaxel 80 mg/m2 (days 1, 8, and 15) every 28 days for 24 weeks, until disease progression, intolerable toxicity, or withdrawal of consent. Primary end point was objective response rate (ORR). Primary and secondary end points were assessed in a hierarchic model to compare the regimens and pick the winner. RESULTS We conducted an international multicenter randomized phase II study in 60 centers between December 2013 and November 2017. Median follow-up was 28.6 months. A total of 91 patients were randomly assigned: 46 to cisplatin plus FU and 45 to carboplatin plus paclitaxel. ORR was 57% (95% CI, 39.4% to 73.7%) for cisplatin plus FU versus 59% (95% CI, 42.1% to 74.4%) for carboplatin plus paclitaxel. More serious adverse events were noted in the cisplatin plus FU arm (62%) compared with the carboplatin plus paclitaxel arm (36%; P = .016). Median progression-free survival was 5.7 months (95% CI, 3.3 to 9.0 months) for cisplatin plus FU compared with 8.1 months (95% CI, 6.6 to 8.8 months) for carboplatin plus paclitaxel. Median overall survival was 12.3 months for cisplatin plus FU (95% CI, 9.2 to 17.7 months) compared with 20 months (95% CI, 12.7 months to not reached) for carboplatin plus paclitaxel (hazard ratio, 2.00; 95% CI, 1.15 to 3.47; P = .014). CONCLUSION This is the first international randomized trial to our knowledge conducted in chemotherapy-naïve advanced anal cancer. Although there was no difference in ORR, the association with clinically relevant reduced toxicity and a trend toward longer survival suggest that carboplatin plus paclitaxel should be considered as a new standard of care.

Introduction: A multimodal approach in operable early-stage oesophago-gastric (OG) cancer has evolved in the last decade, leading to improvement in overall outcomes.Areas covered: A review of the p...

We identify mechanisms through which open-loop control of thermoacoustic instability is achieved in a laminar combustor and characterize them using synchronization theory. The thermoacoustic system comprises two nonlinearly coupled damped harmonic oscillators – acoustic and unsteady heat release rate (HRR) field – each possessing different eigenfrequencies. The frequency of the preferred mode of HRR oscillations is less than the third acoustic eigenfrequency where thermoacoustic instability develops. We systematically subject the limit-cycle oscillations to an external harmonic forcing at different frequencies and amplitudes. We observe that forcing at a frequency near the preferred mode of the HRR oscillator leads to a greater than 90 % decrease in the amplitude of the limit-cycle oscillations through the phenomenon of asynchronous quenching. Concurrently, there is a resonant amplification in the amplitude of HRR oscillations. Further, we show that the flame dynamics plays a key role in controlling the frequency at which quenching is observed. Most importantly, we show that forcing can cause asynchronous quenching either by imposing out-of-phase relation between pressure and HRR oscillations or by inducing period-2 dynamics in pressure oscillations while period-1 in HRR oscillations, thereby causing phase drifting between the two subsystems. In each of the two cases, acoustic driving is very low and hence thermoacoustic instability is suppressed. We show that the characteristics of forced synchronization of the pressure and HRR oscillations are significantly different. Thus, we find that the simultaneous characterization of the two subsystems is necessary to quantify completely the nonlinear response of the forced thermoacoustic system.

Methylation in IKZF1 and BCAT1 are common events in colorectal cancer (CRC). They are often detected in blood as circulating tumor DNA (ctDNA) at diagnosis and disappear after surgery in most CRC patients. A prospective study was conducted to determine the relationship between detection of these markers following surgery and risk for residual disease and for recurrence. ctDNA status with methylated BCAT1 and IKZF1 was determined within 12 months of surgical resection of CRC, and was related to presence of or risk for residual disease (margins involved, metastases present or nature of node involvement), and to recurrence-free survival. Blood was collected from 172 CRC patients after surgery and 28 (16%) were ctDNA positive. Recurrence was diagnosed in 23 of the 138 with clinical follow-up after surgery (median follow-up 23.3 months, IQR 14.3–29.5). Multivariate modeling indicated that features suggestive of residual disease were an independent predictor of post-surgery ctDNA status: cases with any of three features (close resection margins, apical node involved, or distant metastases) were 5.3 times (95% CI 1.5–18.4, p = 0.008) more likely to be ctDNA positive. Multivariate analysis showed that post-surgery ctDNA positivity was independently associated with an increased risk of recurrence (HR 3.8, 1.5–9.5, p = 0.004). CRC cases positive for methylated ctDNA after surgery are at increased risk of residual disease and subsequently recurrence. This could have implications for guiding recommendations for adjuvant therapy and surveillance strategies. Randomized studies are now indicated to determine if monitoring cases with these biomarkers leads to survival benefit.

Aim Observation with close follow-up ("watch and wait") is a recognized treatment option in patients who achieve a complete clinical response to long course chemoradiotherapy. This review of a prospective database aims to evaluate the clinical outcomes among patients with a complete clinical response managed with observation. Methods A prospective study of 32 patients who achieved a complete clinical response was undertaken. The primary outcomes measured were overall and recurrence-free survival, and rate of organ preservation in patients who deferred immediate surgery. Results Seven patients developed local regrowth over a median follow-up period of 38 months (range, 9-91 months). Median time to detection was 12 months. All seven underwent salvage surgery with complete surgical clearance. One patient developed combined local and systemic recurrence following a low anterior resection. Organ preservation was possible in 25 (78%) patients who sustained a complete clinical response with no evidence of local regrowth or disease recurrence. Among the patients who sustained a complete response, two developed isolated systemic disease. Overall and recurrence-free survival was 95.7% and 87.0%, respectively. Conclusion The majority of patients with rectal cancer who achieved a complete clinical response after chemoradiotherapy and managed with a "watch and wait" approach preserved their rectum and did not develop cancer relapse. Salvage surgery was achieved in all patients who developed local regrowth. The study supports a period of observation in rectal cancer patients who achieve a complete clinical response.

// Sing Y. Moorcraft 1 , Thomas Jones 2 , Brian A. Walker 1 , George Ladas 2 , Eleftheria Kalaitzaki 1 , Lina Yuan 1 , Ruwaida Begum 1 , Zakaria Eltahir 1 , Andrew Wotherspoon 1 , Angeles Montero-Fernandez 2 , Larissa S. Teixeira Mendes 1 , David Gonzalez de Castro 1 , Sanna Hulkki Wilson 1 , Paula Proszek 1 , Ye M. To 1 , Eliza Hawkes 1 , Amitesh Roy 1 , David Cunningham 1 , Sheela Rao 1 , David Watkins 1 , Naureen Starling 1 , Anne M. Bowcock 3 and Ian Chau 1 1 The Royal Marsden NHS Foundation Trust, London and Sutton, United Kingdom 2 The Royal Brompton and Harefield NHS Foundation Trust, London, United Kingdom 3 National Heart and Lung Institute, Imperial College, London, United Kingdom Correspondence to: Ian Chau, email: ian.chau@rmh.nhs.uk Keywords: colorectal cancer, heterogeneity, metastasectomy, pulmonary metastases, RAS Received: October 06, 2016 Accepted: March 29, 2017 Published: April 11, 2017 ABSTRACT This study aimed to molecularly characterise colorectal pulmonary metastases (PM) and investigate whether their molecular profiles were concordant with those of the primary tumour. Clinical data and archival formalin fixed paraffin embedded tissue samples were retrospectively collected from patients who underwent ≥ 1 pulmonary metastasectomies for colorectal cancer between 1997–2012. Primary tumour and metastatic samples were analysed using a targeted capture sequencing panel of 46 cancer-associated genes. The 5-year progression-free and overall survival rates for the 81 patients in this study were 32% (95% CI 22–42%) and 77% (95% CI 66–85%) respectively. Fifty-four patients had samples available from ≥ 1 PM, and sequencing data were successfully obtained from 33 PM from 24 patients. The most frequently mutated genes were APC (71%), KRAS (58%) and TP53 (46%). Seventy-three percent of the 15 patients with matched primary and PM samples and 6 of the 7 patients (86%) with data from ≥ 2 PM had concordant molecular profiles. The concordance for KRAS and NRAS was 100%. At our institutions, patients with resectable colorectal PM had a favourable prognosis. RAS mutations were commonly detected in PM and the molecular profiles of colorectal PM were highly concordant with the primary tumour.

The open air amphitheatre at Delphi in Greece is a structure of sublime architectural beauty, admired the world over. This study explores, through architectural and fluid mechanical modelling, the connection between layout, natural topography, the amphitheatre's orientation, and the prevalent climatic conditions and relates these factors to their contribution to the erosion of the theatre by chemical breakdown. A study on the phenomenon of natural dust transport and saltation mechanisms, and eventually the weathering of the fabric of the theatre was realized through the simulation of PM2.5 and PM10 concentrations, carried out using sophisticated environmental fluid mechanical software ENVI-met, for the very first time. Thereafter, a relationship is drawn between the concentration of dust simulated in the region to that deposited on the boundary walls of the theatre in a brief discourse. The simulation also quantitatively compiles the effect of scattering random trees of a specific height, akin to the ones found around the theatre. Moreover, the study gives a qualitative description on the mechanism of dust accumulation over a period of time and draws a limit on their accretion for building spaces. The paper further considers how the presence of strategically placed trees around the site of heritage is a simple and yet effectively quantified means to decrease the deposition of dust and hence diminish the effects of weathering, significantly. The basic chemistry of the degradation due to SO 2 and NO 2 has been examined in order to depict the successive mechanisms involved in the chemical breakdown. Safer and yet unconventional methods of cleaning such as the use of Fuller's Earth has been suggested as a measure of conservation of structures that have been chemically and physically damaged. This phenomenon exemplifies how dust particles carried by winds are slowly affecting structures that hold cultural value to nations.

Background: The preferred management of patients with unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemo-radiotherapy (CRT). Acute CRT-related toxicities are well defined, however, less is known about late toxicities. The aim of the study was to examine the outcomes and late toxicities in Stage III NSCLC treated with CRT. Methods: A retrospective review of the data from patients with stage III NSCLC treated with CRT was performed between May 2000 and June 2010. Demographics, tumour and treatment characteristics, toxicities and survival data were examined from hospital records of the patients. Progression free survival (PFS) and overall survival (OS) were evaluated by standard Kaplan-Meier survival curves. The censor date was set on 31 October 2016. Results: Sixty-three patients were identified with a median age of 66.6 years [interquartile range (IQR) 57.2–72.1], two-third (n=41, 65.1%) were male, majority were current or ex-smokers (n=52, 82.5%), 42 (66.7%) patients had stage IIIB disease and 21 (33.3%) had stage IIIA disease. The most common histologic subtype was adenocarcinoma 30 (47.6%). The median PFS and OS of the whole population was 10.6 months (95% CI, 4.1–17.3 months) and 21 months (95% CI, 12.7–29.3 months) respectively. The 5-year OS rates for stage IIIA and IIIB were 24% and 16% respectively. The 1-, 3- and 5-year OS rates for all patients were 63.5%, 46% and 18.7% respectively. Acute grade 3 and 4 toxicities included 28 haematological and 17 non-haematological events. The incidence of late toxicities was 58.9%. Thirty-three events of late grade 3 and 4 toxicities were recorded. The most common late toxicity was symptomatic radiation-induced pulmonary fibrosis (39.3%), others include ototoxicity (7.1%), persistent dysphagia (7.1%) and one case of acute myeloid leukaemia. All patients that were alive at the censor date had developed radiation-induced fibrosis with associated symptoms of respiratory insufficiency. Conclusions: The 5-year OS of patients with stage III NSCLC treated with CRT was in keeping with survival figures reported from prospective clinical trials. There is, however, significant morbidity associated with long-term survival and this should be taken into account when making informed treatment decisions.

Background: Studies have reported significant differences in baseline characteristics and outcomes of metastatic colorectal cancer (mCRC) patients when managed in private versus public hospitals. Aim: To compare disease, treatment and survival outcomes of patients with mCRC in public versus private hospitals in South Australia. Methods: Analysis of prospectively collected data from the SA mCRC Registry. Patterns of care and outcome data according to location of care and socioeconomic status based on Index of Relative Socio‐Economic Advantage and Disadvantage (IRSAD) were analyzed. Results: 3470 patient's data were analysed during February 2006 ‐ January 2015. Majority (70%) of patients received treatment in public hospitals. Patients in the upper 50% for IRSAD score were more likely to receive treatment at a private hospital (41.2% v 21.5%) compared to 3 lines of treatment had an average survival increase of over 15 months, 15.7 (95% CI 13.41, 17.99, p

Background Microsatellite instability (MSI) is the molecular marker for DNA mismatch repair deficiency (dMMR) in colorectal cancer (CRC) and has been associated with better survival outcomes in early stage disease. In metastatic CRC (mCRC), outcomes for patients with MSI are less clear. There is evolving evidence that treatment pathways forMSI CRC should include programmed-death 1 (PD-1) antibodies. Objective An analysis was performed to explore the impact of MSI status on overall survival (OS) in mCRC. Patients and methods South Australian Metastatic CRC Registry data were analysed to assess patient characteristics and survival outcomes, comparing patients with MSI CRC with those whose tumours were microsatellite stable (MSS). Kaplan–Meier survival analysis was used to assess OS. Cox regression analysis was undertaken to assess the independence of MSI as a prognostic factor. Results Of 4359 patients registered on the database, 598 (14%) had been tested for, and 62 (10.1%) of these patients had, demonstrable MSI. There were significantly higher rates of right-sided primary (p < 0.001), poorly differentiated pathology (p = 0.002), and BRAF V600E mutation (p < 0.001) in the MSI group. The MSI group were also less likely to receive chemotherapy (p < 0.001) or to have liver surgery, but more likely to be diagnosed at an early stage. The median overall survival was 9.5 months for those with MSI CRC versus 21.3 months for MSS CRC patients (p =0.052). Cox regression analysis indicated that MSI was not an independent predictor of OS. Independent predictors of better OS included having liver surgery for metastasis, having chemotherapy, and being initially diagnosed at an early stage. Conclusions Only 14% of patients with mCRC were tested for MSI, and 1 in 10 were found to be MSI high. The clinical characteristics of MSI mCRC are in keeping with those previously reported. MSI in this population-based registry was associated with a numerically lower survival which did not attain statistical significance. Refereed/Peer-reviewed

3579 Background: Recurrence of colorectal cancer has been linked to the presence of epigenetic circulating tumour DNA (ctDNA) in patient plasma after surgery. The prognostic significance of ctDNA prior to treatment remains unknown. This study investigated the correlation between pre-treatment ctDNA and current radiological (MRI) prognostic markers in patients with rectal cancer. Methods: Forty-two patients with rectal cancer were enrolled, with all having staging MRI prior to treatment. Plasma was taken for ctDNA at diagnosis. The presence of either methylated branched-chain amino acid transaminase 1 (BCAT1) or Ikaros family zinc finger (IKZF1) in cell-free DNA from plasma was deemed a positive ctDNA result. Correlation of MRI prognostic indicators and ctDNA results was assessed with chi-square tests. Univariable and multivariable cox regression analyses were performed to determine variables associated with overall survival (OS). Results: Mean age was 64.4 years (SD 12.5) and majority were male (30/42, 71.4%). 11, 13, 9 & 9 patients had stages I, II, III, IV respectively. Patients had a minimum follow-up of 36 months. Thirty-three (78.6%) patients received neoadjuvant chemoradiotherapy. 29 (69.0%) patients underwent surgical resection. 3-year survival rate was 64% in the overall group. 67% (n=28/42) of patients were positive for the methylated ctDNA at diagnosis. 11 out of 12 patients with a positive circumferential resection margin (CRM +) were ctDNA positive (p=0.03). Univariable analysis showed that prognostic indicators for OS were presence of extramural venous invasion (EMVI) (HR 3.0, 95% CI 1.1-8.4), CRM+ (HR 12.2, 95%CI 3.9-37.6), metastatic disease (HR 7.32, 95% CI 2.63-20.37) and ctDNA% methylation (HR 1.1, 95% CI 1.04-1.13) (Table 1). The presence of CRM+ and a positive ctDNA had a HR of 20.5 (95% CI 5.1-82.3). With multivariable analysis, including adjustment for age and EMVI, only CRM+/ctDNA+ variable was an independent predictor for poor survival (HR 20.2, 95% CI 4.5-90.9). Conclusions: In rectal cancer, almost all patients with CRM involvement have ctDNA, and these patients had the worst prognosis. Future studies with longitudinal ctDNA assessment pre and post treatment could potentially inform prognosis and help tailor patients’ treatment.[Table: see text]

3528 Background: Residual disease after treatment for colorectal cancer (CRC) poses a risk for recurrence but imaging and CEA are limited in their capacity to detect residual disease. A simple test is needed for assessing treatment response. This study determined whether levels of methylated BCAT1/IKZF1 DNA in blood correlate with tumor burden and whether post-treatment levels inform efficacy of different treatments for CRC. Methods: Patients with primary CRC had blood collected prior to treatment (n = 282, 59.9% males, median age 68.5y). Cell free DNA (cfDNA) was extracted from plasma and assayed for methylation in BCAT1 and IKZF1. Detection of methylation in either gene deemed a sample positive; levels were expressed as %methylation (average methylation/average cfDNA). Positive patients had additional samples collected post-treatment for early stage CRC (surgery, n = 31), advanced/metastatic CRC (surgery + adjuvant chemotherapy, n = 15), and rectal cancer (neoadjuvant therapy, surgery +/- chemotherapy, n = 6), or following mid-therapy suspension of treatment in advanced CRC (n = 24). Tumor size was expressed as the maximum diameter of the primary (assessed surgically or by MRI). Results: Pretreatment results increased with CRC stage. Positivity by stage was: I, 23.7% (14/59); II, 62.1% (54/87); III, 68.6% (70/102); IV, 85.3% (29/34). Level by stage: I, 0.0%; II, 0.06%; III, 0.07%; IV, 4.07%, p < 0.001). Pretreatment levels correlated significantly with tumor size (r = 0.372, p < 0.001). Post-treatment blood was collected a median 2.4mo (IQR 1.7-3.9) after therapy completion. Positivity decreased after completing treatment (Table), with 88.4% of cases (46/52) becoming ctDNA negative. All cases with complete treatment had a reduction in biomarker levels, whereas in those with incomplete therapy, 54.5% (12/22) remained positive and the pre- and post-treatment levels were not significantly different. Of those positive after treatment, 13 had a further blood sample: 8 had become ctDNA negative and all but one remained disease free. Five remained positive and all had further suspected or confirmed disease. Conclusions: Levels of methylated BCAT1 and IKZF1 DNA in blood correlated with tumor burden; levels became undetectable in the majority of patients following completion of planned curative intent treatment. The methylated ctDNA blood test aids monitoring of responses to therapy and identification of those cases with residual cancer who might benefit from ongoing therapy.[Table: see text]

Background: Hepatic resection for colorectal (CRC) metastasis is considered a standard of care. Resection of metastasis isolated to lung also is considered potentially curable, although there is still some variation in recommendations. We explore outcomes for patients undergoing lung resection for mCRC, with the liver resection group as the comparator. Methods: South Australian (SA) metastatic CRC registry data were analysed to assess patient characteristics and survival outcomes for patients suitable for lung or liver resection. Results: A total of 3241 patients are registered on the database to December 2014. One hundred two (3.1 %) patients were able to undergo a lung resection compared with 420 (12.9 %) who had a liver resection. Of the lung resection patients, 62 (61 %) presented with lung disease only, 21 % initially presented with liver disease only, 11 % had both lung and liver, and 7 % had brain or pelvic disease resection. Of these patients, 79 % went straight to surgery without any neoadjuvant treatment and 34 % had lung resection as the only intervention. Chemotherapy for metastatic disease was given more often to liver resection patients: 76.9 versus 53.9 %, p = 0.17. Median overall survival is 5.6 years for liver resection and has not been reached for lung resection (hazard ratio 0.82, 95 % confidence interval 0.54–1.24, p = 0.33). Conclusions: Lung resection was undertaken in 3.1 % of patients with mCRC in our registry. These data provide further support for long-term survival after lung resection in mCRC, survival that is at least comparable to those who undergo resection for liver metastasis in mCRC. Refereed/Peer-reviewed

Exercise and a healthy diet are beneficial after cancer, but are not uniformly adopted by cancer survivors. This study reports on the feasibility, acceptability, and effectiveness of a self-management-based nutrition and exercise intervention for Australian cancer survivors. Adult survivors (n = 25) during curative chemotherapy (stratum 1[S1]; n = 11) or post-treatment (stratum 2 [S2]; n = 14) were recruited prospectively from a single center. The Flinders Living Well Self-Management Program™ (FLW Program) was utilized to establish patient-led nutrition and exercise goals and develop a tailored 12-wk intervention plan. Fortnightly reviews occurred with assessments at baseline, 6 and 12 wk. A recruitment and retention rate of 38% and 84% were observed. Both strata maintained total skeletal muscle mass. Small reductions in body mass index, hip circumference, and percentage body fat, and small increases in hand grip strength and exercise capacity among subjects in both strata were observed. No significant differences were observed between strata; however, significant increases in exercise capacity and global health status for S2 were observed from baseline to 12 wk. FLW Program is a feasible mode of delivering nutrition and exercise intervention to cancer survivors and it appears that there are no barriers to implementing this program early during chemotherapy. Hence, the additive effect of gains achieved over a longer duration is promising and this should be explored in randomized controlled trials adequately powered to observe clinically and statistically significant improvements in relevant outcomes.

BackgroundTo evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of eftilagimod alpha (efti), a soluble lymphocyte activation gene-3 protein, in combination with the programmed cell death-1 (PD-1) antagonist pembrolizumab.MethodsThe study was divided into two parts; parts A and B, where part A was the dose escalation part and part B was an extension part of the study. Patients with metastatic melanoma were treated with efti plus the standard dose of pembrolizumab. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect efti antibody formation and determine long-lived CD8 T cell responses and associated pharmacodynamic parameters.ResultsTwenty-four patients with melanoma received pembrolizumab and bi-weekly subcutaneous (s.c.) injections of efti at doses 1 mg, 6 mg or 30 mg/injection for up to 6 months (part A) or 30 mg/injection for up 12 months (part B). No dose-limiting toxicities were reported and the main adverse event for efti was injection site reactions. Sustained systemic exposure to the product was obtained in all patients following s.c. injections of 30 mg dose. Treatment induced an increase in activated CD8 and CD4 T cell counts, and in some of the soluble biomarkers, particularly interferon (IFN)-γ, a Th1 signature cytokine. An overall response rate (ORR) of 33% was observed in patients partly with pembrolizumab-refractory of part A and ORR of 50% was observed in patients with PD-1 naïve of part B.ConclusionsEfti was well tolerated in combination with pembrolizumab with encouraging antitumor activity. This warrants further clinical studies of this new combination therapy combining an antigen-presenting cell activator with an immune checkpoint inhibitor.

e16796 Background: Locally advanced pancreatic adenocarcinoma (LAPC) carries a poor prognosis with median overall survival of 12-18m. The optimal treatment is controversial. Nab-paclitaxel is active in advanced pancreatic cancer and has exhibited radio-sensitising anti-tumour efficacy. Methods: We conducted an investigator-initiated open-label, phase-I dose escalation trial of nab-paclitaxel with standard external beam radiotherapy (EBRT). All patients had biopsy-proven, untreated, localised, inoperable pancreatic adenocarcinoma; Patients received nab-paclitaxel on a weekly schedule for 6 weeks, concurrently with EBRT. A 3+3 cohort design was employed, with doses of nab-paclitaxel increasing from 25 mg/m2 (cohort 1), to 50 mg/m2 (cohort 2), 75 mg/m2 (cohort 3) and 100 mg/m2 (cohort 4). This principal objective of the trial was to establish the maximum tolerated dose (MTD) of nab-paclitaxel given concurrently with radiotherapy. Secondary objectives included safety and efficacy evaluation, including response rate, median PFS, median and 1- year OS. Results: Fourteen patients were recruited to the study, with a median age of 69 (range 40-86). 69% had a head or neck of pancreas tumour. Majority of patients had grade 1 or 2 toxicities with nausea (92%), fatigue (69%), diarrhoea (54%) and vomiting (54%) being the most common. Three patients were recruited in each of the first three cohorts, without any dose limiting toxicities (DLT). In cohort 4, DLT of febrile neutropenia and enterocolitis was observed in patient 1. The cohort was expanded with a subsequent DLT of febrile neutropenia and enterocolitis observed in patient 5. Both DLT events lead to death (grade 5). The MTD and recommended phase II study dose has been established as 75mg/ m2. The disease control (PR and SD) rate was 67%, median PFS 4.7 months (95% CI 2.5-27.5), 1 year OS 43% and median OS 11.4 months (95%CI 6.37-25.2). Conclusions: The combination of weekly nab-paclitaxel and fractionated radiation was generally well-tolerated at doses of nab-paclitaxel below 100 mg/m2. There were two treatment related DLTs leading to death in the nab-paclitaxel 100 mg/m2 cohort. The MTD and recommended phase II study dose for nab-paclitaxel combined with radiation therapy in the treatment of LAPC is 75mg/m2. Clinical trial information: ACTRN12613001013752 .