Bi-national Review of Phaeochromocytoma Care: Is ICU Admission Always Necessary?

BACKGROUND: Post-operative management after phaeochromocytoma resection includes monitoring of blood pressure and blood sugar, and vigilance for haemorrhage. Guidelines recommend 24 h of continuous blood pressure monitoring, usually necessitating HDU/ICU admission. We hypothesised that most patients undergoing phaeochromocytoma resection do not require post-operative HDU/ICU admission. We aim to describe current Australian and New Zealand perioperative management of phaeochromocytoma and determine whether it is safe to omit HDU/ICU care for most patients. METHODS: We collected retrospective data on patients undergoing excision of phaeochromocytoma in 12 centres around Australia and New Zealand between 2007 and 2019. Data collected included preoperative medical management, anaesthetic management, vasopressor support, HDU/ICU admission and complications. RESULTS: A total of 223 patients were included in the study, 173 (77%) of whom were admitted to HDU/ICU post-operatively. The group of patients treated in ICU was similar to the group of patients treated on the ward in terms of demographic and tumour characteristics, and there were significant differences in the proportion of patients admitted to HDU/ICU between centres. Of patients admitted to ICU, 71 (41%) received vasopressor support. This was weaned within 24 h in 55 (77%) patients. Patients with larger tumours (> 6 cm) and a transfusion requirement are more likely to require prolonged inotropic support. Among patients admitted to the ward, there were no complications that required escalation of care. CONCLUSIONS: Although not widespread practice in Australia and New Zealand, it appears safe for the majority of patients undergoing minimally invasive resection of phaeochromocytoma to be admitted to the ward post-operatively.

Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression.

Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2-encoded ERß expression in the MTC tumour. ERα and ERß form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERß represses ERα-mediated activation of the ERE and the RET promoter contains three EREs. In vitro, we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo, immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.

Systematic review of peri-operative prognostic biomarkers in pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) continues to be associated with a poor prognosis. This systematic review aimed to summarize the literature regarding potential prognostic biomarkers to facilitate validation studies and clinical application. METHODS: A systematic review was performed (2004-2014) according to PRISMA guidelines. Studies were ranked using REMARK criteria and the following outcomes were examined: overall/disease free survival, nodal involvement, tumour characteristics, metastasis, recurrence and resectability. RESULTS: 256 biomarkers were identified in 158 studies. 171 biomarkers were assessed with respect to overall survival: urokinase-type plasminogen activator receptor, atypical protein kinase C and HSP27 ranked the highest. 33 biomarkers were assessed for disease free survival: CD24 and S100A4 were the highest ranking. 17 biomarkers were identified for lymph node involvement: Smad4/Dpc4 and FOXC1 ranked highest. 13 biomarkers were examined for tumour grade: mesothelin and EGFR were the highest ranking biomarkers. 10 biomarkers were identified for metastasis: p16 and sCD40L were the highest ranking. 4 biomarkers were assessed resectability: sCD40L, s100a2, Ca 19-9, CEA. CONCLUSION: This review has identified and ranked specific biomarkers that should be a primary focus of ongoing validation and clinical translational work in PDAC.

Use of the Nerve Integrity Monitor during Thyroid Surgery Aids Identification of the External Branch of the Superior Laryngeal Nerve.

BACKGROUND: The external branch of the superior laryngeal nerve (EBSLN) is at risk during thyroid surgery. Despite meticulous dissection and visualization, the EBSLN can be mistaken for other structures. The nerve integrity monitor (NIM) allows EBSLN confirmation with cricothyroid twitch on stimulation. AIMS: The aim of this study was to assess any difference in identification of EBSLN and its anatomical sub-types by dissection alone compared to NIM-aided dissection. METHODS: Routine intra-operative nerve monitoring (IONM) was used, when available, for 228 consecutive thyroid operations (129 total thyroidectomies, 99 hemi-thyroidectomies) over a 10-month period. EBSLN identification by dissection alone (with NIM confirmation of cricothyroid twitch) and by NIM-assisted dissection was recorded prospectively. Anatomical sub-types were defined by the Cernea classification. RESULTS: Of 357 nerves at risk, 97.2 % EBSLNs (95 % confidence interval [CI], 95.5-98.9) were identified by visualization and NIM-aided dissection compared to 85.7 % (95 % CI, 82.1-89.3) identified by dissection alone (<0.001). EBSLN frequency was 34 % for type 1, 55 % for type 2a, and 11 % for type 2b. All identified EBSLNs were stimulated to confirm a cricothyroid twitch after superior thyroid vessel ligation. CONCLUSION: Using the NIM and meticulous dissection of the upper thyroid pole improves EBSLN identification. As the EBSLN is at risk during thyroidectomy and can lead to voice morbidity, the NIM can aid identification of the EBSLN and provide a functional assessment of the EBSLN after thyroid resection.

Noncoding RNAs in endocrine malignancy.

Only recently has it been uncovered that the mammalian transcriptome includes a large number of noncoding RNAs (ncRNAs) that play a variety of important regulatory roles in gene expression and other biological processes. Among numerous kinds of ncRNAs, short noncoding RNAs, such as microRNAs, have been extensively investigated with regard to their biogenesis, function, and importance in carcinogenesis. Long noncoding RNAs (lncRNAs) have only recently been implicated in playing a key regulatory role in cancer biology. The deregulation of ncRNAs has been demonstrated to have important roles in the regulation and progression of cancer development. In this review, we describe the roles of both short noncoding RNAs (including microRNAs, small nuclear RNAs, and piwi-interacting RNAs) and lncRNAs in carcinogenesis and outline the possible underlying genetic mechanisms, with particular emphasis on clinical applications. The focus of our review includes studies from the literature on ncRNAs in traditional endocrine-related cancers, including thyroid, parathyroid, adrenal gland, and gastrointestinal neuroendocrine malignancies. The current and potential future applications of ncRNAs in clinical cancer research is also discussed, with emphasis on diagnosis and future treatment.

MicroRNA expression profiles in the management of papillary thyroid cancer.

Papillary thyroid cancer (PTC) is the major contributor to the dramatically increasing incidence of thyroid cancer. Low-risk PTC shows the most rapid rate of increase because of changing trends in neck imaging and the use of fine needle aspiration to investigate thyroid nodules. The need for a paradigm shift in the management of these patients, to provide personalized treatment and surveillance plans, has led to the focus on molecular biomarker research. MicroRNAs (miRNAs) compose a class of molecules with promising applications for every stage of PTC management, including diagnosis, prognosis, treatment, and surveillance. Although most of the miRNA studies are currently preclinical, given the rapid progress of scientific discovery, clinical trials will not be far away. Thyroid clinicians will be expected to have good insights into the current status of PTC-related molecular translational research. This article focuses on the potential roles of miRNA in PTC management in the context of contemporary recommended clinical practice.

MicroRNA-222 and microRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause significant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopathologic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. METHODS: Patients with recurrent PTC (Rc-PTC) and those without recurrence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. RESULTS: MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P = .014 and P = .038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the levels in plasma from healthy volunteers (P < .01 for both). Reductions of 2.7-fold and 5.1-fold were observed in the plasma levels of miR-222 and miR-146b, respectively, after total thyroidectomy (P = .03 for both). CONCLUSIONS: This study demonstrated that tumor levels of miR-222 and miR-146b are associated with PTC recurrence and that miR-222 and miR-146b levels in the circulation correspond to the presence of PTC. The potential of these miRNAs as tumor biomarkers to improve patient stratification according to the risk of recurrence and as circulating biomarkers for PTC surveillance warrants further study.

Tuberculosis: experience in a low endemic area Australian tertiary hospital.

BACKGROUND: Abdominal tuberculosis (ATB) poses a significant diagnostic, management, and resource challenge. In Australia, an increasing number of tuberculosis (TB) cases are being reported, and we describe our experience of ATB in an Australian tertiary institution. METHODS: All diagnosed cases of tuberculosis (TB) at the Royal North Shore tertiary hospital campus of the University of Sydney are entered prospectively into a central registry. Cases of ATB encountered between September 1991 and November 2011 were identified and retrospectively reviewed. RESULTS: In all, 841 cases of TB were identified, of which 20 were abdominal (2.4 %). Median age at presentation was 34 years (range: 22-79 years), and 55 % of patients were women. None of the patients were born in Australia and 11 patients were of South Asian origin. The most common presenting symptom was abdominal pain (65 %). Diagnosis was based primarily on histology (90 % sensitivity), and the sensitivity of PCR analysis in this series was low (44 %). Eleven of the patients required laparoscopy or laparotomy. 40 % of cases involved the peritoneum, and disease was also seen in solid organs (liver, spleen, pancreas, adrenal gland) and bowel (esophagus, small bowel, colon). CONCLUSIONS: In our local experience ATB was seen exclusively in the immigrant population. The presentation of ATB varies greatly, necessitating a high index of suspicion within the context of abdominal symptoms in high-risk groups. The role of surgical involvement is indispensable for both diagnosis and management of ATB-related complications. Surgeons should remain mindful of the diagnosis in an age of increasing worldwide incidence.

Papillary thyroid carcinoma in pregnancy: a variant of the disease?

BACKGROUND: There are conflicting reports in the literature regarding the prognostic influence of pregnancy on patients with papillary thyroid carcinoma (PTC), and there is no literature on specific microRNA (miRNA) profiles of PTC in the context of pregnancy. We aim to examine clinically if pregnancy is an adverse factor in PTC, and if pregnancy-associated PTC are biologically different from those in nonpregnant women in terms of their miRNA profiles. METHODS: Women diagnosed with PTC during or soon after pregnancy were recruited into the pregnancy group. Age-matched nonpregnant females were recruited into the nonpregnancy group. MiRNA microarray was performed on PTC tissue of pregnant patients (10), nonpregnant patients (10), and normal thyroids (5). There were 6 differentially expressed miRNAs from the microarray comparisons validated with RT-PCR. RESULTS: There were 24 patients in the clinical pregnancy group and 30 in the nonpregnancy group. Tumors from the pregnancy group were significantly larger and showed more regional lymph node metastases. The microarray data showed a total of 27 miRNAs that were potential differentiators of PTC tissue samples from pregnant and nonpregnant patients. Of the 6 selected for validation, no significant difference in expression was found. CONCLUSIONS: Our clinical data suggests that PTC during pregnancy may be more locoregionally aggressive. However, no difference in survival or recurrence is demonstrated. The miRNA profiles of the pregnancy-associated PTC have not been shown to be different to the nonpregnancy counterparts. This likely suggests that the differences seen clinically are related to patient factors rather than the disease itself.

Disease spectrum and use of cholecystolithotomy in gallstone ileus transection.

BACKGROUND: Gallstone ileus is a heterogeneous and highly morbid condition that suffers from a lack of consensus regarding the timing and approach to management of the biliary tree and associated fistula. METHODS: We report three cases that demonstrate the spectrum of gallstone ileus with classical examples of both Barnard's and Bouveret's syndromes. Clinical presentation, diagnostic imaging, surgical technique and outcome are discussed. RESULTS: One patient with Barnard's syndrome presented with recurrent gallstone ileus. To minimize the risks of complex, definitive biliary surgery and avoid further recurrent episodes, a cholecystolithotomy was performed with effect. Two cases of Bouveret's syndrome were successfully managed with enterolithotomy/cholecystectomy and multivisceral resection respectively, thus highlighting the diverse nature of this disease and management options. CONCLUSIONS: Following enterolithotomy, potentially morbid, definitive one-stage surgery in typically compromised, elderly patients needs to be weighed against the risk of recurrence and ongoing biliary pathology. We suggest the use of open cholecystolithotomy for the removal of residual gallstones when the patient is not suitable for definitive biliary surgery.

Multivisceral resection of pancreatic neuroendocrine tumours: a report of two cases.

Pancreatic neuroendocrine tumours (pNETs) are rare and surgical resection offers the only possibility of cure for localised disease. The role of surgery in the setting of locally advanced and metastatic disease is more controversial. Emerging data suggests that synchronous surgical resection of pancreas and liver may be associated with increased survival. We report two cases of synchronous, one stage multivisceral resections for pNET and associated reconstruction. We highlight the technical issues involved in such extensive resections and demonstrate that one stage multivisceral operations can be achieved safely.

Intra-splenic ovarian cystadenoma.

Splenic cysts are relatively common and usually involve post-traumatic or infective aetiologies. The management of splenic cysts varies in its aetiology, symptomology and size. Surgical intervention is warranted for symptomatic, larger sized cysts > 5 cm and can involve spleen-preserving laparoscopic cyst fenestrations, marsupialization or potentially a splenectomy. In this case report, we review a rare case of an ectopic ovarian cystadenoma presenting as a large recurrent splenic cyst.

Early outcomes of emergency ventral hernia repair in a cohort of poorly optimized patients.

BACKGROUND: Strangulated and obstructed ventral hernias require emergent repair to mitigate the risk of life-threatening complications. Emergency ventral hernia repairs are associated with a higher rate of surgical complications and recurrence compared to elective repairs. The purpose of this study was to explore the impact of patient factors, hernia and operative characteristics on post-operative outcomes in patients requiring emergency ventral hernia repairs. METHODS: Data were collected from a prospectively held database on 86 consecutive patients undergoing emergency ventral hernia repairs between January 2016 and January 2019 at Logan Hospital. Patient, hernia and operative characteristics were collected for reporting and analysis. RESULTS: Of the 86 patients, 29 (34%) developed a surgical complication, of which 17 patients (59%) had surgical site infections. We identified obesity (P = 0.017), history of smoking (P = 0.008), American Society of Anesthesiologists class of III-IV (P = 0.008), hernia defect size ≥3 cm (P = 0.048) and concomitant small bowel resection (P = 0.028) to be associated with post-operative surgical complication. Multivariate analysis identified smoking (P = 0.005) and concomitant small bowel resection (P = 0.026) as independent predictors for developing surgical complications. Seven patients (8%) recurred at a median of 221 days. Incisional hernias (P = 0.001), recurrent hernias (P < 0.001), greater than one defect (P < 0.001) and bowel involvement (P = 0.049) were associated with higher rates of hernia recurrence. CONCLUSION: Patient factors significantly influence outcomes in the emergency setting. Given that this is not modifiable at the time of surgery, greater emphasis needs to be placed on optimizing the physical and behavioural factors of patients with early symptomatic hernias for an elective repair.

Cohort study of 1241 patients to identify predictors of negative appendicectomy.

BACKGROUND: Acute Appendicitis is the most common surgical presentation within Australia. Despite the increasing use of radiological investigations to aid clinical diagnosis, many appendectomies result in a histologically normal appendix. This study examines the histological negative appendicectomy rate (NAR) in a metropolitan hospital and determine factors associated with a negative appendicectomy (NA). METHODS: Patients who underwent emergency appendicectomy for suspected acute appendicitis at Logan Hospital, Australia, between February 2016 and March 2019 inclusive were included. Clinicopathologic and imaging variables were analysed for associations with NA. RESULTS: A total of 1241 patients underwent emergency appendicectomy of which 121 patients (9.8%) had a NA. The NAR for clinical diagnosis alone (no imaging) was 9.9%, 14.5% for ultrasonography alone and computed tomography scan alone was 4.9%. Univariate analysis revealed age <27 years (P < 0.001), absence of hypertension (P = 0.008), symptoms >48 hours (P < 0.001), absence of leucocytosis (P < 0.001), undergoing ultrasonography only (P < 0.001), undergoing computed tomography scan only (P < 0.001), macroscopically normal appendix (P < 0.001) and time to operation >24 hours (P < 0.001) were associated with NA. Multivariate analysis identified symptoms >48 h at presentation (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.20-3.24; P = 0.007), absence of leucocytosis (OR 2.41, 95% CI 1.52-3.81; P < 0.001) and macroscopically normal appendix (OR 5.70, 95% CI 3.49-9.33; P < 0.001) to be associated with a NA. CONCLUSION: The NAR reported is lowest in an Australian institution. The identified predictors of NA will be useful in identifying patients who would truly benefit from an appendicectomy versus those would have a higher rate of NA who may be suitable to be treated non-operatively to be spared the unnecessary morbidity of surgery.

Management of patients with hepatocellular adenoma: a single-institution experience.

BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign liver tumour that may cause diagnostic and management dilemmas. This study describes the clinical and histopathological characteristics of patients who were treated for HCA in a tertiary referral hospital over a 17-year period. METHODS: A retrospective review was performed of prospectively collected data of all patients treated for HCA within the Northern Upper GI Surgical unit between 2002 and 2018. Immunohistochemical ß-catenin expression was evaluated. RESULTS: Thirty-two patients had histological or radiologically confirmed HCA. Twenty-eight patients underwent 30 operations and four patients were treated conservatively. The median age of the operative group was 43 years (range 19-83) and most patients were female (95%). The median body mass index was 28.7 (range 20-51), and nine patients (33%) were obese. Seven patients (25%) had multifocal HCA. Evidence of prior bleed or rupture or a perceived risk of either a bleed or malignant change (i.e. tumours ≥50 mm) were the most common indications for resection. There were no perioperative mortalities. Nuclear expression of ß-catenin by immunohistochemical staining was negative in all cases and there was no malignancy identified in any of the resected lesions. Two patients required transarterial embolization and two patients required a second liver resection for residual HCA. CONCLUSION: HCA is a rare lesion predominantly affecting females. Haemorrhage is seen frequently on imaging studies, occasionally requiring urgent angioembolization and/or surgical intervention. Malignant transformation and immunohistochemical ß-catenin expression are uncommon. HCA may be multifocal and residual tumours usually require ongoing surveillance and occasionally further intervention.

Dictating genomic destiny: Epigenetic regulation of pancreatic neuroendocrine tumours.

Pancreatic neuroendocrine tumours are a diverse group of neoplasms with an increasingly well-defined genomic basis. Despite this, much of what drives this disease is still unknown and epigenetic influences represent the next tier of gene, and hence disease modifiers that are of unquestionable importance. Moreover, they are of arguably more significance than the genes themselves given their malleable nature and potential to be exploited for not only diagnosis and prognosis, but also therapy. This review summarises what is known regarding the key epigenetic modifiers of disease through the domains of diagnosis, prognosis and treatment.

Management of recurrent bleeding after pancreatoduodenectomy.

BACKGROUND: Re-bleeding after management of a first haemorrhage following pancreatic surgery is an ever-present danger and often presents diagnostic and management dilemmas. METHODS: All cases of post-pancreatectomy haemorrhage (PPH) following pancreatoduodenectomy were identified from a tertiary referral, clinical database (April 2004-April 2013). Only those suffering a second re-bleeding episode were included in the final case notes review. RESULTS: A total of 301 patients underwent pancreatoduodenectomy during the study period (most common indication: pancreatic adenocarcinoma; 49.5%). Twenty-two (7.3%) patients suffered a PPH (five early). Of these cases, three suffered a re-bleeding event (one mortality). Endoscopy, interventional radiology and surgery were employed in each case. CONCLUSION: PPH presents major clinical challenges and is associated with significant morbidity and mortality. Early detection of the site and type of bleeding are critical and multimodal therapy is usually required. Interventional radiology techniques are making a major contribution to overall management.