Synergistic cytotoxicity of oncolytic reovirus in combination with cisplatin-paclitaxel doublet chemotherapy.

Oncolytic reovirus is currently under active investigation in a range of tumour types. Early phase studies have shown that this agent has modest monotherapy efficacy and its future development is likely to focus on combination regimens with cytotoxic chemotherapy. Indeed, phase I/II clinical trials have confirmed that reovirus can be safely combined with cytotoxic drugs, including a platin-taxane doublet regimen, which is currently being tested in a phase III clinical trial in patients with relapsed/metastatic head and neck cancer. Therefore, we have tested this triple (reovirus, cisplatin, paclitaxel) combination therapy in a panel of four head and neck cancer cell lines. Using the combination index (CI) method, the triple therapy demonstrated synergistic cytotoxicity in vitro in both malignant and non-malignant cell lines. In head and neck cancer cell lines, this was associated with enhanced caspase 3 and 7 cleavage, but no increase in viral replication. In vitro analyses confirmed colocalisation of markers of reovirus infection and caspase 3. Triple therapy was significantly more effective than reovirus or cisplatin-paclitaxel in athymic nude mice. These data suggest that the combination of reovirus plus platin-taxane doublet chemotherapy has significant activity in head and neck cancer and underpin the current phase III study in this indication.

Combination of a fusogenic glycoprotein, pro-drug activation and oncolytic HSV as an intravesical therapy for superficial bladder cancer.

BACKGROUND: There are still no effective treatments for superficial bladder cancer (SBC)/non-muscle invasive bladder cancer. Following treatment, 20% of patients still develop metastatic disease. Superficial bladder cancer is often multifocal, has high recurrences after surgical resection and recurs after intravesical live Bacillus Calmette-Guérin. Oncovex(GALV/CD), an oncolytic herpes simplex virus-1, has shown enhanced local tumour control by combining oncolysis with the expression of a highly potent pro-drug activating gene and the fusogenic glycoprotein. METHODS: In vitro fusion/prodrug/apoptotic cell-based assays. In vivo orthotopic bladder tumour model, visualised by computed microtomography. RESULTS: Treatment of seven human bladder carcinoma cell lines with the virus resulted in tumour cell killing through oncolysis, pro-drug activation and glycoprotein fusion. Oncovex(GALV/CD) and mitomycin C showed a synergistic effect, whereas the co-administration with cisplatin or gemcitabine showed an antagonistic effect in vitro. Transitional cell cancer (TCC) cells follow an apoptotic cell death pathway after infection with Oncovex(GALV/CD) with or without 5-FC. In vivo results showed that intravesical treatment with Oncovex(GALV/CD) + prodrug (5-FC) reduced the average tumour volume by over 95% compared with controls. DISCUSSION: Our in vitro and in vivo results indicate that Oncovex(GALV/CD) can improve local tumour control within the bladder, and potentially alter its natural history.

Long-term effects of clinical interventions on nutritional status in patients with chronic pancreatitis - A systematic review.

BACKGROUND AND AIMS: Malnutrition in chronic pancreatitis is complex and multifactorial, with malabsorption, pain, toxic dependencies and co-morbidities, such as diabetes, each playing a role. The aims of this systematic review were to assess the impact of nutritional intervention on markers of nutritional status in this complex patient group. MATERIALS AND METHODS: A systematic review of EMBASE and PubMed was carried out in February 2020, identifying 2620 articles. After screening to exclude those reporting short term changes (less than 3 months), with only one data point, or in the wrong population, eight papers were selected for analysis. RESULTS: Seven studies documented the impact of a nutritional intervention, one was an observational study only. Overall, studies were limited by predominantly retrospective designs, heterogenous populations and poor control of potentially confounding variables. Data could not be combined due to variability in reporting methods. All studies exploring nutritional intervention, whether that consisted of advice by a specialist dietitian, dose escalation of pancreatic enzymes, oral nutritional supplements or enteral feeding, demonstrated improved body weight and pain control, whereas patients who did not receive an intervention deteriorated nutritionally. CONCLUSION: Patients with chronic pancreatitis benefit from nutritional intervention. Further work is required to explore the impact of nutritional intervention on body composition and functional outcomes.

Long-term changes in nutritional status and body composition in patients with malignant pancreatic disease - A systematic review.

BACKGROUND AND AIMS: Patients with pancreatic cancer often experience significant deterioration in nutritional status over time. Malnutrition is complex and multifactorial, with malabsorption, pain, toxic dependencies, co-morbidities and malignant processes all playing a role. The aims of this systematic review were to assess nutritional changes over time and identify tolerance of nutritional intervention, thus identifying potential areas for further research to improve patient outcomes. MATERIALS AND METHODS: A systematic review of MEDLINE, EMBASE and PubMed was carried out in February 2020, identifying 2620 articles. After screening to exclude those reporting short-term measures, with only one data point, or in the wrong population, thirteen papers were selected for analysis (four trials in neo-adjuvant treatment, five in populations undergoing palliative treatment for pancreatic cancer, and four in mixed populations undergoing pancreatic resection). RESULTS: Overall, studies were limited by predominantly retrospective designs, and poor control of potentially confounding variables. Meta-analysis could not be performed due to heterogenicity in study design and reporting methods. Surgery in mixed cohorts did not appear to result in weight loss. Only one small intervention study was identified. Patients with pancreatic cancer experienced a decline in nutritional status, with 44-63% of patients undergoing neoadjuvant chemotherapy having low muscle mass prior to starting treatment. CONCLUSION: There is a paucity of data regarding nutritional intervention in pancreatic cancer. Future work should include the use of validated functional and clinical assessment tools to further explore the impact of nutritional intervention, and the relationship between nutritional status and outcome.

Locoregional intravascular viral therapy of cancer: precision guidance for Paris's arrow?

Viral therapy of cancer includes strategies such as viral transduction of tumour cells with 'suicide genes', using viral infection to trigger immune-mediated tumour cell death and using oncolytic viruses for their direct anti-tumour action. However, problems still remain in terms of adequate viral delivery to tumours. A role is also emerging for single-organ isolation and perfusion. Having begun with the advent of isolated limb perfusion for extremity malignancy, experimental systems have been developed for the perfusion of other organs, particularly the liver, kidneys and lungs. These are beginning to be adopted into clinical treatment pathways. The combination of these two modalities is potentially significant. Locoregional perfusion increases the exposure of tumour cells to viral agents. In addition, the avoidance of systemic elimination through the immune and reticulo-endothelial systems should provide a mechanism for increased transduction/infection of target cells. The translation of laboratory research to clinical practice would occur within the context of perfusion programmes, which are already established in the clinic. Many of these programmes include the use of vasoactive cytokines such as tumour necrosis factor-alpha, which may have an effect on viral uptake. Evidence of activation of specific anti-tumour immunological responses by intratumoural and other existing methods of viral administration raises the intriguing possibility of a locoregional therapy, with the ability to affect distant sites of disease. In this review, we examined the state of the literature in this area and summarized current findings before indicating likely areas of continuing interest.

Prognostic relevance of the posterior resection margin for predicting disease free survival in ampullary adenocarcinoma.

BACKGROUND: Pancreaticoduodenectomy is the only curative treatment option for patients with resectable ampullary adenocarcinoma (AA). Excellent disease free survival (DFS) can be achieved in patients with clear resection margins but it is poorly understood which patients are at increased risk of recurrence and hence would benefit from adjuvant chemotherapy. There is evolving evidence that the anatomical location of incomplete resection margins influences DFS in pancreatic adenocarcinoma. It is unknown if this also pertains to AA and therefore this study aimed to assess individual resection margin status and other predictors of DFS in AA. MATERIAL & METHODS: Consecutive patients undergoing pancreaticoduodenectomy for AA at our institution from 1996 to 2017 were analysed. Pancreas neck, posterior and superior mesenteric vein margins were assessed individually. Cox proportional hazards modelling was used to identify predictors of 5-year DFS. Factors with p < 0.1 on univariate analysis were included for multivariate analysis. RESULTS: Analysis of 104 patients revealed median OS and DFS of 56 and 34 months, respectively. Predictors associated with worse DFS on multivariate analysis were T3-stage (HR 3.6, p = 0.048), N1 (HR 2.9, p = 0.01) and N2 -stage (HR 3.6, p = 0.006), R1 status at the posterior margin (HR 3.0, p = 0.009) and a visible mass on CT (HR 2.0, p = 0.039). CONCLUSION: Routine histopathological assessment of individual resection margins may aid in predicting recurrence of AA. Future studies to assess if routine mesopancreas excision during pancreaticoduodenectomy can reduce the incidence of R1 status at the posterior margin are warranted.

Portal hypertension and chylous ascites complicating acute pancreatitis: the therapeutic value of portal vein stenting.

Chylous ascites as a consequence of acute pancreatitis is very rare. We present an unusual case of a 73-year-old man who developed refractory chylous ascites one month after an acute severe episode of gallstone pancreatitis, associated with portal hypertension. He was successfully treated with portal vein stenting, which has remained patent to date.

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in (V600D/E)BRAF mutant melanoma depends on JNK and TNF-α signaling.

Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of-concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV-1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in (V600D)BRAF/(V600E)BRAF mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in (V600D)BRAF/(V600E)BRAF mutant cell lines and this was associated with TNF-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors.

Oncolytic Vaccinia virus and radiotherapy in head and neck cancer.

OBJECTIVE: Oncolytic forms of attenuated Vaccinia virus are now in clinical development, assessing the compatibility of this novel treatment with radiotherapy may reveal exploitable synergistic relationships. MATERIALS AND METHODS: In vitro analyses of cell killing, cell cycle effects and caspase activation were carried out on HN3, HN5, CAL27, Detroit, SIHN5B, and PJ41 cells. In vivo studies of the virus and X-radiation were performed on H&N xenografts in CD1 nude mice. RESULTS: Cell killing in vitro was demonstrated to be dose- and time-dependent. Infection causes an increase in S-phase and sub-G1 cells. A dose dependent increase in active caspase-3 indicated induction of apoptosis. Xenografts injected with Vaccinia stabilised and frequently completely regressed. Combination with radiation generated additional cell death, induction of caspase activity and in vivo further improved long term regression rates. CONCLUSIONS: These data support continued exploration of this therapy combination and indicates potential for clinical trials in head and neck cancer.

Treatment for breast sarcoma: a large, single-centre series.

AIMS: To report outcomes in breast sarcoma in the context of a major series from a tertiary referral centre. METHODS: Retrospective analysis was performed on patients with histologically-proven breast sarcoma treated between 1996 and 2006. Kaplan-Meier survival curves were constructed and differences assessed by Log-Rank and Wilcoxon tests. RESULTS: 63 patients were identified; 57 underwent treatment with curative intent. 24 patients had undergone previous radiotherapy. 36 patients who underwent primary surgery elsewhere were referred for further treatment, of which 22 had at least one involved margin from primary resection. Surgery performed and margins status varied between patients undergoing primary surgery at this institution (n = 21; WLE = 8, mastectomy = 12, chest wall resection = 1, involved margins = 2 [10%]) or at a referring institution (n = 36; lumpectomy = 25, mastectomy = 11, involved margins = 22 [61%]), although there was no difference in tumour size or previous radiotherapy status. Previous irradiation was associated with poor prognosis. A greater proportion of these patients required primary mastectomy to ensure adequate clearance; the majority of the post-irradiation tumours were angiosarcomas (15/19) and significantly more relapsed locally (P < 0.001). All patient disease-free survival (DFS) rates were 71% at 2 and 42% at 5 years. DFS improved when primary surgery was undertaken at a high-volume sarcoma unit; 2-yr 84%vs75%; 5-yr 58%vs37%. There was a trend towards worse DFS with increasing size and increasing grade of tumour but this did not attain significance. CONCLUSIONS: Radiation-induced breast sarcoma has worse local recurrence rates compared to primary breast sarcoma. Involved margins were fewer at a specialist unit, which may translate into improved outcome.

The surgical management of soft tissue tumours arising in the abdominal wall.

BACKGROUND: Soft-tissue tumours can occur at almost any site, including the abdominal wall and represent a biologically diverse group of benign and malignant tumours. METHODS: A prospectively-kept database was searched to identify all patients with tumours resected that involved the abdominal wall. The histological diagnosis, complication rates and local recurrence rates were reported. Kaplan-Meier analysis of prognostic factors was determined for patients with primary abdominal wall sarcomas. RESULTS: Ninety-two patients underwent resection for tumours involving the abdominal wall. Desmoid tumours (n=30) and primary soft-tissue sarcomas (n=25) were the most common pathologies. Of 92 patients undergoing resection 87 required reconstruction of the abdominal wall defect with polypropelene mesh but only 2 patients required reconstruction of the overlying skin. There were no immediate surgical complications in patients who underwent isolated abdominal wall reconstruction and the long term incision hernia rate was 4%. Kaplan-Meier analysis for patients with primary abdominal wall sarcomas showed that local recurrence was higher in tumours>10cm (p=0.0024) and in high grade tumours (p=0.0021). Disease-specific survival was worst in high grade tumours (p=0.0010) and tumours>10cm (p=0.0042). Desmoid tumours did not recur in any patient after abdominal wall resection, irrespective of microscopic margins. CONCLUSIONS: Tumours involving the abdominal wall exhibit a wide range of pathologies. Abdominal wall reconstruction can be achieved in the vast majority of cases with mesh reconstruction alone with little surgical morbidity. Sarcomas carry a significant risk of local recurrence. Abdominal wall fibromatosis carries a better prognosis than fibromatosis arising in the extremities.