Safety of robotic cholecystectomy as index training procedure: the UK experience.

AIMS: To evaluate the safety profile of robotic cholecystectomy performed within the United Kingdom (UK) Robotic Hepatopancreatobiliary (HPB) training programme. METHODS: A retrospective evaluation of prospectively collected data from eleven centres participating in the UK Robotic HPB training programme was conducted. All adult patients undergoing robotic cholecystectomy for symptomatic gallstone disease or gallbladder polyp were considered. Bile duct injury, conversion to open procedure, conversion to subtotal cholecystectomy, length of hospital stay, 30-day re-admission, and post-operative complications were the evaluated outcome parameters. RESULTS: A total of 600 patients were included. The median age was 53 (IQR 65-41) years and the majority (72.7%; 436/600) were female. The main indications for robotic cholecystectomy were biliary colic (55.5%, 333/600), cholecystitis (18.8%, 113/600), gallbladder polyps (7.7%, 46/600), and pancreatitis (6.2%, 37/600). The median length of stay was 0 (IQR 0-1) days. Of the included patients, 88.5% (531/600) were discharged on the day of procedure with 30-day re-admission rate of 5.5% (33/600). There were no bile duct injuries and the rate of conversion to open was 0.8% (5/600) with subtotal cholecystectomy rate of 0.8% (5/600). CONCLUSION: The current study confirms that robotic cholecystectomy can be safely implemented to routine practice with a low risk of bile duct injury, low bile leak rate, low conversion to open surgery, and low need for subtotal cholecystectomy.

Pancreatic Incidentalomas on CT Colonography: Ignore, Follow up or Investigate?

Background: Increasing use of cross-sectional abdominal imaging such as CT colonography (CTC), has resulted in increased identification of incidental pancreatic cystic lesions. Such incidental findings are a cause for anxiety amongst patients and clinicians and can result in increased cost to healthcare delivery resultant from referral to subsequent investigations. Our study explored the prevalence of incidental cystic pancreatic lesions on CTC at a tertiary pancreatic centre, and their management. Methods: A detailed review of CTC reports and patient case notes between 2010-2016 was undertaken. Patients from both screening (National Bowel Cancer Screening) and non-screening cohorts were included in our study. Results: 136 of 4666 patients who underwent CTC had an incidental finding of a pancreatic lesion (2.9%) and 117 confirmed cystic pancreatic lesions (2.5%). Radiological diagnosis of intraductal papillary mucinous neoplasm (IPMN) was available in the CTC report for 71 patients. Twelve patients (0.2%) were found to have pancreatic ductal adenocarcinoma (PDAC) incidentally at CTC, 2 resectable and 10 unresectable with the diagnosis confirmed on biopsy. Follow-up surveillance imaging recommendations were made for 39.3% of patients within one year of the diagnosis of a cystic pancreatic lesion on CTC. One patient with pancreatic duct dilatation of 7mm was lost in follow-up and was found to develop PDAC at 21 months. Conclusions: Pancreatic lesions are increasingly found incidentally on CTC. All patients with pancreatic cystic tumour should be referred to pancreatic multidisciplinary team for discussion to determine management pathway.

Transition from open and laparoscopic to robotic pancreaticoduodenectomy in a UK tertiary referral hepatobiliary and pancreatic centre - Early experience of robotic pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy is performed using an open technique (OPD) as the gold standard. An increase in those performed laparoscopically (LPD) and robotically (RPD) are now reported. We compared the short-term outcomes of RPD cases with LPD and OPD. METHODS: A retrospective review of a prospectively collected database was undertaken of our first consecutive RPD, our first LPD and consecutive OPD cases. Those requiring venous and/or arterial resection were excluded. RESULTS: RPD (n = 25) had longer median operating times (461 (IQR 358-564) mins) than LPD (n = 41) (330 (IQR 262.5-397.5) mins) and OPD (n = 37) (330 (IQR 257-403) mins, p < 0.0001). Estimated blood loss and transfusion requirement was less after RPD and LPD compared to OPD (p = 0.012 and p < 0.0001 respectively). No RPD cases required conversion to open operation compared to 24.4% of LPD. Morbidity was comparable with a Clavien Dindo score ≥3 in 20.00%, 24.39% and 18.92% for RPD, LPD and OPD respectively (p = 0.83). Post-operative pancreatic fistula rates were seen in 16.00%, 29.27% and 21.62% of our RPD, LPD and OPD cohorts respectively (p = 0.81). 90-day mortality was seen in 0.97% of the total cohort. Length of hospital stay (LOS) was shorter for RPD compared to both LPD (p = 0.030) and OPD (p = 0.002). CONCLUSION: RPD is safe to perform with comparable outcomes to LPD and OPD. Further evidence is provided that a randomised controlled trial for PD techniques is required.

Isolated limb perfusion with melphalan, tumour necrosis factor-alpha and oncolytic vaccinia virus improves tumour targeting and prolongs survival in a rat model of advanced extremity sarcoma.

Isolated limb perfusion (ILP) is a treatment for advanced extremity sarcoma and in-transit melanoma. Advancing this procedure by investigating the addition of novel agents, such as cancer-selective oncolytic viruses, may improve both the therapeutic efficacy of ILP and the tumour-targeted delivery of oncolytic virotherapy. Standard in vitro assays were used to characterise single agent and combinatorial activities of melphalan, tumour necrosis factor-alpha (TNF-α) and Lister strain vaccinia virus (GLV-1h68) against BN175 rat sarcoma cells. An orthotopic model of advanced extremity sarcoma was used to evaluate survival of animals after ILP with combinations of TNF-α, melphalan and GLV-1h68. We investigated the efficiency of viral tumour delivery by ILP compared to intravenous therapy, the locoregional and systemic biodistribution of virus after ILP, and the effect of mode of administration on antibody response. The combination of melphalan and GLV-1h68 was synergistic in vitro. The addition of virus to standard ILP regimens was well tolerated and demonstrated superior tumour targeting compared to intravenous administration. Triple therapy (melphalan/TNF-α/GLV-1h68) resulted in increased tumour growth delay and enhanced survival compared to other treatment regimens. Live virus was recovered in large amounts from perfused regions, but in smaller amounts from systemic organs. The addition of oncolytic vaccinia virus to existing TNF-α/melphalan-based ILP strategies results in survival advantage in an immunocompetent rat model of advanced extremity sarcoma. Virus administered by ILP has superior tumour targeting compared to intravenous delivery. Further evaluation and clinical translation of this approach is warranted.

Successful thrombolysis of a late acute thrombotic occlusion of an aortic prosthesis after endovascular aneurysm repair.

A 79-year-old man with a previous endovascular aneurysm repair (EVAR) for a 5.4-cm abdominal aortic aneurysm presented 3 years after the procedure with sudden onset lower limb paralysis and pain. The diagnosis of acute aortic thrombosis within the aortic prosthesis graft was made and confirmed on computed tomography. Thrombolysis delivered into the graft via a radiologically placed catheter successfully dissolved the thrombus and resulted in improvement of the patient's symptoms. We discuss the presentation of, and role in management of thrombolysis in, this rare complication of aneurysm repair.

What are the true benefits of robotic pancreaticoduodenectomy for patients with pancreatic cancer?

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease, and multimodal treatment including high-quality surgery can improve survival outcomes. Pancreaticoduodenectomy (PD) has evolved with minimally invasive approaches including the implementation of robotic PD (RPD). In this special report, we review the literature whilst evaluating the 'true benefits' of RPD compared to open approach for the treatment of PDAC. AREAS COVERED: We have performed a mini-review of studies assessing PD approaches and compared intraoperative characteristics, perioperative outcomes, post-operative complications and oncological outcomes. EXPERT OPINION: RPD was associated with similar or longer operative times, and reduced intra-operative blood loss. Perioperative pain scores were significantly lower with shorter lengths of stay with the robotic approach. With regards to post-operative complications, post-operative pancreatic fistula rates were similar, with lower rates of clinically relevant fistulas after RPD. Oncological outcomes were comparable or superior in terms of margin status, lymph node harvest, time to chemotherapy and survival between RPD and OPD. In conclusion, RPD allows safe implementation of minimally invasive PD. The current literature shows that RPD is either equivalent, or superior in certain aspects to OPD. Once more centers gain sufficient experience, RPD is likely to demonstrate clear superiority over alternative approaches.

Targeted gene delivery by free-tissue transfer in oncoplastic reconstruction.

Surgery is the most effective curative treatment for various tumour types. Despite a current preference for conservative surgery, radical excision retains a clearly defined role in modern management of locoregional disease. Extirpative defects are reconstructed routinely using free-tissue transfer from a distant donor site. Although these free flaps currently provide no direct therapeutic benefit, advances in gene-delivery techniques offer the possibility to genetically modify flaps to produce potent targeted treatments with greater anatomical control. Several promising therapeutic strategies, including virus-directed enzyme prodrug therapy, genetic radionuclide therapy, and free-flap radioprotection, have the potential to extend the role of the free flap beyond its immediate goal of restoring form and function to patients, but challenges exist. Work to translate therapeutic free-tissue transfer from preclinical study to clinical use is in progress.

Which patients benefit from preoperative biliary drainage in resectable pancreatic cancer?

Recent studies have indicated that preoperative biliary drainage (PBD) should not be routinely performed in all patients suffering from obstructive jaundice before pancreatic surgery. The severity of jaundice that mandates PBD has yet to be defined. The evaluated paper examines the impact of PBD on intra-operative, and post-operative outcomes in patients initially presenting with severe obstructive jaundice (bilirubin ≥250 µmol/L). In this key paper evaluation, the impact of PBD versus a direct surgery (DS) approach is discussed. The arguments for and against each approach are considered with regards to drainage associated morbidity and mortality, resection rates, survival and the impact of chemotherapy and malnutrition. Concentrating on resectable head of pancreas tumors, this mini-review aims to scrutinize the authors' recommendations, alongside those of prominent papers in the field.

Rapid Induction of Liver Regeneration for Major Hepatectomy (REBIRTH): A Randomized Controlled Trial of Portal Vein Embolisation versus ALPPS Assisted with Radiofrequency.

To avoid liver insufficiency following major hepatic resection, portal vein embolisation (PVE) is used to induce liver hypertrophy pre-operatively. Associating liver partition with portal vein ligation for staged hepatectomy assisted with radiofrequency (RALPPS) was introduced as an alternative method. A randomized controlled trial comparing PVE with RALPPS for the pre-operative manipulation of liver volume in patients with a future liver remnant volume (FLRV) ≤25% (or ≤35% if receiving preoperative chemotherapy) was conducted. The primary endpoint was increase in size of the FLRV. The secondary endpoints were length of time taken for the volume gain, morbidity, operation length and post-operative liver function. Between July 2015 and October 2017, 57 patients were randomised to RALPPS (n = 29) and PVE (n = 28). The mean percentage of increase in the FLRV was 80.7 ± 13.7% after a median 20 days following RALPPS compared to 18.4 ± 9.8% after 35 days (p < 0.001) following PVE. Twenty-four patients after RALPPS and 21 after PVE underwent stage-2 operation. Final resection was achieved in 92.3% and 66.6% patients in RALPPS and PVE, respectively (p = 0.007). There was no difference in morbidity, and one 30-day mortality after RALPPS (p = 0.991) was reported. RALPPS is more effective than PVE in increasing FLRV and the number of patients for surgical resection.

Regional chemotherapy by isolated limb perfusion prior to surgery compared with surgery and post-operative radiotherapy for primary, locally advanced extremity sarcoma: a comparison of matched cohorts.

BACKGROUND: Induction chemotherapy by isolated limb perfusion (ILP) with melphalan and tumour necrosis factor-α is an effective strategy to facilitate limb-conserving surgery in locally advanced extremity sarcoma. In a comparison of cohorts matched for grade, size and surgical resectability, we compared the outcome of patients undergoing induction ILP prior to limb-conserving surgery and selective post-operative radiotherapy with patients undergoing limb-conserving surgery and routine post-operative radiotherapy. METHODS: Patients with primary, grade 2/3 sarcomas of the lower limbs over 10 cm in size were identified from prospectively maintained databases at 3 centres. Patients treated at a UK centre underwent limb-conserving surgery and post-operative radiotherapy (Standard cohort). Patients at two German centres underwent induction ILP, limb-conserving surgery and selective post-operative radiotherapy (ILP cohort). RESULTS: The Standard cohort comprised 80 patients and the ILP cohort 44 patients. Both cohorts were closely matched in terms of tumour size, grade, histological subtype and surgical resectability. The median age was greater in the Standard vs the ILP cohort (60.5 years vs 56 years, p = 0.033). The median size was 13 cm in both cohorts. 5-year local-recurrence (ILP 12.2%, Standard 20.1%, p = 0.375) and distant metastases-free survival rates (ILP 49.6%, Standard 46.0% p = 0.821) did not differ significantly between cohorts. Fewer patients received post-operative radiotherapy in the ILP cohort compared with the Standard cohort (27% vs 82%, p < 0.001). CONCLUSION: In comparative cohorts, the outcomes of patients undergoing induction ILP prior to surgery did not differ from those undergoing standard management, although induction ILP was associated with a reduced need for adjuvant radiation.

A totally laparoscopic associating liver partition and portal vein ligation for staged hepatectomy assisted with radiofrequency (radiofrequency assisted liver partition with portal vein ligation) for staged liver resection.

In order to induce liver hypertrophy to enable liver resection in patients with a small future liver remnant (FLR), various methods have been proposed in addition to portal vein embolisation (PVE). Most recently, the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique has gained significant international interest. This technique is limited by the high morbidity associated with an in situ liver splitting and the patient undergoing two open operations. We present the case of a variant ALPPS technique performed entirely laparoscopically with no major morbidity or mortality. An increased liver volume of 57.9% was seen after 14 days. This technique is feasible to perform and compares favourably to other ALPPS methods whilst gaining the advantages of laparoscopic surgery.

Oncolytic vaccinia virus combined with radiotherapy induces apoptotic cell death in sarcoma cells by down-regulating the inhibitors of apoptosis.

Advanced extremity melanoma and sarcoma present a significant therapeutic challenge, requiring multimodality therapy to treat or even palliate disease. These aggressive tumours are relatively chemo-resistant, therefore new treatment approaches are urgently required. We have previously reported on the efficacy of oncolytic virotherapy (OV) delivered by isolated limb perfusion. In this report, we have improved therapeutic outcomes by combining OV with radiotherapy. In vitro, the combination of oncolytic vaccinia virus (GLV-1h68) and radiotherapy demonstrated synergistic cytotoxicity. This effect was not due to increased viral replication, but mediated through induction of intrinsic apoptosis. GLV-1h68 therapy downregulated the anti-apoptotic BCL-2 proteins (MCL-1 and BCL-XL) and the downstream inhibitors of apoptosis, resulting in cleavage of effector caspases 3 and 7. In an in vivo ILP model, the combination of OV and radiotherapy significantly delayed tumour growth and prolonged survival compared to single agent therapy. These data suggest that the virally-mediated down-regulation of anti-apoptotic proteins may increase the sensitivity of tumour cells to the cytotoxic effects of ionizing radiation. Oncolytic virotherapy represents an exciting candidate for clinical development when delivered by ILP. Its ability to overcome anti-apoptotic signals within tumour cells points the way to further development in combination with conventional anti-cancer therapies.

Optimising measles virus-guided radiovirotherapy with external beam radiotherapy and specific checkpoint kinase 1 inhibition.

BACKGROUND AND PURPOSE: We previously reported a therapeutic strategy comprising replication-defective NIS-expressing adenovirus combined with radioiodide, external beam radiotherapy (EBRT) and DNA repair inhibition. We have now evaluated NIS-expressing oncolytic measles virus (MV-NIS) combined with NIS-guided radioiodide, EBRT and specific checkpoint kinase 1 (Chk1) inhibition in head and neck and colorectal models. MATERIALS AND METHODS: Anti-proliferative/cytotoxic effects of individual agents and their combinations were measured by MTS, clonogenic and Western analysis. Viral gene expression was measured by radioisotope uptake and replication by one-step growth curves. Potential synergistic interactions were tested in vitro by Bliss independence analysis and in in vivo therapeutic studies. RESULTS: EBRT and MV-NIS were synergistic in vitro. Furthermore, EBRT increased NIS expression in infected cells. SAR-020106 was synergistic with EBRT, but also with MV-NIS in HN5 cells. MV-NIS mediated (131)I-induced cytotoxicity in HN5 and HCT116 cells and, in the latter, this was enhanced by SAR-020106. In vivo studies confirmed that MV-NIS, EBRT and Chk1 inhibition were effective in HCT116 xenografts. The quadruplet regimen of MV-NIS, virally-directed (131)I, EBRT and SAR-020106 had significant anti-tumour activity in HCT116 xenografts. CONCLUSION: This study strongly supports translational and clinical research on MV-NIS combined with radiation therapy and radiosensitising agents.

Does the two-week rule pathway improve the diagnosis of soft tissue sarcoma? A retrospective review of referral patterns and outcomes over five years in a regional sarcoma centre.

INTRODUCTION: The NHS Cancer Plan was introduced in 2000 and included guidelines for the rapid assessment and referral of cases of suspected malignancy. We wished to assess the efficiency and appropriateness of patients referred under the Department of Health's general practitioner referral guidelines implemented for sarcomas in December 2000. PATIENTS AND METHODS: A retrospective case-note review was performed of all patients referred to our regional soft tissue sarcoma unit between 1 January 2004 and 31 December 2008. Patients referred under the two-week guidelines and all patients referred routinely were analysed. The main outcome measures were the total number of patients referred on the basis of the two-week guidelines and the proportion they constitute of all referrals. The referring criteria were noted and compared to the observed criteria recorded. The final histological diagnosis of patients referred on the basis of the two-week guidelines are documented. RESULTS: A total of 2746 referrals for suspected sarcoma were made from January 2004 to December 2008. Of these, 154 referrals were made under the two-week rule of which 102 were referred purely on the clinical criteria for suspected soft tissue sarcoma. The remaining patients were referred after non-urgent special investigations indicated the possibility of sarcoma. Twelve patients referred under the two-week rule were proved to have sarcoma, nine after specific investigations including imaging or histological diagnosis. Of the 102 patients referred on clinical suspicion of a sarcoma, two patients had proven soft tissue sarcomas and one patient a cutaneous sarcoma. Between 2004 and 2008, the number of 2-week referrals rose 25-fold but accounted for an increase of less than 1% of the sarcomas treated in this unit. CONCLUSIONS: The numbers of all referrals for suspected sarcoma are increasing; however, the rate of increase of 2-week referrals is increasing faster than routine referrals and will exceed it in 2012 if current trends continue. There has not been a commensurate rise in the detection of sarcoma or, more specifically, diagnosis of the deep sarcomas associated with worse prognosis. Current clinical guidelines have essentially had no impact on the early diagnosis and treatment of soft tissue sarcoma, and may negatively impact on the treatment of patients with proven sarcoma by delaying treatment within a regional centre because of redirection of a large number of patients with benign abnormalities to such centres.