Patients with pancreatic cancer normally present with advanced disease that is lethal and notoriously difficult to treat. Survival has not improved dramatically despite routine use of chemotherapy and radiotherapy; this situation signifies an urgent need for novel therapeutic approaches. Over the past decade, a large number of studies have been published that aimed to target the molecular abnormalities implicated in pancreatic tumor growth, invasion, metastasis, angiogenesis and resistance to apoptosis. This research is of particular importance, as data suggest that a large number of genetic alterations affect only a few major signaling pathways and processes involved in pancreatic tumorigenesis. Although laboratory results of targeted therapies have been impressive, until now only erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor, has demonstrated modest survival benefit in combination with gemcitabine in a phase III clinical trial. Whilst the failures of targeted therapies in the clinical setting are discouraging, lessons have been learnt and new therapeutic targets that hold promise for the future management of the disease are continuously emerging. This Review describes some of the important developments and targeted agents for pancreatic cancer that have been tested in clinical trials.

BackgroundPulmonary artery sarcoma (PAS) is a rare but aggressive malignancy that leads to heart failure and death without treatment. Here we reviewed the presentation and management of patients treated at a national centre for pulmonary endarterectomy (PEA) and its associated hospital in Cambridge, UK.MethodsDetails of PAS patients treated at Papworth and Addenbrooke’s Hospitals between 2000 and 2014 were reviewed.ResultsTwenty patients were diagnosed with PAS (11 males, 9 females), with a median age of presentation of 57 years (range 27–77). Presenting symptoms include dyspnoea (20), chest pain/tightness (7), oedema (5), constitutional symptoms (5), cough (3) and haemoptysis (3). Twelve patients were in group III/IV of the NYHA functional classification of symptoms. Initial CT scans were suggestive of thromboembolism in seven patients. Histological findings were of intimal sarcoma (13) and high grade sarcoma NOS (6).Median overall survival (OS) was 17 months. Fourteen patients underwent PEA to relieve vascular obstruction, while six had inoperable and/or metastatic disease. There were three peri-operative deaths. Although there was no difference in median OS between patients who had PEA and those who did not (20 vs 17 months, P = 0.2488), surgery provided significant symptomatic improvement and some with long-term survival. Five patients received post-surgical chemotherapy (anthracycline +/− ifosfamide), and after completion four also had radiotherapy. Patients who received post-operative chemo- and radio-therapy showed a trend towards better survival compared to those who had surgery alone (24 vs 8 months, P = 0.3417). For palliative chemotherapy, partial responses were observed with the VID regimen and pegylated liposomal doxorubicin. Stable disease was achieved in a patient with intimal sarcoma with rhabdomyosarcomatous differentiation on third-line cisplatin and topotecan. The longest surviving patient (102 months) has had PEA, adjuvant epirubicin and radiotherapy. She developed lung metastases 7 years later, which were treated with radiofrequency ablation.ConclusionsPAS often presents with symptoms mimicking pulmonary hypertension, heart failure or thromboembolic disease. PEA provides good symptomatic relief and in some cases, offers a chance of long-term survival. Although outcome appears to be better when PEA is combined with post-operative chemo- and radio-therapy, further studies are warranted.

Targeted therapy of cancer using oncolytic viruses has generated much interest over the past few years in the light of the limited efficacy and side effects of standard cancer therapeutics for advanced disease. In 2006, the world witnessed the first government-approved oncolytic virus for the treatment of head and neck cancer. It has been known for many years that viruses have the ability to replicate in and lyse cancer cells. Although encouraging results have been demonstrated in vitro and in animal models, most oncolytic viruses have failed to impress in the clinical setting. The explanation is multifactorial, determined by the complex interactions between the tumor and its microenvironment, the virus, and the host immune response. This review focuses on discussion of the obstacles that oncolytic virotherapy faces and recent advances made to overcome them, with particular reference to adenoviruses.

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PRSS3 plays an important role in the progression, metastasis and prognosis of human pancreatic cancer. Targeting the PRSS3 signalling pathway may be an effective and feasible approach for treatment of this lethal cancer.

Multifunctional GdF 3 :Eu 3+ nanoparticles were synthesized using a hydrothermal method. Photoluminescent excitation and emission spectra, and lifetime were measured. The average lifetime of the nanoparticles is about 11 ms. The nanoparticle exhibits paramagnetism at both 293 and 77 K, ascribing to noninteracting localized nature of the magnetic moment in the compound. The magnetic properties of GdF 3 :Eu 3+ is intrinsic to the Gd 3+ ions, which is unaffected by the doping concentration of the Eu 3+ luminescent centers. A measured magnetization of approximately 2 emu/g is close to reported values of other nanoparticles for bioseparation.

Nearly pure near-infrared to near-infrared (NIR-to-NIR) upconversion in GdF 3 host with 23% Yb 3+ and 1% Tm 3+ under 980 nm excitation is firstly reported. The ratio of the intensity of the emission at 807 nm to that at 478 nm can reach to 105, and the intensity of the emission at 807 nm is preserved. Moreover, the excitation and the emission at 980 and 807 nm are away from the visible region. These are beneficial to deeper tissue penetration and reduced autofluorescence. Raman spectroscopy measurements suggest the high probability of NIR emission in GdF 3 host. Our results indicate that the reported multifunctional nanoparticles are promising in bio-imaging and bio-separation. ©2010 Optical Society of America

Multifunctional KGdF4:18%Yb(3+),2%Er(3+) nanoparticles with upconversion fluorescence and paramagnetism are synthesized. The average sizes of the nanoparticles capped with branched polyethyleneimine (PEI) and 6-aminocaproic acid (6AA) are ~14 and ~13 nm, respectively. Our KGdF4 host does not exhibit any phase change with the decrease of particle size, which can prevent the detrimental significant decrease in upconversion luminescence caused by this effect observed in the well-known NaYF4 host. The branched PEI and 6AA capping ligands endow our nanoparticles with water-dispersibility and biocompatibility, which can favor internalization of our nanoparticles into the cytoplasm of HeLa cells and relatively high cell viability. The strong upconversion luminescence detected at the cytoplasm of HeLa cells incubated with the branched PEI-capped nanoparticles is probably attributed to the reported high efficiency of cellular uptake. The magnetic mass susceptibility of our nanoparticle is 8.62 × 10(-5) emu g(-1) Oe(-1). This is the highest value ever reported in trivalent rare-earth ion-doped KGdF4 nanoparticles of small size (≤14 nm), and is very close to that of nanoparticles used as T1 contrast agents in magnetic resonance imaging. These suggest the potential of our KGdF4:Yb(3+),Er(3+) nanoparticles as small-sized multifunctional bioprobes.