Publications by authors named "Catherine Mitchell"

82 Publications

Molecular and genomic characterisation of a panel of human anal cancer cell lines.

Cell Death Dis 2021 Oct 18;12(11):959. Epub 2021 Oct 18.

Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Anal cancer is a rare disease that has doubled in incidence over the last four decades. Current treatment and survival of patients with this disease has not changed substantially over this period of time, due, in part, to a paucity of preclinical models to assess new therapeutic options. To address this hiatus, we set-out to establish, validate and characterise a panel of human anal squamous cell carcinoma (ASCC) cell lines by employing an explant technique using fresh human ASCC tumour tissue. The panel of five human ASCC cell lines were validated to confirm their origin, squamous features and tumourigenicity, followed by molecular and genomic (whole-exome sequencing) characterisation. This panel recapitulates the genetic and molecular characteristics previously described in ASCC including phosphoinositide-3-kinase (PI3K) mutations in three of the human papillomavirus (HPV) positive lines and TP53 mutations in the HPV negative line. The cell lines demonstrate the ability to form tumouroids and retain their tumourigenic potential upon xenotransplantation, with varied inducible expression of major histocompatibility complex class I (MHC class I) and Programmed cell death ligand 1 (PD-L1). We observed differential responses to standard chemotherapy, radiotherapy and a PI3K specific molecular targeted agent in vitro, which correlated with the clinical response of the patient tumours from which they were derived. We anticipate this novel panel of human ASCC cell lines will form a valuable resource for future studies into the biology and therapeutics of this rare disease.
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http://dx.doi.org/10.1038/s41419-021-04141-5DOI Listing
October 2021

Variables Associated with Coronavirus Disease 2019 Vaccine Hesitancy Amongst Patients with Neurological Disorders.

Infect Dis Rep 2021 Aug 30;13(3):763-810. Epub 2021 Aug 30.

John A. Burns School of Medicine, University of Hawai'i at Mānoa, Honolulu, HI 96813, USA.

Introduction: Given that the success of vaccines against coronavirus disease 2019 (COVID-19) relies on herd immunity, identifying patients at risk for vaccine hesitancy is imperative-particularly for those at high risk for severe COVID-19 (i.e., minorities and patients with neurological disorders).

Methods: Among patients from a large neuroscience institute in Hawaii, vaccine hesitancy was investigated in relation to over 30 sociodemographic variables and medical comorbidities, via a telephone quality improvement survey conducted between 23 January 2021 and 13 February 2021.

Results: Vaccine willingness ( = 363) was 81.3%. Univariate analysis identified that the odds of vaccine acceptance reduced for patients who do not regard COVID-19 as a severe illness, are of younger age, have a lower Charlson Comorbidity Index, use illicit drugs, or carry Medicaid insurance. Multivariable logistic regression identified the best predictors of vaccine hesitancy to be: social media use to obtain COVID-19 information, concerns regarding vaccine safety, self-perception of a preexisting medical condition contraindicated with vaccination, not having received the annual influenza vaccine, having some high school education only, being a current smoker, and not having a prior cerebrovascular accident. Unique amongst males, a conservative political view strongly predicted vaccine hesitancy. Specifically for Asians, a higher body mass index, while for Native Hawaiians and other Pacific Islanders (NHPI), a positive depression screen, both reduced the odds of vaccine acceptance.

Conclusion: Upon identifying the variables associated with vaccine hesitancy amongst patients with neurological disorders, our clinic is now able to efficiently provide ancillary COVID-19 education to sub-populations at risk for vaccine hesitancy. While our results may be limited to the sub-population of patients with neurological disorders, the findings nonetheless provide valuable insight to understanding vaccine hesitancy.
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http://dx.doi.org/10.3390/idr13030072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8482072PMC
August 2021

Retroperitoneal liposarcoma in a nonagenarian.

Autops Case Rep 2021 8;11:e2020224. Epub 2020 Dec 8.

Monash University, Eastern Health Clinical School, Box Hill, Victoria, Australia.

Retroperitoneal liposarcomas are rare tumors arising from the soft tissue of the retroperitoneum and are of mesenchymal cell origin. They can reach a large size prior to causing symptoms and generally have a poor prognosis. We present the case of a 93-year-old lady presenting with a large retroperitoneal liposarcoma at the site of a previous colonic anastomosis for the adenocarcinoma treatment. It caused minimal symptoms initially, but surgical resection was undertaken when the tumor was found to be growing significantly in size. However, due to the tumor's location and its invasion into surrounding structures, the resection was not feasible and subsequently abandoned. A retroperitoneal liposarcoma arising from the site of a previous colonic resection has not been previously described. A review of the diagnosis and current management of these lesions is also given.
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http://dx.doi.org/10.4322/acr.2020.224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8101656PMC
December 2020

Appendiceal pseudomyxoma peritonei: predictors of recurrence and iterative surgery.

Colorectal Dis 2021 Sep 12;23(9):2368-2375. Epub 2021 Jul 12.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Aim: Appendiceal pseudomyxoma peritonei (PMP) is a rare entity, with recurrence rates up to 26% despite optimal cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Evidence specific to PMP originating from non-infiltrative appendiceal mucinous neoplasms (low grade - LAMN and high grade - HAMN) is lacking. The aim of this study was to identify patterns of recurrence and predictive factors for patients appropriate for iterative surgery.

Method: A bi-institutional retrospective analysis was performed on patients undergoing complete cytoreduction and HIPEC for PMP derived from perforated LAMN or HAMN. Multivariate logistic regression was performed to identify independent predictors for re-do CRS. Five-year overall survival (OS) was stratified according to surgical intervention, and 5-year disease-free survival (DFS) was stratified according to histological PMP grade. Cox regression analysis was performed to identify independent predictors for OS and DFS.

Results: Sixty of 239 (25.1%) patients developed peritoneal recurrence between 2007 and 2020. The median time to recurrence was 20.7 months. The risk of disease recurrence was highest with high-grade PMP (P <0.001) and increasing PCI (P <0.001). Patients with high-grade histology from their index procedure and aged over 60 years were less likely to be offered iterative surgery on multivariate analysis. Patients who underwent iterative CRS and HIPEC had a 5-year survival of 100%.

Conclusion: Iterative CRS and HIPEC is feasible in selected patients with recurrent PMP, displaying good oncological outcomes. Age, index histology and level of abdominal quadrant involvement are predictive of proceeding to re-do surgery.
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http://dx.doi.org/10.1111/codi.15778DOI Listing
September 2021

Selenoprotein P Modulates Methamphetamine Enhancement of Vesicular Dopamine Release in Mouse Nucleus Accumbens Via Dopamine D2 Receptors.

Front Neurosci 2021 13;15:631825. Epub 2021 Apr 13.

Department of Cell and Molecular Biology, John A. Burns School of Medicine, University of Hawai'i at Mânoa, Honolulu, HI, United States.

Dopamine (DA) transmission plays a critical role in processing rewarding and pleasurable stimuli. Increased synaptic DA release in the nucleus accumbens (NAc) is a central component of the physiological effects of drugs of abuse. The essential trace element selenium mitigates methamphetamine-induced neurotoxicity. Selenium can also alter DA production and turnover. However, studies have not directly addressed the role of selenium in DA neurotransmission. Selenoprotein P (SELENOP1) requires selenium for synthesis and transports selenium to the brain, in addition to performing other functions. We investigated whether SELENOP1 directly impacts (1) DA signaling and (2) the dopaminergic response to methamphetamine. We used fast-scan cyclic voltammetry to investigate DA transmission and the response to methamphetamine in NAc slices from C57/BL6J SELENOP1 KO mice. Recordings from SELENOP1 KO mouse slices revealed reduced levels of evoked DA release and slower DA uptake rates. Methamphetamine caused a dramatic increase in vesicular DA release in SELENOP1 KO mice not observed in wild-type controls. This elevated response was attenuated by SELENOP1 application through a selenium-independent mechanism involving SELENOP1-apolipoprotein E receptor 2 (ApoER2) interaction to promote dopamine D2 receptor (D2R) function. In wild-type mice, increased vesicular DA release in response to methamphetamine was revealed by blocking D2R activation, indicating that the receptor suppresses the methamphetamine-induced vesicular increase. Our data provide evidence of a direct physiological role for SELENOP1 in the dopaminergic response to methamphetamine and suggest a signaling role for the protein in DA transmission.
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http://dx.doi.org/10.3389/fnins.2021.631825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076559PMC
April 2021

Molecular Imaging of Neuroendocrine Differentiation of Prostate Cancer: A Case Series.

Clin Genitourin Cancer 2021 08 9;19(4):e200-e205. Epub 2021 Feb 9.

Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.

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http://dx.doi.org/10.1016/j.clgc.2021.01.008DOI Listing
August 2021

Dyslipidemia, Insulin Resistance, Ectopic Lipid Accumulation, and Vascular Function in Resistance to Thyroid Hormone β.

J Clin Endocrinol Metab 2021 04;106(5):e2005-e2014

Wellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK.

Purpose: In resistance to thyroid hormone due to mutations in thyroid hormone receptor β, peripheral tissues are variably refractory to the action of circulating thyroid hormones. We evaluated parameters contributing to atherosclerotic risk in this disorder.

Methods: We measured low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), nonesterified fatty acids (NEFA), intrahepatic lipid (IHL) and intramyocellular lipid (IMCL), Homeostasis-model assessment of insulin resistance (HOMA-IR), augmentation index (AIx) and pulse wave velocity (PWV), flow-mediated dilatation, and carotid intima-media thickness (cIMT) in an unselected, genetically confirmed cohort of adult RTHβ patients (n = 27-77) and compared these with measurements in healthy subjects (up to n = 100) and thyrotoxic patients (n = 40).

Results: Resistance to thyroid hormone beta (RTHβ) patients exhibited higher LDL-C (P = 0.008) and TG (P = 0.002) and lower HDL-C concentrations (P = 0.015 × 10-2) than control subjects, with LDL-C being higher than in thyrotoxic patients with comparable hyperthyroxinemia. Proprotein convertase subtilisin/kexin 9 (P = 0.002) and apolipoprotein B (P = 0.0009) levels were reduced in thyrotoxic patients but not lower in RTHβ patients or control subjects. Intrahepatic lipid (P = 0.02 × 10-4), IMCL (P = 0.002), HOMA-IR (P = 0.01 × 10-2), and NEFA (P = 0.04 × 10-6) were significantly higher in RTHβ patients than control subjects. Flow-mediated dilatation was increased (P = 0.04) but cIMT (P = 0.71), PWV P = 0.81), and AIx (P = 0.95) were unaltered in RTHβ patients.

Conclusions: We have documented mixed dyslipidemia with hepatic and IMCL accumulation in RTHβ, suggesting that surveillance for these metabolic abnormalities is warranted. How they combine with enhanced endothelial function and unaltered vessel wall thickness and compliance to determine overall cardiometabolic risk in this disorder remains to be defined.
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http://dx.doi.org/10.1210/clinem/dgab002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063262PMC
April 2021

The role of F-FDG PET/CT in retroperitoneal sarcomas-A multicenter retrospective study.

J Surg Oncol 2021 Mar 14;123(4):1081-1087. Epub 2021 Jan 14.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Background: The role of F-fluorodeoxyglucose positron emission tomography/computed tomography ( F-FDG PET/CT) in the evaluation of retroperitoneal sarcomas is poorly defined. We evaluated the correlation of maximum standardized uptake value (SUVmax) with pathologic tumor grade in the surgical specimen of primary retroperitoneal dedifferentiated liposarcoma (DDLPS) and leiomyosarcoma (LMS).

Methods: Patients with the above histological subtypes in three participating institutions with preoperative F-FDG PET/CT scan and histopathological specimen available for review were included. The association between SUVmax and pathological grade was assessed. Correlation between SUVmax and relapse-free survival (RFS) and overall survival (OS) were also studied.

Results: Of the total 58 patients, final pathological subtype was DDLPS in 44 (75.9%) patients and LMS in 14 (24.1%) patients. The mean SUVmax was 8.7 with a median 7.1 (range, 2.2-33.9). The tumors were graded I, II, III in 6 (10.3%), 35 (60.3%), and 17 (29.3%) patients, respectively. There was an association of higher histological grade with higher SUVmax (r  = 0.40, p = .002). Increasing SUVmax was associated with worse RFS (p = .003) and OS (p = .003).

Conclusion: There is a correlation between SUVmax and pathologic tumor grade; increasing SUVmax was associated with worse OS and RFS, providing a preoperative noninvasive surrogate marker of tumor grade and biological behavior.
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http://dx.doi.org/10.1002/jso.26379DOI Listing
March 2021

SFRP4 drives invasion in gastric cancer and is an early predictor of recurrence.

Gastric Cancer 2021 May 4;24(3):589-601. Epub 2020 Dec 4.

Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Parkville, VIC, Australia.

Objective: Gastric cancer patients generally have a poor outcome, particularly those with advanced-stage disease which is defined by the increased invasion of cancer locally and is associated with higher metastatic potential. This study aimed to identify genes that were functional in the most fundamental hallmark of cancer, namely invasion. We then wanted to assess their value as biomarkers of gastric cancer progression and recurrence.

Design: Data from a cohort of patients profiled on cDNA expression arrays was interrogated using K-means analysis. This genomic approach classified the data based on patterns of gene expression allowing the identification of the genes most correlated with the invasion of GC. We evaluated the functional role of a key protein from this analysis in invasion and as a biomarker of recurrence after curative resection.

Results: Expression of secreted frizzled-related protein 4 (SFRP4) was identified as directly proportional to gastric cancer invasion. This finding was validated in multiple, independent datasets and its functional role in invasion was also confirmed using invasion assays. A change in serum levels of SFRP4 after curative resection, when coupled with AJCC stage, can accurately predict the risk of disease recurrence after curative therapy in an assay we termed PredictR.

Conclusions: This simple ELISA-based assay can help predict recurrence of disease after curative gastric cancer surgery irrespective of adjuvant therapy. The results require further evaluation in a prospective trial but would help in the rational prescription of cancer therapies and surveillance to prevent under or over treatment of patients after curative resection.
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http://dx.doi.org/10.1007/s10120-020-01143-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064978PMC
May 2021

Clinical Trial Protocol for LuTectomy: A Single-arm Study of the Dosimetry, Safety, and Potential Benefit of Lu-PSMA-617 Prior to Prostatectomy.

Eur Urol Focus 2021 Mar 7;7(2):234-237. Epub 2020 Nov 7.

Prostate Cancer Theranostics and Imaging Centre of Excellence, Peter MacCallum Cancer Centre, Melbourne, Australia; The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia. Electronic address:

LuTectomy is an open-label phase 1/2 nonrandomised clinical trial evaluating the dosimetry, efficacy, and toxicity of the lutetium-177-radiolabelled small molecule PSMA-617 in men with high-risk localised/locoregional advanced prostate cancer with high prostate-specific membrane antigen expression who are undergoing radical prostatectomy and pelvic lymph node dissection.
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http://dx.doi.org/10.1016/j.euf.2020.09.021DOI Listing
March 2021

Immune molecular profiling of a multiresistant primary prostate cancer with a neuroendocrine-like phenotype: a case report.

BMC Urol 2020 Oct 28;20(1):171. Epub 2020 Oct 28.

Tumor Suppression Laboratory, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Understanding the drivers of recurrence in aggressive prostate cancer requires detailed molecular and genomic understanding in order to aid therapeutic interventions. We provide here a case report of histological, transcriptional, proteomic, immunological, and genomic features in a longitudinal study of multiple biopsies from diagnosis, through treatment, and subsequent recurrence.

Case Presentation: Here we present a case study of a male in 70 s with high-grade clinically-localised acinar adenocarcinoma treated with definitive hormone therapy and radiotherapy. The patient progressed rapidly with rising PSA and succumbed without metastasis 52 months after diagnosis. We identified the expression of canonical histological markers of neuroendocrine PC (NEPC) including synaptophysin, neuron-specific enolase and thyroid transcription factor 1, as well as intact AR expression, in the recurrent disease only. The resistant disease was also marked by an extremely low immune infiltrate, extensive genomic chromosomal aberrations, and overactivity in molecular hallmarks of NEPC disease including Aurora kinase and E2F, as well as novel alterations in the cMYB pathway. We also observed that responses to both primary treatments (high dose-rate brachytherapy and androgen deprivation therapies) were consistent with known optimal responses-ruling out treatment inefficacy as a factor in relapse.

Conclusions: These data provide novel insights into a case of locally recurrent aggressive prostate cancer harbouring NEPC pathology, in the absence of detected metastasis.
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http://dx.doi.org/10.1186/s12894-020-00738-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592533PMC
October 2020

Characterising the immune microenvironment in liposarcoma, its impact on prognosis and the impact of radiotherapy.

J Surg Oncol 2021 Jan 20;123(1):117-126. Epub 2020 Oct 20.

Peter MacCallum Cancer Centre, Melbourne, Australia.

Background And Objectives: Limited literature exists examining the immune microenvironment in liposarcoma, particularly with regard to the impact of radiotherapy. A major problem is the lack of scoring system for the tumour-infiltrating lymphocytes (TILs) in sarcoma. This study aims to describe the immune environment pre- and postradiotherapy and identify the optimal immune infiltrate scoring system for sarcoma.

Methods: Thirty-nine paired tissue samples (pre- and postradiotherapy) from patients with liposarcoma were scored by two pathologists for TILs using pre-existing systems (for breast cancer and melanoma) and compared for interobserver reliability. Immunohistochemical staining was performed for various immune markers.

Results: The TIL scoring system for breast cancer yielded perfect agreement (κ = 1.000). 21% of patients had increased TILs after radiotherapy, 87.5% of whom had dedifferentiated liposarcoma. Immune suppressor expression was increased frequently after radiotherapy (CD68 increased in 59.4%, PD-L1 increased in 25%). Immune effector expression (CD8) was unchanged in 84.4%.

Conclusions: Breast cancer TIL scoring is reproducible in liposarcoma and has high interobserver reliability. Radiotherapy was observed to have a limited impact on immune effectors but seemed to have more impact in upregulating immune suppressors, suggesting radiotherapy may contribute to disease control through immunomodulatory effects. Dedifferentiated liposarcoma represents a uniquely responsive subtype.
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http://dx.doi.org/10.1002/jso.26261DOI Listing
January 2021

A MXI1-NUTM1 fusion protein with MYC-like activity suggests a novel oncogenic mechanism in a subset of NUTM1-rearranged tumors.

Lab Invest 2021 01 1;101(1):26-37. Epub 2020 Sep 1.

Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.

Most NUTM1-rearranged neoplasms (NRNs) have fusions between NUTM1 and BRD (bromodomain-containing) family members and are termed NUT carcinomas (NCs) because they show some squamous differentiation. However, some NRNs are associated with fusions between NUTM1 and members of the MAD (MAX dimerization) gene family of MYC antagonists. Here we describe a small round cell malignancy from the gastro-esophageal junction with a previously unreported fusion between NUTM1 and the MAD family member MXI1. In contrast to NCs, the MXI1-NUTM1 tumor did not show squamous differentiation and did not express MYC, TP63 or SOX2, genes known to be targets of BRD-NUTM1 proteins and critical for NC oncogenesis. Transcriptome analysis showed paradoxical enrichment of MYC target genes in the MXI1-NUTM1 tumor despite the lack of MYC expression. When expressed in vitro MXI1-NUTM1 partially phenocopied MYC, enhancing cell proliferation and cooperating with oncogenic HRAS to produce anchorage-independent cell growth. These data provide evidence that MAD family members, which are normally repressors of MYC activity, can be converted into MYC-like mimics by fusion to NUTM1. The pathological features and novel oncogenic mechanism of the MXI1-NUTM1 tumor show that identification of NUTM1 fusion partners can be important for accurate diagnostic classification of some NRN subtypes, and potentially may guide therapeutic options.
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http://dx.doi.org/10.1038/s41374-020-00484-3DOI Listing
January 2021

GRB7 is an oncogenic driver and potential therapeutic target in oesophageal adenocarcinoma.

J Pathol 2020 11 15;252(3):317-329. Epub 2020 Sep 15.

Division of Cancer Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Efficacious therapeutic approaches are urgently needed to improve outcomes in patients with oesophageal adenocarcinoma (OAC). However, oncogenic drivers amenable to targeted therapy are limited and their functional characterisation is essential. Among few targeted therapies available, anti-human epidermal growth factor receptor 2 (HER2) therapy showed only modest benefit for patients with OAC. Herein, we investigated the potential oncogenic role of growth factor receptor bound protein 7 (GRB7), which is reported to be co-amplified with HER2 (ERBB2) in OAC. GRB7 was highly expressed in 15% of OAC tumours, not all of which could be explained by co-amplification with HER2, and was associated with a trend for poorer overall survival. Knockdown of GRB7 decreased proliferation and clonogenic survival, and induced apoptosis. Reverse phase protein array (RPPA) analyses revealed a role for PI3K, mammalian target of rapamycin (mTOR), MAPK, and receptor tyrosine kinase signalling in the oncogenic action of GRB7. Furthermore, the GRB7 and HER2 high-expressing OAC cell line Eso26 showed reduced cell proliferation upon GRB7 knockdown but was insensitive to HER2 inhibition by trastuzumab. Consistent with this, GRB7 knockdown in vivo with an inducible shRNA significantly inhibited tumour growth in cell line xenografts. HER2 expression did not predict sensitivity to trastuzumab, with Eso26 xenografts remaining refractory to trastuzumab treatment. Taken together, our study provides strong evidence for an oncogenic role for GRB7 in OAC and suggests that targeting GRB7 may be a potential therapeutic strategy for this cancer. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693356PMC
November 2020

Malignant transformation of an ileostomy stoma scar: an unusual presentation.

ANZ J Surg 2020 09 16;90(9):1770-1772. Epub 2020 Jul 16.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/ans.16171DOI Listing
September 2020

High dose-rate brachytherapy of localized prostate cancer converts tumors from cold to hot.

J Immunother Cancer 2020 06;8(1)

Cancer Immunology Research, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

Background: Prostate cancer (PCa) has a profoundly immunosuppressive microenvironment and is commonly immune excluded with few infiltrative lymphocytes and low levels of immune activation. High-dose radiation has been demonstrated to stimulate the immune system in various human solid tumors. We hypothesized that localized radiation therapy, in the form of high dose-rate brachytherapy (HDRBT), would overcome immune suppression in PCa.

Methods: To investigate whether HDRBT altered prostate immune context, we analyzed preradiation versus postradiation human tissue from a cohort of 24 patients with localized PCa that received HDRBT as primary treatment (RadBank cohort). We performed Nanostring immune gene expression profiling, digital spatial profiling, and high-throughput immune cell multiplex immunohistochemistry analysis. We also resolved tumor and nontumor zones in spatial and bioinformatic analyses to explore the immunological response.

Results: Nanostring immune profiling revealed numerous immune checkpoint molecules (eg, B7-H3, CTLA4, PDL1, and PDL2) and TGFβ levels were increased in response to HDRBT. We used a published 16-gene tumor inflammation signature (TIS) to divide tumors into distinct immune activation states (high:, intermediate and low:) and showed that most localized PCa are cold tumors pre-HDRBT. Crucially, HDRBT converted 80% of these 'cold'-phenotype tumors into an 'intermediate' or 'hot' class. We used digital spatial profiling to show these HDRBT-induced changes in prostate TIS scores were derived from the nontumor regions. Furthermore, these changes in TIS were also associated with pervasive changes in immune cell density and spatial relationships-in particular, between T cell subsets and antigen presenting cells. We identified an increased density of CD4 FOXP3 T cells, CD68 macrophages and CD68 CD11c dendritic cells in response to HDRBT. The only subset change specific to tumor zones was PDL1 macrophages. While these immune responses were heterogeneous, HDRBT induced significant changes in immune cell associations, including a gained T cell and HMWCK PDL1 interaction in tumor zones.

Conclusion: In conclusion, we showed HDRBT converted "cold" prostate tumors into more immunologically activated "hot" tissues, with accompanying spatially organized immune infiltrates and signaling changes. Understanding and potentially harnessing these changes will have widespread implications for the future treatment of localized PCa, including rational use of combination radio-immunotherapy.
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http://dx.doi.org/10.1136/jitc-2020-000792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7319782PMC
June 2020

High-dimensional analyses reveal a distinct role of T-cell subsets in the immune microenvironment of gastric cancer.

Clin Transl Immunology 2020 May 5;9(5):e1127. Epub 2020 May 5.

Upper Gastrointestinal Translational Research Laboratory Peter MacCallum Cancer Centre Melbourne VIC Australia.

Objectives: To facilitate disease prognosis and improve precise immunotherapy of gastric cancer (GC) patients, a comprehensive study integrating immune cellular and molecular analyses on tumor tissues and peripheral blood was performed.

Methods: The association of GC patients' outcomes and the immune context of their tumors was explored using multiplex immunohistochemistry (mIHC) and transcriptome profiling. Potential immune dysfunction mechanism/s in the tumors on the systemic level was further examined using mass cytometry (CyTOF) in complementary peripheral blood from selected patients. GC cohorts with mIHC and gene expression profiling data were also used as validation cohorts.

Results: Increased CD4FOXP3 T-cell density in the GC tumor correlated with prolonged survival. Interestingly, CD4FOXP3 T cells had a close interaction with CD8 T cells rather than tumor cells. High densities of CD4FOXP3 T cells and CD8 T cells (High-High) independently predicted prolonged patient survival. Furthermore, the interferon-gamma (IFN-γ) gene signature and PDL1 expression were up-regulated in this group. Importantly, a subgroup of genomically stable (GS) tumors and tumors with chromosomal instability (CIN) within this High-High group also had excellent survival. The High-High GS/CIN tumors were coupled with increased frequencies of TbetCD4 T cells and central memory CD4 T cells in the peripheral blood.

Conclusion: These novel findings identify the combination of CD8 T cells and FOXP3CD4 T cells as a significant prognostic marker for GC patients, which also could potentially be targeted and applied in the combination therapy with immune checkpoint blockades in precision medicine.
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http://dx.doi.org/10.1002/cti2.1127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200219PMC
May 2020

RAF1 rearrangements are common in pancreatic acinar cell carcinomas.

Mod Pathol 2020 09;33(9):1811-1821

University of Sydney, Sydney, NSW, 2006, Australia.

There is now evidence that gene fusions activating the MAPK pathway are relatively common in pancreatic acinar cell carcinoma with potentially actionable BRAF or RET fusions being found in ~30%. We sought to investigate the incidence of RAF1 fusions in pancreatic malignancies with acinar cell differentiation. FISH testing for RAF1 was undertaken on 30 tumors comprising 25 'pure' acinar cell carcinomas, 2 mixed pancreatic acinar-neuroendocrine carcinomas, 1 mixed acinar cell-low grade neuroendocrine tumor and 2 pancreatoblastomas. RAF1 rearrangements were identified in 5 cases and confirmed by DNA and RNA sequencing to represent oncogenic fusions (GATM-RAF1, GOLGA4-RAF1, PDZRN3-RAF1, HERPUD1-RAF1 and TRIM33-RAF1) and to be mutually exclusive with BRAF and RET fusions, as well as KRAS mutations. Large genome-wide copy number changes were common and included 1q gain and/or 1p loss in all five RAF1 FISH-positive acinar cell carcinomas. RAF1 expression by immunohistochemistry was found in 3 of 5 (60%) of fusion-positive cases and no FISH-negative cases. Phospho-ERK1/2 expression was found in 4 of 5 RAF1-fusion-positive cases. Expression of both RAF1 and phospho-ERK1/2 was heterogeneous and often only detected at the tumor-stroma interface, thus limiting their clinical utility. We conclude that RAF1 gene rearrangements are relatively common in pancreatic acinar cell carcinomas (14.3% to 18.5% of cases) and can be effectively identified by FISH with follow up molecular testing. The combined results of several studies now indicate that BRAF, RET or RAF1 fusions occur in between one third and one-half of these tumors but are extremely rare in other pancreatic malignancies. As these fusions are potentially actionable with currently available therapies, a strong argument can be made to perform FISH or molecular testing on all pancreatic acinar cell carcinomas.
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http://dx.doi.org/10.1038/s41379-020-0545-9DOI Listing
September 2020

Germline whole exome sequencing of a family with appendiceal mucinous tumours presenting with pseudomyxoma peritonei.

BMC Cancer 2020 May 1;20(1):369. Epub 2020 May 1.

Research Division, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre Building, 305 Grattan St., Melbourne, Victoria, VIC 3000, Australia.

Background: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours.

Methods: Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both individuals to identify regions of LOH.

Results: Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes (EXOG, RANBP2, RANBP6 and TNFRSF1B) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 individuals with presumed sporadic AMTs or PMP; no LoF or rare missense germline variants were identified.

Conclusion: Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
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http://dx.doi.org/10.1186/s12885-020-6705-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195761PMC
May 2020

Laparoscopic high anterior resection for unicentric Castleman's disease of the sigmoid mesocolon.

ANZ J Surg 2020 10 2;90(10):2137-2138. Epub 2020 Mar 2.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia.

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http://dx.doi.org/10.1111/ans.15792DOI Listing
October 2020

Correlation between percutaneous biopsy and final histopathology for retroperitoneal sarcoma: a single-centre study.

ANZ J Surg 2020 04 16;90(4):497-502. Epub 2020 Feb 16.

Department of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Background: Retroperitoneal sarcomas are rare soft tissue tumours accounting for 10-15% of soft tissue sarcomas. Patient prognosis and treatment recommendations (including extent of surgery and neoadjuvant strategies) are determined by the pre-operative histopathological subtype and grade obtained from biopsy and thus it is important to understand the accuracy of biopsy in retroperitoneal masses.

Methods: This study presents a case series of primary retroperitoneal sarcomas managed at Peter MacCallum Cancer Centre (PMCC) between 2008 and 2019. Statistical analyses were performed to determine correlation between histopathology from percutaneous biopsy and surgical excision.

Results: A total of 117 patients who underwent percutaneous core biopsy and surgical excision of retroperitoneal sarcoma were included. Diagnostic accuracy varied with histopathological diagnosis, but overall precise concordance between biopsy and final histopathology was seen in 61% (κ = 0.57). Biopsy was most sensitive for identifying well-differentiated liposarcoma (WDLPS) (sensitivity 85%, 95% CI 0.06-0.96) and leiomyosarcoma (sensitivity 81%, 95% CI 0.54-0.96) and was least sensitive for identifying de-differentiated liposarcoma (DDLPS) (sensitivity 40%, 95% CI 0.25-0.56). Overall agreement between biopsy and final histopathology increased with use of PET/CT scan pre-biopsy and with use of fluorescence in situ hybridisation testing on biopsy, however, neither test improved recognition of de-differentiated components within WD/DDLPS on core biopsy.

Conclusions: Pre-operative biopsy is important for clinical decision making in the treatment of retroperitoneal sarcoma. A significant portion of patients with a WDLPS will have a de-differentiated component identified at the time of resection that was not identified on initial biopsy.
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http://dx.doi.org/10.1111/ans.15723DOI Listing
April 2020

Systematic review of neurotrophic tropomyosin-related kinase inhibition as a tumor-agnostic management strategy.

Future Oncol 2020 Feb 16;16(4):61-74. Epub 2020 Jan 16.

F Hoffmann-La Roche Ltd., Global Access, 4070 Basel, Switzerland.

To conduct a systematic review and meta-analysis feasibility of clinical, quality of life and economic evidence for neurotrophic tropomyosin-related receptor tyrosine kinases () inhibitors in patients with gene fusion-positive tumors. Databases were searched for studies on inhibitors in adult and pediatric patients. 27 publications reported clinical data for seven interventions. Efficacy/safety data were available for two interventions only. Four trials each reported data for larotrectinib and entrectinib with pooled analyses reporting objective response rates of 75% (95% CI: 61-85) and 57.4% (43.2-70.8), respectively. No publications reported economic or quality of life evidence. Preliminary data demonstrate that inhibitors are well tolerated and show impressive clinical benefit; corroboration of existing studies and real-world data are required.
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http://dx.doi.org/10.2217/fon-2019-0534DOI Listing
February 2020

E6AP Promotes a Metastatic Phenotype in Prostate Cancer.

iScience 2019 Dec 2;22:1-15. Epub 2019 Nov 2.

Tumour Suppression Laboratory, Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia; Department of Pathology, Peter MacCallum Cancer Centre, Melbourne 3000, Australia; Department of Clinical Pathology, University of Melbourne, Parkville, VIC 3010, Australia; Department of Biochemistry and Molecular Biology, Monash University, Melbourne 3800, Australia. Electronic address:

Although primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer.
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http://dx.doi.org/10.1016/j.isci.2019.10.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864340PMC
December 2019

Macrophage spatial heterogeneity in gastric cancer defined by multiplex immunohistochemistry.

Nat Commun 2019 09 2;10(1):3928. Epub 2019 Sep 2.

Upper Gastrointestinal Translational Research Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.

Tumor-associated macrophages (TAMs), one of the most abundant immune components in gastric cancer (GC), are difficult to characterize due to their heterogeneity. Multiple approaches have been used to elucidate the issue, however, due to the tissue-destructive nature of most of these methods, the spatial distribution of TAMs in situ remains unclear. Here we probe the relationship between tumor context and TAM heterogeneity by multiplex immunohistochemistry of 56 human GC cases. Using distinct expression marker profiles on TAMs, we report seven predominant populations distributed between tumor and non-tumor tissue. TAM population-associated gene signatures reflect their heterogeneity and polarization in situ. Increased density of CD163+ (CD206-) TAMs with concurrent high CD68 expression is associated with upregulated immune-signaling and improved patient survival by univariate, but not multivariate analysis. CD68-only and CD206+ TAMs are correlated with high PDL1 expression.
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http://dx.doi.org/10.1038/s41467-019-11788-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6718690PMC
September 2019

Predicting disease progression and poor outcomes in patients with moderately active rheumatoid arthritis: a systematic review.

Rheumatol Adv Pract 2019 15;3(1):rkz002. Epub 2019 Feb 15.

Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds and NIHR Leeds Biomedical Research Centre, Leeds, UK.

Objectives: Access to biologic DMARDs for RA is often restricted to those with severe disease. This systematic review aimed to identify prognostic factors in patients with moderate disease activity who may be at risk of disease progression and poor clinical outcomes.

Methods: MEDLINE, Embase and Cochrane databases were searched (final search 22 September 2017), and data from patients with moderate disease [28-joint DAS (DAS28) >3.2-≤5.1] were included. Studies were evaluated according to the measure(s) of progression/poor outcome used: radiographic, disease activity or other indicators.

Results: The searches identified 274 publications, of which 30 were selected for data extraction. Fourteen studies were prioritized, because they specifically analysed patients with moderate RA. Nine studies reported radiographic progression outcomes for 3241 patients, three studies reported disease activity progression for 1516 patients, and two studies reported other relevant outcomes for 2094 patients. Prognostic factors with consistent evidence for progression/poor outcome prediction were as follows: DAS28 ≥ 4.2, the presence of anti-CCP antibodies, and power Doppler ultrasound score ≥1. Some predictors were specific to either disease activity or radiographic progression.

Conclusion: Several criteria used in standard clinical practice were identified that have the potential to inform the selection of patients with moderate RA who are at greater risk of a poor outcome. A combination of two or more of these factors might enhance their predictive potential. Further work is required to derive clinical decision rules incorporating these factors.
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http://dx.doi.org/10.1093/rap/rkz002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6649936PMC
February 2019

Association analysis between quantitative MRI features and hypoxia-related genetic profiles in prostate cancer: a pilot study.

Br J Radiol 2019 Dec 30;92(1104):20190373. Epub 2019 Jul 30.

The University of Sydney, Sydney, New South Wales, Australia.

Objective: To investigate the association between multiparametric MRI (mpMRI) imaging features and hypoxia-related genetic profiles in prostate cancer.

Methods: mpMRI was acquired from six patients prior to radical prostatectomy. Sequences included weighted (TW) imaging, diffusion-weighted imaging, dynamic contrast enhanced MRI and blood oxygen-level dependent imaging. Imaging data were co-registered with histology using three-dimensional deformable registration methods. Texture features were extracted from W images and parametric maps from functional MRI. Full transcriptome genetic profiles were obtained using next generation sequencing from the prostate specimens. Pearson correlation coefficients were calculated between mpMRI data and hypoxia-related gene expression levels. Results were validated using glucose transporter one immunohistochemistry (IHC).

Results: Correlation analysis identified 34 candidate imaging features (six from the mpMRI data and 28 from W texture features). The IHC validation showed that 16 out of the 28 W texture features achieved weak but significant correlations ( < 0.05).

Conclusions: Weak associations between mpMRI features and hypoxia gene expressions were found. This indicates the potential use of MRI in assessing hypoxia status in prostate cancer. Further validation is required due to the low correlation levels.

Advances In Knowledge: This is a pilot study using radiogenomics approaches to address hypoxia within the prostate, which provides an opportunity for hypoxia-guided selective treatment techniques.
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http://dx.doi.org/10.1259/bjr.20190373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6913351PMC
December 2019

Characterizing high-grade serous papillary carcinoma of tunica vaginalis.

Urol Case Rep 2019 Sep 21;26:100949. Epub 2019 Jun 21.

Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia.

Serous carcinomas of the testis or para-testis are extremely rare tumors of Mullerian type. We report a case of high-grade serous papillary carcinoma of the tunica vaginalis, treated with radical orchiectomy and hemi-scrotectomy after being referred for a rapidly growing painless scrotal mass. In addition to negative testicular tumor markers, scrotal ultrasound, and conventional computerized tomography (CT) scanning, this patient's workup included a positron emission tomography (PET) scan using F-18-fluoro-deoxyglucose (FDG), demonstrating metabolically avid uptake of the disease. This patient is completing ongoing close follow up and is currently disease free at nine months post definitive treatment.
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http://dx.doi.org/10.1016/j.eucr.2019.100949DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6600708PMC
September 2019

Revision of an undergraduate nursing oncology course using the Taylor Curriculum Review Process.

Can Oncol Nurs J 2019 1;29(1):47-51. Epub 2019 Feb 1.

Assistant Professor, Faculty of Nursing, University of Calgary.

Patients diagnosed with cancer require intensive nursing care and support across all healthcare settings (Canadian Association of Nurses in Oncology [CANO], 2015). Advances in this nursing specialty and the resulting changes to practice add to the complexity of the nursing role. Clinical improvements impact the preparation of nursing students transitioning into this area of practice. The inclusion of an oncology curriculum in undergraduate programs can help to develop fundamental competencies for undergraduates in this specialty (Lockhart et al., 2013). A fourth-year undergraduate nursing oncology course was recently evaluated at the University of Calgary to ensure content was congruent with current practice. Since the course was initially developed in 2011, there have only been minor updates, potentially resulting in out-of-date content. A curriculum review process outlined by the Taylor Institute of Teaching and Learning was used to complete this course revision (Dyjur & Kalu, 2016). The findings of this course revision indicate the need to provide more student-centred learning, to discuss the implementation of recent treatments, and to provide more clinically centered literature on recent developments in oncology.
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http://dx.doi.org/10.5737/236880762914751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516238PMC
February 2019

Révision d’un cours d’oncologie de premier cycle en sciences infirmières à l’aide du processus d’évaluation des programmes de Taylor.

Can Oncol Nurs J 2019 1;29(1):52-57. Epub 2019 Feb 1.

Professeure adjointe, Faculté des sciences infirmières, Université de Calgary.

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http://dx.doi.org/10.5737/236880762915257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516241PMC
February 2019

The role of F-FDG-PET/CT in evaluating retroperitoneal masses -Keeping your eye on the ball!

Cancer Imaging 2019 May 29;19(1):28. Epub 2019 May 29.

Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, Australia.

Background: Testicular germ cell tumour is the commonest malignancy affecting males aged between 15 and 35, with an increased relative risk amongst those with a history of cryptorchidism. In patients presenting with locoregional metastatic disease, retroperitoneal and pelvic soft tissue masses are common findings on ultrasound and computed tomography, which has several differential diagnoses within this demographic cohort. On staging F-FDG-PET/CT, understanding the typical testicular lymphatic drainage pathway facilitates prompt recognition of the pathognomonic constellation of unilateral absence of testicular scrotal activity, and FDG-avid nodal masses along the drainage pathway. We describe the cases of three young males presenting with abdominopelvic masses, in whom FDG-PET/CT was helpful in formulating a unifying diagnosis of metastatic seminoma, retrospectively corroborated by a history of testicular maldescent.

Case Presentations: In all three cases, the patients were males aged in their 30s and 40s who were brought to medical attention for back and lower abdominal pain of varying duration. Initial imaging evaluation with computed tomography and/or ultrasound revealed large abdominopelvic soft tissue masses, with lymphoproliferative disorders or soft tissue sarcomas being high on the list of differential diagnoses. As such, they were referred for staging FDG-PET/CT, all of whom demonstrated the pathognomonic constellation of, 1) unilateral absence of scrotal testicular activity, and 2) FDG-avid nodal masses along the typical testicular lymphatic drainage pathway. These characteristic patterns were corroborated by a targeted clinical history and examination which revealed a history of cryptorchidism, and elevated β-hCG in two of three patients. All were subsequently confirmed as metastatic seminoma on biopsy and open resection.

Conclusion: These cases highlight the importance of clinical history and examination for the clinician, as well as a sound knowledge of the typical testicular lymphatic drainage pathway for the PET physician, which would assist with prompt recognition of the characteristic imaging patterns on FDG-PET/CT. It further anecdotally supports the utility of FDG-PET/CT in evaluating undiagnosed abdominopelvic masses, as well as a potential role in the initial staging of germ cell tumours in appropriately selected patients.
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http://dx.doi.org/10.1186/s40644-019-0217-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542013PMC
May 2019
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