Single stage management of suspected gallbladder cancer guided by intraoperative frozen section analysis: A retrospective cohort study.

BACKGROUND: The management of radiologically suspected gallbladder cancers (GBC) that lack definitive radiological features usually involves performing a first-stage routine laparoscopic cholecystectomy, followed by an open second-stage liver resection (segments IVB and V) and hilar lymphadenectomy (extended cholecystectomy) if subsequent formal histology confirms a malignancy. Performing a cholecystectomy with an intraoperative frozen section to guide the need for conversion to an extended cholecystectomy as a single-stage procedure has multiple benefits compared to a two-stage approach. However, the safety and efficacy of this approach have not yet been evaluated in a tertiary setting. METHODS: A retrospective cohort study was performed using a database of all consecutive patients with suspected GBC who had been referred to our tertiary unit. Following routine cholecystectomy, depending on the operative findings, the gallbladder specimen was removed and sent for frozen-section analysis. If malignancy was confirmed, the depth of tumour invasion was evaluated, followed by simultaneous extended cholecystectomy, when appropriate. The sensitivity and specificity of frozen section analysis for the diagnosis of GBC were measured using formal histopathology as a reference standard. RESULTS: A total of 37 consecutive cholecystectomies were performed. In nine cases, GBC was confirmed by intraoperative frozen section analysis, three of which had standard cholecystectomy only as their frozen section showed adenocarcinoma to be T1a or below (n=2) or were undetermined (n=1). In the remaining six cases, malignant invasion beyond the muscularis propria (T1b or above) was confirmed; thus, a synchronous extended cholecystectomy was performed. The sensitivity (95% CI 66.4%-100%) and specificity (95% CI 87.7%-100%) for identifying GBC using frozen section analysis were both 100%. The net cost of the single-stage pathway in comparison to the two-stage pathway resulted in overall savings of £3894. CONCLUSION: Intraoperative frozen section analysis is a reliable tool for guiding the use of a safe, single-stage approach for the management of GBC in radiologically equivocal cases. In addition to its lower costs compared to a conventional two-stage procedure, intraoperative analysis also affords the benefit of a single hospital admission and single administration of general anaesthesia, thus greatly enhancing the patient's experience and relieving the burden on waiting lists.

Pancreaticoduodenectomy with right hemicolectomy for advanced malignancy: a single UK hepatopancreaticobiliary centre experience.

AIM: Locally advanced intestinal neoplasms including colon cancer may require radical en bloc pancreaticoduodenectomy and right hemicolectomy (PD-RC) to achieve curative, margin-negative resection, but the safety and benefit of this uncommon procedure has not been established. The Association of Coloproctology of Great Britain and Ireland IMPACT initiative has also highlighted a lack of awareness about current services available within the UK for patients with advanced colorectal cancer and concerns about low-volume centres managing complex cases. Thus, we aimed to review the feasibility, safety and long-term outcomes of this procedure at a single high-volume hepatopancreaticobiliary surgery unit in the UK. METHOD: A retrospective cohort study was performed using a database of all consecutive patients with intestinal cancer who had been referred to our regional advanced multidisciplinary team and undergone PD-RC in a 7-year period (2013-2020). Clinico-pathological and outcome data were reviewed. RESULTS: Ten patients (mean age 54 ± 13, 8/10 men) were identified. Final histology revealed the primary tumour sites were colon (n = 7) and duodenum (n = 3). R0 resection was achieved in all cases. The major complication rate (Clavien-Dindo ≥ 3) was 10% (1/10) with no deaths within 90 days of surgery. The Kaplan-Meier estimated 5-year overall survival was 83.3% (95% CI 58.3%-100%). Univariate survival analysis identified perineural invasion and extra-colonic origin as predictors of poor survival (log-rank P < 0.05). CONCLUSION: En bloc PD-RC for locally advanced intestinal cancer can be performed safely with a high proportion of margin-negative resections and resultant long-term survival in carefully selected patients.

MTL-CEBPA, a Small Activating RNA Therapeutic Upregulating C/EBP-α, in Patients with Advanced Liver Cancer: A First-in-Human, Multicenter, Open-Label, Phase I Trial.

PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.

Tumor infiltration in the medial resection margin predicts survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.

BACKGROUND: Microscopic tumor involvement (R1) in different surgical resection margins after pancreaticoduodenectomy (PD) for pancreatic ductal adenocarcinoma (PDAC) has been debated. METHODS: Clinico-pathological data for 258 patients who underwent PD between 2001 and 2010 were retrieved from a prospective database. The rates of R1 resection in the circumferential resection margin (pancreatic transection, medial, posterior, and anterior surfaces) and their prognostic influence on survival were assessed. RESULTS: For PDAC, the R1 rate was 57.1% (48/84) for any margin, 31.0% (26/84) for anterior surface, 42.9% (36/84) for posterior surface, 29.8% (25/84) for medial margin, and 7.1% (3/84) for pancreatic transection margin. Overall and disease-free survival for R1 resections were significantly worse than those for R0 resection (17.2 vs. 28.7 months, P = 0.007 and 12.3 vs. 21.0 months, P = 0.019, respectively). For individual margins, only medial positivity had a significant impact on survival (13.8 vs. 28.0 months, P < 0.001), as opposed to involvement in the anterior (19.7 vs. 23.3 months, P = 0.187) or posterior margin (17.5 vs. 24.2 months, P = 0.104). Multivariate analysis demonstrated R0 medial margin was an independent prognostic factor (P = 0.002, HR = 0.381; 95% CI 0.207-0.701). CONCLUSION: The medial surgical resection margin is the most important after PD for PDAC, and an R1 resection here predicts poor survival.

Array comparative genomic hybridization identifies novel potential therapeutic targets in cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma (CC) is a rare tumour with a dismal prognosis. As conventional medical management offers minimal survival benefit, surgery currently represents the only chance of cure. We evaluated DNA copy number (CN) alterations in CC to identify novel therapeutic targets. METHODS: DNA was extracted from 32 CC samples. Bacterial artificial chromosome (BAC) array comparative genomic hybridization was performed using microarray slides containing 3400 BAC clones covering the whole human genome at distances of 1 Mb. Data were analysed within the R statistical environment. RESULTS: DNA CN gains (89 regions) occurred more frequently than DNA CN losses (55 regions). Six regions of gain were identified in all cases on chromosomes 16, 17, 19 and 22. Twenty regions were frequently gained on chromosomes 1, 5, 7, 9, 11, 12, 16, 17, 19, 20 and 21. The BAC clones covering ERBB2, MEK2 and PDGFB genes were gained in all cases. Regions covering MTOR, VEGFR 3, PDGFA, RAF1, VEGFA and EGFR genes were frequently gained. CONCLUSIONS: We identified CN gains in the region of 11 useful molecular targets. Findings of variable gains in some regions in this and other studies support the argument for molecular stratification before treatment for CC so that treatment can be tailored to the individual patient.

Liver resection with bipolar radiofrequency device: Habib 4X.

BACKGROUND: Intraoperative blood loss has been shown to be an important factor correlating with morbidity and mortality in liver surgery. In spite of the technological advances in hepatic parenchymal transection devices, bleeding remains the single most important complication of liver surgery. The role of radiofrequency (RF) in liver surgery has been expanded from tumour ablation to major hepatic resections in the last decade. Habib 4X, a new bipolar RF device designed specifically for liver resection is described here. METHODS: Habib 4X is a bipolar, handheld, disposable RF device and consists of two pairs of opposing electrodes which is introduced perpendicularly into the liver, along the intended transection line. It produces controlled RF energy between the electrodes and the heat produced seals even major biliary and blood vessels and enables resection of the liver parenchyma with a scalpel without blood loss or biliary leak. RESULTS: Three hundred and eleven patients underwent 384 liver resections from January 2002 to October 2007 with this device. There were 109 major resections and none of the patients had vascular inflow occlusion (Pringle's manoeuvre). Mean intraoperative blood loss was 305 ml (range 0-4300) ml, with less than 5% (n=18) rate of transfusion. CONCLUSION: Habib 4X is an additional device for hepatobiliary surgeons to perform liver resections with minimal blood loss and low morbidity and mortality rates.

Repeat hepatic resection using a radiofrequency-assisted technique.

BACKGROUND: Repeat hepatic resection for recurrent primary or secondary liver cancer is performed due to advances in resection techniques and evidence of survival benefit. This paper presents the safety and efficacy of repeat radiofrequency-assisted hepatic resection to highlight the utility of the technique. METHODS: 264 consecutive hepatic resections performed on 218 patients were identified. The subset of patients with recurrent disease (n = 24) suitable for repeat hepatic resection had their records reviewed. RESULTS: Including initial (n = 24), second (n = 24) and third hepatic resection (n = 6), a total of 54 hepatic resections were performed in 24 patients. Non-anatomical resection in the form of metastasectomy was the most common procedure. There were no post-operative deaths. Four patients (17%) had complications after their second resection and 1 (17%) after the third resection. There were no cases of bile leak or liver failure. The proportion of repeat hepatic resection for recurrent disease was high: 50% of recurrences were suitable for further resection after initial resection and 43% after second resection. CONCLUSION: Radiofrequency-assisted repeat hepatic resection is a safe procedure and may increase the proportion of patients who can be considered for a curative repeat hepatic resection.