Research Spotlight

Raj, S. D., J. Phillips, T. S. Mehta, L. M. Quintana, M. D. Fishman, V. Dialani and P. J. Slanetz (2018). “Management of BIRADS 3, 4A, and 4B Lesions Diagnosed as Pure Papilloma by Ultrasound-Guided Core Needle Biopsy: Is Surgical Excision Necessary?” Acad Radiol Oct 6. [Epub ahead of print].

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RATIONALE AND OBJECTIVES: There is lack of consensus on managing papillomas due to varied upgrade rates in the literature related to variability in the studied populations. We specifically studied upgrade rates of pure papilloma diagnosed with ultrasound core biopsy (UCB) using spring-loaded (SLB) and vacuum-assisted (VAB) biopsy devices in patients with low-to-intermediate pre-test probability for malignancy on imaging. MATERIALS & METHODS: From 01/01/2008 to 06/30/2016, 227 patients with 248 pure papillomas classified as BI-RADS 3, 4a, and 4b were diagnosed by UCB and underwent surgical excision or clinical and/or imaging follow-up. Imaging features, biopsy device, and final pathology were documented. RESULTS: 177 lesions were biopsied with SLB (14-gauge) and 71 lesions with VAB (9-13 gauges). At surgery, upgrade rates to high-risk lesions and malignancy for SLB were 14.3% (22/154) and 1.9% (3/154), and for VAB were 3.5% (2/57) and 0% (0/57), respectively (p <0.05). The combined surgical upgrade rate to high-risk lesions and malignancy was 11.4% (24/211) and 1.4% (3/211), respectively. The overall upgrade rate (including surgical and clinical and/or imaging follow-up) to high-risk lesions and malignancy was 9.7% (24/248) and 1.2% (3/248), respectively. No ultrasound features were predictive of upgrade. Rates of complete excision were 7.1% (11/154) for SLB and 19.3% (11/57) for VAB (p < 0.05). CONCLUSION: BI-RADS 3, 4a, or 4b masses biopsied with UCB revealed pure papilloma upgrade to malignancy in less than 2% of cases. SLB was associated with greater upgrades compared with VAB. Therefore, follow-up imaging is a reasonable alternative to excision, particular in those sampled by VAB. Excision could be considered if the diagnosis of a high-risk lesion would change clinical management.

Quist, J., H. Mirza, M. C. U. Cheang, M. L. Telli, J. O’Shaughnessy, C. J. Lord, A. N. J. Tutt and A. Grigoriadis (2018). “A four-gene decision tree signature classification of triple-negative breast cancer: Implications for targeted therapeutics.” Mol Cancer Ther Oct 10. [Epub ahead of print].

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The molecular complexity of triple-negative breast cancers (TNBCs) provides a challenge for patient management. We set out to characterise this heterogeneous disease by combining transcriptomics and genomics data, with the aim of revealing convergent pathway dependencies with the potential for treatment intervention. A Bayesian algorithm was used to integrate molecular profiles in two TNBC cohorts, followed by validation using five independent cohorts (n = 1,168), including three clinical trials. A four-gene decision tree signature was identified which robustly classified TNBCs into six subtypes. All four genes in the signature (EXO1, TP53BP2, FOXM1 and RSU1) are associated with either genomic instability, malignant growth, or treatment response. One of the six subtypes, MC6, encompassed the largest proportion of tumours (~50%) in early diagnosed TNBCs. In TNBC patients with metastatic disease, the MC6 proportion was reduced to 25%, and was independently associated with a higher response rate to platinum-based chemotherapy. In TNBC cell line data, platinum-sensitivity was recapitulated, and a sensitivity to the inhibition of the phosphatase PPM1D was revealed. Molecularly, MC6-TNBCs displayed high levels of telomeric allelic imbalances, enrichment of CD4+ and CD8+ immune signatures, and reduced expression of genes negatively regulating the mitogen-activated protein kinase (MAPK) signalling pathway. These observations suggest that our integrative classification approach may identify TNBC patients with discernible and theoretically pharmacologically tractable features that merit further studies in prospective trials.

O’Brien, A., P. S. Kamath and J. Trotter (2018). “MACHT – Outpatient albumin infusions do not prevent complications of cirrhosis in patients on the liver transplant waiting list.” J Hepatol Oct 9. [Epub ahead of print].

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Albumin has long been an important option in the treatment of patients with cirrhosis and ascites. Albumin improves circulatory function; and is widely recommended for use in inpatients with cirrhosis complicated by hepatorenal syndrome and spontaneous bacterial peritonitis, as well as to prevent post paracentesis circulatory dysfunction following large volume paracentesis (LVP). Albumin has beneficial immunomodulatory and endothelial effects.5 Therefore, many centres use albumin as an unproven, but seemingly effective agent as an adjuvant to chronic diuretic therapy for ascites in patients with cirrhosis. In particular, patients regarded to have the greatest potential benefit are those with chronic renal insufficiency who tolerate diuretic therapy poorly. Midodrine, an α‐adrenergic agonist, has been shown to improve systemic and renal hemodynamics in patients with ascites. However, a meta‐analysis of 10 trials using midodrine to treat ascites showed no beneficial effect on survival and when used as an alternative to albumin in LVP, the mortality was higher for midodrine than albumin.7 Furthermore, the addition of the somatostatin analogue, octreotide to midodrine was not superior to albumin in preventing ascites recurrence compared to albumin. In the current issue of this Journal, Sola et al. report on the MACHT trial (midodrine and albumin for cirrhotic patients in the waiting list for liver transplantation) conducted by the centre with the best record of performing clinically important trials in advanced liver disease. This study showed that in patients with cirrhosis awaiting liver transplantation, outpatient treatment with midodrine and albumin (40 g every 2 weeks) slightly suppressed the vasoconstrictor activity, but neither prevented complications of cirrhosis nor improved survival. (Excerpt from text, p. 1-2.)

Meng, F., L. Kennedy, L. Hargrove, J. Demieville, H. Jones, T. Madeka, A. Karstens, K. Chappell, G. Alpini, A. Sybenga, P. Invernizzi, F. Bernuzzi, S. DeMorrow and H. Francis (2018). “Ursodeoxycholate inhibits mast cell activation and reverses biliary injury and fibrosis in Mdr2(-/-) mice and human primary sclerosing cholangitis.” Lab Invest 98(11): 1465-1477.

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Ursodeoxycholic acid (UDCA) is used to treat biliary disorders; and, bile acids alter mast cell (MC) histamine release. MCs infiltrate Mdr2(-/-) mice liver (model of primary sclerosing cholangitis (PSC)). MC-derived histamine increases inflammation, hepatic stellate cell (HSC) activation and fibrosis. The objective was to determine the effects of UDCA treatment on MC infiltration, biliary damage, inflammation and fibrosis in Mdr2(-/-) mice and human PSC. Wild-type and Mdr2(-/-) mice were fed bile acid control diet or UDCA (0.5% wt/wt). Human samples were collected from control and PSC patients treated with placebo or UDCA (15 mg/kg/BW). MC infiltration was measured by immunhistochemistry and quantitative polymerase chain reaction (qPCR) for c-Kit, chymase, and tryptase. The HDC/histamine/histamine receptor (HR)-axis was evaluated by EIA and qPCR. Intrahepatic bile duct mass (IBDM) and biliary proliferation was evaluated by CK-19 and Ki-67 staining. Fibrosis was detected by immunostaining and qPCR for fibrotic markers. Inflammatory components were measured by qPCR. HSC activation was measured by SYP-9 staining. Inflammation was detected by qPCR for CD68. In vitro, MCs were treated with UDCA (40 muM) prior to HA secretion evaluation and coculturing with cholangiocytes or HSCs. BrDU incorporation and fibrosis by qPCR was performed. UDCA reduced MC number, the HDC/histamine/HR-axis, IBDM, HSC activation, inflammation, and fibrosis in Mdr2(-/-) mice and PSC patients. In vitro, UDCA decreases MC-histamine release, which was restored by blocking ASBT and FXRbeta. Proliferation and fibrosis decreased after treatment with UDCA-treated MCs. We conclude that UDCA acts on MCs reducing histamine levels and decreases the inflammatory/hyperplastic/fibrotic reaction seen in PSC. Ursodeoxycholic acid (UDCA) is used to treat biliary disorders; and, bile acids alter mast cell (MC) histamine release. Following liver injury like primary sclerosing cholangitis in mice and humans, MCs infiltrate. MC-derived histamine increases biliary damage, fibrosis, and inflammation. UDCA treatment decreases these parameters via reduced MC activation.

Magombedze, G., N. M. Ferguson and A. C. Ghani (2018). “A trade-off between dry season survival longevity and wet season high net reproduction can explain the persistence of Anopheles mosquitoes.” Parasit Vectors Nov 3;11(1):576.

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BACKGROUND: Plasmodium falciparum malaria remains a leading cause of death in tropical regions of the world. Despite efforts to reduce transmission, rebounds associated with the persistence of malaria vectors have remained a major impediment to local elimination. One area that remains poorly understood is how Anopheles populations survive long dry seasons to re-emerge following the onset of the rains. METHODS: We developed a suite of mathematical models to explore the impact of different dry-season mosquito survival strategies on the dynamics of vector populations. We fitted these models to an Anopheles population data set from Mali to estimate the model parameters and evaluate whether incorporating aestivation improved the fit of the model to the observed seasonal dynamics. We used the fitted models to explore the impact of intervention strategies that target aestivating mosquitoes in addition to targeting active mosquitoes and larvae. RESULTS: Including aestivation in the model significantly improved our ability to reproduce the observed seasonal dynamics of vector populations as judged by the deviance information criterion (DIC). Furthermore, such a model resulted in more biologically plausible active mosquito survival times (for A. coluzzii median wet season survival time of 10.9 days, 95% credible interval (CrI): 10.0-14.5 days in a model with aestivation versus 38.1 days, 95% CrI: 35.8-42.5 days in a model without aestivation; similar patterns were observed for A. arabiensis). Aestivation also generated enhanced persistence of the vector population over a wider range of both survival times and fecundity levels. Adding vector control interventions that target the aestivating mosquito population is shown to have the potential to enhance the impact of existing vector control. CONCLUSIONS: Dry season survival attributes appear to drive vector population persistence and therefore have implications for vector control. Further research is therefore needed to better understand these mechanisms and to evaluate the additional benefit of vector control strategies that specifically target dormant mosquitoes.