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.

Efficacy of local anaesthetic infiltration via wound catheters after open hepatic surgery: a systematic review and meta-analysis.

BACKGROUND: This study analysed whether local anaesthetic wound catheter infiltration (LA-WCI) as an adjunct to intravenous patient-controlled analgesia (IV-PCA) provides superior outcomes compared to IV-PCA alone following liver resection. METHODS: A systematic review and meta-analysis was conducted for randomised control trials (RCTs) comparing LA-WCI with IV-PCA(LA-WCI group) versus IV-PCA alone (IV-PCA group). PubMed and the Cochrane Library were searched for relevant articles. RESULTS: Six RCTs with a total of 440 patients were included. Opioid use in the initial 48 h was less in the LA-WCI group [MD -21.27 mg (-39.39,-3.15), p = 0.02]. Pain scores were lower in the LA-WCI group at rest at POD0 (post-operative day 0)6-8 h (p = 0.0009), POD1AM(p = 0.01), POD1PM(p = 0.02) and POD2 (p = 0.0006), and exertion at POD0 0-2 h (p = 0.05), POD1AM(p = 0.03), POD1PM(p = 0.03), POD2 (p = 0.03) and POD3 (p = 0.01). LA-WCI group had reduced length of hospital stay [MD -1.32 days (-2.23,-0.40),p = 0.005], time to ambulation [MD -5.94 h (-8.47,-3.42),p = 0.00001] and incidence of nausea and vomiting (PONV) [OR 0.17 (0.07,0.43),p = 0.0002]. No differences were observed in length of intensive care unit (ICU) stay or incidence of surgical site infections. DISCUSSION: LA-WCI as an adjunct to opiate IV-PCA post-hepatectomy reduces opioid use, pain scores at multiple time points at rest and exertion, length of hospital stay, time to ambulation and PONV. However, LA-WCI use does not alter length of ICU stay or incidence of wound infection.

PRIME-HCC: phase Ib study of neoadjuvant ipilimumab and nivolumab prior to liver resection for hepatocellular carcinoma.

BACKGROUND: After liver resection (LR), patients with hepatocellular cancer (HCC) are at high risk of recurrence. There are no approved anti-cancer therapies known to affect such risk, highlighting the acute need for novel systemic therapies to control the probability of disease relapse. Immunotherapy is expanding as a novel treatment option for HCC. Emerging data from cohort 4 of the CA209-040 study, which investigated the safety and preliminary efficacy of nivolumab/ipilimumab co-administration in advanced HCC, suggest that the combination can be delivered safely with an acceptable proportion of reversible grade 3-4 toxicities (27.1%) and a low discontinuation rate (2%) in patients with HCC. Here, we describe the design and rationale of PRIME-HCC, a two-part, multi-centre, phase Ib study to assess safety and bioactivity of the nivolumab/ipilimumab combination prior to LR in early-stage HCC. METHODS: The study involves an initial safety run-in phase (Part 1) to allow for preliminary safety characterisation within the first 6 patients enrolled and a subsequent expansion (Part 2). Ipilimumab will be administered once only on Day 1. Nivolumab will be administered on Day 1 and Day 22 (± 3 days) for a total of two 21-day cycles (i.e. 6 weeks of treatment). The primary objective of the study is to determine the safety and tolerability of the nivolumab/ipilimumab combination prior to LR. The secondary objective is to preliminarily characterize the efficacy of the combination prior to LR, including objective response rate (ORR) and pathologic response rates. Additional exploratory objectives include preliminary evidence of long-term disease control and to identify predictive correlates of response to the nivolumab/ipilimumab combination in HCC. DISCUSSION: The results of this study will help define the positioning of neoadjuvant nivolumab/ipilimumab combination in the perioperative management of HCC, with potential to improve survival outcomes in this patient population. TRIAL REGISTRATION: EudraCT Number: 2018-000987-27 Clinical trial registry & ID: ClinicalTrials.gov : NCT03682276 .

No difference in mortality among ALPPS, two-staged hepatectomy, and portal vein embolization/ligation: A systematic review by updated traditional and network meta-analyses.

BACKGROUND: There is an ongoing debate on the feasibility, safety, and oncological efficacy of the associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) technique. The aim of this study was to compare ALPPS, two-staged hepatectomy (TSH), and portal vein embolization (PVE)/ligation (PVL) using updated traditional meta-analysis and network meta-analysis (NMA). DATA SOURCES: Electronic databases were used in a systematic literature search. Updated traditional meta-analysis and NMA were performed and compared. Mortality and major morbidity were selected as primary outcomes. RESULTS: Nineteen studies including 1200 patients were selected from the pool of 436 studies. Of these patients, 315 (31%) and 702 (69%) underwent ALPPS and portal vein occlusion (PVO), respectively. Ninety-day mortality based on updated traditional meta-analysis, subgroup analysis of the randomized controlled trials (RCTs), and both Bayesian and frequentist NMA did not demonstrate significant differences between the ALPPS cohort and the PVE, PVL, and TSH cohorts. Moreover, analysis of RCTs did not demonstrate significant differences of major morbidity between the ALPPS and PVO cohorts. The ALPPS cohort demonstrated significantly more favorable outcomes in hypertrophy parameters, time to operation, definitive hepatectomy, and R0 margins rates compared with the PVO cohort. In contrast, 1-year disease-free survival was significantly higher in the PVO cohort compared to the ALPPS cohort. CONCLUSIONS: This study is the first to use updated traditional meta-analysis and both Bayesian and frequentist NMA and demonstrated no significant differences in 90-day mortality between the ALPPS and other hepatic hypertrophy approaches. Furthermore, two high quality RCTs including 147 patients demonstrated no significant differences in major morbidity between the ALPPS and PVO cohorts.

Effectiveness of Terlipressin on Modulation of Portal Vein Pressure after Hepatic Resections in Non-Cirrhotic Patients. A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Background-Objectives: It has been reported, that high posthepatectomy portal vein pressure (PVP) has deleterious effect on the liver parenchyma and causes posthepatectomy liver failure (PHLF) and increased 90-day mortality. Terlipressin, is widely used to mitigate the effects of portal hyper-tension. Randomised clinical trials (RCTs) demonstrated encouraging results of use of terlipressin for modulation of increased posthepatectomy PVP. The aim of the present study was to evaluate the effectiveness of the pharmacological modulation of the increased posthepatectomy PVP after major hepatectomy. Methods: Systematic literature searches of electronic databases in accordance with PRISMA was conducted. Meta-analysis was conducted using both fixed- and random-effects models. Results: Three randomised controlled trials (RCTs) comparing terlipressin versus placebo including 284 patients of pooled 60 studies were selected. Placebo cohort patients were significantly younger by 5 years compared to terlipressin cohort. However, the terlipressin cohort demonstrated significantly shorter intensive care unit (ICU) stay compared to placebo cohort. Conclusions: The first meta-analysis demonstrated that terlipressin cohort patients although significantly older by 5 years had significantly shorter ICU stay compared to placebo cohort. Furthermore, though statistically nonsignificant only 6% of terlipressin patients needed inotropic support compared to 16.4% of placebo cohort.

Preliminary qualification of a novel, hypoxic-based radiologic signature for trans-arterial chemoembolization in hepatocellular carcinoma.

BACKGROUND: Survival advantage following trans-arterial chemoembolization (TACE) is variable in patients with hepatocellular carcinoma (HCC). We combined pre-TACE radiologic features to derive a novel prognostic signature in HCC. METHODS: A multi-institutional dataset of 98 patients was generated from two retrospective cohorts from United Kingdom (65%) and Italy (36%). The prognostic impact of a number baseline imaging parameters was assessed and factors significant on univariate analysis were combined to create a novel radiologic signature on multivariable analyses predictive of overall survival (OS) following TACE. RESULTS: Median OS was 15.4 months. Tumour size > 7 cm (p < 0.001), intra-tumour necrosis (ITN) (p = 0.02) and arterial ectatic neovascularisation (AEN) (p = 0.03) emerged as individual prognostic factors together with radiologic response (p < 0.001) and elevated alpha-fetoprotein (AFP) (p = 0.01). Combination of tumour size > 7 cm, ITN and AEN identified patients with poor prognosis (p < 0.001). CONCLUSIONS: We identified a coherent signature based on commonly available imaging biomarkers likely to be reflective of differential patterns of relative hypoxia and neovascularisation. Large tumours displaying AEN and ITN are characterised by a shorter survival after TACE.

Oncological Outcomes of Major Liver Resection Following Portal Vein Embolization: A Systematic Review and Meta-analysis.

BACKGROUND: Preoperative portal vein occlusion with either percutaneous portal vein embolization (PVE) or portal vein ligation is routinely used to induce liver hypertrophy prior to major liver resection in patients with hepatic malignancy. While this increases the future liver remnant, and hence the number of patients suitable for resection, recent evidence suggests that induction of liver hypertrophy preoperatively may promote tumor growth and increase recurrence rates. The aims of this current study were to evaluate the impact of PVE on hepatic recurrence rate and survival in patients with colorectal liver metastases (CRLM). METHODS: The MEDLINE, EMBASE and Web of Science databases were searched to identify studies assessing the oncological outcomes of patients undergoing major liver resection for CRLM following PVE. Studies comparing patients undergoing one-stage liver resection with or without preoperative PVE were included. The primary outcome was postoperative hepatic recurrence (PHR), while secondary outcomes were 3- and 5-year overall survival (OS). RESULTS: Of the 2131 studies identified, six non-randomized studies (n = 668) met the eligibility criteria, comparing outcomes of patients undergoing major liver resection with or without PVE (n = 182 and n = 486, respectively). No significant difference was observed in PHR (odds ratio [OR] 0.78; 95 % confidence interval [CI] 0.42-1.44), 3-year OS (OR 0.80; 95 % CI 0.56-1.14) or 5-year OS (OR 1.12; 95 % CI 0.40-3.11). CONCLUSIONS: PVE does not have any adverse effect on PHR or OS in patients undergoing major liver resection for CRLM. Further studies based on individual patient data are needed to provide definitive answers.

Short and long-term post-operative outcomes of duodenum preserving pancreatic head resection for chronic pancreatitis affecting the head of pancreas: a systematic review and meta-analysis.

BACKGROUND: To evaluate the short and long term outcomes of duodenum preserving pancreatic head resection (DPPHR) procedures in the treatment of painful chronic pancreatitis. METHODS: A systematic literature search was performed to identify all comparative studies evaluating long and short term postoperative outcomes (pain relief, morbidity and mortality, pancreatic exocrine and endocrine function). RESULTS: Five published studies fulfilled the inclusion criteria including 1 randomized controlled trial comparing the Beger and Frey procedure. In total, 323 patients underwent surgical procedures for chronic pancreatitis, including Beger (n = 138) and Frey (n = 99), minimal Frey (n = 32), modified Frey (n = 25) and Berne's modification (n = 29). Two studies comparing the Beger and Frey procedure were entered into a meta-analysis and showed no difference in post-operative pain (RD = -0.06; CI -0.21 to 0.09), mortality (RD = 0.01; CI -0.03 to 0.05), morbidity (RD = 0.12; CI -0.00 to 0.24), exocrine insufficiency (RD = 0.04; CI -0.10 to 0.18) and endocrine insufficiency (RD = -0.14 CI -0.28 to 0.01). CONCLUSION: All procedures are equally effective for the management of pain for chronic pancreatitis. The choice of procedure should be determined by other factors including the presence of secondary complications of pancreatitis and intra-operative findings. Registration number CRD42015019275. Centre for Reviews and Dissemination, University of York, 2009.

Novel RNA oligonucleotide improves liver function and inhibits liver carcinogenesis in vivo.

UNLABELLED: Hepatocellular carcinoma (HCC) occurs predominantly in patients with liver cirrhosis. Here we show an innovative RNA-based targeted approach to enhance endogenous albumin production while reducing liver tumor burden. We designed short-activating RNAs (saRNA) to enhance expression of C/EBPα (CCAAT/enhancer-binding protein-α), a transcriptional regulator and activator of albumin gene expression. Increased levels of both C/EBPα and albumin mRNA in addition to a 3-fold increase in albumin secretion and 50% decrease in cell proliferation was observed in C/EBPα-saRNA transfected HepG2 cells. Intravenous injection of C/EBPα-saRNA in a cirrhotic rat model with multifocal liver tumors increased circulating serum albumin by over 30%, showing evidence of improved liver function. Tumor burden decreased by 80% (P = 0.003) with a 40% reduction in a marker of preneoplastic transformation. Since C/EBPα has known antiproliferative activities by way of retinoblastoma, p21, and cyclins, we used messenger RNA (mRNA) expression liver cancer-specific microarray in C/EBPα-saRNA-transfected HepG2 cells to confirm down-regulation of genes strongly enriched for negative regulation of apoptosis, angiogenesis, and metastasis. Up-regulated genes were enriched for tumor suppressors and positive regulators of cell differentiation. A quantitative polymerase chain reaction (PCR) and western blot analysis of C/EBPα-saRNA-transfected cells suggested that in addition to the known antiproliferative targets of C/EBPα, we also observed suppression of interleukin (IL)6R, c-Myc, and reduced STAT3 phosphorylation. CONCLUSION: A novel injectable saRNA-oligonucleotide that enhances C/EBPα expression successfully reduces tumor burden and simultaneously improves liver function in a clinically relevant liver cirrhosis/HCC model.

Exploiting human CD34+ stem cell-conditioned medium for tissue repair.

Despite the progress in our understanding of genes essential for stem cell regulation and development, little is known about the factors secreted by stem cells and their effect on tissue regeneration. In particular, the factors secreted by human CD34+ cells remain to be elucidated. We have approached this challenge by performing a cytokine/growth factor microarray analysis of secreted soluble factors in medium conditioned by adherent human CD34+ cells. Thirty-two abundantly secreted factors have been identified, all of which are associated with cell proliferation, survival, tissue repair, and wound healing. The cultured CD34+ cells expressed known stem cell genes such as Nanog, Oct4, Sox2, c-kit, and HoxB4. The conditioned medium containing the secreted factors prevented cell death in liver cells exposed to liver toxin in vitro via inhibition of the caspase-3 signaling pathway. More importantly, in vivo studies using animal models of liver damage demonstrated that injection of the conditioned medium could repair damaged liver tissue (significant reduction in the necroinflammatory activity), as well as enable the animals to survive. Thus, we demonstrate that medium conditioned by human CD34+ cells has the potential for therapeutic repair of damaged tissue in vivo.

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.

Reactive lymphoid hyperplasia of the pancreas: a clinical conundrum.

CONTEXT: Localized reactive lymphoid hyperplasia is a rare condition characterized by the presence of lymphoid follicles. CASE REPORT: We describe a case of a 60-year-old woman who presented with right upper quadrant pain and was found to have a reactive nodular hyperplasia of the pancreas involving the uncinate process, body and tail of the gland. Due to the multifocal distribution of these hypoechoic vascular lesions, a total pancreatectomy was performed since malignancy could not be safely excluded. CONCLUSION: There have been a handful of cases reporting reactive lymphoid hyperplasia affecting the pancreas; however, it is uncommon to perform such a radical pancreatic resection for this benign condition.

Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms.

Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs.

Use of bipolar radiofrequency in parenchymal transection of the liver, pancreas and kidney.

BACKGROUND: Intraoperative blood loss has been shown to be an important factor correlating with increased morbidity and mortality in oncological surgery. Despite technological advances in parenchymal transection devices, bleeding remains the single most important complication. To address this, we designed and developed a bipolar radiofrequency (RF) device, the Habib 4X (Angiodynamics, Inc., Queensbury, N.Y., USA), which was initially used specifically for liver resections. METHODS: A search using Medline, Embase and Google™ Scholar was performed for the period January 2001 to August 2011. The following Mesh terms were used: 'bipolar radiofrequency', 'Habib 4X', 'laparoscopic', 'liver resection', 'partial nephrectomy' and 'distal pancreatectomy'. The references of the studies included were also reviewed. Series from our centre were excluded. RESULTS: There were seven series published, reporting a total of 188 liver resections [113 minor (< 3 segments) and 75 major (≥ 3 segments)] assisted by the bipolar RF (Habib 4X) device over this period. The median blood loss reported ranged from 15 to 427 ml with a transfusion rate of 0-14% In addition, five series of partial nephrectomies were also identified, reporting a total of 149 (45 open and 104 laparoscopic) cases. Hilar clamping was not used in any of the cases, and the mean blood loss reported was 100-337 ml whilst the transfusion rate ranged from 0 to 7.1%. There was only one published series of distal pancreatectomies; these were laparoscopic and included 14 patients. CONCLUSION: This review of bipolar RF-assisted liver resections, partial nephrectomies and distal pancreatectomies reported in the literature to date shows that there are significant advantages in using this device in these types of operation.

HOW TO PERFORM LAPAROSCOPIC DISTAL PANCREATECTOMY USING THE CLOCKWISE TECHNIQUE.

BACKGROUND: Laparoscopic pancreatectomy is currently a widely used approach for benign and malignant lesions of the pancreas. AIMS: This study aimed to describe how to perform a laparoscopic distal pancreatectomy using The Clockwise Technique. METHODS: An 18-year-old female patient presented with a well-defined tumor in the pancreatic body with 4 cm in diameter that suggested a diagnosis of solid pseudopapillary tumor (Frantz's tumor). The patient was recommended for laparoscopic distal pancreatectomy by using The Clockwise Technique. RESULTS: The clockwise, caudal-to-cephalic approach appears to have other significant technical advantages that facilitate the performance of the procedure. CONCLUSIONS: A laparoscopic distal pancreatectomy performed using The Clockwise Technique provides satisfactory outcomes.

Radiofrequency-assisted hepatic resection.

BACKGROUND: The only curative procedure to date for liver tumors is surgical resection, which remains a major procedure with marked morbidity and mortality. Radiofrequency (RF) has increasingly been used for both ablation and resection. On the basis of this technique, a new bipolar RF device, Habib 4X, has been developed and used clinically. We present our technique of liver resection with this device in a patient with colorectal liver metastases. METHODS: A patient with situs inversus who had colorectal liver metastases in her left lobe underwent left lateral segmentectomy with the new device, a four-electrode bipolar resection device that uses RF energy for tissue necrosis. After laparotomy and intraoperative ultrasound, the plane resection was marked 1 cm away from the edge of the lesion. Coagulative desiccation was performed along this plane using this sealer connected to a RF generator. The necrosed band of parenchyma was then divided with a scalpel and resection completed. RESULTS: The length of the procedure was 105 minutes; resection time was 35 minutes. Total blood loss was 100 ml. No blood transfusions were required, and the patient was not admitted to the intensive care unit after surgery. The patient was discharged 10 days after surgery without any surgical complications. CONCLUSIONS: We think that RF-assisted liver resection with this new device is safe and effective. It is quicker than conventional RF and may reduce overall hospital stay in liver resection patients.

A systematic review into patient reported outcomes following pancreaticoduodenectomy for malignancy.

BACKGROUND: Pancreaticoduodenectomy is associated with high rates of morbidity. This combined with the psychological burden of cancer, may impact on a patient's quality of life (QoL), which can be measured by using patient-reported outcomes (PRO). OBJECTIVE: To perform a systematic review to evaluate the measurement of PRO after pancreaticoduodenectomy for cancer. METHODS: 7 different databases were searched using 2 groups of search terms, one relating to pancreaticoduodenectomy, and one to PRO. Three authors screened the search results independently in a systematic manner based on predefined inclusion and exclusion criteria. RESULTS: 27 studies, with 2173 eligible patients were included in the final analysis. Most of the included studies used validated instruments. The European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was most popular and used in 12 studies. The methodology of all included studies was also scrutinised. 12 studies were deemed to have high quality methodology according to pre-defined criteria. CONCLUSION: The instruments and methods used to measure PRO are variable. The quality of PRO within the available literature has improved over time, as has the number of studies measuring PRO. PRO should be measured with uniformity in future trials so that patients can be provided with more comprehensive information regarding post-operative recovery and QoL during the shared decision-making process preoperatively.

Upregulation of C/EBPα Inhibits Suppressive Activity of Myeloid Cells and Potentiates Antitumor Response in Mice and Patients with Cancer.

PURPOSE: To evaluate the mechanisms of how therapeutic upregulation of the transcription factor, CCAAT/enhancer-binding protein alpha (C/EBPα), prevents tumor progression in patients with advanced hepatocellular carcinoma (HCC) and in different mouse tumor models. EXPERIMENTAL DESIGN: We conducted a phase I trial in 36 patients with HCC (NCT02716012) who received sorafenib as part of their standard care, and were given therapeutic C/EBPα small activating RNA (saRNA; MTL-CEBPA) as either neoadjuvant or adjuvant treatment. In the preclinical setting, the effects of MTL-CEBPA were assessed in several mouse models, including BNL-1ME liver cancer, Lewis lung carcinoma (LLC), and colon adenocarcinoma (MC38). RESULTS: MTL-CEBPA treatment caused radiologic regression of tumors in 26.7% of HCC patients with an underlying viral etiology with 3 complete responders. MTL-CEBPA treatment in those patients caused a marked decrease in peripheral blood monocytic myeloid-derived suppressor cell (M-MDSC) numbers and an overall reduction in the numbers of protumoral M2 tumor-associated macrophages (TAM). Gene and protein analysis of patient leukocytes following treatment showed CEBPA activation affected regulation of factors involved in immune-suppressive activity. To corroborate this observation, treatment of all the mouse tumor models with MTL-CEBPA led to a reversal in the suppressive activity of M-MDSCs and TAMs, but not polymorphonuclear MDSCs (PMN-MDSC). The antitumor effects of MTL-CEBPA in these tumor models showed dependency on T cells. This was accentuated when MTL-CEBPA was combined with checkpoint inhibitors or with PMN-MDSC-targeted immunotherapy. CONCLUSIONS: This report demonstrates that therapeutic upregulation of the transcription factor C/EBPα causes inactivation of immune-suppressive myeloid cells with potent antitumor responses across different tumor models and in cancer patients. MTL-CEBPA is currently being investigated in combination with pembrolizumab in a phase I/Ib multicenter clinical study (NCT04105335).