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P S Mortimer

Publications and source records attributed to P S Mortimer.

At least 19 recordsLinked to original sources
PubMed2006

Chemokine-mediated migration of melanoma cells towards lymphatics--a mechanism contributing to metastasis.

The mechanisms that cause tumors such as melanomas to metastasize into peripheral lymphatic capillaries are poorly defined. Non-mutually-exclusive mechanisms are lymphatic endothelial cell (LEC) chemotaxis and proliferation in response to tumor cells (chemotaxis-lymphangiogenesis hypothesis) or LECs may secrete chemotactic agents that attract cancer cells (chemotactic metastasis hypothesis). Using migration assays, we found evidence supporting both hypotheses. Conditioned medium (CM) from metastatic malignant melanoma (MMM) cell lines attracted LEC migration, consistent with the lymphangiogenesis hypothesis. Conversely, CM from mixed endothelial cells or LECs, but not blood endothelial cells, attracted MMM cells but not non-metastatic melanoma cells, consistent with the chemotactic metastasis hypothesis. MMM cell lines expressed CCR7 receptors for the lymphatic chemokine CCL21 and CCL21 neutralizing antibodies prevented MMM chemotaxis in vitro. To test for chemotactic metastasis in vivo tumor cells were xenotransplanted into nude mice approximately 1 cm from an injected LEC depot. Two different MMM grew directionally towards the LECs, whereas non-metastatic melanomas did not. These observations support the hypothesis that MMM cells grow towards regions of high LEC density owing to chemotactic LEC secretions, including CCL21. This chemotactic metastasis may contribute to the close association between metastasizing tumor cells and peri-tumor lymphatic density and promote lymphatic invasion.

Animals↗
PubMed2006

Vascular endothelial growth factor-C (VEGF-C) expression in normal human tissues.

OBJECTIVE: To characterize vascular endothelial growth factor-C (VEGF-C) protein expression in normal human tissues by immunohistochemistry (IHC). VEGF-C is a growth factor for lymphatic endothelial cells. VEGF-C mRNA and protein are expressed in a variety of cancerous tissues, but the localization of VEGF-C protein in many normal human tissues has not been clearly demonstrated to date. We therefore performed an immunohistochemical survey of the distribution of intracellular VEGF-C protein in a range of normal human tissue types. METHODS: Five microm sections were cut from archived human tissues. Sections were dewaxed, rehydrated, and subjected to microwave pretreatment. They were incubated with VEGF-C antibody before detection with biotinylated secondary antibody using 'Elite' avidin-biotin enzyme complex and diaminobenzidine substrate. The primary antibody recognized the C-terminus of the VEGF-C propeptide that is cleaved before secretion and hence only cellular protein was detected. Negative controls used the same concentration of normal goat IgG. RESULTS: Staining manifested as small punctate cytoplasmic granules. Strong expression was observed in large intestine epithelium, and mammary duct epithelium, skeletal and cardiac muscle, thyroid, ovary, and the prostate. Weaker expression was also detected in the hepatocytes close to the terminal hepatic venules of the liver, vascular smooth muscle, and placenta. No expression was consistently detected in spleen or thymus. CONCLUSIONS: Intracellular VEGF-C protein is widely expressed in many normal human adult tissues. Its expression in cancer is not therefore per se indicative of a prolymphangiogenic change. To demonstrate the latter, a quantitative change in expression level is required.

Female↗
PubMed2006

Squamous cell carcinoma of the penis in a patient with chronic isolated penile lymphoedema.

Squamous cell carcinoma arising in tissue affected by chronic lymphoedema is rare. We describe, to our knowledge, the first documented case of penile squamous cell carcinoma arising in a patient with a history of idiopathic chronic penile lymphoedema. Patients with chronic lymphoedema should be actively followed for possible malignant changes. We discuss the management and possible aetiology of this unusual case.

Adult↗
PubMed2005

Blood flow in psoriatic plaques before and after selective treatment of the superficial capillaries.

BACKGROUND: Blood flow is substantially raised in psoriatic plaques. In addition, mechanisms of vasoconstriction and vasodilatation (locally and neurally mediated), although intact, are altered in magnitude. The elevated blood flow is considered to be a result of abnormalities (increase in vessel number, width and length) in the superficial capillary loops rather than changes in the deeper feeding vessels (arterioles). OBJECTIVES: To determine if selective thermolysis of psoriatic capillaries with a pulsed dye laser (PDL) leads to normalization of blood flow and also if the vasoconstrictor and vasodilator responses are returned to normal magnitude. METHODS: Laser Doppler red cell flux was recorded from plaques on the forearm or elbow (untreated plaque site) and from clinically uninvolved skin at an equivalent site on the opposite limb. Plaques were treated on three occasions, at 2-weekly intervals, with a PDL. Laser Doppler red cell flux measurements were then repeated, 2 weeks after the final laser treatment was performed (treated plaque site). RESULTS: There was significant clinical improvement in plaques after treatment (P = 0.02), but complete clearance of lesions did not occur. Blood flow in plaques under basal conditions remained significantly elevated above blood flow in clinically uninvolved skin, despite laser treatment (P < 0.001). The physiological tests of resistance vessel function showed that the laser did not impair the ability of psoriatic resistance vessels to constrict and dilate. However, there was only partial resolution of the percentage responses to the provocation tests towards the values recorded in clinically uninvolved skin. CONCLUSIONS: The results indicate that it is unlikely that the reduced resistance of the expanded superficial capillary bed is solely responsible for the massively elevated blood flow in plaque skin. It is more likely that the vascular abnormalities in psoriasis also extend to involve the deeper, larger resistance vessels (arterioles).

Adult↗
PubMed2005

In vivo quantification of the structural abnormalities in psoriatic microvessels before and after pulsed dye laser treatment.

BACKGROUND: Microvascular abnormalities (capillary elongation, widening and tortuosity) are a characteristic feature of psoriasis and form one of the pathological diagnostic criteria. These changes occur early in the progression of a psoriatic plaque, before there is clinical or histological evidence of epidermal hyperplasia. Treatment of psoriatic microvessels with a pulsed dye laser (PDL) has been associated with both clinical improvement and clearance of lesions. OBJECTIVES: To quantify the structural vascular abnormalities in plaque skin using noninvasive techniques in vivo. Investigations were carried out before and after PDL treatment to determine the nature of laser-induced microvascular changes and the relationship between these changes and clinical improvement. METHODS: Plaque microvessels were visualized using native capillaroscopy. Plaques were then treated three times with the PDL at 14-day intervals. Native capillaroscopy was repeated at 2 and 6 weeks after the final laser treatment. Images were analysed using a combination of nonstereological and stereological measurements. RESULTS: Whole body disease was stable. Treated plaques showed a 48% reduction in plaque severity score (P < 0.01). Native studies showed that the PDL significantly reduced plaque microvessel density (P < 0.05), image area fraction (P < 0.01), microvessel length density (P < 0.01) and vessel image width (P < 0.01). The reduction in plaque severity score (which denoted clinical improvement) was related quantitatively to the reduction in microvessel area per unit area of plaque skin, i.e. the image area fraction (correlation coefficient = 0.772, P < 0.01). The greatest response of plaque microvessels was within 2 weeks after the final laser treatment, while the greatest reduction in plaque severity score occurred between 2 and 6 weeks after the final laser treatment, i.e. clinical improvement was preceded by microvascular improvement. CONCLUSIONS: These findings indicate that there is a close correlation between the state of the superficial vasculature and the clinical status of psoriasis. The expanded superficial microvascular bed in plaque skin is a necessary component for maintaining clinical lesions and these blood vessels are thus a legitimate target for treatment.

Adult↗
PubMed2005

Porokeratosis in association with lymphoedema.

We describe four patients in whom porokeratosis coexisted with lympoedema of the legs. A possible pathogenetic link between the two disorders is discussed, as well as the therapeutic implications and the novel physical sign of lymphoedema bulging through the porokeratotic lesions.

Aged↗
PubMed2005

Epithelioid haemangioma in association with a deep arteriovenous malformation.

Epithelioid haemangiomas are benign, vascular tumours characterized by the proliferation of epithelioid endothelial cells with abundant eosinophilic hyaline cytoplasm. We report a case of epithelioid haemangioma in association with a deep arteriovenous malformation of the subclavian artery. The association of reactive vascular proliferations with arteriovenous malformations is uncommonly reported.

Adult↗
PubMed2005

Vulval squamous cell carcinoma arising in chronic hidradenitis suppurativa.

We report a case of vulval squamous cell carcinoma (SCC) arising in chronic hidradenitis suppurativa (HS). The patient had a complex medical history including a 25-year-history of Crohn's disease. In addition she had recently received immunosuppressive therapy for nephrotic syndrome secondary to membranous glomerulonephritis. A painful nodule was noted on the vulva that was clinically very suspicious of SCC. An excision biopsy confirmed the diagnosis. There are few publications in the English literature citing association between HS and the development of SCC. The first report in the English literature of vulval SCC arising in chronic HS was published in 1999. We wish to draw attention to the possibility that patients with HS may develop SCC in lesional skin. A painful lump or ulcer could easily be mistaken for an inflammatory lesion and a low threshold for biopsy is warranted. We suggest constant vigilance with regard to malignant change in ano-genital HS as the diagnosis can be difficult.

Carcinoma, Squamous Cell↗
PubMed2004

Tissue-to-blood transport of radiolabelled immunoglobulin injected into the web spaces of the hands of normal subjects and patients with breast cancer-related lymphoedema.

AIM: The ability to return interstitial protein to central blood is key to the defence against oedema. The aim of this study was to quantify this ability by measuring the rate at which radiolabelled human immunoglobulin (HIgG) accumulated in blood following injection into the subcutis of the hand in normal volunteers and in patients with breast cancer-related lymphoedema (BCRL). METHODS: A total of 37 control subjects (healthy normal volunteers or breast cancer patients prior to treatment) and 18 women with BCRL were studied with dual-isotope lymphoscintigraphy. Each received bilateral subcutaneous depot injection in the dorsal web space of HIgG labelled with Tc-99m on one side and In-111 on the other. Activities remaining at the depot and accumulating in blood were measured at regular intervals for 3 h. Clearance from the depot was exponential and expressed as the rate constant k(depot) (min(-1)). Accumulation in blood was essentially linear and, using an estimate of blood volume based on height and weight, was expressed as the linear constant b(blood) (% administered activity x min(-1)). The time axis intercept of this linear fit was recorded as an index of the minimum time to arrival of radioprotein in blood. The efficiency with which radioprotein that has left the depot (extra-depot activity) is transported into blood [tissue-to-blood (T-B) transport] was quantified (1) as the quotient b(blood)/k(depot), and (2) as a function of time after injection by comparing the total amount of radioprotein in blood at any time with the total amount of radioprotein that was no longer in the depot at the same time. RESULTS: Tc-99m-HIgG and In-111-HIgG behaved similarly and are interchangeable. At all times between 60 and 180 min in controls, about 50% of protein that had left the depot was present in blood. T-B transport was reduced to about 20% in BCRL arms in which the hand was involved in swelling (p < 0.001 versus controls), but remained unchanged in patients in whom the hand was spared. The minimum time to arrival of radioprotein in blood was not reduced in BCRL; on the contrary, there appeared to be a small proportion of injected activity that arrived rapidly in blood in BCRL patients but not in controls. CONCLUSION: We conclude that T-B transport is only impaired in BCRL when radioprotein is injected into swollen tissue. Significant quantities of radioprotein may escape from the arm via local access to blood. Individual variation in this capacity may explain the regional sparing observed in BCRL.

Breast Neoplasms↗
PubMed2004

Lymphatic density and metastatic spread in human malignant melanoma.

Malignant melanoma (MM), the most common cause of skin cancer deaths, metastasises to regional lymph nodes. In animal models of other cancers, lymphatic growth is associated with metastasis. To assess if lymphatic density (LD) was increased in human MM, and its association with metastasis, we measured LD inside and around archival MM samples (MM, n=21), and compared them with normal dermis (n=11), basal cell carcinoma (BCC, n=6) and Merkel cell carcinoma (MCC), a skin tumour thought to metastasise through a vascular route (MCC, n=6). Lymphatic capillary density (mm(-2)), as determined by immunohistochemical staining with the lymphatic specific marker LYVE-1, was significantly increased around MM (10.0+/-2.5 mm(-2)) compared with normal dermis (2.4+/-0.9 mm(-2)), BCC (3.0+/-0.9 mm(-2)) and MCC (2.4+/-1.4 mm(-2)) (P<0.0001). There was a small decrease in LD inside MM (1.1+/-0.7 mm(-2)) compared with normal dermis, but a highly significant decrease in BCC (0.14+/-0.13) and MCC (0.12+/-2.4) (P<0.01 Kruskal-Wallis). Astonishingly, LD discriminated between melanomas that subsequently metastasised (12.8+/-1.6 mm(-2)) and those that did not (5.4+/-1.1 mm(-2), P<0.01, Mann-Whitney). Lymphatic invasion by tumour cells was seen mainly in MM that metastasised (70% compared with 12% not metastasising, P<0.05 Fisher's Exact test). The results show that LD was increased around MMs, and that LD and tumour cell invasion of lymphatics may help to predict metastasis. To this end, a prognostic index was calculated using LD, lymphatic invasion and thickness that clearly discriminated metastatic from nonmetastatic tumours.

Basal Cell Carcinoma↗
PubMed2004

Variation in lymphatic function may predispose to development of breast cancer-related lymphoedema.

AIMS: Breast cancer-related lymphoedema (BCRL) remains a common complication of breast cancer treatment. Many features of this condition remain poorly understood, such as why only approximately 25% of women are affected after similar treatment, and the phenomenon of 'sparing', in which regions of an otherwise swollen arm, most commonly the hand, remain unaffected. This study uses dual-isotope lymphoscintigraphy, involving measurement of rate of clearance of radiolabelled protein from a subcutaneous depot and subsequent appearance in blood, to quantify alterations in lymphatic function in women with BCRL, and to further investigate differences between those in whom the hand is involved with swelling and those in whom it is spared. METHODS: Participants received a depot injection of human immunoglobulin G in the dorsum of both hands, labeled with technetium-99m on one side and indium-111 on the other. Rates of clearance from the depot and appearance in venous blood were measured at regular intervals over a 3 h period. RESULTS: A total of 18 women with a history of BCRL were studied. Significant reductions in both depot clearance and venous appearance were observed in the affected arm compared with the unaffected contralateral control. On sub-group analysis, significant differences were also observed between swollen and spared hand groups, both for the affected and unaffected contralateral arm. DISCUSSION: This study, as well as confirming impaired lymphatic function in arms affected by BCRL, also shows underlying variation in lymphatic function in the unaffected contralateral arm, between those with and without hand sparing. This raises the possibility that the risk of developing BCRL may be, in part, pre-determined.

Arm↗
PubMed2004

Scleroderma and the taxanes. Is there really a link?

Scleroderma has been associated with exposure to many substances in the past ranging from vinyl chloride to silicon dioxide. In recent years there have been a number of case reports linking modern chemotherapy agents, such as the taxanes to the development of scleroderma like changes. We present a further case of scleroderma in association with chemotherapy but question the role of some of the agents previously implicated. A brief review of the current literature is included.

Antineoplastic Agents, Phytogenic↗
PubMed2003

Hidradenitis suppurativa: pathogenesis and management.

Hidradenitis suppurativa (HS) is a chronic disease manifested by recurrent abscesses, sinus tracts and scarring. It arises most commonly, however, not exclusive from apocrine gland bearing skin. This review article sets out to clarify the importance of early diagnosis, the pathogenesis and aetiology of HS, and evidence for medical and surgical therapies for this debilitating disease.HS is caused primarily by follicular occlusion with secondary involvement of the apocrine glands. The aetiology is still poorly understood. There is a genetic component with probable hormonal influence on gene expression. Shearing forces from obesity and tight clothing contribute to its development. Management should be appropriately tailored for the severity and distribution of HS as well as quality of life of the patient. Medical management with appropriate antibiotics, if initiated early, can be successful in mild to moderate severity HS as well as improving disease control prior to attempted curative surgery in severe HS. Other helpful measures include advice on lifestyle changes, intralesional steroids, systemic retinoids, hormonal manipulation, and a revival of interest in the use of radiotherapy for HS. While there is a place for 'conservative' surgical procedures (including CO(2) laser) in selected cases of mild to moderate HS, radical excision of all apocrine-bearing tissue is the definitive treatment. We advocate close interdisciplinary collaboration as well as a cautionary approach to timing and planning of surgery to minimise recurrence rates.

Bandages↗
PubMed2003

Comparison of the microvasculature of basal cell carcinoma and actinic keratosis using intravital microscopy and immunohistochemistry.

BACKGROUND: Angiogenesis is a prerequisite for growth of invasive tumours. We hypothesized that angiogenesis would be present in invasive basal cell carcinoma (BCC) but not in a noninvasive tumour such as actinic keratosis (AK). OBJECTIVES: To investigate both types of tumour for evidence of angiogenesis. METHODS: Patients with BCC or AK underwent intravital videocapillaroscopy. Three regions were examined: the tumour, perilesional skin and a control site. Microvessel width, area fraction and length density were determined from capillaroscopy images. Biopsies were stained for CD34 and a microvessel count was performed. RESULTS: Capillaroscopy demonstrated a grossly disorganized tumour microcirculation in BCC. Compared with control skin, microvessel width was increased 2.4-fold, area fraction was increased 4.9-fold and length density was increased 5.9-fold. In AK, microvessel width was increased 1.7-fold, area fraction 2.5-fold and length density 3.4-fold. Vessel width and area fraction were significantly greater in BCC than AK. Biopsies showed significant increases in microvessel length density for both BCC and AK compared with control skin, with BCC significantly greater than AK. CONCLUSIONS: Angiogenesis was demonstrated in BCC in humans in vivo, and to a lesser extent in AK.

Aged↗