Publications by authors named "Krishna Epari"

11 Publications

  • Page 1 of 1

Early outcomes of two-stage minimally invasive oesophagectomy in an Australian institution.

ANZ J Surg 2019 03 17;89(3):223-227. Epub 2018 Aug 17.

Department of General Surgery, Fremantle Hospital and Fiona Stanley Hospital, Perth, Western Australia, Australia.

Background: Minimally invasive oesophagectomy (MIO) has a steep learning curve. We report our outcomes of a standardized 25 mm circular-stapled anastomosis using a trans-orally placed anvil (Orvil™). The objective of this study is to report the initial experience of introducing two-stage MIO to an Australian tertiary health service.

Methods: We describe our consecutive case series of all MIOs performed from a prospectively maintained database. We assessed the morbidity and mortality of MIO at our institution. We compared our first 30 cases to the second cohort of 32 cases.

Results: There were 62 two-stage MIOs performed from 2011 to 2015. The average age was 65 years. Median length of stay was 13 days (5-72 days). Median number of total lymph nodes was 14. Conversion occurred in three patients (5%). Major morbidity was 45%. Delayed gastric emptying 6% (n = 4), pneumonia 6% (n = 4), chyle leak 6% (n = 4), pulmonary embolus 2% (n = 1) and grade II or III anastomotic leak 5% (n = 4). One conduit ischaemia (2%) required reoperation and formation of oesophagostomy. There was one post-operative death within 30 days. There were five post-oesophagectomy hiatal hernias requiring re-operation (8%). There was a significant improvement in operative time (minutes) from the first to second cohort 588 versus 464 (P-value 0.01).

Conclusion: The introduction of two-stage MIO to the Australian setting can be safely instituted. Our unit was still within a learning curve after 30 cases.
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http://dx.doi.org/10.1111/ans.14740DOI Listing
March 2019

Whole-genome landscape of pancreatic neuroendocrine tumours.

Nature 2017 03 15;543(7643):65-71. Epub 2017 Feb 15.

QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.
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http://dx.doi.org/10.1038/nature21063DOI Listing
March 2017

Hypermutation In Pancreatic Cancer.

Gastroenterology 2017 01 15;152(1):68-74.e2. Epub 2016 Nov 15.

QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia.

Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.
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http://dx.doi.org/10.1053/j.gastro.2016.09.060DOI Listing
January 2017

Genomic analyses identify molecular subtypes of pancreatic cancer.

Nature 2016 Mar 24;531(7592):47-52. Epub 2016 Feb 24.

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Integrated genomic analysis of 456 pancreatic ductal adenocarcinomas identified 32 recurrently mutated genes that aggregate into 10 pathways: KRAS, TGF-β, WNT, NOTCH, ROBO/SLIT signalling, G1/S transition, SWI-SNF, chromatin modification, DNA repair and RNA processing. Expression analysis defined 4 subtypes: (1) squamous; (2) pancreatic progenitor; (3) immunogenic; and (4) aberrantly differentiated endocrine exocrine (ADEX) that correlate with histopathological characteristics. Squamous tumours are enriched for TP53 and KDM6A mutations, upregulation of the TP63∆N transcriptional network, hypermethylation of pancreatic endodermal cell-fate determining genes and have a poor prognosis. Pancreatic progenitor tumours preferentially express genes involved in early pancreatic development (FOXA2/3, PDX1 and MNX1). ADEX tumours displayed upregulation of genes that regulate networks involved in KRAS activation, exocrine (NR5A2 and RBPJL), and endocrine differentiation (NEUROD1 and NKX2-2). Immunogenic tumours contained upregulated immune networks including pathways involved in acquired immune suppression. These data infer differences in the molecular evolution of pancreatic cancer subtypes and identify opportunities for therapeutic development.
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http://dx.doi.org/10.1038/nature16965DOI Listing
March 2016

Whole genomes redefine the mutational landscape of pancreatic cancer.

Nature 2015 Feb;518(7540):495-501

Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.
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http://dx.doi.org/10.1038/nature14169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4523082PMC
February 2015

Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes.

Nature 2012 Nov 24;491(7424):399-405. Epub 2012 Oct 24.

The Kinghorn Cancer Centre, 370 Victoria Street, Darlinghurst, Sydney, New South Wales 2010, Australia.

Pancreatic cancer is a highly lethal malignancy with few effective therapies. We performed exome sequencing and copy number analysis to define genomic aberrations in a prospectively accrued clinical cohort (n = 142) of early (stage I and II) sporadic pancreatic ductal adenocarcinoma. Detailed analysis of 99 informative tumours identified substantial heterogeneity with 2,016 non-silent mutations and 1,628 copy-number variations. We define 16 significantly mutated genes, reaffirming known mutations (KRAS, TP53, CDKN2A, SMAD4, MLL3, TGFBR2, ARID1A and SF3B1), and uncover novel mutated genes including additional genes involved in chromatin modification (EPC1 and ARID2), DNA damage repair (ATM) and other mechanisms (ZIM2, MAP2K4, NALCN, SLC16A4 and MAGEA6). Integrative analysis with in vitro functional data and animal models provided supportive evidence for potential roles for these genetic aberrations in carcinogenesis. Pathway-based analysis of recurrently mutated genes recapitulated clustering in core signalling pathways in pancreatic ductal adenocarcinoma, and identified new mutated genes in each pathway. We also identified frequent and diverse somatic aberrations in genes described traditionally as embryonic regulators of axon guidance, particularly SLIT/ROBO signalling, which was also evident in murine Sleeping Beauty transposon-mediated somatic mutagenesis models of pancreatic cancer, providing further supportive evidence for the potential involvement of axon guidance genes in pancreatic carcinogenesis.
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http://dx.doi.org/10.1038/nature11547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3530898PMC
November 2012

The acute surgical unit: improving emergency care.

ANZ J Surg 2010 Dec 1;80(12):933-6. Epub 2010 Oct 1.

Department of General Surgery, Fremantle Hospital, WA, Australia.

Background: Acute care surgical teams are a new concept in the provision of emergency general surgery. Juggling emergency patients around the surgeons' and staffs' elective commitments resulted in semi-emergency procedures routinely being delayed. In an era of increasing financial pressure and the recent introduction of 'safe work hours' practices, the need for a new system which optimized available resources became apparent.

Methods: At Fremantle Hospital we developed a new system in a concerted effort to minimize the waiting time for general surgical referrals in the Emergency Department, as well as to move semi-urgent operating from the afterhours to the daytime. To analyse the impact of the ASU, data were collected during February, March, and April 2009 and compared with data from the same period in 2008.

Results: Although most referrals were received afterhours, over 85% of operations were performed during working hours compared with 72% in the 2008 period. The time from referral to review decreased from an average of 3.2 h in 2008 to 2.1 h. The mean duration of stay in 2009 was 3 days, which was a reduction from 4.2 days in 2008. An increase in weekend discharge rates was seen after the introduction of the ASU.

Conclusion: Despite an increased workload, more referrals were seen and more operations performed during working hours and the time from referral to review was reduced. Higher discharge rates and reduced length of stays increased the availability of beds. We have demonstrated a successful new model which continues to evolve.
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http://dx.doi.org/10.1111/j.1445-2197.2010.05490.xDOI Listing
December 2010

The outcome of patients on the cholecystectomy waiting list in Western Australia 1999-2005.

ANZ J Surg 2010 Oct 16;80(10):703-9. Epub 2010 Aug 16.

University Department of Surgery, Fremantle Hospital, Western Australia, Australia.

Background: Surgeons are noticing increasing numbers of cholecystectomy waiting list patients presenting with complications of their gallstones. In this study, we analysed the outcome of these to ascertain natural history and outcome.

Methods: Data for 5298 waiting list patients in Western Australia, from 1999 to 2006, were analysed. Negative binomial regression was used to analyse waiting times data with Waitlist Year, Urgency Category and Aboriginality, after adjusting for Gender, Location and Age at Cholecystectomy.

Results: The overall median waiting time for surgery was 40 days (interquartile range (IQR) = 15-103). The median waiting times for Urgent, Semi-Urgent, and Routine categories were 21 (IQR = 8-63), 44 (IQR = 20-97) and 50 (IQR = 17-131) days, respectively. While waiting for surgery, 240 (5%) patients had gallstone-related admissions. Eighty (33.3%) patients had previous gallstone-related admissions prior to their enrolment on the waiting list. Analysis of the crude odds ratio showed that the probability of readmission during wait for surgery was three times more, when the surgery was not performed within the recommended time. Aboriginal and Torres Strait Islanders wait 1.77 times longer than non aboriginals (P < 0.001) and waiting time decreased with more recent calendar years. (P= 0.001) Patients in the metropolitan hospitals waited twice as long compared with the regional hospitals (P < 0.001).

Conclusion: Approximately 5% of patients on the waiting list for an elective cholecystectomy were readmitted to the hospital for gallstone-related problems. Proper categorization of patients and definitive surgical treatment of acute gallbladder disease at index presentation might decrease this readmission rate. More effort needs to be made to ensure equity of access for gallstone patients.
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http://dx.doi.org/10.1111/j.1445-2197.2010.05428.xDOI Listing
October 2010

Oesophagectomy for tumours and dysplasia of the oesophagus and gastro-oesophageal junction.

ANZ J Surg 2009 Apr;79(4):251-7

Hepatobiliary/Upper GI Surgical Unit, St Vincent's Hospital, Melbourne, Victoria, Australia.

Background: Neoadjuvant therapy, radical lymphadenectomy and treatment in high-volume centres have been proposed to improve outcomes for resectable oesophageal tumours. The aim of the present study was to review the oesophagectomy experience of a single surgeon with a moderate caseload who uses neoadjuvant therapy selectively and performs a conservative lymphadenectomy.

Methods: A retrospective review of prospectively collected data was performed. The study included 125 consecutive attempted oesophageal resections performed by a single surgeon (RC) from 1993 to 2006.

Results: All patients were staged with computed tomography and also laparoscopy for lower third and junctional tumours. Endoscopic ultrasound was used in 69%. Seventy-seven per cent were adenocarcinomas. Neoadjuvant therapy was used selectively in 23%. One hundred and twenty-one resections were carried out, giving an overall resection rate of 97% with an R0 resection in 82%. In-hospital mortality was 0.8%, clinical anastomotic leak 1.7% and median length of stay 14 days. Overall median and 5-year survival were 46 months and 47%. Stage-specific 5-year survival was 100%, 71%, 41% and 21% for stages 0, I, II and III, respectively. Isolated local recurrence occurred in 8%.

Conclusions: A moderate volume surgeon with specialist training in oesophageal resectional surgery can achieve a low mortality and anastomotic leak rate with good survival outcomes. The role for neoadjuvant therapy and radical lymphadenectomy is controversial and remains to be clearly defined. Accurate preoperative staging is essential for selection of patients for curative surgery with or without neoadjuvant therapy and for comparison of results.
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http://dx.doi.org/10.1111/j.1445-2197.2009.04855.xDOI Listing
April 2009
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