Publications by authors named "Lucy Fox"

18 Publications

  • Page 1 of 1

Proliferative Glomerulonephritis With Fibrils, Monoclonal κ Light Chain, and C3 Deposits.

Am J Kidney Dis 2021 Mar 24. Epub 2021 Mar 24.

Departments of Nephrology; Department of Medicine (RMH), University of Melbourne, Victoria, Australia.

There is increasing recognition of monoclonal gammopathy as a cause of proliferative glomerulonephritis (GN), including cases in which glomerular deposition of monoclonal immunoglobulin (mIg) is demonstrated. Recently, proliferative GN with mIg deposits (PGNMID) has incorporated a light chain (LC) variant of the disease (termed PGNMID-LC). Intriguingly, glomerular co-deposition of complement C3 is found in addition to monotypic LC, implying complement activation via the alternative pathway (AP). We present a unique case of proliferative GN in a 42-year old man who presented with nephrotic syndrome and was found to have κ-LC multiple myeloma. Immune staining of the glomerulus was positive only for κ-LC and C3, with the striking appearance of non-amyloid fibrils on electron microscopy. Following clonally targeted therapy for myeloma, the renal clinical abnormalities resolved completely. We present detailed molecular studies for LC and complement and consider local mechanisms whereby monoclonal κ-LC fibrils may have triggered AP activation within the glomerulus.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.014DOI Listing
March 2021

Cat-Scratch Disease Masquerading as C3 Glomerulonephritis.

Kidney Int Rep 2020 Dec 3;5(12):2388-2392. Epub 2020 Oct 3.

Department of Nephrology, Royal Melbourne Hospital, Parkville, Victoria, Australia.

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http://dx.doi.org/10.1016/j.ekir.2020.09.034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710836PMC
December 2020

The benefits of including medical students in the ward huddle.

Authors:
Lucy Fox

Med Teach 2020 Jul 31:1-2. Epub 2020 Jul 31.

University College London Medical School, London, UK.

This personal view, about the role of medical students in huddle, is based on my own experience as an undergraduate. The huddle is a gathering of the multidisciplinary team on the ward to discuss patients, their safety and raise concerns. However, medical students are not actively invited to join these meetings. Students regularly report feeling out of place and excluded during ward activities, fostering a sense of redundancy. This can lead to a vicious cycle of student disaffection and reduced attendance. I highlight the use of the huddle to enable medical students to take a more active role in the ward team, encourage an inclusive environment during clinical placements and importantly, to introduce themes of patient safety and raising concerns earlier in their training.
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http://dx.doi.org/10.1080/0142159X.2020.1798913DOI Listing
July 2020

Diagnostic evaluation and considerations in hypocellular bone marrow failure-A focus on genomics.

Int J Lab Hematol 2020 Jun 5;42 Suppl 1:82-89. Epub 2020 Mar 5.

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

Hypocellular bone marrow failure (BMF) has myriad differential diagnoses, most simply considered as acquired and inherited disorders, which are frequently indistinguishable upon morphologic examination of the blood and bone marrow. Accurate diagnosis is critical to optimization of management and begins with a detailed history (including family history) and physical examination. Next-generation sequencing technologies complement traditional testing techniques (such as chromosomal fragility and telomere length assessment) and have a broad application in the diagnosis and prognostication of BMF, with the importance of detection of both germline changes and also somatic variants increasingly well understood and appreciated. There is increasing awareness of germline predisposition to haematological malignancy, which incorporates but is not limited to the traditional inherited BMF syndromes and which raises challenges for counselling, monitoring and treatment of people who harbour a germline lesion. There are many benefits to both patients and their kindred of accurate determination of the precise germline change underlying heritable bone marrow diseases, along with its associated mode of inheritance. While individually, these diseases are rare, collectively they are not so and there are many collaborative efforts underway to document the natural history of these disorders, the associated phenotypes and the ever-increasing list of variants which have sufficient evidence to warrant the ascription of a pathogenic classification. We describe the many diagnostic considerations when evaluating newly presenting patients with hypocellular BMF, with a focus on genomic assessment, which is relevant in both germline and acquired diseases.
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http://dx.doi.org/10.1111/ijlh.13179DOI Listing
June 2020

Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes.

Haematologica 2021 01 1;106(1):64-73. Epub 2021 Jan 1.

Clinical Haematology, Peter MacCallum Cancer Centre/Royal Melbourne Hospital, Melbourne, Australia.

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients.
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http://dx.doi.org/10.3324/haematol.2019.237693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7776333PMC
January 2021

Integrating 'TAB' into student teamwork assessment.

Authors:
Lucy Fox

Clin Teach 2020 02 9;17(1):111-112. Epub 2019 Dec 9.

University College London, London, UK.

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http://dx.doi.org/10.1111/tct.13117DOI Listing
February 2020

The natural history of vascular and other complications in patients treated with nilotinib for chronic myeloid leukemia.

Blood Adv 2019 04;3(7):1084-1091

Department of Clinical Haematology, Austin Hospital, Melbourne, Australia.

Although second-generation tyrosine kinase inhibitors (TKIs) show superiority in achieving deep molecular responses in chronic myeloid leukemia in chronic phase (CML-CP) compared with imatinib, the differing adverse effect (AE) profiles need consideration when deciding the best drug for individual patients. Long-term data from randomized trials of nilotinib demonstrate an increased risk of vascular AEs (VAEs) compared with other TKIs, although the natural history of these events in response to dose modifications or cessation has not been fully characterized. We retrospectively reviewed the incidence of nilotinib-associated AEs in 220 patients with CML-CP at 17 Australian institutions. Overall, AEs of any grade were reported in 95 patients (43%) and prompted nilotinib cessation in 46 (21%). VAEs occurred in 26 patients (12%), with an incidence of 4.1 events per 100 patient-years. Multivariate analysis identified age ( = .022) and dyslipidemia ( = .007) as independent variables for their development. There was 1 fatal first VAE, whereas the remaining patients either continued nilotinib (14 patients) or stopped it immediately (11 patients). Recurrent VAEs were associated with ongoing therapy in 7 of 14 who continued (with 2 fatal VAEs) vs 1 of 11 who discontinued ( = .04). Nineteen of the 23 evaluable patients surviving a VAE ultimately stopped nilotinib, of whom 14 received an alternative TKI. Dose reduction or cessation because of VAEs did not adversely affect maintenance of major molecular response. These findings demonstrate that in contrast to other AEs, VAEs are ideally managed with nilotinib cessation because of the increased risk of additional events with its ongoing use.
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http://dx.doi.org/10.1182/bloodadvances.2018028035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457217PMC
April 2019

Role of bone marrow biopsy for fever of unknown origin in the contemporary Australian context.

Intern Med J 2019 07;49(7):850-854

Diagnostic Haematology, The Royal Melbourne Hospital, Melbourne, Victoria, Australia.

Background: Bone marrow biopsy (BMB) is an accepted investigation in fever of unknown origin (FUO) to uncover haematological malignancies, such as lymphoma, and sometimes infections. With the advance in imaging modalities, such as 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) to identify the focus of lymphoma, BMB may not contribute to the diagnosis when there are no other clinical features to suggest an underlying haematological disease.

Aim: To investigate the utility of BMB in determining the cause of FUO, when there are no other indications for BMB.

Methods: Medical records of adult patients who had BMB performed for FUO or febrile illness from 1 January 2005 to 31 December 2014 in four metropolitan tertiary hospitals in Melbourne, Australia were reviewed. Patients with other concurrent indications for BMB, known human immunodeficiency virus infection and previously diagnosed connective tissue diseases were excluded.

Results: Seventy-three patients were included in the study. Fifty-one patients had a final diagnosis for fever (systemic inflammatory diseases, infective, malignancy or other) while 22 patients had no diagnoses. In only 10 patients (13.7%) did BMB contribute to the diagnosis, finding either malignancy or granulomata. However, all these diagnoses could have been made without BMB. Two patients with diffuse large B-cell lymphoma had normal BMB. FDG-PET was helpful in making a diagnosis in eight (25%) out of 32 patients.

Conclusion: Performing BMB in patients with FUO and no other haematological abnormalities is of very limited value, and other investigations, such as FDG-PET, may be more likely to help establish a definitive diagnosis.
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http://dx.doi.org/10.1111/imj.14147DOI Listing
July 2019

Revisiting acquired aplastic anaemia: current concepts in diagnosis and management.

Intern Med J 2019 02;49(2):152-159

Haematology Department, St Vincent's Hospital, Melbourne, Victoria, Australia.

Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.
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http://dx.doi.org/10.1111/imj.14140DOI Listing
February 2019

Molecular Mechanisms of Disease Progression in Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type during Ibrutinib Therapy.

Int J Mol Sci 2018 06 13;19(6). Epub 2018 Jun 13.

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

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is one of the well-recognized extranodal lymphomas commonly addicted to the B-cell receptor-MYD88 superpathway. We aimed to describe the genomic changes in a patient who progressed through treatment with ibrutinib, a Bruton’s tyrosine kinase (BTK) inhibitor. An 80-year-old woman presented with multiply relapsed PCDLBCL-LT after multiple lines of chemoimmunotherapy and radiotherapy. Pre-treatment testing of the localized cutaneous tumor lesion on a lymphoid amplicon panel demonstrated an p.L265P mutation. Ibrutinib therapy was subsequently commenced, resulting in complete resolution of the skin disease. Despite an ongoing skin response, the patient developed progressive nodal disease at two months. Genomic analysis of the cutaneous tumor sample at baseline was compared to that of the inguinal lymph node upon progression, and revealed the acquisition of multiple genomic changes. These included several aberrations expected to bypass BTK inhibition, including two -activating mutations, and a deleterious mutation in the nuclear factor kappa B (NF-κB) negative regulator, . In addition, an IgH-IRF8 translocation was detected (which brings the IRF8 transcription factor under control of the immunoglobulin heavy chain locus), representing a third plausible mechanism contributing to ibrutinib resistance. Several copy-number changes occurred in both samples, including an amplification of 18q, which encodes the anti-apoptotic protein BCL2. We describe the first case of novel genomic changes of PCDLBCL-LT that occurred while on ibrutinib, providing important mechanistic insights into both pathogenesis and drug resistance.
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http://dx.doi.org/10.3390/ijms19061758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6032268PMC
June 2018

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Intern Med J 2018 06;48(6):624-636

Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto-antibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.
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http://dx.doi.org/10.1111/imj.13804DOI Listing
June 2018

Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand.

Nephrology (Carlton) 2018 Jun;23(6):507-517

Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. While TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4-8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 activity (a disintegrin and metalloprotease thrombospondin, number 13). A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin-associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC-HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC-HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. While early confirmation of aHUS is often not possible, except in the minority of patients in whom autoantibodies against factor H are identified, genetic testing ultimately reveals a complement-related mutation in a significant proportion of aHUS cases. The presence of other TMA-associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.
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http://dx.doi.org/10.1111/nep.13234DOI Listing
June 2018

The incidence and natural history of dasatinib complications in the treatment of chronic myeloid leukemia.

Blood Adv 2017 May 15;1(13):802-811. Epub 2017 May 15.

Austin Hospital, Melbourne, Australia.

Dasatinib has shown superiority over imatinib in achieving molecular responses (MRs) in chronic phase chronic myeloid leukemia but with a different toxicity profile, which may impact its overall benefit. Reported toxicities include pleural effusions and pulmonary hypertension, and although the incidence of these events is well described, response to therapy and impact of dose modifications on toxicity has not been comprehensively characterized in a real-world setting. We retrospectively reviewed the incidence of dasatinib adverse events in 212 chronic phase chronic myeloid leukemia patients at 17 Australian institutions. Adverse events were reported in 116 patients (55%), most commonly pleural effusions (53 patients, 25%), which was the predominant cause of permanent drug cessation. Age and dose were risk factors for pleural effusion ( < .01 and .047, respectively). Recurrence rates were higher in those who remained on 100 mg compared with those who dose reduced ( = .041); however, recurrence still occurred at 50 mg. Patients who developed pleural effusions were more likely to have achieved MR4.5 after 6 months of dasatinib than those without effusions ( = .008). Pulmonary hypertension occurred in 5% of patients, frequently in association with pleural effusion, and was reversible upon dasatinib cessation in 6 of 7 patients. Dose reductions and temporary cessations had minimal impact on MR rates. Our observations suggest that by using the lowest effective dose in older patients to minimize the effusion risk, dose modification for cytopenias, and care with concomitant antiplatelet therapy, the necessity for permanent dasatinib cessation due to toxicity is likely to be minimal in immunologically competent patients.
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http://dx.doi.org/10.1182/bloodadvances.2016003889DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5727806PMC
May 2017

Hot and bothered: management and outcomes for patients with febrile nonhemolytic transfusion reactions.

Transfusion 2017 07;57(7):1639-1641

Transfusion Research Unit, School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

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http://dx.doi.org/10.1111/trf.14153DOI Listing
July 2017

Eureka moments.

Authors:
Lucy J Fox

Pharos Alpha Omega Alpha Honor Med Soc 2003 ;66(4):44

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February 2004