P S Mortimer

University of London, Londinium, England, United Kingdom

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Publications (275)

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    Full-text Dataset · Sep 2016
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    Full-text Dataset · Sep 2016
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    Full-text Dataset · Sep 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background and Aims Ano-genital granulomatosis is a rare chronic granulomatous condition of the skin that causes lymphoedema of the external genitalia. There is a reported association with Crohn’s disease. Mechanisms of disease, and optimal methods of treatment are poorly understood. Methods A retrospective case note review of 25 male patients with ano-genital granulomatosis presenting with genital lymphoedema was performed to determine the clinical and histopathological features of this condition and its relationship to intestinal Crohn’s disease. Results A combination of penile and scrotal oedema was reported at presentation in 80% of patients. 40% of patients had associated intestinal Crohn’s disease. The average time from symptom onset to diagnosis was 52.7 months. Half of cutaneous biopsies contained non-caseating granulomas and 14% contained intra-lymphatic granulomas. 72% of patients responded to oral steroids initially but recurrence was common. Complete or partial response was achieved in 60% of patients treated with azathioprine. Three of 6 patients responded to anti-TNF therapy. A small proportion of patients required circumcision or de-bulking surgery for more debilitating disease. Conclusions Ano-genital granulomatosis is a rare condition that presents with genital lymphoedema and there is frequently a protracted delay in diagnosis. There is a very strong association with intestinal Crohn’s disease. Genital lymphoedema associated with gastrointestinal symptoms should prompt careful evaluation to exclude both ano-genital granulomatosis and Crohn’s disease.
    Article · Sep 2016 · Journal of Crohn s and Colitis
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    Full-text Dataset · Aug 2016
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    Full-text Dataset · Aug 2016
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    Full-text Dataset · Aug 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate.
    Full-text Article · Jul 2016 · Journal of Clinical Investigation
  • Viviana Cintolesi · Anthony W.B. Stanton · Salena K. Bains · [...] · Peter S. Mortimer
    [Show abstract] [Hide abstract] ABSTRACT: Background: It has previously been shown that the lymph drainage rate in both upper limbs is greater in women destined to develop breast cancer-related lymphedema (BCRL) than in those who do not develop BCRL, indicating a constitutive predisposition. We explored constitutive differences further by measuring the maximum lymphatic pump pressure (Ppump) and the rate of (99m)Tc-Nanocoll transport generated by the contractile upper limb lymphatics before and after breast cancer surgery in a group of women who were followed for 2 years to determine their eventual BCRL or non-BCRL status. Methods and results: Ppump and tracer transport rate were measured by lymphatic congestion lymphoscintigraphy in the ipsilateral upper limb in 26 women pre- and post-breast cancer surgery. BCRL occurred in 10/26 (38.5%) cases. Ppump in the women who later developed BCRL (40.0 ± 8.2 mmHg) was 1.7-fold higher than in those who did not develop BCRL (23.1 ± 10.8 mmHg, p = 0.001). Moreover, the rate of lymph tracer transport into the forearm was 2.2-fold greater in the women who later developed BCRL (p = 0.052). Surgery did not significantly reduce Ppump measured 21 weeks postsurgery, but impaired forearm tracer transport in pre-BCRL women by 58% (p = 0.047), although not in those who did not develop BCRL. Conclusions: Women destined to develop BCRL have higher pumping pressures and lymph transport, indicating harder-working lymphatics before cancer treatment. Axillary lymphatic damage from surgery appears to compromise lymph drainage in those women constitutively predisposed to higher lymphatic pressures and lymph transport.
    Article · Jun 2016 · Lymphatic Research and Biology
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    [Show abstract] [Hide abstract] ABSTRACT: Generalized lymphatic dysplasia (GLD) is a rare form of primary lymphoedema characterized by a uniform, widespread lymphoedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. This may present prenatally as non-immune hydrops. Here we report homozygous and compound heterozygous mutations in PIEZO1, resulting in an autosomal recessive form of GLD with a high incidence of non-immune hydrops fetalis and childhood onset of facial and four limb lymphoedema. Mutations in PIEZO1, which encodes a mechanically activated ion channel, have been reported with autosomal dominant dehydrated hereditary stomatocytosis and non-immune hydrops of unknown aetiology. Besides its role in red blood cells, our findings indicate that PIEZO1 is also involved in the development of lymphatic structures.
    Full-text Article · Sep 2015 · Nature Communications
  • C. L. Thomas · P. S. Mortimer · J. M. Larkin · [...] · L. Fearfield
    [Show abstract] [Hide abstract] ABSTRACT: We report three cases of skin toxicity associated with oral mitogen-activated protein kinase kinase (MEK) inhibitor treatment for metastatic malignant melanoma (MM). All three patients developed oedema, and a single patient experienced eyelash trichomegaly. This is the first known report of eyelash trichomegaly secondary to MEK inhibitor use. We also discuss possible mechanisms for MEK inhibitor-associated oedema development. This series supports the role of the dermatologist in the screening and management of patients in the rapidly developing oncology setting, as new targeted agents can give rise to marked skin toxicity.
    Article · Sep 2015 · Clinical and Experimental Dermatology
  • [Show abstract] [Hide abstract] ABSTRACT: The RASopathies, which include Noonan syndrome (NS) and Cardiofaciocutaneous syndrome (CFC), are autosomal dominant disorders with genetic heterogeneity associated with germline mutations of genes in the Ras/mitogen-activated protein kinase (MAPK; RAS-MAP kinase) pathway. The conditions overlap and are characterised by facial dysmorphism, short stature and congenital heart disease. NS and CFC, in particular, are known to be associated with lymphatic problems, but this has not been well characterised to date. We describe 11 patients with Noonan or CFC syndrome with significant, persistent and progressive lymphatic dysplasia. The lymphatic disorders in Noonan and CFC syndrome are rare, but have a characteristic pattern with bilateral lower limb lymphoedema, genital swelling with chylous reflux and frequent systemic involvement, including intestinal lymphangiectasia and chylothoraces, which may be progressive. Lymphoscintigraphy demonstrates reflux and/or rerouting of lymphatic drainage associated with incompetent veins on the venous duplex scans.European Journal of Human Genetics advance online publication, 5 August 2015; doi:10.1038/ejhg.2015.175.
    Article · Aug 2015 · European Journal of Human Genetics
  • C. Thomas · P. S. Mortimer · J. M. Larkin · [...] · L. Fearfield
    Conference Paper · Jul 2015
  • Article · Jun 2015 · European Journal of Surgical Oncology
  • Victoria Akhras · Rathi Ramakrishnan · Anthony W.B. Stanton · [...] · Peter S Mortimer
    [Show abstract] [Hide abstract] ABSTRACT: The density of functioning human lymphatics in vivo and of immunohistochemically-defined lymphatics were quantified around melanomas, benign nevi and matched normal skin, to assess the current lymphangiogenesis paradigm. We investigated whether histological and functioning density increased around melanomas compared with benign nevi or matched skin; whether functioning and histological density increased similarly; and whether larger increases occurred around metastatic melanomas. Functioning density was quantified in vivo as the total amount of human dermal microlymphatics taking up fluorescent marker injected at the lesion margin. After tissue excision, perilesion histological density was quantified using podoplanin marker D2-40. Histological density was raised similarly around metastasising and non-metastasising melanomas compared with normal skin (+71%, P<0.0001, n=32); but was also raised significantly around benign nevi (+17%, P=0.03, n=20). By contrast, functioning lymphatic density was substantially reduced around the margins of melanomas (both metastasising and non-metastasising) compared with benign nevi (by 65%, P=0.02) or normal skin (by 53%, P=0.0014). Raised perilesion histological lymphatic density is not unique to melanoma but occurs also around benign nevi. The findings indicated that the number of functioning lateral lymphatics around human melanomas in vivo but not benign nevi is reduced, despite histologically increased numbers of lymphatics. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Article · Jun 2015 · Microcirculation (New York, N.Y.: 1994)
  • [Show abstract] [Hide abstract] ABSTRACT: Background Despite affecting approximately one-quarter of all patients undergoing axillary lymph node dissection, the pathophysiology of breast cancer-related lymphoedema (BCRL) remains poorly understood. More extensive locoregional treatment and higher body mass index have long been identified as major risk factors. This study aimed to identify risk factors for BCRL with a specific focus on the potential impact of chemotherapy on the risk of BCRL.Methods This was a retrospective analysis of a cohort of consecutive patients with breast cancer treated at a major London regional teaching hospital between 1 January 2010 and 31 December 2012. All patients had node-positive disease and underwent axillary lymph node dissection. Data regarding tumour-, patient- and treatment-related characteristics were collected prospectively. The diagnosis of BCRL was based on both subjective and objective criteria. Multivariable Cox proportional hazards regression was used to assess the association between treatment and risk of BCRL.ResultsSome 27·1 per cent of all patients (74 of 273) developed BCRL over the study period. Administration of taxanes showed a strong association with the development of BCRL, as 52 (33·5 per cent) of 155 patients who received taxanes developed BCRL. Multivariable Cox regression analysis demonstrated that patients who received taxanes were nearly three times more likely to develop BCRL than patients who had no chemotherapy (hazard ratio 2·82, 95 per cent c.i. 1·31 to 6·06). No such increase was observed when taxanes were administered in the neoadjuvant setting.Conclusion The present findings suggest that adjuvant taxanes play a key role in the development of BCRL after surgery. This may support the use of taxanes in a neoadjuvant rather than adjuvant setting.
    Article · Jun 2015 · British Journal of Surgery
  • C. L. Thomas · P. S. Mortimer · J. M. Larkin · [...] · L. Fearfield
    Article · May 2015 · Australasian Journal of Dermatology
  • [Show abstract] [Hide abstract] ABSTRACT: Turner syndrome is a complex disorder caused by an absent or abnormal sex chromosome. It affects 1/2000-1/3000 live-born females. Congenital lymphoedema of the hands, feet and neck region (present in over 60% of patients) is a common and key diagnostic indicator, although is poorly described in the literature. The aim of this study was to analyse the medical records of a cohort of 19 Turner syndrome patients attending three specialist primary lymphoedema clinics, to elucidate the key features of the lymphatic phenotype and provide vital insights into its diagnosis, natural history and management. The majority of patients presented at birth with four-limb lymphoedema, which often resolved in early childhood, but frequently recurred in later life. The swelling was confined to the legs and hands with no facial or genital swelling. There was only one case of suspected systemic involvement (intestinal lymphangiectasia). The lymphoscintigraphy results suggest that the lymphatic phenotype of Turner syndrome may be due to a failure of initial lymphatic (capillary) function.European Journal of Human Genetics advance online publication, 25 March 2015; doi:10.1038/ejhg.2015.41.
    Article · Mar 2015 · European Journal of Human Genetics
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    Marco Borri · Maria A Schmidt · Kristiana D Gordon · [...] · Peter S Mortimer
    [Show abstract] [Hide abstract] ABSTRACT: Contrast-Enhanced Magnetic Resonance Lymphangiography (CE-MRL) presents some limitations: (i) it does not quantify lymphatic functionality; and (ii) enhancement of vascular structures may confound image interpretation. Furthermore, although CE-MRL is well described in the published literature for the lower limbs, there is a paucity of data with regards to its use in the upper limbs. In this proof-of-principle study, we propose a new protocol to perform CE-MRL in the upper limbs of patients with breast cancer-related lymphedema (BCRL) which addresses these limitations. CE-MRL was performed using a previously published (morphological) protocol and the proposed protocol (quantitative) on both the ipsilateral (abnormal) and contralateral (normal) arms of patients with BCRL. The quantitative protocol employs contrast agent (CA) intradermal injections at a lower concentration to prevent T2*-related signal decay. Both protocols provided high-resolution three-dimensional images of upper limb lymphatic vessels. CA uptake curves were utilized to distinguish between lymphatic vessels and vascular structures. The quantitative protocol minimized venous enhancement and avoided spurious delays in lymphatic enhancement due to short T2* values, enabling correct CA uptake characterization. The quantitative protocol was therefore employed to measure the lymphatic fluid velocity, which demonstrated functional differences between abnormal and normal arms. The velocity values were in agreement with previously reported lymphoscintigraphy and near infra-red lymphangiography measurements. This work demonstrated the feasibility of CE-MRL of the upper limbs in patients with BRCL, introducing an advanced imaging and analysis protocol suitable for anatomical and functional study of the lymphatic system.
    Full-text Article · Mar 2015 · Lymphatic Research and Biology
  • [Show abstract] [Hide abstract] ABSTRACT: Aim: The aims of this prospective study were (a) to examine the relationship between pre-operative muscle lymph flow and the predisposition to BCRL in women treated by axillary nodal surgery for breast cancer; and (b) to test the 'stopcock' hypothesis that axillary lymph node surgery impairs forearm lymph flow in the short term. Methods: (99m)Tc-nanocoll was injected intramuscularly into both forearms of women undergoing surgery for breast cancer. Lymphatic clearance rate constant, k, representing lymph flow per unit interstitial fluid volume, was measured as the fractional disappearance rate of radioactivity from the depot site by gamma camera imaging. Axillary lymph node activity was calculated as percentage injected activity. BCRL was assessed by clinical examination and upper limb perometry. Results: Of 38 pre-operative women, 33 attended at 8 ± 6 weeks post-operatively and 31 at 58 ± 9 weeks post-operatively. Seven patients (18%) developed BCRL. Prior to surgery the BCRL-destined patients had a higher mean k (0.0962 ± 0.034%/min) than non-BCRL patients (0.0830 ± 0.019%/min) (p = 0.10, unpaired t test). Post-operative k values were not significantly different from pre-operative, in either the ipsilateral (operated) or contralateral limb. Also, post-operative k values did not differ significantly between both upper limbs. Furthermore, there was no significant difference between pre- and post-operative axillary activity. Conclusion: Patients who develop BCRL have high lymph flow pre-surgery, which may predispose them to lymphatic overload and failure. Axillary lymph node surgery has no early, measurable effect on forearm muscle lymph flow despite surgical disruption of routes of lymph drainage.
    Article · Feb 2015 · The Breast

Publication Stats

7k Citations

Institutions

  • 2015
    • University of London
      Londinium, England, United Kingdom
  • 2004
    • London School of Hygiene and Tropical Medicine
      Londinium, England, United Kingdom
  • 1988-2002
    • St George's, University of London
      • Medical School
      Londinium, England, United Kingdom
  • 1999
    • The Royal Marsden NHS Foundation Trust
      • Joint Department of Physics
      Londinium, England, United Kingdom