Pancreatic cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up

The opportunity to detect pancreatic cancer (PC) when potentially curable depends on early diagnosis and an ability to identify and screen high-risk populations before symptoms arise. Identification of a high-risk population is challenging and optimal screening tools remain unclear.1 Older age is the strongest risk factor; incidence peaks at 65-69 years in males and 75-79 years in females.2 A pooled analysis of 117 meta-analyses assigned a relative risk to a number of common risk factors (Supplementary Table S1, available at https://doi.org/10.1016/j.annonc.2023.08.009).3 The vast majority (>80%) of PCs arise due to sporadically occurring somatic mutations. Only a small proportion are due to inherited deleterious germline mutations.1 Familial PC, defined as at least two first-degree relatives with PC, accounts for only 4%-10% of all cases. Variants in BRCA2 are the most common genetic abnormalities seen in familial PC. Other familial syndromes linked to PC are listed in Supplementary Table S2, available at https://doi.org/10.1016/j.annonc.2023.08.009. Individuals from families at risk should receive genetic counselling and be considered for enrolment in investigational screening registries. Currently, in high-risk individuals, annual endoscopic ultrasound (EUS) and/or pancreatic magnetic resonance imaging (MRI) are the procedures of choice for surveillance.4 Surveillance programmes usually begin at age 50 years (or 10 years earlier than the age of the youngest affected relative). Prospective surveillance data in high-risk individuals demonstrated high rates of resectability and encouraging observations of long-term survival.5, 6, 7, 8, 9 In sporadic PC, the major risk factors are tobacco, Helicobacter pylori infection and factors related to dietary habits (high red meat, high alcohol intake, low fruit and vegetable intake, overweight/obesity and type 2 diabetes mellitus).2,3,10 Chronic pancreatitis, irrespective of the cause (alcohol abuse, smoking, genetic mutations), is a risk factor for PC. A proportion of the risk factors associated with PC are potentially modifiable, affording a unique opportunity for primary prevention that is yet to be realised.

A systematic review and meta-analysis of germline BRCA mutations in pancreatic cancer patients identifies global and racial disparities in access to genetic testing.

BACKGROUND: Germline BRCA1 and BRCA2 mutations (gBRCAm) can inform pancreatic cancer (PC) risk and treatment but most of the available information is derived from white patients. The ethnic and geographic variability of gBRCAm prevalence and of germline BRCA (gBRCA) testing uptake in PC globally is largely unknown. MATERIALS AND METHODS: We carried out a systematic review and prevalence meta-analysis of gBRCA testing and gBRCAm prevalence in PC patients stratified by ethnicity. The main outcome was the distribution of gBRCA testing uptake across diverse populations worldwide. Secondary outcomes included: geographic distribution of gBRCA testing uptake, temporal analysis of gBRCA testing uptake in ethnic groups, and pooled proportion of gBRCAm stratified by ethnicity. The study is listed under PROSPERO registration number #CRD42022311769. RESULTS: A total of 51 studies with 16 621 patients were included. Twelve of the studies (23.5%) enrolled white patients only, 10 Asians only (19.6%), and 29 (56.9%) included mixed populations. The pooled prevalence of white, Asian, African American, and Hispanic patients tested per study was 88.7%, 34.8%, 3.6%, and 5.2%, respectively. The majority of included studies were from high-income countries (HICs) (64; 91.2%). Temporal analysis showed a significant increase only in white and Asians patients tested from 2000 to present (P < 0.001). The pooled prevalence of gBRCAm was: 3.3% in white, 1.7% in Asian, and negligible (<0.3%) in African American and Hispanic patients. CONCLUSIONS: Data on gBRCA testing and gBRCAm in PC derive mostly from white patients and from HICs. This limits the interpretation of gBRCAm for treating PC across diverse populations and implies substantial global and racial disparities in access to BRCA testing in PC.

A first-in-human study of the anti-LAG-3 antibody favezelimab plus pembrolizumab in previously treated, advanced microsatellite stable colorectal cancer.

BACKGROUND: Treatment options are limited for participants with microsatellite stable (MSS) metastatic colorectal cancer (mCRC) that progressed after two or more prior therapies. Studies have shown that blockade of both lymphocyte-activation gene 3 (LAG-3) and programmed cell death protein 1 (PD-1) can improve antitumor activity. Here, we evaluate the antitumor activity of the LAG-3 antibody favezelimab alone or in combination with pembrolizumab in participants with MSS mCRC. PATIENTS AND METHODS: Eligible participants with MSS PD-1/programmed death-ligand 1 (PD-L1) treatment-naive mCRC that progressed on two or more prior therapies received 800 mg favezelimab, 800 mg favezelimab plus 200 mg pembrolizumab, or 800 mg favezelimab/200 mg pembrolizumab co-formulation, every 3 weeks. The primary endpoint was safety, the secondary endpoint was objective response rate (ORR), and exploratory endpoints included duration of response, progression-free survival (PFS), and overall survival (OS). RESULTS: At the data cut-off date of 23 October 2020, a total of 20 participants received favezelimab alone, 89 received favezelimab plus pembrolizumab (including as favezelimab/pembrolizumab co-formulation); 48 had PD-L1 combined positive score (CPS) ≥1 tumors. At this interim analysis median follow-up was 5.8 months with favezelimab and 6.2 with favezelimab plus pembrolizumab. Treatment-related adverse events (TRAEs) were 65% with favezelimab and 65.2% with favezelimab plus pembrolizumab. Grade ≥3 TRAEs were 15% with favezelimab and 20% with favezelimab plus pembrolizumab. No grade 5 TRAEs occurred. Common TRAEs (≥15%) included fatigue (20.0%), nausea (15.0%) with favezelimab, and fatigue (16.9%) with favezelimab plus pembrolizumab. Confirmed ORR was 6.3% with favezelimab plus pembrolizumab, with median duration of response of 10.6 months (range 5.6-12.7 months), median OS of 8.3 months (95% confidence interval 5.5-12.9 months), and median PFS of 2.1 months (1.9-2.2 months). In an exploratory analysis of PD-L1 CPS ≥1 tumors, the confirmed ORR was 11.1%, median OS was 12.7 months (4.5 to not reached), and median PFS was 2.2 months (1.8-4.2 months) with favezelimab plus pembrolizumab. CONCLUSIONS: Favezelimab with or without pembrolizumab had a manageable safety profile, with no treatment-related deaths. Promising antitumor activity was observed with combination therapy, particularly in participants with PD-L1 CPS ≥1 tumors.

First-in-human phase 1 study of the anti-TIGIT antibody vibostolimab as monotherapy or with pembrolizumab for advanced solid tumors, including non-small-cell lung cancer☆.

BACKGROUND: In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy or in combination with pembrolizumab. PATIENTS AND METHODS: Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1. RESULTS: Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs-the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs-the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy. CONCLUSIONS: Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.

Identification and diagnosis of Secondary Progressive Multiple Sclerosis during the clinical encounter: Results from a physician survey.

BACKGROUND: It is difficult to characterize the transition from relapsing-remitting multiple sclerosis (RRMS) to secondary progressive MS (SPMS), due to symptomatic variability across patients. Diagnosis of SPMS is prolonged and often established retrospectively, as it is based on patient clinical history and symptoms. This cross-sectional study aimed to identify MS neurologist reported clinical indicators deemed important in diagnosing SPMS in clinical practice. METHODS: A web-based quantitative survey was conducted among MS-treating neurologists across the United States in January 2019. The questionnaire comprised of 17 questions evaluating primary clinical indicators used by neurologists in assessing patient progression to SPMS. Treatment approach and factors influencing treatment decision-making following SPMS diagnosis were also analyzed in the survey. RESULTS: Overall, 300 neurologists completed the survey; most of the respondents were general MS-treating neurologists (63%) and from private care setting (58%). The overall respondents as well as MS-focused neurologists ranked patient history (45% and 42%, respectively) and patients' neurological exam (39% and 44%, respectively) as -primary clinical indicators of SPMS diagnosis. 57% of neurologists always or mostly switched disease modifying therapies after progression to SPMS, and mostly considered 3-6 months' assessment interval to diagnose SPMS. CONCLUSION: The survey indicated that neurologists are able to recognize signs of SPMS within six months of symptomatic assessment. The diagnosis is primarily based on patient history among MS-treating neurologists. Therefore, continued education to neurologists may facilitate early diagnosis and timely introduction of effective treatment to manage the progression of SPMS.

Reshaping preoperative treatment of pancreatic cancer in the era of precision medicine.

This review summarises the recent evidence on preoperative therapeutic strategies in pancreatic cancer and discusses the rationale for an imminent need for a personalised therapeutic approach in non-metastatic disease. The molecular diversity of pancreatic cancer and its influence on prognosis and treatment response, combined with the failure of 'all-comer' treatments to significantly impact on patient outcomes, requires a paradigm shift towards a genomic-driven approach. This is particularly important in the preoperative, potentially curable setting, where a personalised treatment allocation has the substantial potential to reduce pancreatic cancer mortality.

Health-related quality of life in patients with a germline BRCA mutation and metastatic pancreatic cancer receiving maintenance olaparib.

BACKGROUND: Patients with metastatic pancreatic cancer often have a detriment in health-related quality of life (HRQoL). In the randomized, double-blind, phase III POLO trial progression-free survival was significantly longer with maintenance olaparib, a poly(ADP-ribose) polymerase inhibitor, than placebo in patients with a germline BRCA1 and/or BRCA2 mutation (gBRCAm) and metastatic pancreatic cancer whose disease had not progressed during first-line platinum-based chemotherapy. The prespecified HRQoL evaluation is reported here. PATIENTS AND METHODS: Patients were randomized to receive maintenance olaparib (300 mg b.i.d.; tablets) or placebo. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item module at baseline, every 4 weeks until disease progression, at discontinuation, and 30 days after last dose. Scores ranged from 0 to 100; a ≥10-point change or difference between arms was considered clinically meaningful. Adjusted mean change from baseline was analysed using a mixed model for repeated measures. Time to sustained clinically meaningful deterioration (TSCMD) was analysed using a log-rank test. RESULTS: Of 154 randomized patients, 89 of 92 olaparib-arm and 58 of 62 placebo-arm patients were included in HRQoL analyses. The adjusted mean change in Global Health Status (GHS) score from baseline was <10 points in both arms and there was no significant between-group difference [-2.47; 95% confidence interval (CI) -7.27, 2.33; P = 0.31]. Analysis of physical functioning scores showed a significant between-group difference (-4.45 points; 95% CI -8.75, -0.16; P = 0.04). There was no difference in TSCMD for olaparib versus placebo for GHS [P = 0.25; hazard ratio (HR) 0.72; 95% CI 0.41, 1.27] or physical functioning (P = 0.32; HR 1.38; 95% CI 0.73, 2.63). CONCLUSIONS: HRQoL was preserved with maintenance olaparib treatment with no clinically meaningful difference compared with placebo. These results support the observed efficacy benefit of maintenance olaparib in patients with a gBRCAm and metastatic pancreatic cancer. CLINCALTRIALS.GOV NUMBER: NCT02184195.

Publisher's Note: Identification of Nuclear Effects in Neutrino-Carbon Interactions at Low Three-Momentum Transfer [Phys. Rev. Lett. 116, 071802 (2016)].

This corrects the article DOI: 10.1103/PhysRevLett.116.071802.

Direct Measurement of Nuclear Dependence of Charged Current Quasielasticlike Neutrino Interactions Using MINERvA.

Charged-current ν_{µ} interactions on carbon, iron, and lead with a final state hadronic system of one or more protons with zero mesons are used to investigate the influence of the nuclear environment on quasielasticlike interactions. The transferred four-momentum squared to the target nucleus, Q^{2}, is reconstructed based on the kinematics of the leading proton, and differential cross sections versus Q^{2} and the cross-section ratios of iron, lead, and carbon to scintillator are measured for the first time in a single experiment. The measurements show a dependence on the atomic number. While the quasielasticlike scattering on carbon is compatible with predictions, the trends exhibited by scattering on iron and lead favor a prediction with intranuclear rescattering of hadrons accounted for by a conventional particle cascade treatment. These measurements help discriminate between different models of both initial state nucleons and final state interactions used in the neutrino oscillation experiments.

Measurement of Neutral-Current K

Neutral-current production of K^{+} by atmospheric neutrinos is a background in searches for the proton decay p→K^{+}ν[over ¯]. Reactions such as νp→νK^{+}Λ are indistinguishable from proton decays when the decay products of the Λ are below detection threshold. Events with K^{+} are identified in MINERvA by reconstructing the timing signature of a K^{+} decay at rest. A sample of 201 neutrino-induced neutral-current K^{+} events is used to measure differential cross sections with respect to the K^{+} kinetic energy, and the non-K^{+} hadronic visible energy. An excess of events at low hadronic visible energy is observed relative to the prediction of the neut event generator. Good agreement is observed with the cross section prediction of the genie generator. A search for photons from π^{0} decay, which would veto a neutral-current K^{+} event in a proton decay search, is performed, and a 2σ deficit of detached photons is observed relative to the genie prediction.

Evidence for Neutral-Current Diffractive π

The MINERvA experiment observes an excess of events containing electromagnetic showers relative to the expectation from Monte Carlo simulations in neutral-current neutrino interactions with mean beam energy of 4.5 GeV on a hydrocarbon target. The excess is characterized and found to be consistent with neutral-current π^{0} production with a broad energy distribution peaking at 7 GeV and a total cross section of 0.26±0.02(stat.)±0.08(sys.)×10^{-39} cm^{2}. The angular distribution, electromagnetic shower energy, and spatial distribution of the energy depositions of the excess are consistent with expectations from neutrino neutral-current diffractive π^{0} production from hydrogen in the hydrocarbon target. These data comprise the first direct experimental observation and constraint for a reaction that poses an important background process in neutrino-oscillation experiments searching for ν_{µ} to ν_{e} oscillations.

Evidence of Coherent K

Neutrino-induced charged-current coherent kaon production ν_{µ}A→µ^{-}K^{+}A is a rare, inelastic electroweak process that brings a K^{+} on shell and leaves the target nucleus intact in its ground state. This process is significantly lower in rate than the neutrino-induced charged-current coherent pion production because of Cabibbo suppression and a kinematic suppression due to the larger kaon mass. We search for such events in the scintillator tracker of MINERvA by observing the final state K^{+}, µ^{-}, and no other detector activity, and by using the kinematics of the final state particles to reconstruct the small momentum transfer to the nucleus, which is a model-independent characteristic of coherent scattering. We find the first experimental evidence for the process at 3σ significance.

Measurement of Electron Neutrino Quasielastic and Quasielasticlike Scattering on Hydrocarbon at ⟨E_{ν}⟩=3.6 GeV.

The first direct measurement of electron neutrino quasielastic and quasielasticlike scattering on hydrocarbon in the few-GeV region of incident neutrino energy has been carried out using the MINERvA detector in the NuMI beam at Fermilab. The flux-integrated differential cross sections in the electron production angle, electron energy, and Q^{2} are presented. The ratio of the quasielastic, flux-integrated differential cross section in Q^{2} for ν_{e} with that of similarly selected ν_{µ}-induced events from the same exposure is used to probe assumptions that underpin conventional treatments of charged-current ν_{e} interactions used by long-baseline neutrino oscillation experiments. The data are found to be consistent with lepton universality and are well described by the predictions of the neutrino event generator GENIE.

Identification of Nuclear Effects in Neutrino-Carbon Interactions at Low Three-Momentum Transfer.

Two different nuclear-medium effects are isolated using a low three-momentum transfer subsample of neutrino-carbon scattering data from the MINERvA neutrino experiment. The observed hadronic energy in charged-current ν_{µ} interactions is combined with muon kinematics to permit separation of the quasielastic and Δ(1232) resonance processes. First, we observe a small cross section at very low energy transfer that matches the expected screening effect of long-range nucleon correlations. Second, additions to the event rate in the kinematic region between the quasielastic and Δ resonance processes are needed to describe the data. The data in this kinematic region also have an enhanced population of multiproton final states. Contributions predicted for scattering from a nucleon pair have both properties; the model tested in this analysis is a significant improvement but does not fully describe the data. We present the results as a double-differential cross section to enable further investigation of nuclear models. Improved description of the effects of the nuclear environment are required by current and future neutrino oscillation experiments.

Ignition's glow: Ultra-fast spread of global cortical activity accompanying local "ignitions" in visual cortex during conscious visual perception.

Despite extensive research, the spatiotemporal span of neuronal activations associated with the emergence of a conscious percept is still debated. The debate can be formulated in the context of local vs. global models, emphasizing local activity in visual cortex vs. a global fronto-parietal "workspace" as the key mechanisms of conscious visual perception. These alternative models lead to differential predictions with regard to the precise magnitude, timing and anatomical spread of neuronal activity during conscious perception. Here we aimed to test a specific aspect of these predictions in which local and global models appear to differ - namely the extent to which fronto-parietal regions modulate their activity during task performance under similar perceptual states. So far the main experimental results relevant to this debate have been obtained from non-invasive methods and led to conflicting interpretations. Here we examined these alternative predictions through large-scale intracranial measurements (Electrocorticogram - ECoG) in 43 patients and 4445 recording sites. Both ERP and broadband high frequency (50-150 Hz - BHF) responses were examined through the entire cortex during a simple 1-back visual recognition memory task. Our results reveal short latency intense visual responses, localized first in early visual cortex followed (at ∼200 ms) by higher order visual areas, but failed to show significant delayed (300 ms) visual activations. By contrast, oddball image repeat events, linked to overt motor responses, were associated with a significant increase in a delayed (300 ms) peak of BHF power in fronto-parietal cortex. Comparing BHF responses with ERP revealed an additional peak in the ERP response - having a similar latency to the well-studied P3 scalp EEG response. Posterior and temporal regions demonstrated robust visual category selectivity. An unexpected observation was that high-order visual cortex responses were essentially concurrent (at ∼200 ms) with an ultra-fast spread of signals of lower magnitude that invaded selected sites throughout fronto-parietal cortical areas. Our results are compatible with local models in demonstrating a clear task-dependence of the 300 ms fronto-parietal activation. However, they also reveal a more global component of low-magnitude and poor content selectivity that rapidly spreads into fronto-parietal sites. The precise functional role of this global "glow" remains to be elucidated.

A parallel-arm phase I trial of the humanised anti-IGF-1R antibody dalotuzumab in combination with the AKT inhibitor MK-2206, the mTOR inhibitor ridaforolimus, or the NOTCH inhibitor MK-0752, in patients with advanced solid tumours.

BACKGROUND: Two strategies to interrogate the insulin growth factor 1 receptor (IGF-1R) pathway were investigated: vertical inhibition with dalotuzumab and MK-2206 or ridaforolimus to potentiate PI3K pathway targeting and horizontal cross-talk inhibition with dalotuzumab and MK-0752 to exert effects against cellular proliferation, angiogenesis, and stem cell propagation. METHODS: A phase I, multi-cohort dose escalation study was conducted in patients with advanced solid tumours. Patients received dalotuzumab (10 mg kg(-1)) and escalating doses of MK-2206 (90-200 mg) or escalating doses of dalotuzumab (7.5-10 mg kg(-1)) and MK-0752 (1800 mg) weekly. Upon maximum tolerated dose determination, patients with low-RAS signature, high-IGF1 expression ovarian cancer were randomised to dalotuzumab/MK-2206 versus dalotuzumab/ridaforolimus, whereas patients with high IGF1/low IGF2 expression colorectal cancer received dalotuzumab/MK-0752. RESULTS: A total of 47 patients were enrolled: 29 in part A (18 in the dalotuzumab/MK-2206 arm and 11 in the dalotuzumab/MK-0752 arm) and 18 in part B (6 in each arm). Dose-limiting toxicities (DLTs) for dalotuzumab/MK-2206 included grade 4 neutropenia and grade 3 serum sickness-like reaction, maculopapular rash, and gastrointestinal inflammation. For dalotuzumab/MK-0752, DLTs included grade 3 dehydration, rash, and diarrhoea. Seven patients remained on study for >4 cycles. CONCLUSIONS: Dalotuzumab/MK-2206 and dalotuzumab/MK-0752 combinations were tolerable. Further developments of prospectively validated predictive biomarkers to aid in patient selection for anti-IGF-1R therapies are needed.

Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.

BACKGROUND: The BRCA1/2 proteins are involved in regulation of cellular proliferation by DNA damage repair via homologous recombination. Therefore, BRCA1/2 mutation carriers with pancreatic cancer may have distinct biologic outcomes. METHODS: Patients with BRCA1/2-associated pancreatic ductal adenocarcinoma (PDAC) diagnosed between January 1994 and December 2012 were identified from databases at three participating institutions. Clinical data were collected. Disease-free survival and overall survival (OS) were analysed. RESULTS: Overall, 71 patients with PDAC and BRCA1 (n=21), BRCA2 (n=49) or both (n=1) mutations were identified. Mean age at diagnosis was 60.3 years (range 33-83), 81.7% (n=58) had any family history of malignancy; 30% (n=21) underwent primary resection. Out of 71 participants, 12 received experimental therapy; one patient had missing data, these 13 cases were excluded from OS analysis. Median OS for 58 patients was 14 months (95% CI 10-23 months). Median OS for patients with stage 1/2 disease has not been reached with 52% still alive at 60 months. Median OS for stage 3/4 was 12 months (95% CI 6-15). Superior OS was observed for patients with stage 3/4 treated with platinum vs those treated with non-platinum chemotherapies (22 vs 9 months; P=0.039). CONCLUSION: Superior OS was observed for advanced-disease BRCA-associated PDAC with platinum exposure.

Ascites-derived pancreatic ductal adenocarcinoma primary cell cultures as a platform for personalised medicine.

BACKGROUND: Challenges in developing drugs for pancreatic ductal adenocarcinoma (PDAC) include obtaining metastatic cancer tissue for research and validating biomarkers predicative for personalised therapeutic decisions. We have recently developed a novel therapeutic model for PDAC to address these challenges based on the isolation of viable PDAC cells derived from ascites fluid. METHODS: Ascites fluid was obtained from PDAC patients undergoing palliative paracentesis. Ascites-derived PDAC primary cells were isolated, cultured and characterised in ovo and in vitro. RESULTS: We successfully established ascites-derived primary cell cultures within 2-7 days from 92% (93 out of 101) of the ascites fluid samples obtained (from 36 different patients). Homogeneous epithelial PDAC-enriched cell cultures were identified and characterised. We observed a wide range in doubling times and migration properties among the different patient-derived cell cultures. The diverse nature of each individual patient's cell cultures was further demonstrated by differences in therapeutic susceptibility and resistance. The tumorigenicity and invasiveness of the cells were demonstrated in vivo using chicken chorioallantoic membrane grafts. CONCLUSIONS: We have developed a unique ascites-derived PDAC primary cell culture model. This model has the potential to study signalling pathways in PDAC progression and to evaluate targeted therapies for the individual patient expeditiously, thereby supporting personalised treatment decisions.

The CXCR4 antagonist AMD3100 impairs survival of human AML cells and induces their differentiation.

The chemokine stromal cell-derived factor-1 (SDF-1) and its receptor, CXCR4, participate in the retention of acute myeloblastic leukemia (AML) cells within the bone marrow microenvironment and their release into the circulation. AML cells also constitutively express SDF-1-dependent elastase, which regulates their migration and proliferation. To study the molecular events and genes regulated by the SDF-1/CXCR4 axis and elastase in AML cells, we examined gene expression profiles of the AML cell line, U937, under treatment with a neutralizing anti-CXCR4 antibody or elastase inhibitor, as compared with non-treated cells, using DNA microarray technology. Unsupervised hierarchical clustering analysis demonstrated similar gene expression profiles of anti-CXCR4 antibody or elastase inhibitor-treated cells, as compared with control. Pathway and functional analysis showed a greater tendency toward differentiation in cells under either one of both treatment modalities. Thus given, we further analyzed the effects of CXCR4 inhibition on AML cell growth and differentiation using the antagonist AMD3100. AMD3100 arrested proliferation in AML cell lines and triggered changes that mimicked differentiation, including morphological changes and the expression of myeloid differentiation antigens. Inhibition of elastase also triggered the differentiation of AML cells. Our study defines a new role for the SDF-1/CXCR4 axis in the regulation of leukemic cell survival and differentiation.