Recent Submissions

  • Reporting of Surgically Removed Lymph Nodes for Breast Tumors: Recommendations From the International Collaboration on Cancer Reporting.

    Deb, Rahul
    CONTEXT.—: The International Collaboration on Cancer Reporting (ICCR), supported by major pathology and cancer organizations, aims at the standardization of evidence-based pathology reporting of different types of cancers, with the inclusion of all parameters deemed to be relevant for best patient care and future data collection. Lymph node metastasis is one of the most important prognostic factors in breast cancer. OBJECTIVE.—: To produce a histopathology reporting guide by a panel of recognized experts from the fields of pathology and surgery with elements deemed to be core (required) and noncore (recommended) to report when assessing regional lymph nodes of patients with breast cancer. DATA SOURCES.—: Published literature, previous guidelines/recommendations, and current cancer staging principles were the basis of the data set drafted by the expert panel. This was discussed in a series of teleconferences and email communications. The draft data set was then made available for public consultation through the ICCR Web site. After this consultation and ICCR ratification, the data set was finalized. CONCLUSIONS.—: The ICCR has published a data set for the reporting of surgically removed lymph nodes (including sentinel lymph node biopsy, axillary lymph node dissection, targeted axillary surgery, and lymph node sampling specimens) for breast tumors. This is part of a series of 4 ICCR breast cancer-related data sets. It includes 10 core elements along with 2 noncore elements. This should allow for synoptic reporting, which is more precise, uniform, and complete than nonsynoptic reporting, and leads to improved patient outcomes.
  • Effectiveness of telemedicine in outpatient parenteral antimicrobial therapy (Tele-OPAT): A systematic review.

    Durojaiye, OC
    INTRODUCTION: Telemedicine is increasingly used to deliver healthcare in many clinical specialities. However, the adoption of telemedicine in the delivery of outpatient parenteral antimicrobial therapy (OPAT) has been relatively slow and limited. This study aims to collate current evidence for telemedicine in OPAT regarding clinical efficacy, safety, acceptability and cost-effectiveness. METHODS: We systematically searched the Cochrane Library, CINAHL, EMCARE, EMBASE and MEDLINE databases through 24 July 2022, for relevant studies published in English. Research articles and conference abstracts were included if they involved any form of telephone or video consultation in delivering parenteral antibiotics in the home or outpatient setting. Study findings were synthesised into three main themes: patient outcomes and safety, patient and provider satisfaction and cost-effectiveness. The mixed methods appraisal tool was used to review the methodological quality of the studies. PROSPERO CRD42022342874. RESULTS: The literature search yielded 311 articles, of which 12 (five full-length articles and seven conference abstracts) reporting over 1245 telemedicine interventions were reviewed. The reported outcomes were heterogeneous. Telemedicine was cost-effective and associated with high patient satisfaction and comparable complication rates compared to conventional OPAT. Considering six comparative studies, rehospitalisation risk was lower for telemedicine than conventional OPAT (risk ratio, 0.58; 95% confidence interval, 0.38-0.88; I2  =  31%). DISCUSSION: The results of this review demonstrate that telemedicine has a role in delivering safe and cost-effective OPAT care, especially for patients residing in remote and geographically isolated locations. Nevertheless, high-quality studies and publication of existing data and experiences are needed to further validate this model of care delivery.
  • The BAC recommended code of practice for cytology laboratories participating in the United Kingdom cervical screening programmes (2022) - a new edition for a new decade.

    Cropper, Alison
    The last update of the British Association for Cytopathology (BAC) code of practice (CoP) was published in 2017, since when there have been such significant changes to the UK cervical screening programmes (CSPs) in, most notably the implementation of primary screening for high-risk Human Papilloma Virus (hrHPV), that a major revision is required. Previous versions of the CoP have provided a valuable resource for cytology laboratories and other key stakeholders, and it is hoped that this latest edition will continue to do so.
  • JAK2 ex13InDel drives oncogenic transformation and is associated with chronic eosinophilic leukemia and polycythemia vera.

    Addada, Jo (2019-12)
    The V617F mutation in the JH2 domain of Janus kinase 2 (JAK2) is an oncogenic driver in several myeloproliferative neoplasms (MPNs), including essential thrombocythemia, myelofibrosis, and polycythemia vera (PV). Other mutations in JAK2 have been identified in MPNs, most notably exon 12 mutations in PV. Here, we describe a novel recurrent mutation characterized by a common 4-amino-acid deletion and variable 1-amino-acid insertion (Leu583-Ala586DelInsSer/Gln/Pro) within the JH2 domain of JAK2. All 4 affected patients had eosinophilia, and both patients with Leu583-Ala586DelInsSer fulfilled diagnostic criteria of both PV and chronic eosinophilic leukemia (CEL). Computational and functional studies revealed that Leu583-Ala586DelInsSer (herein referred to as JAK2ex13InDel) deregulates JAK2 through a mechanism similar to JAK2V617F, activates signal transducer and activator of transcription 5 and extracellular signal-regulated kinase, and transforms parental Ba/F3 cells to growth factor independence. In contrast to JAK2V617F, JAK2ex13InDel does not require an exogenous homodimeric type 1 cytokine receptor to transform Ba/F3 cells and is capable of activating β common chain family cytokine receptor (interleukin-3 receptor [IL-3R], IL-5R, and granulocyte-macrophage colony stimulating factor receptor) signaling in the absence of ligand, with the maximum effect observed for IL-5R, consistent with the clinical phenotype of eosinophilia. Recognizing this new PV/CEL-overlap MPN has significant clinical implications, as both PV and CEL patients are at high risk for thrombosis, and concomitant cytoreduction of red cells, neutrophils, and eosinophils may be required for prevention of thromboembolic events. Targeted next-generation sequencing for genes recurrently mutated in myeloid malignancies in patients with unexplained eosinophilia may reveal additional cases of Leu583-Ala586DelInsSer/Gln/Pro, allowing for complete characterization of this unique MPN.
  • The association between hepatocellular carcinoma and direct-acting anti-viral treatment in patients with decompensated cirrhosis

    Lawson, A (2019-07)
    BACKGROUND: Direct-acting anti-viral therapy (DAA) has transformed hepatitis C virus (HCV) care, particularly in patients with decompensated cirrhosis. However, their impact on hepatocellular carcinoma (HCC) remains unclear. AIM: To use a national registry of patients with advanced liver disease to explore the relationship between DAA therapy and HCC. METHODS: All patients with de novo HCC post DAA therapy were frequency matched with patients who did not develop HCC. Demographic, clinical and laboratory data were obtained. Cross-sectional imaging and multidisciplinary team reports were reviewed for dates of HCC diagnosis and HCC progression. Patients were categorised by treatment outcome and time of HCC development. Data were examined by multivariable analysis and Kaplan-Meier estimation. RESULTS: Eighty patients with HCC were compared with 165 patients without HCC, treated between June 2014 and September 2015. Mean follow-up from start of DAA therapy was 32.4 months. Twenty-eight patients were diagnosed with early HCC (within 6 months of therapy) and 52 presented late. Baseline nonmalignant lesions (HR: 1.99), thrombocytopaenia (HR: 1.59) and diabetes (HR: 1.68) increased likelihood of HCC. Response to therapy was reduced in patients who developed liver cancer (SVR in patients with HCC = 54/80 (68%), SVR in patients without HCC = 143/165 (87%), P < 0.001, OR: 3.13, 95% CI: 1.64-5.99). We found no difference between tumour size, progression or survival between viraemic and nonviraemic patients. CONCLUSION: There is no alteration in prognosis or cancer progression following HCC development after HCV treatment. However, baseline nonmalignant liver lesions, diabetes and thrombocytopaenia increase the risk of HCC, and HCC is associated with a decreased SVR rate.
  • Proliferation and AKT activity biomarker analyses after Capivasertib (AZD5363) treatment of patients with ER+ invasive breast cancer (STAKT).

    Deb, Rahul (2019-12)
    PURPOSE: The STAKT study examined short-term exposure (4.5 days) to oral selective pan-AKT inhibitor capivasertib (AZD5363) to determine if this drug can reach its therapeutic target in sufficient concentration to significantly modulate key biomarkers of the AKT pathway and tumor proliferation. METHODS: STAKT was a two-stage, double-blind, randomized, placebo-controlled, 'window-of-opportunity' study in patients with newly diagnosed ER+ invasive breast cancer. Stage 1 assessed capivasertib 480 mg bid (recommended monotherapy dose) and placebo, and stage 2 assessed capivasertib 360 and 240 mg bid. Primary endpoints were changes from baseline in AKT pathway markers pPRAS40, pGSK3β and proliferation protein Ki67. Pharmacologic and pharmacodynamic properties were analyzed from blood sampling, and tolerability by adverse-event monitoring. RESULTS: After 4.5 days' exposure, capivasertib 480 mg bid (n=17) produced significant decreases from baseline versus placebo (n=11) in pGSK3β (H-score absolute change -55.3, P=0.006) and pPRAS40 (-83.8, P<0.0001), and a decrease in Ki67 (absolute change in percentage positive nuclei: -9.6%, P=0.031). Significant changes also occurred in secondary signaling biomarker pS6 (-42.3, P=0.004), while pAKT (and nuclear FOXO3a) also increased in accordance with capivasertib's mechanism (pAKT: 81.3, P=0.005). At doses of 360 mg bid (n=5) and 240 mg bid (n=6), changes in primary and secondary biomarkers were also observed, albeit of smaller magnitude. Biomarker modulation was dose and concentration dependent, and no new safety signals were evident. CONCLUSIONS: Capivasertib 480 mg bid rapidly modulates key biomarkers of the AKT pathway and decreases proliferation marker Ki67, suggesting future potential as an effective therapy in AKT-dependent breast cancers.
  • Technical and clinical accuracy of three blood glucose meters: clinical impact assessment using error grid analysis and insulin sliding scales

    Reynolds, Tim; Sutheran, Hannah Lise (2016)
    Aims Manufacturers of point-of-care testing (POCT) glucose systems must adhere to International Organisation for Standardisation (ISO) 15197 performance standards, a tightened version of which becomes mandatory in May 2016. Using methods deviating from the evaluation requirements of ISO 15197, we investigated the accuracy and clinical utility of three glucose testing systems. Methods Whole blood glucose was measured on 62 EDTA-preserved samples with each system followed by plasma glucose determination with a laboratory hexokinase method. Technical accuracy was assessed using linear regression, Bland-Altman plots and bias. Clinical utility was evaluated using consensus error grid analysis and insulin dosing algorithms. Results The correlation coefficient of the glucose measuring devices with the comparator method was between 0.979 and 0.993 (n=61). Bias against the reference method was +0.7–+4.4%. The FreeStyle Lite (0.7±4.4%) and ACCU-CHEK Aviva (1.3±7.3%) systems had the least bias to the reference. Error grid analysis depicts all meters to be clinically accurate, with all results falling within Zones A and B. Conclusions Conformité Européene-marked devices are presumed to have adequate accuracy, but postmarket evaluations are imperative to assess total system accuracy and whether regulatory targets are achievedmaintenance requirements and cost.2 The substantial cost of SMBG is attributed to the cost of the disposable test strips. Conscious healthcare spending has spurred local clinical commissioning groups to standardise blood glucose meter prescriptions.
  • Histopathological evidence for macrophage activation driving post-transfusion hyperhaemolysis syndrome.

    Hebballi, S; McKernan, A; Hamilton, R; Robinson, Ivan (2019-04)
    Post-transfusion hyperhaemolysis syndrome (PTHS) is a rare life-threatening transfusion complication reported mainly in sickle cell patients. Its pathogenesis is poorly understood. Antibody-mediated haemolysis and bystander effect have been proposed as putative mechanisms, but in half of cases, red cell antibodies are undetectable, and PTHS develops despite transfusion of cross-matched compatible RBC. An alternate hypothesis proposes activated macrophages as the main drivers of red cell destruction through direct phagocytosis. We report the histopathological findings of two patients with PTHS showing extensive macrophage expansion and erythrophagocytosis, supportive of macrophage activation driving PTHS. This supports a possible role for novel therapies that target macrophage activation.Pre. 12 Month embargo on post
  • Identification of rare diseases by screening a population selected on the basis of routine pathology results-the PATHFINDER project: lysosomal acid lipase/cholesteryl ester storage disease substudy.

    Reynolds, Tim; Mewies, Clare (2018-07)
    AIMS: Lysosomal acid lipase deficiency (LALD) is an autosomal recessive disorder of cholesterol ester storage associated with hepatic disease, cirrhosis and accelerated atherosclerosis. Its prevalence in the general population, patients with dyslipidaemia and raised transaminases is unclear. This study attempted to identify the prevalence of LALD from patients with abnormal results in laboratory databases. METHODS: Electronic laboratory databases were interrogated to identify from clinical biochemistry records patients with a phenotype of low high-density lipoprotein-cholesterol (≤0.85 mmol/L; 33 mg/dL) and with elevated alanine or aspartate transaminases (≥60 IU/L) on one occasion or more over a 3-year time interval. Patients were recalled, and a dried blood spot sample was collected for lysosomal acid lipase determination by a fluorimetric enzyme assay. Histopathology databases of liver biopsies were interrogated for patients with features of 'microvesicular cirrhosis' or 'cryptogenic cirrhosis' in the report. Histological blocks were sampled, and samples were analysed by next-generation sequencing for the presence of mutations in the LAL gene. RESULTS: Samples were obtained from 1825 patients with dyslipidaemia and elevated transaminases. No cases of LALD were identified. Liver biopsies were obtained from six patients. DNA extraction was successful from four patients. Two patients were homozygous for the LAL c.46A>C;p.Thr16Pro unclassified variant in exon 2. CONCLUSIONS: Pathology databases hold routine information that can be used to identify patients with specific patterns of results or those who had biopsies to allow targeted testing for possible causes of disease. Biochemical screening suggests that the gene frequency of LAL deficiency in adults is less than 1 in 100.
  • Differential Diagnosis for Chronic Hypokalaemia.

    Stimson, Laura; Reynolds, Tim (2018-06)
    Doctors will often see patients with chronic hypokalaemia, frequently this is secondary to gastrointestinal losses, diuretics or renal disease. However, in this case report we review a rarer cause of chronic hypokalaemia-Gitelman syndrome (GS).GS is an uncommon genetic disorder which causes primary renal tubular hypokalaemic metabolic alkalosis with secondary hypomagnesaemia and hypocalciuria. Although rare, it is important to remember GS when considering differential diagnoses for chronic hypokalaemia. We report the case of a woman who presented to the ophthalmology department with sclerochoroidal calcification. An ophthalmologist was reviewing the medical literature, which prompted them to investigate for GS. A diagnosis was formed at that time based on the blood and urine chemistry results. However, later we were able to offer the patient genetic testing, which confirmed our provisional diagnosis.
  • Eltrombopag and Romiplostim: A snapshot from Derby Teaching Hospitals

    Khan, I; Lala, J; Smith, A; Millar, C; Addada, Jo (2018-04)
    Severe Idiopathic Thrombocytopenic Purpura (ITP) is a relatively common disorder with a small but definite associated mortality. For many years, first line therapy has consisted of steroid or Intravenous Immunoglobulin. A plethora of second line treatment options have traditionally included splenectomy, Rituximab, Mycophenolate, other immunosupressants & Danazol. Each has had its own risks and uncertain efficacy and treatment sequencing for refractory patients has always been very much at the discretion of individual clinicians. Recently the Thrombopoietin Receptor Agonists (TPO-RA) Romi-plostim and Eltrombopag have been available in the UK (NICE approved in 2011 and 2013 respectively). Both are regarded as highly effective but costly treatments. We present here our recent experience of using TPO-RA in a large clinical unit serving a population of 600,000. We audited patients on TPO-RA between March 2016 and April 2017. TPO-RAs were used in 34 episodes (30 patients, 4 patients required switching from one to other). Eltrombopag was used in 25 episodes and Romi-plostim in 9 episodes. Patient demographics were as follows: 21 females, 9 males; Age range 28-91 (median 65.4). 26 out of 30 patients were treated in accordance with NICE guidance. These patients were refractory to other standard treatment for ITP and/or had severe disease and a high risk of bleeding requiring frequent rescue therapy. Splenectomy was considered inappropriate in 20 out of 26 (76.9%) patients. 6 out of 26 (23%) patients were post splenectomy and had refractory ITP. 4 out of 30 patients were treated with TPO (Eltrombopag) out with NICE guidance. Splenectomised patients had a median of 5.5 previous treatment lines compared with non-splenectomised patients (1.36). Eltrombopag doses ranged from 25-75 mg/day. Romiplostim doses ranged from 2-10 mcg/kg/week. 4 patients switched between Romiplostim and Eltrombopag due to loss/failure of response. Doses were individualized to maintain platelet counts in a safe range. All patients showed a positive response to one or the other agent (defined as greater than 50 x 10/l) In general both treatments were well tolerated and no drug needed discontinuation due to side effects. Main side effects with Eltrombopag were fatigue (2 patients), headache (2) and grade 1 diarrhoea (1). Side effects experienced with Romiplastim were dyspepsia (1) and occasional mild headache (1). In our experience TPO-RA treatments are well tolerated and all patients audited showed an effective response. Furthermore, we also noticed that our clinicians do not consider splenectomy to be a favoured second line treatment in the era of TPO-RAs. This suggests that the current treatment paradigm should be reviewed.
  • NHS Breast Screening multidisciplinary working group guidelines for the diagnosis and management of breast lesions of uncertain malignant potential on core biopsy (B3 lesions).

    Deb, Rahul (2018-05)
    Needle core biopsy is considered the histological diagnostic method of choice for screen-detected breast lesions. Although the majority are definitively diagnosed as normal, benign, or malignant, approximately 7% are categorised as B3, of uncertain malignant potential. These include a wide range of lesions with different risks of associated malignancy from <2% to approaching 40% from literature review in UK practice. Historically, these have typically been surgically excised as a diagnostic procedure but the majority are then proven to be benign. An alternative approach, for many of these lesions, is thorough sampling/excision by vacuum-assisted biopsy techniques to exclude the presence of co-existing carcinoma. This would potentially reduce the benign open biopsy rate whilst maintaining accuracy of cancer diagnosis. A group from the Radiology, Surgery, and Pathology NHS Breast Screening Programme Co-ordinating Committees and an additional co-opted expert were charged with review and development of guidelines for the clinical management of B3 lesions. The guidelines reflect suggested practice as stated by the NHS Breast Screening Programme and approved by the Royal College of Radiologists.
  • An update on trials of novel lipid-lowering drugs.

    Reynolds, Tim (2018-03)
    PURPOSE OF REVIEW: A number of novel trials have assessed the efficacy of new lipid-lowering therapies in cardiovascular disease (CVD). RECENT FINDINGS:Proprotein convertase subtilisin kexin-9 inhibitors reduce low-density lipoprotein cholesterol (LDL-C) by 50-55%. A CVD outcome trial in patients with acute coronary syndromes with evolocumab achieved a LDL-C of 0.8 mmol/l (31 mg/dl) and a 20% relative risk reduction in CVD events in 2.2 years. Cholesterol ester transfer protein inhibitors raise high-density lipoprotein cholesterol and can lower LDL-C. Anacetrapib reduced coronary artery disease events by 7%, but not wider composite CVD outcomes, in a population with chronic CVD with pretreatment LDL-C of 1.6 mmol/l (62 mg/dl). The conflicting outcomes of cholesterol ester transfer protein inhibitor trials means these compounds are not being developed further. Trials using lipid drugs targeting inflammation have previously been generally unsuccessful, but recent data on the interleukin-1B receptor antagonist canakinumab has proven the concept of intervention on inflammation in atherosclerosis by showing a reduction in acute coronary interventions, but at the predictable cost of increased infections. SUMMARY: Despite the success of proprotein convertase subtilisin kexin-9 inhibition, the ability to achieve low LDL-C with off-patent medications and the costs of novel therapies will limit their use even in high-risk patients and confine them to the highest-risk sub-groups of patients.

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