Invasive fungal disease in children with solid tumors: An Australian multicenter 10-year review.

Invasive fungal disease (IFD) occurs less frequently during treatment for solid compared to hematological malignancies in children, and risk groups are poorly defined. Retrospective national multicenter cohort data (2004-2013) were analyzed to document prevalence, clinical characteristics, and microbiology of IFD. Amongst 2067 children treated for solid malignancy, IFD prevalence was 1.9% overall and 1.4% for proven/probable IFD. Of all IFD episodes, 42.5% occurred in patients with neuroblastoma (prevalence 7.0%). Candida species comprised 54.8% of implicated pathogens in proven/probable IFD. In children with solid tumors, IFD is rare, and predominantly caused by yeasts.Routine prophylaxis may not be warranted.

High activation levels maintained in receptor-binding domain-specific memory B cells in people with severe coronavirus disease 2019.

The long-term health consequences of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are still being understood. The molecular and phenotypic properties of SARS-CoV-2 antigen-specific T cells suggest a dysfunctional profile that persists in convalescence in those who were severely ill. By contrast, the antigen-specific memory B-cell (MBC) population has not yet been analyzed to the same degree, but phenotypic analysis suggests differences following recovery from mild or severe coronavirus disease 2019 (COVID-19). Here, we performed single-cell molecular analysis of the SARS-CoV-2 receptor-binding domain (RBD)-specific MBC population in three patients after severe COVID-19 and four patients after mild/moderate COVID-19. We analyzed the transcriptomic and B-cell receptor repertoire profiles at ~2 months and ~4 months after symptom onset. Transcriptomic analysis revealed a higher level of tumor necrosis factor-alpha (TNF-α) signaling via nuclear factor-kappa B in the severe group, involving CD80, FOS, CD83 and TNFAIP3 genes that was maintained over time. We demonstrated the presence of two distinct activated MBCs subsets based on expression of CD80hi TNFAIP3hi and CD11chi CD95hi at the transcriptome level. Both groups revealed an increase in somatic hypermutation over time, indicating progressive evolution of humoral memory. This study revealed distinct molecular signatures of long-term RBD-specific MBCs in convalescence, indicating that the longevity of these cells may differ depending on acute COVID-19 severity.

Days alive and out of hospital after laparoscopic cholecystectomy.

BACKGROUND: Days alive and out of hospital (DAOH) is a metric that incorporates several outcomes into a single, standardized measure. This study aimed to explore the utility of DAOH in assessing the outcomes of a retrospective cohort of patients undergoing laparoscopic cholecystectomy (LC). METHODS: Patients undergoing LC at Auckland City Hospital between 1 January 2010 and 31 August 2015 were included. DAOH values were calculated for the 90 days from the date of surgery (DAOH90 ) and described using median and interquartile ranges (IQR). DAOH90 distributions were compared using a two-tailed (non-parametric) Wilcoxon-Mann-Whitney test. RESULTS: 1652 patients undergoing LC were studied. Patients experiencing complications (n = 70, 4.2%) had fewer DAOH90 (median 83, IQR 79, 86) than patients who underwent uncomplicated LC (median 88, IQR 86, 88), P < 0.001. Patients who were converted to open cholecystectomy (n = 70, 4.2%) also had fewer DAOH90 (median 82.5, IQR 79, 84) than patients who underwent uncomplicated LC, P < 0.001. Post-operative complications and conversion had a statistically significant effect on DAOH90 at each of the tested quantiles, except for conversion at the 0.1 quantile. CONCLUSION: DAOH90 is readily calculable from existing New Zealand administrative data sources and is sensitive to the occurrence of complications after LC.

Transarterial Radioembolization for Hepatic Metastases of Pancreatic Adenocarcinoma: A Systematic Review.

PURPOSE: To assess the safety and effectiveness of transarterial radioembolization (TARE) in the treatment of hepatic metastases from pancreatic ductal adenocarcinoma (PDAC). MATERIALS AND METHODS: A systematic search of the Embase and MEDLINE databases was conducted using keywords and Medical Subject Headings terms related to TARE and hepatic metastases from PDAC. Observational studies and clinical trials reporting overall survival (OS), hepatic progression-free survival (hPFS), or tumor response after TARE were included. RESULTS: Eight studies, comprising 145 patients with metastatic PDAC, met the inclusion criteria. No randomized controlled trials were identified, and 4 studies were prospective. Forty-four (30.3%) patients underwent previous pancreatic resection, and 66 (45.5%) had extrahepatic metastases at the time of TARE. Most studies (n = 6) used resin microspheres for TARE. The pooled disease control rate was 69.4% at a median of 3 months. The median OS from the time of TARE ranged from 3.7 to 9 months. The median hPFS ranged from 2.4 to 5.2 months. There were 31 Grade 3-4 biochemical toxicities and 4 treatment-related deaths. CONCLUSIONS: The role of TARE in patients with hepatic metastases from PDAC remains unclear owing to low patient numbers, limited prospective data, and heterogeneity in the study design. Further prospective studies are required to evaluate the role of TARE in carefully selected patients with liver-only metastatic disease.

Portal vein embolization with absolute ethanol to induce hypertrophy of the future liver remnant.

BACKGROUND: Preoperative portal vein embolization (PVE) is widely used prior to major liver resection to reduce the risk of post-hepatectomy liver failure (PHLF). We evaluated the efficacy and safety of PVE using absolute ethanol. METHODS: Consecutive patients undergoing preoperative PVE between February 2003 and February 2020 at a high-volume tertiary institution were retrospectively reviewed. Hypertrophy of the future liver remnant (FLR) was determined by comparing volumetric data using semi-automated software on computed tomography or magnetic resonance imaging before and after PVE. Efficacy of absolute ethanol was evaluated by the percentage increase in the FLR volume and the ratio of the FLR to the total liver volume (TLV). Technical success and complications following PVE were evaluated. Feasibility of hepatectomy following PVE and the incidence of PHLF were determined. RESULTS: Sixty-two patients underwent preoperative PVE using absolute ethanol. The technical success rate was 95.2%. Median time interval between PVE and follow-up imaging was 34 days (range 6-144 days). The mean increase in FLR volume and ratio of the FLR to TLV were 43.6 ± 34.4% and 12.3 ± 7.7% respectively. Major adverse events occurred in 3 cases (4.8%) and did not preclude consideration of surgery. Forty-two patients (67.8%) proceeded to surgery for intended hepatectomy of which 36 patients (58.1%) underwent liver resection. Major post-operative complications occurred in 4 patients (11.1%) and there were no cases of PHLF. CONCLUSION: Preoperative PVE with absolute ethanol is effective and safe in inducing hypertrophy of the FLR before partial hepatectomy to prevent PHLF.

Totally extraperitoneal laparoscopic inguinal hernia repair post-radical prostatectomy.

BACKGROUND: Previous radical prostatectomy (RP) is considered a relative contraindication to the laparoscopic approach for inguinal hernia repair (LIHR). This study aimed to compare feasibility, safety and outcomes for patients undergoing totally extraperitoneal (TEP) LIHR who have previously undergone RP. METHODS: This single surgeon, case-control study was performed using a prospective database of all patients undergoing TEP LIHR between 1995 and 2020. Patients who underwent previous RP were identified and compared to matched controls. Pre-operative, operative and post-operative data were analysed. The type of RP, open, laparoscopic or robotic, was identified and operative outcomes compared between the three groups. RESULTS: 6532 LIHR cases were identified. 165 had previously undergone RP and 6367 had undergone primary LIHR without prior RP. The groups were matched for age, demographics and co-morbidities. All operations were commenced laparoscopically, three converted to open in the LIHR + RP group and none in the LIHR group. Median operative time in patients with previous RP was longer, for unilateral (40 min vs. 21 min, p < 0.0001) and bilateral (71 vs. 30 min, p < 0.0001) LIHR. The majority of cases were performed as day stay procedures. There was no difference in immediate recovery parameters including time to discharge, complication rates, return to normal function, return to driving or post-operative analgesia. At 3 months of follow-up there was no difference in hernia recurrence for unilateral (2/128 vs 6/2234, p = 0.0658) or bilateral (0/24 vs 3/1490, p ≥ 0.999) LIHR, nor chronic pain as measured by patient awareness or restriction of activity. No differences in operative and post-operative outcomes were identified between the three types of RP, other than difference in operative time (p = 0.0336). CONCLUSIONS: Previous RP should not be an absolute contraindication for TEP LIHR. Although previous RP adds complexity, in experienced hands TEP LIHR can be done safely, with outcomes equivalent to patients who have not previously undergone RP.

Selective internal radiation therapy for hepatic metastases of uveal melanoma: a systematic review.

OBJECTIVE: Uveal melanoma (UM) commonly metastasizes to the liver. Treatment usually consists of liver-directed therapies, such as selective internal radiation therapy (SIRT). This review aimed to assess the effectiveness and safety of SIRT for hepatic metastases from UM. METHODS: The study protocol is available at OSF (https://osf.io/vhyct/). EMBASE and MEDLINE were searched until July 2020, using terms related to SIRT and hepatic metastases from UM. Studies reporting outcomes of SIRT in patients with UM and at least one hepatic metastasis were included. Data on overall survival (OS), hepatic progression free survival (hPFS) or tumor response were collected. The Newcastle-Ottawa Scale (NOS) was used to assess risk of bias. RESULTS: 11 studies were included, reporting outcomes for 268 patients with hepatic metastases from UM. Most studies (n = 9, 81.8%) were retrospective. Disease control was achieved in 170 patients (67.5%) and the median OS from time of SIRT was 12.3 months. Median hPFS was 5.4 months. Low-grade side-effects were common but serious complications were infrequent. There were two treatment-related deaths. The median NOS score was 6 (moderate risk of bias). CONCLUSION: SIRT appears to be a safe and effective treatment for patients with unresectable hepatic metastases from UM. The certainty of our results is unclear due to predominantly retrospective data with moderate risk of bias. Further prospective studies are required to explore the role of SIRT in UM. ADVANCES IN KNOWLEDGE: SIRT appears to be a safe treatment for patients with unresectable hepatic metastases from UM. Further prospective work is required.

Reporting of Clinical Outcomes After Endovascular Aortic Aneurysm Repair: A Systematic Review.

BACKGROUND: Endovascular aneurysm repair (EVAR) is an established treatment for many patients with infra-renal abdominal aortic aneurysm (AAA). Reporting standards were published in 2002 to ensure consistent measurement and reporting of outcomes following EVAR. We aimed to assess the range of clinical outcomes reported after EVAR and whether recent studies adhere to established reporting standards. METHODS: We searched MEDLINE and Embase from January 2014 until December 2018, using terms for 'EVAR' and 'AAA'. We included prospective studies and randomised controlled trials which reported clinical outcomes of elective infra-renal AAA repair. Data on clinical outcome reporting were extracted and compared with established reporting standards. RESULTS: 84 studies were included. Technical success was reported in 49 (58.3%) studies, but only defined in 40 (47.6%), with 22 distinct definitions. Clinical success was reported and defined in 19 (22.6%) studies. Aneurysm rupture was reported in 27 (32.1%) studies and death from rupture in 11 (13.1%) studies. All-cause and aneurysm-related mortality were reported in 72 (85.7%) and 52 (61.9%) studies, respectively. Endoleak type I (n = 61, 72.6%) and II (n = 52, 61.9%) were more commonly reported than type III (n = 45, 53.6%) or IV (n = 13, 15.5%). Complications and mortality were reported by a mean of 18 (21.4%) and 42 (50%) studies, respectively. CONCLUSIONS: A wide variety of clinical outcomes were reported following EVAR. Few studies adhered to reporting guidelines. We recommend modification of reporting standards to reflect advances in endovascular technology and creation of a core outcome set for EVAR.

Invasive fungal disease in children with acute myeloid leukaemia: An Australian multicentre 10-year review.

BACKGROUND: Invasive fungal disease (IFD) is a common and important complication in children with acute myeloid leukaemia (AML). We describe the epidemiology of IFD in a large multicentre cohort of children with AML. METHODS: As part of the retrospective multicentre cohort TERIFIC (The Epidemiology and Risk factors for Invasive Fungal Infections in immunocompromised Children) study, proven/probable/possible IFD episodes occurring in children with primary or relapsed/refractory AML from 2003 to 2014 were analysed. Crude IFD prevalence, clinical characteristics, microbiology and treatment were assessed. Kaplan-Meier survival analysis was used to estimate 6-month survival. RESULTS: There were 66 IFD episodes diagnosed in 63 children with AML. The majority (75.8%) of episodes occurred in the context of primary AML therapy. During primary AML therapy, the overall prevalence was 20.7% (95% CI 15.7%-26.5%) for proven/probable/possible IFD and 10.3% (95% CI 6.7%-15.0%) for proven/probable IFD. Of primary AML patients, 8.2% had IFD diagnosed during the first cycle of chemotherapy. Amongst pathogens implicated in proven/probable IFD episodes, 74.4% were moulds, over a third (37.9%) of which were non-Aspergillus spp. Antifungal prophylaxis preceded 89.4% of IFD episodes, most commonly using fluconazole (50% of IFD episodes). All-cause mortality at 6 months from IFD diagnosis was 16.7% with IFD-related mortality of 7.6% (all in cases of proven IFD). CONCLUSIONS: IFD is a common and serious complication during paediatric AML therapy. Mould infections, including non-Aspergillus spp. predominated in this cohort. A systematic approach to the identification of patients at risk, and a targeted prevention strategy for IFD is needed.

Migratory cues controlling B-lymphocyte trafficking in human lymph nodes.

B-cell migration within lymph nodes (LNs) is crucial to adaptive immune responses. Chemotactic gradients are proposed to drive migration of B cells into follicles, followed by their relocation to specific zones of the follicle during activation, and ultimately egress. However, the molecular drivers of these processes and the cells generating chemotactic signals that affect B cells in human LNs are not well understood. We used immunofluorescence microscopy, flow cytometry and functional assays to study molecular mechanisms of B-cell migration within human LNs, and found subtle but important differences to previous murine models. In human LNs we find CXCL13 is prominently expressed at the follicular edge, often associated with fibroblastic reticular cells located in these areas, whereas follicular dendritic cells show minimal contribution to CXCL13 expression. Human B cells rapidly downregulate CXCR5 on encountering CXCL13, but recover CXCR5 expression in the CXCL13-low environment. These data suggest that the CXCL13 gradient in human LNs is likely to be different from that proposed in mice. We also identify CD68+ CD11c+ PU.1+ tingible body macrophages within both primary and secondary follicles as likely drivers of the sphingosine-1-phosphate (S1P) gradient that mediates B-cell egress from LNs, through their expression of the S1P-degrading enzyme, S1P lyase. Based on our findings, we present a model of B-cell migration within human LNs, which has both similarities and interesting differences to that proposed for mice.

Diagnostic inflammatory markers of acute cholangitis in liver transplant recipients.

BACKGROUND: Acute cholangitis (AC) after liver transplantation occurs in 8-12% patients and remains a significant cause of patients' morbidity and mortality. The 2018 Tokyo guidelines use white blood cell count and C-reactive protein (CRP) as diagnostic criteria in AC. However, these and other common inflammatory markers have not been assessed in immunosuppressed liver transplant (LT) recipients with AC. The aims of this study were to compare the discriminative powers of common inflammatory markers, define the best inflammatory marker and determine the diagnostic cut-off values for the inflammatory markers in LT recipients with AC. METHODS: This was a retrospective cohort study. Over 16 years 212 LT recipients who underwent endoscopic biliary decompression were identified from hospital records. Thirty LT recipients with AC and 30 LT recipients without AC were randomly drawn in a 1:1 ratio. RESULTS: Among inflammatory markers, CRP had the highest discriminative power for diagnosing AC. The areas under the receiver operating characteristics curves for CRP, white blood cell count, lymphocyte count and neutrophil-to-lymphocyte ratio were 95% (95% confidence interval (CI): 91-98), 59% (95% CI: 50-68), 65% (95% CI: 53-77) and 70% (95% CI: 59-80), respectively. The cut-off value of CRP for diagnosing AC was equal to or above 9.5 mg/L. CONCLUSION: CRP has the best discriminative power compared with other commonly used inflammatory markers for diagnosing AC in LT recipients. The optimal cut-off value for CRP concentration in diagnosing AC is equal to or above 9.5 mg/L.

Distinctive Subpopulations of Stromal Cells Are Present in Human Lymph Nodes Infiltrated with Melanoma.

Metastasis of human tumors to lymph nodes (LN) is a universally negative prognostic factor. LN stromal cells (SC) play a crucial role in enabling T-cell responses, and because tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Here, we identify distinctive subpopulations of CD90+ SCs present in melanoma-infiltrated LNs and compare them with their counterparts in normal LNs. The first population (CD90+ podoplanin+ CD105+ CD146+ CD271+ VCAM-1+ ICAM-1+ α-SMA+) corresponds to fibroblastic reticular cells that express various T-cell modulating cytokines, chemokines, and adhesion molecules. The second (CD90+ CD34+ CD105+ CD271+) represents a novel population of CD34+ SCs embedded in collagenous structures, such as the capsule and trabeculae, that predominantly produce extracellular matrix. We also demonstrated that these two SC subpopulations are distinct from two subsets of human LN pericytes, CD90+ CD146+ CD36+ NG2- pericytes in the walls of high endothelial venules and other small vessels, and CD90+ CD146+ NG2+ CD36- pericytes in the walls of larger vessels. Distinguishing between these CD90+ SC subpopulations in human LNs allows for further study of their respective impact on T-cell responses to tumor antigens and clinical outcomes.

Invasive fungal infections in children with acute lymphoblastic leukaemia: Results from four Australian centres, 2003-2013.

BACKGROUND: Invasive fungal infections (IFI) are an important complication of acute lymphoblastic leukaemia (ALL) treatment. Our study describes the prevalence and outcomes of IFI in children with ALL. METHODS: IFI episodes in children with primary or relapsed ALL, identified for The Epidemiology and Risk Factors for Invasive Fungal Infections in Immunocompromised Children study, were analysed. IFI were classified according to European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group criteria with a 'modified-possible' category included. RESULTS: A total of 123 IFI episodes in 119 patients with ALL were included. A proven, probable, possible and modified-possible IFI was diagnosed in 56 (45.5%), 22 (17.9%), 39 (31.7%) and six (4.9%) episodes, respectively. The prevalence was 9.7% (95% confidence interval [CI] 8-11.4%) overall and 23.5% (95% CI 14.5-32.5%) for relapsed/refractory ALL. For non-relapsed ALL, the IFI prevalence was significantly higher for children with high-risk compared to standard-risk ALL (14.5% vs 7.3%, P = .009), and IFI were more common during induction, consolidation and delayed intensification phases. Mould infections occurred more frequently than non-mould infections. Thirteen children (10.9%) died within 6 months of IFI diagnosis with five deaths (4.2%) attributable to an IFI. CONCLUSIONS: IFI is more common in children with high-risk ALL and in relapsed disease. Overall survival was encouraging, with IFI contributing to very few deaths.

Preoperative immunonutrition in patients undergoing liver resection: A prospective randomized trial.

BACKGROUND: Preoperative supplementation with immunonutrients, including arginine and n-3 fatty acids, has been shown in a number of systematic reviews to reduce infectious complications in patients who have undergone gastrointestinal surgery. Limited information, however, is available on the benefits of nutritional supplementation enriched with arginine and n-3 fatty acids in patients undergoing liver resection. AIM: To evaluate the effects of preoperative nutritional supplementation enriched with arginine and n-3 fatty acids on inflammatory and immunologic markers and clinical outcome in patients undergoing liver resection. METHODS: Thirty-four patients undergoing liver resection were randomized to either five days of preoperative Impact® [1020 kcal/d, immunonutrition (IMN) group], or standard care [no supplementation, standard care (STD) group]. Nutritional status was measured at study entry by subjective global assessment (SGA). Functional assessments (grip strength, fatigue and performance status) were carried out at study entry, on the day prior to surgery, and on postoperative day (POD) 7 and 30. Inflammatory and immune markers were measured at study entry, on the day prior to surgery, and POD 1, 3, 5, 7, 10 and 30. Postoperative complications were recorded prospectively until POD30. RESULTS: A total of 32 patients (17 IMN and 15 STD) were analysed. All except four patients were SGA class A. The plasma ratio of (eicosapentaenoic acid plus docosahexaenoic acid) to arachidonic acid was higher in IMN patients on the day prior to surgery and POD 1, 3, 5 and 7 (P < 0.05). Plasma interleukin (IL)-6 concentrations were elevated in the IMN group (P = 0.017 for POD7). No treatment effect was detected for functional measures, immune response (white cell count and total lymphocytes) or markers of inflammation (C-reactive protein, tumour necrosis factor-α, IL-8, IL-10). There were 10 patients with infectious complications in the IMN group and 4 in the STD group (P = 0.087). Median hospital stay was 9 (range 4-49) d in the IMN group and 8 (3-34) d in the STD group (P = 0.476). CONCLUSION: In well-nourished patients undergoing elective liver resection, this study failed to show any benefit of preoperative immunonutrition.

Measurement of patient-reported outcomes after laparoscopic cholecystectomy: a systematic review.

BACKGROUND: Patient-reported outcome (PRO) measures (PROMs) are increasingly used as endpoints in surgical trials. PROs need to be consistently measured and reported to accurately evaluate surgical care. Laparoscopic cholecystectomy (LC) is a commonly performed procedure which may be evaluated by PROs. We aimed to evaluate the frequency and consistency of PRO measurement and reporting after LC. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for prospective studies reporting PROs of LC, between 2013 and 2016. Data on the measurement and reporting of PROs were extracted. RESULTS: A total of 281 studies were evaluated. Forty-five unique multi-item questionnaires were identified, most of which were used in single studies (n = 35). One hundred and ten unique rating scales were used to assess 358 PROs. The visual analogue scale was used to assess 24 different PROs, 17 of which were only reported in single studies. Details about the type of rating scale used were not given for 72 scales. Three hundred and twenty-three PROs were reported in 162 studies without details given about the scale or questionnaire used to evaluate them. CONCLUSIONS: Considerable variation was identified in the choice of PROs reported after LC, and in how they were measured. PRO measurement for LC is focused on short-term outcomes, such as post-operative pain, rather than longer-term outcomes. Consideration should be given towards the development of a core outcome set for LC which incorporates PROs.

Epidemiology of invasive fungal infections in immunocompromised children; an Australian national 10-year review.

BACKGROUND: A thorough understanding of local and contemporary invasive fungal infection (IFI) epidemiology in immunocompromised children is required to provide a rationale for targeted prevention and treatment strategies. METHODS: Retrospective data over 10 years from four tertiary pediatric oncology and hematopoietic stem cell transplant (HSCT) units across Australia were analyzed to report demographic, clinical, and mycological characteristics of IFI episodes, and crude IFI prevalence in select oncology/HSCT groups. Kaplan-Meier survival analyses were used to calculate 180-day overall survival. RESULTS: A total of 337 IFI episodes occurred in 320 children, of which 149 (44.2%), 51 (15.1%), and 110 (32.6%) met a modified European Organization for Research and Treatment of Cancer (mEORTC) criteria for proven, probable, and possible IFI, respectively. There were a further 27 (8.0%) that met a "modified possible IFI" criteria. Median age at IFI diagnosis was 8.4 years. Crude mEORTC IFI prevalence in acute lymphoblastic leukemia, acute myeloid leukemia, solid tumor, and allogeneic HSCT cohorts was 10.6%, 28.2%, 4.4%, and 11.7%, respectively. Non-Aspergillus species represented 48/102 (47.1%) molds identified, and non-albicans Candida represented 66/93 (71.0%) yeasts identified. There were 56 deaths among 297 children who met mEORTC criteria, with 180-day overall survival for proven, probable, and possible IFIs of 79.7%, 76.2%, and 84.4%, respectively. CONCLUSION: Non-Aspergillus molds and non-albicans Candida contributed substantially to pediatric IFI in our study, with high IFI prevalence in leukemia and allogeneic HSCT cohorts. Inclusion of IFIs outside of European Organization for Research and Treatment of Cancer criteria revealed an IFI burden that would go otherwise unrecognized in published reports.

Hepatitis B virus-related hepatocellular carcinoma presenting at an advanced stage: is it preventable?

AIM: Earlier diagnosis of hepatitis B virus (HBV) related hepatocellular carcinoma (HCC) increases treatment options and survival. The aim of this study is to evaluate which factors are associated with late presentation of HBV-related HCC. METHOD: This is a retrospective review of all cases of HBV-related HCC diagnosed with late-stage/incurable HCC in New Zealand between 2003 and 2017. Cases were defined as patients with a positive hepatitis B surface antigen (HBsAg), and advanced (not amenable to potentially curable treatments) HCC at initial diagnosis. Patients were categorised into four groups according to potential reasons for late presentation: no previous diagnosis of HBV infection (Group A); known HBV diagnosis but not receiving HCC surveillance (Group B); known HBV diagnosis and receiving suboptimal HCC surveillance (Group C); and known HBV diagnosis and receiving optimised HCC surveillance (Group D). RESULTS: A total of 368 patients were reviewed. The average age at death was 59 years, and the majority of patients were Maori (39%), Pacific (34%) or Asian (20%). The incidence of patients presenting with HBV-related advanced HCC increased from 4.5 cases to 6.3 cases per million people over the review period. Of the cases, 40% were categorised into Group A, 26% into Group B, 12% into Group C and 23% in Group D. Overall, the median survival was 138 days, and this did not change during the study period. Patients receiving optimised surveillance (Group D) survived longer (mean 469 days) than patients in Group A (90 days), Group B (145 days) or Group C (152 days) (p<0.05). Patients in Group D were more likely to be treated with transarterial chemoembolisation than patients in other groups (40% vs 15%, p<0.05). CONCLUSION: This study has highlighted the need for improved rates of HBV diagnosis, better follow-up of those infected and the importance of optimal HCC surveillance. In New Zealand, HBV-related HCC disproportionately affects minority ethnic groups, and given the increasing incidence, provides a potential domain to reduce health inequities.

Recurrent loss of heterozygosity correlates with clinical outcome in pancreatic neuroendocrine cancer.

Pancreatic neuroendocrine tumors (pNETs) are uncommon cancers arising from pancreatic islet cells. Here we report the analysis of gene mutation, copy number, and RNA expression of 57 sporadic well-differentiated pNETs. pNET genomes are dominated by aneuploidy, leading to concordant changes in RNA expression at the level of whole chromosomes and chromosome segments. We observed two distinct patterns of somatic pNET aneuploidy that are associated with tumor pathology and patient prognosis. Approximately 26% of the patients in this series had pNETs with genomes characterized by recurrent loss of heterozygosity (LoH) of 10 specific chromosomes, accompanied by bi-allelic MEN1 inactivation and generally poor clinical outcome. Another ~40% of patients had pNETs that lacked this recurrent LoH pattern but had chromosome 11 LoH, bi-allelic MEN1 inactivation, and universally good clinical outcome. The somatic aneuploidy allowed pathogenic germline variants (e.g., ATM) to be expressed unopposed, with RNA expression patterns showing inactivation of downstream tumor suppressor pathways. No prognostic associations were found with tumor morphology, single gene mutation, or expression of RNAs reflecting the activity of immune, differentiation, proliferative or tumor suppressor pathways. In pNETs, single gene mutations appear to be less important than aneuploidy, with MEN1 the only statistically significant recurrently mutated driver gene. In addition, only one pNET in the series had clearly actionable single nucleotide variants (SNVs) (in PTEN and FLCN) confirmed by corroborating RNA expression changes. The two clinically relevant patterns of LoH described here define a novel oncogenic mechanism and a plausible route to genomic precision oncology for this tumor type.

Human immunodeficiency virus-infected young people in Australia: data from the Australian HIV Observational Database.

BACKGROUND: Individuals aged 13-24 years undergo vast physical, cognitive, social and psychological changes. Australian data regarding clinical outcomes of those diagnosed with HIV in this age are sparse. AIM: We aimed to describe demographic factors, virologic and clinical outcomes of individuals aged 13-24 years diagnosed with human immunodeficiency virus (HIV). METHODS: Patients diagnosed with HIV after 1997 in the Australian HIV Observational Database were divided into young adults, diagnosed at age <25 years (n = 223), and older adults (n = 1957). Demographic and clinical factors were compared between groups. RESULTS: Young adults had a median age at diagnosis of 22 years (inter quartile range (IQR) 20-24) and median age at treatment initiation of 24 years (IQR 22-26). They were more likely to be female than the older cohort (21.1 vs 10.8%; P < 0.001). Men who have sex with men was the most common exposure category in both groups. CD4 count at diagnosis was significantly higher in younger than older adults (median 460 vs 400 cells/mm3 , P = 0.006), whereas HIV viral load at diagnosis was lower (35 400 vs 61 659 copies/mL, P = 0.011). The rate of loss to follow up (LTFU) was higher in young adults (8.0 vs 4.3 per 100PY, P < 0.001). Young adults were more likely to have a treatment interruption compared to older adults (5.3 vs 4.0 per 100PY, P = 0.039). Rates of treatment switch, time to treatment change, and CD4 and viral load responses to treatment were similar between groups. CONCLUSIONS: Young adults were diagnosed with HIV at higher CD4 counts and lower viral loads than their older counterparts. LTFU and treatment interruption were more common highlighting the need for extra efforts directed towards retention in care and education regarding the risks of treatment interruptions.