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Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.

11534 Background: GISTs are the most common mesenchymal tumours of the gastrointestinal tract with an annual incidence of 10-15 per million. 10% of GISTS have activating mutations in the PDGFRA gene. We report our 13 year experience of all the PDGFRA-mutated GISTs in our regional centre in Cambridge. Methods: PDGFRA-mutant GISTs were identified from the Cambridge GIST database. Demographics, clinical and histopathological features, survival and response to tyrosine kinase inhibitors of all the patients from 2008-2021 were reviewed. Results: n = 50 (male:female 1.5:1) Median age 68 years (range 19-87). 8% of patients were under the age of 40 years. Tumour size ranged from 1-26 cm with a median of 5 cm. Mitotic index ranged from 1-51 with a median of 1 mitosis/5mm2. 52% of GISTs were located in the gastric body. Histological subtypes: 44% epithelioid, 36% mixed and 20% spindle cell. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were DOG1-positive (94%). 76% had radical surgery, 60% had laparoscopic resection. 24% were assessed as being high risk GISTs using the modified AFIP model contrasted to 13% being high risk with prognostic contour mapping. 13% developed metastatic disease with liver being the most common metastatic site. The table shows PDGFRA mutational analysis results: 58% had a D842V mutation. None had a KIT mutation. With a median follow up of 55.1 months, 82% were alive. 6 patients died from metastatic GIST and 3 from other causes. Median time to metastatic disease in resected GISTs was 30.1 months and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had poor survival compared with patients with localised disease ( p=0.001). 8 patients were treated with tyrosine kinase inhibitors including imatinib, sunitinib and regorafenib prior to 2020 with no objective responses. 3 patients were treated with Avapritinib since 2020 within the compassionate use programme. All 3 patients had partial responses and 2 patients are continuing Avapritinib with no grade 3 adverse events. Conclusions: We report the largest single centre PDGFRA-mutant GIST cohort from Europe. Male preponderance and exclusive gastric location were observed. KIT expression was patchy to negative in the majority of patients. 58% had PDGFRA D842V mutations for which Avapritinib has been recently approved. No objective responses were seen with imatinib, sunitinib or regorafenib. Our early experience with Avapritinib is promising.[Table: see text]

417 Background: Following relapse from first line chemotherapy, 30-60% of patients with germ cell tumors (GCTs) can be salvaged with further chemotherapy. Oxaliplatin-based therapies may offer reduced toxicity. Methods: Eligible patients with GCTs who progressed following cisplatin-based chemotherapy were recruited into this single-arm, phase II clinical trial (NCT01782339). Participants were recruited from six centers and received four 21-day cycles of: Actinomycin D 1mg/m2, high dose Methotrexate 5-8g/m2 day 1, Paclitaxel 80mg/m2 days 1, 8 and 15, Oxaliplatin 85mg/m2 days 4 and 8 with Pegfilgrastim support. Participants underwent an FDG-PET scan at baseline, prior to cycle 2 and on completion of treatment. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS) and toxicity. Results: 44 patients received at least one dose of the study medication between November 2012 and February 2020. In this full analysis set (FAS) population, the median age was 38 (range 20-57), with 9 (20%) with seminoma, 23 (52%) non-seminoma and 12 (27%) of other histology. 31 (70%) patients had at least intermediate risk disease by IPFSG risk group criteria (n = 16, 36% intermediate risk, n = 6, 14% high risk, n = 9, 20% very high risk). 39 patients received 2 or more cycles of the treatment regimen and were deemed part of the subgroup of patients in the evaluable population. The ORR of the FAS population was 52.3% and 59.0% in the evaluable population. The metabolic response rate (MRR) was 52.3% in the FAS population and 59.0% in the evaluable population. The median radiological PFS in the FAS population was 17.0 months (95% CI, 5.7 months- not reached, NR) with a radiological PFS rate at two years of 38.7% (95% CI, 22.3%-54.9%). The median combined radiological or tumour marker PFS in the FAS population was 8.3 months (95% CI, 2.6 months-17.4 months) with a combined radiological or tumour marker PFS rate at two years of 28.9% (95% CI, 16.0%-43.1%). At a median follow-up of 26.8 months, the median OS in the FAS population was not reached (95% confidence interval [CI], 17.0 months-NR) with an OS rate at two years of 62.5% (95% CI, 46.1%-75.2%). Toxicity data and correlation between early metabolic response and outcomes will be presented at the meeting. Conclusions: The GAMMA chemotherapy regimen has demonstrated encouraging anti-tumor activity in relapsed GCT, despite recruiting a cohort of patients with relatively unfavorable outcomes. Clinical trial information: NCT01782339.

Contains fulltext : 170336.pdf (Publisher’s version ) (Open Access) Desmoid tumour/aggressive fibromatosis (DT/AF) is a rare soft-tissue neoplasm that is locally aggressive but does not metastasize. There is no standard systemic treatment for symptomatic patients, although a number of agents are used. Tyrosine kinase inhibitors have recently been reported to show useful activity. We reviewed our bi-institutional (Royal Marsden Hospital, Cambridge University Hospitals) experience with the tyrosine kinase inhibitor pazopanib in the treatment of progressing DT/AF. Eight patients with DT/AF were treated with pazopanib at Royal Marsden Hospital and Cambridge University Hospitals between June 2012 and June 2016. The median age of the patients was 37.5 (range: 27-60) years. The median duration of pazopanib treatment was 12 (range: 5-22) months and for three patients the treatment is ongoing. Three patients discontinued treatment early (patient preference, intolerable toxicity and logistical reasons, respectively). None of the patients showed radiological progression while on treatment, best responses according to Response Evaluation Criteria In Solid Tumors 1.1 were partial response in 3/8 and stable disease in 5/8 cases. Six patients derived clinical benefit from treatment in terms of improved function and/or pain reduction. Median progression-free survival was 13.5 (5-36) months. Only one patient experienced intolerable toxicity (grade 3 hypertension) leading to early treatment discontinuation. In our series of patients with DT/AF, pazopanib demonstrated important activity both in terms of symptom control (75%) and absence of radiological progression (100%). Results of ongoing confirmatory trials are eagerly awaited.

Objectives: The combination of 5-fluorouracil (5-FU), irinotecan and oxaliplatin (FOLFIRINOX) is considered the first-line chemotherapy for fit patients with advanced pancreatic ductal adenocarcinoma (PDAC) but carries an unfavourable adverse event (AE) profile. We retrospectively evaluated the tolerability and efficacy of a modified FOLFIRINOX (mFOLFIRINOX) regimen: intravenous oxaliplatin 85 mg/m2, irinotecan 135 mg/m2, folinic acid 400 mg/m2 and 5-FU infusion 2,400 mg/m2 over 46 h, with routine subcutaneous filgrastim on a 14-day cycle. Methods: Records of 18 patients with advanced PDAC who received treatment with mFOLFIRINOX were reviewed. Imaging of measurable disease was assessed for response, and survival was measured from the date of commencing chemotherapy to disease progression and/or death. Results: Grade 3 or 4 AEs (n; %) included vomiting (5; 28), nausea (4; 22), diarrhoea (3; 17) and non-neutropaenic fever (3; 17). For patients with stage IV disease, 12/15 (80%) achieved at least stable disease as the best radiological response, with 7/15 (47%) objective responses. In this subgroup, median overall and progression-free survival were 9.3 months (95% CI 8.3-10.4) and 7.2 months (95% CI 4.7-9.6), respectively. Conclusion: Compared to full-dose FOLFIRINOX, our modified regimen resulted in lower haematological but only marginally improved non-haematological toxicity rates, with comparable efficacy outcomes. Prospective studies are required to validate these findings.

Metastatic renal cancer is resistant to standard chemotherapy. Although some patients with indolent disease can be initially managed with observation, the majority of patients will require aggressive treatment soon after diagnosis. Options include cytoreductive nephrectomy, resection of a solitary metastasis in highly selected cases, or systemic therapy options. The TKIs sunitinib and pazopanib are currently the first-line treatments of choice. Whilst axitinib and cabozantinib have important roles in the second line the PD-1 checkpoint inhibitor, nivolumab, is now established as standard second line therapy. Inhibitors of the mammalian target of rapamycin (mTOR) pathway, everolimus and temsirolimus, interleukin-2 as well as the anti-angiogenic antibody bevacizumab have also been shown to be effective. The treatment paradigm of metastatic renal cancer is constantly changing as evidence from clinical trials continues to emerge. With the development of agents addressing novel targets such as T-cell regulation, the future certainly looks brighter for patients diagnosed with this disease.

Tyrosine kinase inhibitors have revolutionized the treatment of metastatic renal cell carcinoma (RCC). Drugs such as sorafenib, sunitinib and pazopanib act on the VEGF receptor pathway, but they can also inhibit other kinases, resulting in off-target toxicities. Tivozanib was developed due to its potency and selectivity against VEGF receptors 1-3. It has a favorable pharmacokinetic profile after oral administration and a long plasma half-life. In the Phase III TIVO-1 trial, it demonstrated a higher response rate and longer progression-free survival than sorafenib with a better side-effect profile. It is currently awaiting approval to be used in the first-line treatment of metastatic RCC. An early-phase trial has also shown its tolerability at full dose when given with the mTOR inhibitor temsirolimus, suggesting its potential in combination treatment. This article examines tivozanib from its laboratory to clinical development, as well as its relevance and future role in the treatment of RCC in the era of the tyrosine kinase inhibitors.

Introduction Phase I oncology trials have evolved over the years, and these changes could have implications for future studies and patients. Methods Adult trials sponsored by Cancer Research UK Centre for Drug Development between 1995 and 2013 were analysed. Forty-nine trials were divided into two groups based on the starting date for recruitment: 1995–2003 (24 trials, n = 603) and 2004–2013 (25 trials, n = 750) for comparative purposes. Results From 1995–2003 to 2004–2013, there was a shift towards studying non-cytotoxic agents that are administered orally. In later trials, patients tended to have better performance status, were older, had greater disease burden, and were more likely to have received prior treatment. In 2004–2013, wider variety of dose escalation designs were used, and studies were more likely to be multicentre, target/disease specific, conducted in first-/any-line setting and to require tumour biopsy. The overall incidence of dose-limiting toxicities (DLTs) was unchanged (10.9%; risk of death 0.4%), but DLTs such as neuropathy, stomatitis and thrombocytopaenia were less frequent in the more recent trials, while elevated liver enzymes were more frequent. Non-classical DLTs emerged in the later trials, including hypertension, hypophosphataemia, cardiac and ophthalmic toxicities. Disease control rate (DCR) increased from 27.9% (1995–2003) to 36.0% (2004–2013; P = 0.0033) due to higher rates of disease stabilisation. Conclusion Changes in trial designs, therapeutic agents, patient characteristics and DLTs were observed. Although the nature of DLTs changed, the incidence was similar in the two time periods and DCR improved, suggesting that the benefit-risk balance for patients participating in early-phase trials remains acceptable.

Metastasis accounts for the poor outcome of patients with pancreatic cancer. We recently discovered PRSS3 to be over-expressed in metastatic human pancreatic cancer cells. This study aimed to elucidate the role of PRSS3 in the growth and metastasis of human pancreatic cancer.PRSS3 expression in human pancreatic cancer cell lines was detected by qPCR and immunoblotting. The effect of PRSS3 on cancer cell proliferation, migration and invasion in vitro, tumour growth and metastasis in vivo were investigated by manipulation of PRSS3 expression in human pancreatic cancer cell lines. VEGF expression was detected by ELISA, and the pathway through which PRSS3 regulates VEGF expression was investigated. The therapeutic effect of targeting this pathway on metastasis was assessed in vivo. Immunohistochemistry was employed to detect PRSS3 expression in human pancreatic cancer tissues.PRSS3 was over-expressed in the metastatic PaTu8988s cell line, but not in the non-metastatic PaTu8988t cell line. Over-expression of PRSS3 promoted pancreatic cancer cell proliferation as well as invasion in vitro, and tumour progression and metastasis in vivo. Stepwise investigations demonstrated that PRSS3 upregulates VEGF expression via the PAR1-mediated ERK pathway. ERK inhibitor significantly delayed the progression of metastases of pancreatic cancer and prolonged the survival of animals bearing metastatic pancreatic cancer (p0.05). 40.54% of human pancreatic cancers (n=74) were positive for PRSS3 protein. A significant correlation was observed between PRSS3 expression and metastasis (p0.01). Multivariate Cox regression analysis indicated that patients with PRSS3 expression in their tumours had a shorter survival time compared to those without PRSS3 expression (p0.05).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.

Pancreatic cancer is a lethal disease and notoriously difficult to treat. Only a small proportion is curative by surgical resection, whilst standard chemotherapy for patients with advanced disease has only modest effect with substantial toxicity. Clearly there is a need for the continual development of novel therapeutic agents to improve the current situation. Improvement of our understanding of the disease has generated a large number of studies on biological approaches targeting the molecular abnormalities of pancreatic cancer, including gene therapy and signal transduction inhibition, antiangiogenic and matrix metalloproteinase inhibition, oncolytic viral therapy and immunotherapy. This article provides a review of these approaches, both investigated in the laboratories and in subsequent clinical trials.

403 Background: Metastatic germ cell tumour (GCT) to the liver is considered rare and usually caries adverse outcomes. We aimed to determine the outcome of patients with metastatic GCT to the liver. Methods: We identified retrospectively 36 patients with metastatic germ cell tumour to the liver between the years 2001 and 2015, from which 34 were non-seminomatous germ cell tumours (NSGCT) and two seminomas. 35 patients had other sites of metastases including lungs, bones and brain. Elevated tumour markers were seen in the vast majority of patients (97.2%). 15 patients received treatment with dose intense regime including actinomycin-D, high-dose methotrexate, etoposide and cisplatin (GAMEC) every 14 days, 20 patients received the standard protocol of bleomycin, etoposide and cisplatin (BEP) every 21 days and one patient received POMB/ACE chemotherapy. 20 patients had an induction cycle of cisplatin, vincristine and bleomycin (Baby-BOP) prior to initial treatment. Results: 12 patients had radiological complete response (CR) and 19 patients had radiological partial response (PR) in the liver, with five patients having a CR in all sites with negative markers. Five patients underwent liver resection with no viable tumour seen. Three patients that underwent liver resection also had retroperitoneal lymph node dissection (RPLND) the histology from which was viable seminoma in one case, mature teratoma in one case and necrosis in the final patient.16 patients had marker negative PR, 10 patients had marker positive PR and 5 patients had a marker negative CR. 15 patients eventually relapsed and 10 died with only one liver relapse. Median Overall survival for patients that received BEP was 35.38 months (not reached for GAMEC) (p = 0.0147). The median progression free survival (PFS) for the BEP group was 24.45 months (not reached for GAMEC) (p = 0.22) and the 2-years PFS for the GAMEC and BEP groups were 73% and 55% respectively. Conclusions: Within this cohort, liver metastasis from germ-cell tumour had a good response to chemotherapy, with progression occurring mainly in extra-hepatic sites. There was also a suggestion that dose dense GAMEC regime may offer superior efficacy compared with BEP.These results also question the role of liver metastectomy after initial response to chemotherapy.

Interferon-α (IFN-α) and interleukin-2 (IL-2) used to be the standard treatment for metastatic renal cell carcinoma (RCC), even at the beginning of the twenty-first century. However in recent years, increased understanding of the importance of angiogenesis in RCC progression has led to the development of the tyrosine kinase inhibitors (TKIs). TKIs have good oral bioavailability and have manageable side effects. More importantly, they have significant antitumoral efficacy with resulting prolongation of patient survival when used in the first-line setting or after failure of cytokine therapy.

► Nintedanib is an anti-angiogenic agent that has demonstrated activity in relapsed ovarian cancer. ► Our patient had prolonged response to nintedanib, allowing her to have potentially curative surgery 6 years after her diagnosis. ► The relationship between angiogenesis and BRCA mutation is worth exploring in ovarian cancer.

Oncolytic adenoviruses based on serotype 5 (Ad5) have several shortcomings, including the downregulation of its receptor in cancer cells, high prevalence of neutralizing antibodies and hepatotoxicity. Another adenoviral serotype, Ad11, could overcome these obstacles. Here, we show that human cancer cell lines express higher levels of the Ad11 receptor CD46, resulting in much better infectivity than Ad5. Surprisingly, only 36% (9/25) of the cell lines were more sensitive to Ad11- than to Ad5-mediated cytotoxicity. Investigations revealed that it was the transcription of Ad11 E1A, not CD46 expression or virus infectivity, which determined the cell's sensitivity to Ad11 killing. Ad11 E1A mRNA levels have an effect on viral DNA replication, structural protein synthesis and infectious particle production. To test the hypothesis that increased E1A transcription would lead to improved Ad11 replication in Ad5-sensitive (but Ad11-less sensitive) cells, two Ad11 mutants (Ad11-Ad5-P and Ad11-Ad5-EP) were constructed where either the E1A promoter or enhancer-promoter, respectively, was replaced by that of Ad5. Ad11-Ad5-EP demonstrated increased E1A mRNA levels and replication, together with enhanced oncolytic potency in vitro and in vivo. This effect was found in both the Ad5-sensitive and Ad11-sensitive cancer cells, broadening the range of tumors that could be effectively killed by Ad11-Ad5-EP.

Pancreatic cancer continues to be one of the most difficult malignancies to treat. It is ranked tenth in cancer incidence but is the fourth leading cause of cancer mortality [1]. At present, surgery for resectable tumor and gemcitabine-based chemotherapy for advanced disease are the main forms of treatment; yet disturbingly, its 5-year survival rate of 5% has not improved over the last 30 years. Clearly, there is an urgent need for new therapeutic strategies. Years of intensive research have made pancreatic cancer one of the most described diseases in terms of its molecular biology and pathogenesis, and with that, many therapeutic targets have been identified [2]. One example is the activation of the EGF-receptor (EGFR) signaling pathway. Erlotinib, an EGFR tyrosine kinase inhibitor, was the first targeted therapy to be approved by the US FDA in 2005 for pancreatic cancer treatment. Although it has shown a statistically significant benefit in combination with gemcitabine in a Phase III trial of advanced pancreatic cancer, improvement in survival was small (median survival of 6.24 vs 5.91 months with gemcitabine alone) and appears to favor a subgroup of patients, such as males and those who developed a more severe skin rash [3]. However, cetuximab, a monoclonal antibody that also inhibits EGFR, was ineffective against advanced pancreatic cancer [4]. In fact, a number of other targeted agents have been tested in Phase III trials, including those against VEGF (bevacizumab), gastrin (G17DT), gastrin receptor (gastrazole), Ras farnesyltransferase (tipifarnib) and matrix metalloproteinases (marimastat and tanomastat), but have all failed to make any measurable impact on patient survival [2]. More recently, a Phase III trial of immunotherapy using the GV1001 telomerase peptide vaccine (telomerase is expressed in the majority of pancreatic cancers and contributes to cell immortalization) was stopped prematurely as results showed no survival benefit in combination with gemcitabine in advanced pancreatic cancer patients [5].

2534 Background: Phase I oncology trials are crucial in cancer drug development and have evolved over the years. We examined the trends in trial characteristics, dose-limiting toxicities (DLTs) and...

2607 Background: AZD2014 (A) is a dual mTORC1/mTORC2 inhibitor and a previous phase I study determined the maximal tolerated dose (MTD) of A to be 50 mg BD 7/7. We have shown high p-P70S6K levels i...

Background Desmoplastic small round cell tumour (DSRCT) is a rare but frequently fatal sarcoma, and many of its characteristics still require further clarification. Methods We retrospectively analysed 41 patients treated at or referred to two regional referral centres in the UK between 1991 and 2012. A review of the current literature was also performed. Results The median age of presentation was 27 years (range 16 to 45 years), with a male-to-female ratio of 3:1. Ninety percent of patients had disease in the abdomen. The median size of the presenting tumour was 13 cm (range 3.5 to 23 cm), and 80% had metastatic disease at diagnosis, mainly in the liver (33%) and lungs (21%). Time-to-progression (TTP) was 3.9, 2.3 and 1.1 months after first-, second- and third-line chemotherapy, respectively. First-line treatment with VIDE chemotherapy appeared to confer the longest TTP (median 14.6 months). Ifosfamide and doxorubicin resulted in TTP of >3.8 months when used in any-line setting. Eleven patients received targeted agents as part of a clinical trial. After a median follow-up of 14 months, the overall median survival (MS) was 16 months. There was no difference in MS with regards to age, gender, or size of the presenting tumour. Patients with extra-abdominal disease survived longer compared to those with tumours in the abdomen (all still alive vs MS of 15 months; P = 0.0246). Patients with non-metastatic intra-abdominal disease who underwent surgery had an MS of 47 months (16 months for those who did not have surgery; P = 0.0235). Radiotherapy for locoregional control in patients with metastatic intra-abdominal DSRCT was associated with longer survival (MS of 47 vs 14 months; P = 0.0147). Conclusions DSRCT is a rare but often fatal disease that mainly affects younger male patients. Those with intra-abdominal DSRCT have a poorer prognosis, although surgical resection for localised disease and radiotherapy in the metastatic setting are associated with improved survival. A patient’s age, gender and size of presenting tumour do not have prognostic significance.

e21503 Background: Historically, GISTs were often misdiagnosed as other tumours. However, with the increasing awareness of GISTs, one needs to be careful in confirming the diagnosis since other tumours can simulate GISTs on endoscopy/imaging/histology. We report our 8 year experience of GIST mimics from the CGSG database. Methods: 250 cases discussed in the specialist multidisciplinary meeting from 2004 – 2012 were reviewed. Tumours initially suspected to be GISTs but turned out to be other tumours were included in this analysis. Patient demographics, endoscopic, imaging and histological features were analysed in 41 GIST mimics. Central review by specialist histopathologist was undertaken with immunohistochemical and molecular analysis to differentiate these tumours from GISTs. Results: GIST mimics N= 41. Median age 56 years (range 11 – 82 years), male:female ratio 1:1. Median size 8 cm (range 1.9 – 30 cm). Site of origin of tumours: stomach 34%, oesophagus/junction 15%, mesentery 12%, small bowel 10%, colon 5%, retroperitoneum 5%, pancreas 5%, liver 2% and indeterminate site of origin 12%. Suspicion of GIST was raised from imaging (46%), endoscopy (41%) and histology (39%). The histological subtypes of GIST mimics are summarised in the Table. Conclusions: Many benign and malignant tumours do mimic GISTs on imaging/endoscopy or histology. The diagnosis of GISTs should be made by a specialist multidisciplinary team with experience in imaging and histopathology. Distinguishing GISTs from their mimics is of critical importance both for prognosis and management. [Table: see text]

Background: Oncolytic virotherapy is a promising approach to treat cancers resistant to conventional therapies. Vaccinia virus, an enveloped DNA virus from the poxvirus family, has been used as a vector for cancer vaccines and oncolytic viral gene therapy. Wild type vaccinia virus has a natural tropism for cancer cells both in vitro and in vivo due to their increased proliferation, abnormalities in epidermal growth factor and interferon signalling, in addition to other unknown mechanisms. We have recently demonstrated that the anti-tumor efficacy of the Lister strain vaccinia virus, unlike some replicating oncolytic vectors, is not attenuated by hypoxia and even augmented 20 fold in some pancreatic ductal adenocarcinoma (PDAC) cells lines (CT Hiley et al. Gene Therapy 2009. In press). The underlying mechanism is not fully understood. Methods: Vascular Endothelial Growth Factor (VEGF) was detected by an enzyme-linked immunosorbent assay. The effect of VEGF on vaccinia virus infection in human cancer cells was investigated by manipulation of VEGF expression using siRNAs or gene over-expression. Normal human bronchial epithelial cells (NHBE) were used to assess the effect of VEGF on non-transformed cells. Results: Induction of VEGF by hypoxia was found in the supernatants of cancer cell lines showing sensitisation to vaccinia virus under hypoxia. Replication of vaccinia virus was correlated with the level of VEGF expression in a panel of human cancer cell lines. Knockdown of VEGF expression in Suit2 cells by siRNAs reduced transgene expression over 7 fold at 24 and 48 hours post infection (PI) (P Conclusion: This novel finding suggests that VEGF expression by cancer cells is at least partly responsible for some of the tumour tropism of wild type Lister vaccinia virus and highlights its suitability for use in poor prognosis tumour types, notably those with high levels of hypoxia and VEGF expression. Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 589.

Background Pulmonary 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. Methods Details of PAS patients treated at Papworth and Addenbrooke’s Hospitals between 2000 and 2014 were reviewed. Results Twenty 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. Conclusions PAS 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.