Publications by authors named "David L Morris"

360 Publications

Novel Use of Bromelain and Acetylcysteine (BromAc®) for Pleural Involvement in Pseudomyxoma Peritonei.

Case Rep Oncol 2021 Jan-Apr;14(1):628-633. Epub 2021 Mar 31.

Department of Surgery, Peritonectomy Unit, St George Hospital, Kogarah, New South Wales, Australia.

Pseudomyxoma peritonei (PMP) is a rare mucinous disease most commonly arising from the appendix. Pleural involvement arising from established PMP is seen in a small number of cases. Combined cytoreductive surgery and hyperthermic intrathoracic chemotherapy is the treatment of choice when managing intra-thoracic PMP. In cases of recurrence, surgical intervention may be technically challenging and carry higher rates of complications, morbidity, and mortality. Bromelain and acetylcysteine (BromAc) is a novel treatment modality that has demonstrated mucolytic properties. When injected directly into mucinous disease, it facilitates tumour dissolution and allows it to be aspirated. It has recently been tested in the treatment of inoperable peritoneal mucinous disease, with an acceptable safety profile and positive objective response. Here we describe the first two cases of BromAc administered directly into pleural adenomucinosis, with striking differences in response between the two patients likely due to differences in tumour hardness.
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http://dx.doi.org/10.1159/000514273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077436PMC
March 2021

The Combination of Bromelain and Acetylcysteine (BromAc) Synergistically Inactivates SARS-CoV-2.

Viruses 2021 03 6;13(3). Epub 2021 Mar 6.

Department of Surgery, St. George Hospital, Sydney, NSW 2217, Australia.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection is the cause of a worldwide pandemic, currently with limited therapeutic options. The spike glycoprotein and envelope protein of SARS-CoV-2, containing disulfide bridges for stabilization, represent an attractive target as they are essential for binding to the ACE2 receptor in host cells present in the nasal mucosa. Bromelain and Acetylcysteine (BromAc) has synergistic action against glycoproteins by breakage of glycosidic linkages and disulfide bonds. We sought to determine the effect of BromAc on the spike and envelope proteins and its potential to reduce infectivity in host cells. Recombinant spike and envelope SARS-CoV-2 proteins were disrupted by BromAc. Spike and envelope protein disulfide bonds were reduced by Acetylcysteine. In in vitro whole virus culture of both wild-type and spike mutants, SARS-CoV-2 demonstrated a concentration-dependent inactivation from BromAc treatment but not from single agents. Clinical testing through nasal administration in patients with early SARS-CoV-2 infection is imminent.
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http://dx.doi.org/10.3390/v13030425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999995PMC
March 2021

Acute Kidney Injury Following Hyperthermic Intraperitoneal Chemotherapy With Cisplatin.

Anticancer Res 2021 Mar;41(3):1641-1646

Hepatobilliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, Kogarah, NSW, Australia.

Background/aim: Cisplatin increases the risk of acute kidney injury (AKI) during systemic chemotherapy. However, little is known about its risk of inducing AKI when used during intraperitoneal chemotherapy. This study aimed to determine the incidence of AKI in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) with cisplatin.

Patients And Methods: A retrospective analysis of patients who received cisplatin-based HIPEC from November 2008 to March 2018 was undertaken to determine the incidence of AKI.

Results: A total of 111 patients were identified. The incidence of AKI was 15.3% (17/111). Univariate analysis showed increased peritoneal cancer index (PCI), low intraoperative and post-operative urine output were significantly associated with the development of AKI. Multivariate analyses did not identify any significant predictors factors for AKI.

Conclusion: Cisplatin-based HIPEC is associated with AKI. At our centre, the incidence of AKI was 15.3%. Risk factors that may influence its development include high PCI and low perioperative diuresis.
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http://dx.doi.org/10.21873/anticanres.14926DOI Listing
March 2021

Identification of 38 novel loci for systemic lupus erythematosus and genetic heterogeneity between ancestral groups.

Nat Commun 2021 02 3;12(1):772. Epub 2021 Feb 3.

Department of Medicine, The University of Hong Kong, Hong Kong, China.

Systemic lupus erythematosus (SLE), a worldwide autoimmune disease with high heritability, shows differences in prevalence, severity and age of onset among different ancestral groups. Previous genetic studies have focused more on European populations, which appear to be the least affected. Consequently, the genetic variations that underlie the commonalities, differences and treatment options in SLE among ancestral groups have not been well elucidated. To address this, we undertake a genome-wide association study, increasing the sample size of Chinese populations to the level of existing European studies. Thirty-eight novel SLE-associated loci and incomplete sharing of genetic architecture are identified. In addition to the human leukocyte antigen (HLA) region, nine disease loci show clear ancestral differences and implicate antibody production as a potential mechanism for differences in disease manifestation. Polygenic risk scores perform significantly better when trained on ancestry-matched data sets. These analyses help to reveal the genetic basis for disparities in SLE among ancestral groups.
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http://dx.doi.org/10.1038/s41467-021-21049-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7858632PMC
February 2021

Distinguishing peritoneal tuberculosis from peritoneal carcinomatosis: a challenge.

ANZ J Surg 2020 Dec 23. Epub 2020 Dec 23.

Department of Surgery, St George Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.16523DOI Listing
December 2020

Outcomes in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for maximal volume (PCI 39) appendiceal tumours.

Eur J Surg Oncol 2020 Nov 27. Epub 2020 Nov 27.

Department of Surgery, St George Hospital, Sydney, NSW, Australia; St George & Sutherland Clinical School, University of New South Wales, Sydney, Australia.

Background: Higher Peritoneal Cancer Index (PCI) requires more extensive surgery and maybe associated with more limited outcomes. The aim of this study in a high-volume centre in Australia was to analyse the outcomes in PCI 39 patients regarding short and long term outcomes in appendiceal tumours.

Methods: A retrospective analysis of prospectively maintained database of patients that underwent primary cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) with PCI 39 at St George Hospital, Sydney from 1996 to 2018. Patients with appendiceal tumours (inclusive of high and low grade) were analysed. Factors contributing to high grade (III/IV Clavien-Dindo) morbidity and mortality were assessed.

Results: Of the 1201 patients in the database, 58 patients had a PCI 39 from appendix tumours at their first operation. The overall survival rate at 1, 3 and 5 year was 91.2%, 79.5% and 62.9% respectively. The median survival was 87.2 months (96% CI 51.8-NR). The rate of major morbidity was 71%. The postoperative mortality incidence was 1.7%. The median hospital length of stay was 34 days (IQR:27-54 days).

Conclusions: In an experienced centre CRS + HIPEC is safe in selected patients with PCI 39. Despite the high morbidity, the overall survival for appendiceal tumours appear considerably better than debulking surgery.
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http://dx.doi.org/10.1016/j.ejso.2020.11.138DOI Listing
November 2020

Impact of signet ring cells on overall survival in peritoneal disseminated appendix cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Eur J Surg Oncol 2021 01 28;47(1):194-198. Epub 2020 Nov 28.

Hepatobilliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, Kogarah, NSW, Australia; St George and Sutherland Clinical School, University of New South Wales, Sydney, NSW, Australia. Electronic address:

Introduction: To determine the effect of signet ring cell (SRC) histopathology in appendix cancer with peritoneal dissemination on overall survival (OS) in patients undergoing cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC).

Materials And Methods: Retrospective cohort study from a prospectively maintained database of patients that underwent CRS/HIPEC for appendix cancer from April 1999 to December 2019.

Results: 255 patients were identified. 174 had high-grade disease with no SRC component, 35 with a low count of SRC and 46 with a high count of SRC. Median OS without SRC was 93.8 months vs 58.2 months for low count SRC and 23.7 months for high count SRC (P < 0.001). 5-year OS was 60% for patients with no SRC, 35.5% and 10% in those with low count and high count SRC respectively. On multivariate analysis, presence of SRC and complete cytoreduction score were identified as independent factors that affect OS.

Conclusion: The presence of SRC in appendix cancer with peritoneal dissemination is associated with worse OS when compared to an absence of SRC in patients undergoing CRS/HIPEC.
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http://dx.doi.org/10.1016/j.ejso.2020.11.134DOI Listing
January 2021

Decision-Making Analysis for Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer: A Survey by the Executive Committee of the Peritoneal Surface Oncology Group International (PSOGI).

Oncology 2021 11;99(1):41-48. Epub 2020 Sep 11.

Department of Radiation Oncology, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland.

Objectives: To assess the individual treatment strategies among international experts in peritoneal carcinosis, specifically their decision-making in the process of patient selection for hyperthermic intraperitoneal chemotherapy (HIPEC) in women suffering from ovarian cancer, to identify relevant decision-making criteria, and to quantify the level of consensus for or against HIPEC.

Methods: The members of the executive committee of the Peritoneal Surface Oncology Group International (PSOGI) were asked to describe the clinical conditions under which they would recommend HIPEC in patients with ovarian cancer and to describe any disease or patient characteristics relevant to their decision. All answers were then merged and converted into decision trees. The decision trees were then analyzed by applying the objective consensus methodology.

Results: Nine experts in surgical oncology provided information on their multidisciplinary treatment strategy including HIPEC for patients with advanced ovarian cancer. Three of the total of 12 experts did not perform HIPEC. Five criteria relevant to the decision on whether HIPEC is performed were applied. In patients with resectable disease, a peritoneal cancer index (PCI) <21, and epithelial ovarian cancer without distant metastasis, consent was received by 75% to perform HIPEC for women suffering from recurrent disease. Furthermore, in the primary disease setting, consent was received by 67% to perform HIPEC according to the same criteria.

Discussion And Conclusion: Among surgical oncology experts in peritoneal surface malignancy and HIPEC, HIPEC plays an important role in primary and recurrent ovarian cancer, and the PCI is the most important criterion in this decision.
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http://dx.doi.org/10.1159/000510098DOI Listing
January 2021

Mucinous appendiceal neoplasms with or without pseudomyxoma peritonei: a review.

ANZ J Surg 2020 10 5;90(10):1888-1894. Epub 2020 Aug 5.

Department of Surgery, University of New South Wales, St George Hospital, Sydney, Australia.

Mucinous appendiceal neoplasms (MANs) are rare tumours and the primary cause of pseudomyxoma peritonei. These tumours have a much more benign course than typical colorectal cancers, generally growing for many years before giving any clinical signs. The spectrum of presentations, tumour stages and the underlying cytology is very wide, warranting from the simplest operation like an appendicectomy to the most complicated operation like a complete cytoreduction surgery and hyperthermic intraperitoneal chemotherapy. Fortunately, most patients can be offered a curative treatment, but limiting operative morbidity without compromising oncologic outcomes is the biggest challenge in managing these patients. Histopathology is the cornerstone of decision making for MANs, but is also subject to ongoing debate because of a lack of terminology consensus amongst pathologists. Combined with the rarity of this disease, the multiple histopathologic classification updates of MANs explain the ongoing confusion amongst clinicians in regard to individual optimal treatment. This review will cover the most recent histological classification of MANs and attempt to clarify optimal management of patients with different clinical presentation and histologic combinations.
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http://dx.doi.org/10.1111/ans.16185DOI Listing
October 2020

Independent Replication on Genome-Wide Association Study Signals Identifies as a Novel Locus for Systemic Lupus Erythematosus.

Front Genet 2020 3;11:600. Epub 2020 Jul 3.

Department of Pediatrics, Union Hospital Affiliated to Fujian Medical University, Fuzhou, China.

Systemic lupus erythematosus (SLE) is a genetically complex autoimmune disease. Despite the significant progress made in identifying susceptibility genes for SLE, the genetic architecture of the disease is far from being understood. In this study, we set to replicate a number of suggestive association signals found in genome-wide association studies (GWASs) in additional independent cohorts. Replication studies were performed on Han Chinese cohorts from Hong Kong and Anhui, involving a total of 2,269 cases and 5,073 controls. We identified a missense variant in (rs7251) reaching genome-wide significance through a joint analysis of GWAS and replication data (OR = 0.876, P = 4.40E-08). A significant correlation was observed between rs7251 and lupus nephritis (LN) by subphenotype stratification (OR = 0.785, P = 0.0128). IRF3 is a key molecule in type I interferon production upon nucleic acid antigen stimulations and may inhibit regulatory T cell differentiation. Further elucidation of the mechanism of this association could help us better understand the pathogenesis of SLE.
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http://dx.doi.org/10.3389/fgene.2020.00600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7348047PMC
July 2020

Complement genes contribute sex-biased vulnerability in diverse disorders.

Nature 2020 06 11;582(7813):577-581. Epub 2020 May 11.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men, whereas schizophrenia affects men with greater frequency and severity relative to women. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.
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http://dx.doi.org/10.1038/s41586-020-2277-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319891PMC
June 2020

Neutropenia in colorectal cancer treated with oxaliplatin-based hyperthermic intraperitoneal chemotherapy: An observational cohort study.

World J Gastrointest Oncol 2020 May;12(5):549-558

Department of Surgery, University of New South Wales, Sydney 2217, New South Wales, Australia.

Background: The implications of neutropenia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) treatment have never been investigated.

Aim: To evaluate the occurrence of neutropenia and its effect on the risk of increased Clavien-Dindo morbidity as well as its effect on overall or disease-free survival.

Methods: All patients with colorectal peritoneal metastases (1996-2015) completing cytoreductive surgery and oxaliplatin-based HIPEC treatment from a bi-institutional database (Uppsala and Sydney) were included in the study. Clavien-Dindo grade 3-4 morbidity differences between the neutropenia group non-neutropenia group were calculated and Kaplan-Meier curves with log rank test were rendered. Univariate and multivariable Cox regression models for disease-free survival were implemented.

Results: Two hundred and forty-six patients were identified - 32 postoperative any-grade neutropenia patients and 214 non-neutropenia patients. The neutropenia group had more combination oxaliplatin + irinotecan treatment than the non-neutropenia group (66% 13%, = 0.0001). The neutropenia group was not associated with increased Clavien-Dindo grade 3-4 morbidity. Median overall survival was 53 mo 37 mo for the neutropenia and non-neutropenia group, = 0.07. Median disease-free survival was 16 mo 11 mo, respectively, = 0.02. Neutropenia was an independent prognostic factor for disease-free survival with hazard ratio: 0.58, 95% confidence interval: 0.36-0.95, = 0.03.

Conclusion: 13% of patients developed neutropenia which was not associated with increased Clavien-Dindo grade 3-4 morbidity. Neutropenia was an independent positive prognostic factor for disease-free survival and was associated with more intense HIPEC treatment. This is in direct contrast to the current paradigm of decreasing the treatment intensity.
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http://dx.doi.org/10.4251/wjgo.v12.i5.549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235182PMC
May 2020

Intestinal schistosomiasis mimicking caecal malignancy.

ANZ J Surg 2020 12 21;90(12):2576-2577. Epub 2020 May 21.

Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.15944DOI Listing
December 2020

Impact of Cytoreductive Surgery and HIPEC on Intraoperative Gastrointestinal Wall Thickness and Patient Outcomes.

Anticancer Res 2020 May;40(5):2865-2869

Department of Surgery, St. George Hospital, Kogarah, NSW, Australia

Background: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is associated with significant postoperative ileus (POI). This study examined intraoperative gastrointestinal wall thickness (GWT) and its association with patient outcomes.

Patients And Methods: A prospective study of patients undergoing CRS and HIPEC. Proximal and distal small intestine GWT, before and after HIPEC were recorded.

Results: Thirty-four patients (mean age=56.1 years, 61.8% female) were recruited. After HIPEC, the mean proximal (4.5 vs. 3.0 mm, p=0.03) and distal (4.3 vs. 3.4 mm, p<0.01) GWT were increased. Increased GWT was associated with prolonged operative time (10 vs. 8.5 h, p=0.03) and total length of stay (35.71 vs. 21.25 days, p=0.02). Postoperative ileus occurred in 23.5% of patients but differences between GWT groups did not reach significance (28.6% vs. 20%, p=0.56).

Conclusion: GWT increased significantly during CRS and HIPEC and is reflective of tissue trauma and oedema. This was associated with prolonged operative time, total length of stay and post-operative ileus.
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http://dx.doi.org/10.21873/anticanres.14262DOI Listing
May 2020

Genome-wide assessment of genetic risk for systemic lupus erythematosus and disease severity.

Hum Mol Genet 2020 06;29(10):1745-1756

Department of Medical and Molecular Genetics, King's College London, London, UK.

Using three European and two Chinese genome-wide association studies (GWAS), we investigated the performance of genetic risk scores (GRSs) for predicting the susceptibility and severity of systemic lupus erythematosus (SLE), using renal disease as a proxy for severity. We used four GWASs to test the performance of GRS both cross validating within the European population and between European and Chinese populations. The performance of GRS in SLE risk prediction was evaluated by receiver operating characteristic (ROC) curves. We then analyzed the polygenic nature of SLE statistically. We also partitioned patients according to their age-of-onset and evaluated the predictability of GRS in disease severity in each age group. We found consistently that the best GRS in the prediction of SLE used SNPs associated at the level of P < 1e-05 in all GWAS data sets and that SNPs with P-values above 0.2 were inflated for SLE true positive signals. The GRS results in an area under the ROC curve ranging between 0.64 and 0.72, within European and between the European and Chinese populations. We further showed a significant positive correlation between a GRS and renal disease in two independent European GWAS (Pcohort1 = 2.44e-08; Pcohort2 = 0.00205) and a significant negative correlation with age of SLE onset (Pcohort1 = 1.76e-12; Pcohort2 = 0.00384). We found that the GRS performed better in the prediction of renal disease in the 'later onset' compared with the 'earlier onset' group. The GRS predicts SLE in both European and Chinese populations and correlates with poorer prognostic factors: young age-of-onset and lupus nephritis.
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http://dx.doi.org/10.1093/hmg/ddaa030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322569PMC
June 2020

Volume-Time Index Is Not an Indicator of Outcome for Patients Undergoing CRS/HIPEC for Treatment of High-Grade Appendiceal Carcinomatosis.

Anticancer Res 2019 Dec;39(12):6813-6817

St George & Sutherland Clinical School, University of New South Wales, Sydney, Australia

Background/aim: Completeness of cytoreduction score (CC-score) and tumour grade have been shown to be independent prognostic factors in patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of high-grade appendiceal carcinomatosis (PMCA). In patients with colorectal cancer with peritoneal metastases (CRPM) that undergo CRS/HIPEC, volume time index (VTI) has been shown to be an independent prognostic factor for overall survival (OS). This analysis was conducted to evaluate VTI as a prognostic factor in PMCA.

Patients And Methods: We performed A retrospective cohort study of 131 patients who underwent CRS-HIPEC for PMCA from 1996 to 2017. VTI was calculated and analyses were performed to determine the association with patients' outcomes.

Results: Median overall survival by high vs. low VTI groups were 69 months (95%CI=45-NA) vs. 63 months [95% Confidence Interval (CI)=48-not available (NA)], with an associated difference in 5-year survival rates of 52.1 (95%CI=39.5-68.8) vs. 50.6 (95%CI=35.2-72.6) respectively, with a non-significant p-value of 0.968. For the 82 patients with complete recurrence data, the median RFS stratified by high vs. low VTI were 16 months (95%CI=10-25) vs. 20 months (95%CI=13-34) respectively, with no statistically significant difference in 5-year recurrence-free survival (RFS).

Conclusion: VTI for PMCA was not shown to be correlated with overall survival (OS) for patients undergoing CRS/HIPEC, and suggests that the rate of tumour growth does not affect the patients' outcome. Neither high PCI nor rapid tumour growth following primary tumour resection should, therefore, be a contraindication for CRS/HIPEC in patients with PMCA.
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http://dx.doi.org/10.21873/anticanres.13897DOI Listing
December 2019

A commentary on "Postoperative outcomes in elderly patients undergoing pancreatic resection for pancreatic adenocarcinoma: A systematic review and meta-analysis" [Int. J. Surg. 2019, 72:59-68].

Int J Surg 2020 01 20;73:87-88. Epub 2019 Nov 20.

Department of Surgery, St George Hospital, Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.ijsu.2019.11.016DOI Listing
January 2020

Early postoperative intraperitoneal chemotherapy for lower gastrointestinal neoplasms with peritoneal metastasis: a systematic review and critical analysis.

Pleura Peritoneum 2019 Sep 4;4(3):20190007. Epub 2019 Oct 4.

Department of Surgery, University of New South Wales, St George Hospital, Kogarah, New South Wales, Australia.

Background: Early postoperative intraperitoneal chemotherapy (EPIC) can be used in combination with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) to treat patients with peritoneal carcinomatosis (PC) of multiple origins. The present study is a systematic review to evaluate the role of EPIC after CRS + HIPEC for appendiceal and colorectal cancers with PC.

Content: We conducted a systematic search in PubMed according to the PRISMA guidelines and included all studies published before June 27 of 2019 comparing EPIC to HIPEC or the combination of both. Our search found 79 articles. After excluding non-relevant articles, a total of 13 retrospective clinical studies reporting on the efficacy and safety of EPIC compared to HIPEC or as a combination therapy for lower gastrointestinal neoplasms were analyzed. Initial EPIC reports led to its declined usage because of concerns with increased postoperative morbidity and uncertain added benefit on survival. Recent retrospective studies have been promising, showing significant improvements in OS and fewer issues with complications when adding EPIC to CRS + HIPEC.

Conclusions: Current evidence is entirely retrospective and is conflicting. It is hoped that ongoing clinical trials and additional studies will clarify EPIC's role in the treatment of patients with PC.
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http://dx.doi.org/10.1515/pp-2019-0007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6812220PMC
September 2019

Pericardiobiliary fistula causing acute pericarditis and tamponade following extensive cytoreductive surgery.

ANZ J Surg 2020 05 2;90(5):919-920. Epub 2019 Oct 2.

Department of Surgery, St George Hospital, The University of New South Wales, Sydney, New South Wales, Australia.

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http://dx.doi.org/10.1111/ans.15417DOI Listing
May 2020

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in a patient with peritoneal carcinomatosis from a pancreatic cystadenocarcinoma: A case report.

Int J Surg Case Rep 2019 17;63:48-52. Epub 2019 Sep 17.

Department of Surgery, University of New South Wales, St George Hospital, Sydney, Australia.

Introduction: Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is a well-established procedure commonly employed in the management of peritoneal carcinomatosis (PC) from tumors of various specific origins. However, it is not traditionally used in the management of PC of pancreatic origin due to various reasons, including the aggressive nature of pancreatic tumors.

Case Presentation: A 67-year-old female presented with a large amount of intractable malignant ascites. Computed tomography (CT) imaging showed a nodule in the right paracolic gutter. A diagnostic laparoscopy and omental biopsy showed a well-differentiated adenocarcinoma of pancreatic origin. She was initially not considered suitable for CRS and HIPEC due to apparent liver metastases on CT imaging and was arranged to undergo palliative chemotherapy; however, due to her large amount of refractory ascites and a suspected ruptured right krukenberg tumor, surgical intervention was offered. We performed CRS, bilateral salpingo-oophorectomy, and an omentectomy with a CC (completeness of cytoreduction) score of 1. HIPEC with mitomycin C was also administered. Notably, our patient remains clinically well at 48-months post CRS and HIPEC, with no signs or symptoms suggestive of tumor recurrence.

Conclusion: Despite the current lack of evidence supporting the use of CRS and HIPEC in the curation of PC of pancreatic origin, this case report highlights the importance of patient selection in determining suitability for CRS. In the presence of positive prognostic factors and favorable tumor histology, CRS and HIPEC is a potential curative procedure that could be offered to highly selected patients presenting with PC from a primary pancreatic malignancy.
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http://dx.doi.org/10.1016/j.ijscr.2019.08.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796650PMC
September 2019

Intraoperative packed red blood cell transfusion (iPRBT) and PCI-normalised iPRBT rates (iPRBT/PCI ratio) negatively affect short- and long-term outcomes of patients undergoing cytoreductive surgery and intraperitoneal chemotherapy - An analysis of 880 patients.

Eur J Surg Oncol 2019 Dec 30;45(12):2412-2423. Epub 2019 Jul 30.

Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, Kogarah, NSW, Australia. Electronic address:

Background: Most studies on the effects of intraoperative packed red blood cell transfusions (iPRBT) on patients undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) have shown deleterious outcomes. It is unclear if this is a result of the transfusion itself or because iPRBTs serve as a surrogate of more advanced disease.

Methods: A retrospective analysis of 880 patients treated from 1996 to 2017. The effect of any exposure to iPRBT as well as the effect of peritoneal cancer index (PCI)-normalised iPRBT rates (ratio of iPRBT/PCI) on patients short- and long-term outcomes (recurrence-free (RFS) and overall survival (OS)) were assessed. Equally, the prognostic effect of postoperative PRBTs was analysed and adjusted for.

Results: Of the 880 patients included, only 26.4% had no iPRBT whereas 59.2% of patients had no postoperative PRBT. Patients with no iPRBTs had significantly lower PCIs, less high-grade complications, shorter ICU and hospital length of stay, as well as improved RFS and OS. Furthermore, high PCI-normalised iPRBTs resulted in worse perioperative and long-term outcomes, with a median OS of 41 months vs. 103 months (5-year survival rate 36.6% vs. 66.1%; p < 0.001) and median RFS of 13 months vs. 30 months (5-year RFS rate 18.3% vs. 37.6% p < 0.001) compared to those with a low iPRBT/PCI ratio. This independent effect was confirmed upon multivariable Cox regression analysis which corrected for important confounders including complexity of procedures and postoperative PRBTs (adjusted HR [aHR]2.04, 95%CI 1.36-3.04, p = 0.001 for OS; aHR 1.38, 95%CI 1.06-1.81, p = 0.017 for RFS). However, subgroup analysis (stratified by histopathologic disease entities) revealed that this independent prognostic effect was seen in high-grade mucinous appendiceal neoplasms, whereas PCI-normalised IPRBTs were not significantly prognostic in other histopathologic subgroups.

Conclusion: iPRBTs significantly and independently impact perioperative and long-term outcomes of patients undergoing CRS/HIPEC. However, this effect mainly seems to occur in patients with high-grade mucinous neoplasms, whereas it may only be of borderline prognostic significance in other patient groups. The development of blood-sparing protocols may help improve outcomes of patients undergoing this complex oncologic procedure.
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http://dx.doi.org/10.1016/j.ejso.2019.07.031DOI Listing
December 2019

Long-term survival outcomes of cytoreductive surgery and perioperative intraperitoneal chemotherapy: Single-institutional experience with 1225 cases.

J Surg Oncol 2019 Sep 16;120(4):794-802. Epub 2019 Jul 16.

Department of Surgery, St George Hospital & University of New South Wales, Sydney, New South Wales, Australia.

Background And Objectives: To review long-term survival outcomes of patients with Peritoneal metastasis (PM) who underwent colorectal cancer (CRS) and intraperitoneal chemotherapy (PIC).

Methods: Patients that underwent CRS, with or without PIC, from January 1996 to March 2018 at the Peritonectomy Unit of St. George Hospital, Sydney were retrospectively analyzed from a prospectively maintained database.

Results: The study comprised of 1225 cases, including 687 females (56.1%) and 538 males (43.9%). Diagnoses included CRC (n = 363), followed by HAMN (n = 317), LAMN (n = 297), mesothelioma (n = 101), ovarian cancer (n = 55), and others including gastric, sarcoma, and neuroendocrine tumor (n = 92). The median OS, 5- and 10-year survivals for CRC were 35 months, 33% and 8%, respectively. Patients with LAMN, in relative to HAMN, experienced a higher median OS, 5- and 10-year survivals (248 months vs 63 months; 82% vs 52% and 59% vs 28%). The median OS for mesothelioma was 60 months with 5- and 10-year survivals of 48% and 19%, respectively. In ovarian cancer, the median OS was 30 months with 5- and 10-year survivals of 26% and 10%, respectively. For the remaining histological diagnoses, median OS and 5-year survival were 28 months and 27%, respectively.

Conclusion: Our large-cohort data showed that CRS/PIC can provide long-term survival benefit to patients with PM of gastrointestinal and ovarian origin.
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http://dx.doi.org/10.1002/jso.25642DOI Listing
September 2019

Short- and Long-Term Outcomes of Patients Requiring Gastrectomy During Cytoreductive Surgery and Intraperitoneal Chemotherapy for Lower-Gastrointestinal Malignancies: A Propensity Score-Matched Analysis.

Ann Surg Oncol 2019 Oct 10;26(11):3627-3635. Epub 2019 Jul 10.

Liver and Peritonectomy Unit, St George Hospital, Sydney, Australia.

Objectives: This study was designed to assess the short- and long-term outcomes of gastric resection in cytoreductive surgery (CRS) and intraperitoneal chemotherapy (IPC) for lower gastrointestinal (GI) malignancies.

Methods: Patients with adenocarcinoma and appendiceal mucinous neoplasms were included. Redo and incomplete cytoreductions were excluded. A total of 756 patients were identified. Of these, 65 underwent gastric resection, 11 underwent wedge, 43 distal, and 11 subtotal and total gastrectomy. Preoperative differences were assessed for and addressed with matching. Perioperative outcomes, overall survival (OS), and risk-free survival (RFS) were assessed in two analyses: first all gastric resections were included and the second excluded wedge resections. Subgroup analysis according to diagnosis subtype was conducted.

Results: Demographic analysis revealed that markers of tumor aggression and poor nutrition were prevalent in the gastrectomy group. The matched analysis for gastric resections revealed higher rates of reoperation (38% vs. 22%, p = 0.028). After excluding wedge resections, increased rates of reoperation (40% vs. 22%, 0.019), grade 3/4 morbidity (76% vs. 59%, p = 0.036), and hospital stay (34 vs. 27 days, p = 0.012) were observed. For the unmatched cohort, OS (103 vs. 69 months, p = 0.501) and RFS (17 vs. 18 months, p = 0.181) for patients with CC = 0 were insignificantly different. In comparison for CC > 0, OS (31 vs. 83 months, p < 0.001) and RFS (9 vs. 20 months, p < 0.001) were significantly reduced in gastric resection. For the matched cohort, after excluding wedges, gastrectomy did not significantly decrease OS. However, RFS was decreased (11 vs. 20 months, p = 0.016).

Conclusions: Despite high postoperative morbidity, when complete cytoreduction is achieved, the need for gastric resection is not associated with inferior long-term outcomes.
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http://dx.doi.org/10.1245/s10434-019-07510-9DOI Listing
October 2019

Long term survival and perioperative propensity score matched outcomes of diaphragmatic resections compared to stripping in cytoreductive surgery + intra-peritoneal chemotherapy.

Am J Surg 2020 04 23;219(4):673-680. Epub 2019 Jun 23.

Liver & Peritonectomy Unit, St George Hospital, Sydney, Australia; St George & Sutherland Clinical School, University of New South Wales, Sydney, Australia; College of Medicine, Al Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia. Electronic address:

Objectives: To assess the impact of short and long term outcomes of diaphragm resection and repair in cyto-reductive surgery (CRS) and intra-peritoneal chemotherapy (IPC).

Methods: 1230 consecutive CRS/IPC procedures were performed between 1996 and 2018 in Sydney, Australia. Among these, 652 underwent diaphragmatic intervention. The analysis was preformed according to histological subtype. First diaphragm interventions were compared to non-diaphragmatic CRS. Secondly, diaphragm resection was compared to diaphragm stripping. Overall survival and recurrence free survival was assessed based on histological diagnosis.

Results: There were no differences between the resection and stripping groups for the colorectal cohort. For mesothelioma, increased incidences of pleural effusions in the resection group were noted (63% vs.28%, p = 0.017). In HAMNs, the resection group was associated with increased reoperations (42% vs. 15%, p = 0.03) and in hospital death (16.7% vs. 0.6%, p = 0.012). Resection in LAMNs were linked with increased transfusion requirements (9 vs. 6, p = 0.01), reoperation (39% vs. 23%, p = 0.05) and prolonged length of stay (34 days vs. 25 days, p = 0.02). There were no differences in overall survival and recurrence free survival in colorectal cancer. Median overall survival was decreased in mesothelioma by 20 months. In LAMNs the median survival was significantly decreased for the resection group. Similarly, the resection group had a 4-month earlier recurrence.

Conclusion: We conclude that diaphragm interventions are an essential part of CRS. They are associated with increased perioperative morbidity. This morbidity is not attributable to whether the patient underwent diaphragm stripping or resection. However in mesothelioma and LAMNs, requiring diaphragm resection is likely to be an indicator for tumor aggression.
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http://dx.doi.org/10.1016/j.amjsurg.2019.06.018DOI Listing
April 2020

Early recurrence in peritoneal metastasis of appendiceal neoplasm: Survival and prognostic factors.

Eur J Surg Oncol 2019 Dec 22;45(12):2392-2397. Epub 2019 Jun 22.

Department of Surgery, St George Hospital & University of New South Wales, Sydney, New South Wales, Australia.

Introduction: Early recurrence (ER) is defined as development of loco-regional peritoneal disease within 12-month of the initial CRS/PIC. Our aims were to identify overall survival (OS), recurrence-free survival (RFS) and independent prognostic factors associated with ER in PM of appendiceal neoplasm.

Materials And Methods: A prospectively-maintained database for patients with appendiceal neoplasm undergoing cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) from year 1996-2018 was retrospectively analysed.

Results: 208 female and 185 male patients were identified. With a median follow-up of 40-month, 40.2% of the patients developed ER. The median OS for ER was 24 months compared to late (LR) at 64 months. Median OS was not reached in non-recurrence (NR). 5-year survival for ER was less favourable compared to LR and NR (19.3%vs54.6%vs94%). No patients in ER group survived beyond 10-year. Independent negative predictors associated with ER on multivariate analysis were male patient (p = 0.013), blood transfusion of >8 units (p = 0.013), elevated preoperative CEA levels (>5 ng/ml; p = 0.002) and hard intraoperative tumour consistency (p < 0.001). Protective factor was a combination of CC1, hard tumour consistency and use of EPIC (p = 0.039). Independent prognostic factors that predicted recurrence of appendiceal PM were PCI >20 (p = 0.049), non-use of EPIC (p = 0.012), hard tumour consistency (p = 0.004) and use of previous chemotherapy (p = 0.023).

Conclusion: ER following CRS and PIC of appendiceal PM is associated with reduced survival outcomes. Our data alludes to the importance of optimising the risk factors in order to delay loco-regional recurrence and improve long-term survival of these patients.
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http://dx.doi.org/10.1016/j.ejso.2019.06.015DOI Listing
December 2019

Preoperative Nutrition Status and Postoperative Outcomes in Patients Undergoing Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

Ann Surg Oncol 2019 Aug 23;26(8):2622-2630. Epub 2019 May 23.

Liver and Peritonectomy Unit, Department of Surgery, St George Hospital, University of New South Wales, Research and Education Centre, Kogarah, Sydney, NSW, Australia.

Background: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a complex surgery to treat peritoneal surface malignancy (PSM). PSM and gastrointestinal (GI) resection from CRS can lead to significant GI symptoms and malnutrition. There is limited research into the nutrition status of this patient group and the impact of malnutrition on morbidity.

Objective: This study aims to determine if preoperative malnutrition, assessed using the Subjective Global Assessment (SGA), is associated with postoperative morbidity and increased length of stay (LOS) in patients undergoing CRS/HIPEC for PSM.

Methods: This study prospectively assessed the nutritional status of patients undergoing CRS/HIPEC using a validated nutrition assessment tool. Preoperative clinical symptoms, Peritoneal Cancer Index (PCI), intraoperative blood transfusions, operative time, GI resections, postoperative morbidity, and LOS, as well as pre- and postoperative nutritional interventions, were recorded. The impact of preoperative nutritional status was assessed in relation to postoperative complications and hospital LOS.

Results: The study included 102 participants; 34 patients (33%) were classified as malnourished (SGA = B or C). Preoperative weight loss (15% vs. 74%; p ≤ 0.001) and the presence of clinical symptoms (18% vs. 47%; p = 0.002) were significantly higher in malnourished patients. While PCI, intraoperative blood transfusions, and GI resections were independent predictors of morbidity, malnutrition was significantly associated with infectious complications and LOS. For each grade of worsening malnutrition, LOS increased by an average of 7.65 days.

Conclusions: Preoperative malnutrition is prevalent in patients undergoing CRS/HIPEC and postoperative morbidity is common. Malnutrition is linked to LOS and plays a role in postoperative outcomes such as infection. Clear pre- and postoperative nutrition pathways are needed to optimize nutrition support and postoperative recovery.
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http://dx.doi.org/10.1245/s10434-019-07415-7DOI Listing
August 2019

Interferon inducible X-linked gene CXorf21 may contribute to sexual dimorphism in Systemic Lupus Erythematosus.

Nat Commun 2019 05 15;10(1):2164. Epub 2019 May 15.

Department of Medical & Molecular Genetics, King's College London, London, SE1 9RT, UK.

Systemic lupus erythematosus (SLE) is an autoimmune disease, characterised by increased expression of type I interferon (IFN)-regulated genes and a striking sex imbalance towards females. Through combined genetic, in silico, in vitro, and ex vivo approaches, we define CXorf21, a gene of hitherto unknown function, which escapes X-chromosome inactivation, as a candidate underlying the Xp21.2 SLE association. We demonstrate that CXorf21 is an IFN-response gene and that the sexual dimorphism in expression is magnified by immunological challenge. Fine-mapping reveals a single haplotype as a potential causal cis-eQTL for CXorf21. We propose that expression is amplified through modification of promoter and 3'-UTR chromatin interactions. Finally, we show that the CXORF21 protein colocalises with TLR7, a pathway implicated in SLE pathogenesis. Our study reveals modulation in gene expression affected by the combination of two hallmarks of SLE: CXorf21 expression increases in a both an IFN-inducible and sex-specific manner.
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http://dx.doi.org/10.1038/s41467-019-10106-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6520347PMC
May 2019

The effect of intraoperative fluid administration on outcomes of patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

J Gastrointest Oncol 2019 Apr;10(2):235-243

Hepatobilliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, Kogarah, NSW, Australia.

Background: Determine the effect of intraoperative fluids (IOFs) administered during cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) on postoperative patient outcomes.

Methods: Retrospective cohort study of patients that underwent CRS/HIPEC from February 2010 to June 2017.

Results: A total of 335 patients formed the cohort study. Patients who received higher IOFs had longer hospital length of stay (LOS) (34 22.5 days; P<0.001), extended intensive care unit (ICU) admission (5.3 3.2 days; P<0.001) and a 12% increase in grade 3/4 complications (P<0.001). Greater amounts of blood product transfusion were associated with longer hospital LOS (33.7 23 days; P<0.001), and ICU admission (5 3.4 days; P<0.001) and 12% increase in grade 3/4 complications (P<0.001). When corrected for weight and peritoneal cancer index (PCI), increased transfusion of blood products still resulted in longer hospital LOS (31.2 25.2 days; P=0.04) and longer ICU admission (4.7 3.6 days; P=0.03). On multivariable analysis, less blood product transfusions demonstrated a decreased LOS in hospital by 4.8 days (P=0.01) and fewer grade 3/4 complications (OR 0.59; 95% CI, 0.35-0.99; P=0.05).

Conclusions: Greater IOF administration is associated with an increase in postoperative morbidity, including hospital LOS, ICU admission and grade 3/4 complications, in patients undergoing CRS/HIPEC.
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http://dx.doi.org/10.21037/jgo.2018.12.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6465479PMC
April 2019

The volume-time index (VTI) is prognostic in patients with colorectal cancer peritoneal metastases undergoing cytoreductive surgery and intraperitoneal chemotherapy.

Am J Surg 2020 01 1;219(1):58-64. Epub 2019 Apr 1.

Hepatobiliary and Surgical Oncology Unit, Department of Surgery, St George Hospital, Kogarah, NSW, Australia; St George Hospital Clinical School, University of New South Wales, Sydney, NSW, Australia. Electronic address:

Background: Peritoneal cancer index (PCI) is an important prognostic factor in colorectal cancer peritoneal metastases (CRPM), however it fails to consider the time period over which disease burden develops. The volume-time index (VTI) is the ratio between PCI and time from primary tumour resection.

Methods: A retrospective cohort study of 182 patients managed from 1996 to 2017 was performed.

Results: As stratified by high vs low VTI groups, median overall survival (OS) was 23 months (95% 17-46) vs 44 months (95% 35-72) with a difference in 5-year OS of 20.3% (95%CI 10.2-40.4) vs 40.1% (95%CI 29.7-54.1), p = 0.002. No difference in 5-year recurrence free survival (RFS) exists. On multivariable analysis, an elevated VTI was independently associated with poorer OS (adjusted HR 3.20, 95%CI 1.64-6.23, p < 0.001) and RFS (adjusted HR 1.90, 95%CI 1.10-3.29, p = 0.02).

Conclusion: VTI is an independent prognostic factor for OS and RFs in patients with CRPM undergoing CRS/IPC, behaving as a surrogate of tumour aggressiveness.
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http://dx.doi.org/10.1016/j.amjsurg.2019.03.023DOI Listing
January 2020

Case report: Intraoperative thrombosis cardiac arrest in extended right hepatectomy involving use of local haemostatic agent in intraoperative cell salvage (ICS) and administration of recombinant activated factor VII (rFVIIa).

Int J Surg Case Rep 2019 6;57:48-51. Epub 2019 Mar 6.

Department of Surgery, St George Hospital, University of New South Wales, Sydney, New South Wales, Australia.

Introduction: In modern surgical era, local haemostatic agents and blood components such as recombinant activated factor VII (rFVIIa) have expanded surgeons' armamentarium in controlling "surgical" and "nonsurgical bleeding". We report a case of intraoperative thrombosis and cardiac arrest involving use of local haemostatic agent in intraoperative cell salvage and rFVIIa administration in extended right hepatectomy.

Presentation Of Case: A 46-year-old lady underwent extended right hepatectomy using cardiopulmonary bypass (CPB) and autotransfusion with ICS for metastatic gastrointestinal stromal tumour. She became extremely coagulopathic following weaning of CPB despite an array of fluid and blood products replacements. Decision to administer rFVIIa as a measure to arrest bleeding was unsuccessful. Extensive systemic thrombosis occurred which resulted in cardiac arrest and mortality.

Discussion: The thromboembolic event was unclear but likely multifactorial. Two important hypotheses were the administration of rFVIIa and use of local haemostatic agent in ICS.

Conclusion: Reported incidence of thromboembolism with use of rFVIIa in refractory bleeding is variable. More randomised controlled trials are needed to ascertain the efficacy and safety profile of the haemostatic agent. At present, off-label use of rFVIIa should be guided by the risk:benefit profile on a case-to-case basis. The authors also feel strongly against the use of local haemostatic gel in conjunction with ICS due to potential systemic circulation of the thrombin.
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http://dx.doi.org/10.1016/j.ijscr.2019.02.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429545PMC
March 2019