Immune evasion is key to cancer initiation and later at metastasis, but its dynamics at intermediate stages, where potential therapeutic interventions could be applied, is undefined. Here we show, ...using multi-dimensional analyses of resected tumours, their adjacent non-tumour tissues and peripheral blood, that extensive immune remodelling takes place in patients with stage I to III hepatocellular carcinoma (HCC). We demonstrate the depletion of anti-tumoural immune subsets and accumulation of immunosuppressive or exhausted subsets along with reduced tumour infiltration of CD8 T cells peaking at stage II tumours. Corresponding transcriptomic modification occur in the genes related to antigen presentation, immune responses, and chemotaxis. The progressive immune evasion is validated in a murine model of HCC. Our results show evidence of ongoing tumour-immune co-evolution during HCC progression and offer insights into potential interventions to reverse, prevent or limit the progression of the disease.
Introduction
An increasing body of evidence is being published about single-incision laparoscopic cholecystectomy (SILC), but there are no well-powered trials with an adequate evaluation of ...post-operative pain. This randomized trial compares SILC against four-port laparoscopic cholecystectomy (LC) with post-operative pain as the primary endpoint.
Methods
Hundred patients were randomized to either SILC (
n
= 50) or LC (
n
= 50). Exclusion criteria were (1) Acute cholecystitis; (2) ASA 3 or above; (3) Bleeding disorders; and (4) Previous open upper abdominal surgery. Patients and post-operative assessors were blinded to the procedure performed. The site and severity of pain were compared at 4 h, 24 h, 14 days and 6 months post-procedure using the visual analog scale; non-inferiority was assumed when the lower boundary of the 95 % confidence interval of the difference was above −1 and superiority when
p
≤ 0.05.
Results
The study arms were demographically similar. At 24 h post-procedure, SILC was associated with less pain at extra-umbilical sites (rest:
p
= 0.004; movement:
p
= 0.008). Pain data were inconclusive at 24 h at the umbilical site on movement; SILC was otherwise non-inferior for pain at all other points. Operating duration was longer in SILC (79.46 vs 58.88 min,
p
= 0.003). 8 % of patients in each arm suffered complications (
p
= 1.000). Re-intervention rates, analgesic use, return to function, and patient satisfaction did not differ significantly.
Conclusions
SILC has improved short-term pain outcomes compared to LC and is not inferior in both short-term and long-term pain outcomes. The operating time is longer, but remains feasible in routine surgical practice.
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EMUNI, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
Abstract
Intra-tumor heterogeneity (ITH) is a key challenge in cancer treatment, but previous studies have focused mainly on the genomic alterations without exploring phenotypic (transcriptomic and ...immune) heterogeneity. Using one of the largest prospective surgical cohorts for hepatocellular carcinoma (HCC) with multi-region sampling, we sequenced whole genomes and paired transcriptomes from 67 HCC patients (331 samples). We found that while genomic ITH was rather constant across stages, phenotypic ITH had a very different trajectory and quickly diversified in stage II patients. Most strikingly, 30% of patients were found to contain more than one transcriptomic subtype within a single tumor. Such phenotypic ITH was found to be much more informative in predicting patient survival than genomic ITH and explains the poor efficacy of single-target systemic therapies in HCC. Taken together, we not only revealed an unprecedentedly dynamic landscape of phenotypic heterogeneity in HCC, but also highlighted the importance of studying phenotypic evolution across cancer types.
Using a prospective cohort for Hepatocellular Carcinoma (the PLANET study), this work revealed a dynamic landscape of phenotypic intra-tumor heterogeneity, providing several novel approaches for patient treatment and prognosis prediction.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Pyrexia of Unknown Origin: A Perplexing Case Koshy, Kiren George; Suresh, Moothezhathu Kesavadas; John, Jithin ...
Journal of clinical and diagnostic research,
04/2019, Volume:
13, Issue:
4
Journal Article
Peer reviewed
Open access
Pyrexia of Unknown Origin (PUO) is a common diagnostic dilemma in the medical wards. We present the case of a 64-year-old man who had presented with fever, fatigue, dry cough and bloody diarrhea. ...Over the next few days, he developed severe testicular pain and renal failure. Blood results revealed anaemia, raised ESR, negative ANA and negative ANCA. Renal biopsy showed crescentic glomerulonephritis. Repeat value of c-ANCA was positive which clinched the diagnosis of Granulomatosis with Polyangiitis (GPA). We present this case in order to illustrate the masquerading nature of the vasculitic syndromes and to emphasise the need to integrate clinical and laboratory clues to reach a diagnosis.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Living donor liver transplant(LDLT)is a major surgi-cal undertaking.Detailed pre-operative assessment of the vascular and biliary anatomy is crucial for safe and successful harvesting of the graft ...and transplantation.Computed tomography(CT)and magnetic resonance imaging(MRI)are currently the imaging modalities of choice in pre-operative evaluation.These cross-sec-tional imaging techniques can reveal the vascular and biliary anatomy,assess the hepatic parenchyma and perform volumetric analysis.Knowledge of the broad indications and contraindications to qualify as a recipi-ent for LDLT is essential for the radiologist reporting scans in a pre-transplant patient.Similarly,awareness of the various anatomical variations and pathological states in the donor is essential for the radiologist to generate a meaningful report of his/her observations.CT and MRI have largely replaced invasive techniques such as catheter angiography,percutaneous cholan-giography and endoscopic retrograde cholangiopan-creatography.In order to generate a meaningful report based on these pre-operative imaging scans,it is also mandatory for the radiologist to be aware of the sur-geon’s perspective.We intend to provide a brief over-view of the common surgical concepts of LDLT and give a detailed description of the minimum that a radiologist is expected to seek and report in CT and MR scans per-formed for LDLT related evaluation.
AIM: To compare the surgical outcomes between laparoscopic liver resection(LLR) and open liver resection(OLR) as a curative treatment in patients with hepatocellular carcinoma(HCC). METHODS: A Pub ...Med database search was performed systematically to identify comparative studies of LLR vs OLR for HCC from 2000 to 2014. An extensive text word search was conducted, using combinations of search headings such as "laparoscopy", "hepatectomy", and "hepatocellular carcinoma". A comparative study was also performed in our institution where we analysed surgical outcomes of 152 patients who underwent liver resection between January 2005 to December 2012, of which 42 underwent laparoscopic or hand-assisted laparoscopic resection and 110 underwent open resection. RESULTS: Analysis of our own series and a review of 17 high-quality studies showed that LLR was superior to OLR in terms of short-term outcomes, as patients in the laparoscopic arm were found to have less intraoperative blood loss, less blood transfusions, and a shorter length of hospital stay. In our own series, both LLR and OLR groups were found to have similar overall survival(OS) rates, but disease-free survival(DFS) rates were higher in the laparoscopic arm. CONCLUSION: LLR is associated with better short-term outcomes compared to OLR as a curative treatment for HCC. Long-term oncologic outcomes with regards to OS and DFS rates were found to be comparable in both groups. LLR is hence a safe and viable option for curative resection of HCC.
Lifestyle and environmental-related exposures are important risk factors for hepatocellular carcinoma (HCC), suggesting that epigenetic dysregulation significantly underpins HCC. We profiled 30 ...surgically resected tumours and the matched adjacent normal tissues to understand the aberrant epigenetic events associated with HCC.
We identified tumour differential enhancers and the associated genes by analysing H3K27 acetylation (H3K27ac) chromatin immunoprecipitation sequencing (ChIP-seq) and Hi-C/HiChIP data from the resected tumour samples of 30 patients with early-stage HCC. This epigenome dataset was analysed with previously reported genome and transcriptome data of the overlapping group of patients from the same cohort. We performed patient-specific differential expression testing using multiregion sequencing data to identify genes that undergo both enhancer and gene expression changes. Based on the genes selected, we identified two patient groups and performed a recurrence-free survival analysis.
We observed large-scale changes in the enhancer distribution between HCC tumours and the adjacent normal samples. Many of the gain-in-tumour enhancers showed corresponding upregulation of the associated genes and vice versa, but much of the enhancer and gene expression changes were patient-specific. A subset of the upregulated genes was activated in a subgroup of patients’ tumours. Recurrence-free survival analysis revealed that the patients with a more robust upregulation of those genes showed a worse prognosis.
We report the genomic enhancer signature associated with differential prognosis in HCC. Findings that cohere with oncofoetal reprogramming in HCC were underpinned by genome-wide enhancer rewiring. Our results present the epigenetic changes in HCC that offer the rational selection of epigenetic-driven gene targets for therapeutic intervention or disease prognostication in HCC.
Lifestyle and environmental-related exposures are the important risk factors of hepatocellular carcinoma (HCC), suggesting that tumour-associated epigenetic dysregulations may significantly underpin HCC. We profiled tumour tissues and their matched normal from 30 patients with early-stage HCC to study the dysregulated epigenetic changes associated with HCC. By also analysing the patients’ RNA-seq and clinical data, we found the signature genes – with epigenetic and transcriptomic dysregulation – associated with worse prognosis. Our findings suggest that systemic approaches are needed to consider the surrounding cellular environmental and epigenetic changes in HCC tumours.
Display omitted
•Epigenetic dysregulation is prevalent in HCC, accompanied by de novo enhancers.•Differential enhancers and the associated gene expression changes are heterogeneous.•Differential enhancer genes included cellular proliferation and foetal liver markers.•Patients with tumour-activated gain-in-tumour enhancer genes showed worse prognosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of this study was to review the role of laparoscopic assessment in the staging algorithm of suspected hilar cholangiocarcinoma and to identify factors highly likely to be associated with ...unresectable disease. Data prospectively collected between 1992 and 2003 were analyzed. Demographics, symptoms, preoperative radiologic staging, laparoscopic assessment, and final outcome were recorded. Yield was defined as the number of unresectable patients detected by laparoscopic assessment divided by the total number of patients undergoing laparoscopic assessment. Accuracy was defined as the number of unresectable patients detected by laparoscopic assessment divided by the total number of unresectable cases. Eighty-four patients underwent laparoscopic assessment for suspected hilar cholangiocarcinoma, of which 20 (23.8%) underwent resection. The yield from laparoscopy alone was 24.3% (20 of 82), which increased to 41.5% (35 of 82) with the addition of intraoperative ultrasound. The overall accuracy was 53.1% (35 of 66). The use of a preoperative radiologic staging system predicted the likelihood of unresectable disease (
P
=
0.007). The use of laparoscopic assessment in the preoperative staging of patients with suspected hilar cholangiocarcinoma is justified given it will spare 42.2% of patients an unnecessary laparotomy. Accurate staging of cholangiocarcinoma remains a challenge, but the use of a preoperative radiologic staging system may help to stratify a patient's risk of unresectable disease.
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EMUNI, FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UL, UM, UPUK, VKSCE, ZAGLJ
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