Biomedical subjects

K MacLennan

Publications and source records attributed to K MacLennan.

At least 19 recordsLinked to original sources

PubMed2006

A phase III trial comparing CHOP to PMitCEBO with or without G-CSF in patients aged 60 plus with aggressive non-Hodgkin's lymphoma.

The management of older patients with aggressive non-Hodgkin's lymphoma presents a challenge to the physician. Age is a poor prognostic indicator, due to reduced ability to tolerate and maintain dose-intensive chemotherapy. Generally, older patients demonstrate a lower response rate, reduced survival and increased toxicity, although the majority of large randomised trials exclude older patients. This randomised trial was conducted in patients 60 years or over to compare CHOP (cyclophosphamide 750 mg m(-2), doxorubicin 50 mg m(-2), vincristine 1.4 mg m(-2), prednisolone 100 mg) with PMitCEBO (mitoxantrone 7 mg m(-2), cyclophosphamide 300 mg m(-2), etoposide 150 mg m(-2), vincristine 1.4 mg m(-2), bleomycin 10 mg m(-2) and prednisolone 50 mg). Due to the myelosuppressive nature of these regimens, patients were also randomised to the addition of G-CSF. The formal results of this trial with long-term follow-up are now reported. Data were analysed to assess efficacy and toxicity. Overall response rate was 84% in the CHOP arm and 83% in the PMitCEBO arm, with overall response rates of 83% for the use of G-CSF and 84% for no G-CSF. At median 44 months follow-up, there was no significant difference in failure-free, progression-free or overall survival between the CHOP and PMitCEBO arms. At 3 years, the actuarial failure-free survival was 44% in CHOP recipients and 42% in PMitCEBO recipients and the 3-year actuarial overall survival was 46% and 45% respectively. There was no significant difference in the failure-free, progression-free or overall survival with the addition of G-CSF.

Age Factors↗

PubMed2005

Serpin expression in the parasitic stages of Trichostrongylus vitrinus, an ovine intestinal nematode.

Members of the genus Trichostrongylus, such as T. vitrinus, being endemic in Northern Europe, are among the principal causative nematodes which contribute to parasitic gastro-enteritis in sheep world-wide, inhabiting the proximal small intestine and causing damage to the mucosa. This results in impaired nutrient absorption as well as a pronounced inflammatory response with cellular infiltration of the mucosa, including a pronounced mast cell response. These mast cells release serine proteinases that enhance the passage of effector cells and macromolecules across epithelial boundaries and into direct contact with the invading parasite. The adult and larval stages of T. vitrinus release a number of serine proteinases in vitro that may contribute to tissue invasion and nutrient acquisition in vivo. This study describes the molecular cloning and characterization of a serine proteinase inhibitor (serpin) that is present in extracts of all the parasitic stages, becoming more abundant as the life-cycle progresses. The serpin is present in the in vitro excretory/secretory products (ES) of 4th-stage larval and adult parasites, being more abundant in the former. The serpin was expressed in E. coli and the recombinant protein was a potent inhibitor of several host serine proteinases including mast cell proteinases. The serpin may regulate the activity of the parasite serine proteinases or it may modulate the host immune response to the parasite by inhibiting the activity of serine proteinases released from host inflammatory cells.

Amino Acid Sequence↗

PubMed2002

The cause of death in patients with head and neck squamous cell carcinoma.

For patients with head and neck squamous cell carcinoma the cause of death is not well described in world literature. We report data on 106 patients diagnosed with head and neck squamous cell carcinoma who subsequently died. The literature related to this topic is discussed, and recommendations are made for data collection.

Adult↗

PubMed2002

Cervical metastasis in papillary carcinoma of the thyroid: a histopathological study.

The tendency of well differentiated thyroid carcinoma to remain localised, and the slow progression of these tumours, have supported the belief that this disease behaves as a low grade malignancy. However, with differentiated carcinomas of the thyroid the incidence of nodal metastasis is highest in the papillary subgroup, and the importance of cervical metastases is being increasingly recognised. We have performed and prospectively analysed 17 neck dissections in 13 patients with clinically N+ve necks and papillary carcinoma of the thyroid. In all 17 neck dissections, metastatic deposits of papillary carcinoma of the thyroid were seen, with metastases found in all levels. Our findings of positive lymph nodes in all levels of the neck, with no predictable pattern of spread, and skip metastases, support an aggressive surgical approach to the treatment of cervical metastatic papillary carcinoma of the thyroid.

Adult↗

PubMed2001

Mitoxantrone is superior to doxorubicin in a multiagent weekly regimen for patients older than 60 with high-grade lymphoma: results of a BNLI randomized trial of PAdriaCEBO versus PMitCEBO.

A prospective, multicenter, randomized trial was undertaken to compare the efficacy and toxicity of adriamycin with mitoxantrone within a 6-drug combination chemotherapy regimen for elderly patients (older than 60 years) with high-grade non-Hodgkin lymphoma (HGL) given for a minimum of 8 weeks. A total of 516 previously untreated patients aged older than 60 years were randomized to receive 1 of 2 anthracycline-containing regimens: adriamycin, 35 mg/m(2) intravenously (IV) on day 1 (n = 259), or mitoxantrone, 7 mg/m(2) IV on day 1 (n = 257); with prednisolone, 50 mg orally on days 1 to 14; cyclophosphamide, 300 mg/m(2) IV on day 1; etoposide, 150 mg/m(2) IV on day 1; vincristine, 1.4 mg/m(2) IV on day 8; and bleomycin, 10 mg/m(2) IV on day 8. Each 2-week cycle was administered for a minimum of 8 weeks in the absence of progression. Forty-three patients were ineligible for analysis. The overall and complete remission rates were 78% and 60% for patients receiving PMitCEBO and 69% and 52% for patients receiving PAdriaCEBO (P =.05, P =.12, respectively). Overall survival was significantly better with PMitCEBO than PAdriaCEBO (P =.0067). However, relapse-free survival was not significantly different (P =.16). At 4 years, 28% of PAdriaCEBO patients and 50% of PMitCEBO patients were alive (P =.0001). Ann Arbor stage III/IV, World Health Organization performance status 2-4, and elevated lactate dehydrogenase negatively influenced overall survival from diagnosis. In conclusion, the PMitCEBO 8-week combination chemotherapy regimen offers high response rates, durable remissions, and acceptable toxicity in elderly patients with HGL.

Aged↗

PubMed2000

Vascular endothelial growth factor (VEGF) in breast cancer: comparison of plasma, serum, and tissue VEGF and microvessel density and effects of tamoxifen.

The assessment of angiogenesis in breast cancer is of importance as a key indicator of survival and response to therapy. Circulating vascular endothelial growth factor (VEGF) measurements may provide a less subjective analysis than microvessel density (MVD) or immunohistochemical analysis of VEGF expression; however, most studies have used serum, which is now known to largely reflect platelet-derived VEGF concentrations. This study examined for the first time both plasma (VEGFp) and serum (VEGFs) VEGF concentrations in 201 blood samples from pre- and postmenopausal healthy controls and from patients with benign breast disease, localized breast cancer, breast cancer in remission, or metastatic breast cancer and related these to other clinicopathological markers. VEGFp but not VEGFs concentrations of patients with localized disease were significantly elevated compared with normal controls (P = 0.016). Patients with metastatic disease had higher VEGFp and VEGFs levels than normal controls (P < 0.001, P = 0.044 respectively), and higher VEGFp, but not VEGFs, than patients with benign disease (P = 0.009) and patients with localized disease (P = 0.004). However, the highest VEGFp and VEGFs concentrations were seen in patients in remission compared with normal controls (P < 0.001 and P = 0.008, respectively). VEGFp concentrations in patients in remission were also higher than in patients with benign disease (P = 0.01) or patients with localized disease (P = 0.005). Tamoxifen treatment was significantly associated with higher circulating and platelet-derived VEGF levels. Circulating VEGF did not correlate with any clinicopathological factor, including MVD or VEGF expression. VEGF expression was significantly correlated with estrogen receptor status and inversely correlated with tumor grade. MVD correlated with tumor size. Tamoxifen-induced increases in VEGF may be important in clinical prognosis or associated pathologies.

Adult↗

PubMed2000

Cancer spread in the larynx: a pathologic basis for conservation surgery.

BACKGROUND: Previous pathologic studies of the spread of laryngeal carcinoma have drawn inferences about the site of origin of tumors, their mechanisms of growth, or the role of structures as potential barriers to tumor spread. Most of the information is based on the study of advanced or recurrent tumors and is difficult to apply to conservation surgical technique. We carried out a systematic analysis of a wide range of laryngeal tumors with the aim of providing a basis for conservation surgery. METHODS: We analyzed tumor invasion of the laryngeal spaces and the laryngeal framework in relation to the mucosal tumor extent by axial sectioning of 80 sequential partial and total laryngectomy specimens. RESULTS: Invasion of a particular laryngeal space could be accurately predicted by mucosal tumor extent and vocal cord mobility. Invasion of the laryngeal framework was associated with tumor extension to the ventricle, subglottis, or pyriform fossa. The thyroid cartilage and the cricothyroid space and ligament were the most frequent sites of invasion. CONCLUSIONS: The mucosal distribution of a tumor and observation of vocal cord mobility can be used to determine accurately the extent of tumor invasion of the laryngeal spaces and framework and therefore the extent of resection necessary.

Biopsy, Needle↗

PubMed2000

Cervical node metastases in laryngeal and hypopharyngeal cancer: a prospective analysis of prevalence and distribution.

BACKGROUND: We have prospectively analyzed the prevalence and distribution of histologic cervical node metastases in laryngeal and hypopharyngeal squamous carcinoma to determine the most appropriate form of neck dissection. METHODS: We have examined specimens from 100 consecutive patients in whom neck dissection was part of the primary treatment of laryngeal and hypopharyngeal carcinoma. Fifty eight patients were treated by unilateral or bilateral selective dissection of levels I to IV +/- VI for N0 disease and 42 by comprehensive dissection for N+ disease. Assessment was by separation of the specimens into node levels at the time of surgery and embedding all the resected material for histologic analysis. RESULTS: Nodal metastases were found in 36% of ipsilateral and 27% of contralateral dissections in the N0 cases. The corresponding prevalences in N+ cases were 90% and 37%, respectively. All metastases in N0 and N1 disease were confined to levels II, III, IV, and VI. Metastases to levels I and V were infrequent even in N+ disease. CONCLUSIONS: Our results support the use of elective dissection of node levels II to IV for N0 laryngeal and hypopharyngeal carcinoma. We suggest the inclusion of level VI nodes for tumors invading the subglottis, pyriform fossa apex, and postcricoid region. The prevalence of bilateral metastases is great enough in midline or bilateral tumors to justify bilateral selective dissection. It is possible that selective neck dissection is also adequate for small palpable metastases, but greater numbers are required to confirm this.

Carcinoma, Squamous Cell↗

PubMed1999

Expression of CD44 by rhabdomyosarcoma: a new prognostic marker?

The expression pattern of CD44 standard and variant isoforms are prognostically significant in a number of malignancies. The aim of this study was to evaluate the role of the standard isoform of CD44 in predicting the clinical behaviour of rhabdomyosarcoma. Immunohistochemical analysis of CD44 was undertaken using a panel of antibodies recognizing the three core domains of the CD44 molecule. Labelling was repeated in triplicate and reported blind with respect to histological type and outcome. Tumours were characterized as positive in more than 60% of tumour cells labelled and negative if less than 40% of tumour cells labelled. Tumours with 40-60% of tumour cells labelling were considered indeterminate. Eleven of 20 favourable histology tumours were positive for CD44 compared with one of seven unfavourable tumours (P = 0.07). Eleven of 12 patients with CD44-positive tumours are alive in first remission compared with five of 15 CD44-negative tumours (P = 0.001). Expression of CD44 correlates directly with prognosis; however, larger studies are required so that multivariate analysis can be undertaken.

Adolescent↗

PubMed1998

Cytogenetics and the surgeon: an invaluable tool in diagnosis, prognosis and counselling of patients with solid tumours.

BACKGROUND: Cytogenetic studies have become an important part of tumour characterization. In a minority of tumours cytogenetic and/or molecular studies may be of help for diagnosis, selection of treatment protocols and predicting outcome. METHODS: This article reviews the literature on solid tumour translocations and established family cancer syndromes. In addition, the potential importance of genetics in management of patients with breast, ovarian and pancreatic carcinoma is reviewed. RESULTS AND CONCLUSION: Cytogenetic analysis of tumours may help confirm the diagnosis when conventional histology demonstrates no evidence of differentiation along a particular tissue pathway. For patients with well defined cancer syndromes, cytogenetic and molecular analysis offers the prospect of screening to reduce the risk of malignant disease. For many malignancies the underlying genetic anomalies are gradually being elucidated. Further studies designed to demonstrate the significance of these findings can only be undertaken if tumour material is collected and stored in optimal conditions for cytogenetic and/or molecular biological studies.

Age of Onset↗

PubMed1998

Increased intestinal permeability and altered mucosal immunity in cholestatic jaundice.

OBJECTIVE: To examine the effects of cholestatic jaundice on gut barrier function. SUMMARY BACKGROUND DATA: Gut barrier failure occurs in animal models of jaundice. In humans, the presence of endotoxemia indirectly implicates failure of this host defense, but this has not previously been investigated in jaundiced patients. METHODS: Twenty-seven patients with extrahepatic obstructive jaundice and 27 nonicteric subjects were studied. Intestinal permeability was measured using the lactulose-mannitol test. Small intestinal morphology and the presence of mucosal immunologic activation were examined in endoscopic biopsies of the second part of the duodenum. Systemic antiendotoxin core IgG antibodies and serum interleukin-6 and C-reactive protein were also quantified. Intestinal permeability was remeasured in 9 patients 5 weeks after internal biliary drainage. RESULTS: The median lactulose-mannitol ratio was significantly increased in the jaundiced patients. This was accompanied by upregulation of HLA-DR expression on enterocytes and gut-associated lymphoid tissue, suggesting immune activation. A significant increase in the acute phase response and circulating antiendotoxin core antibodies was also observed in the jaundiced patients. After internal biliary drainage, intestinal permeability returned toward normal levels. CONCLUSIONS: A reversible impairment in gut barrier function occurs in patients with cholestatic jaundice. Increased intestinal permeability is associated with local immune cell and enterocyte activation. In view of the role of gut defenses in the modern paradigm of sepsis, these data may directly identify an important underlying mechanism contributing to the high risk of sepsis in jaundiced patients.

Acute-Phase Reaction↗

PubMed1998

Gut barrier function in malnourished patients.

BACKGROUND: The integrity of the gastrointestinal mucosa is a key element in preventing systemic absorption of enteric toxins and bacteria. In the critically ill, breakdown of gut barrier function may fuel sepsis. Malnourished patients have an increased risk of postoperative sepsis; however, the effects of malnutrition on intestinal barrier function in man are unknown. AIMS: To quantify intestinal barrier function, endotoxin exposure, and the acute phase cytokine response in malnourished patients. PATIENTS: Malnourished and well nourished hospitalised patients. METHODS: Gastrointestinal permeability was measured in malnourished patients and well nourished controls using the lactulose:mannitol test. Endoscopic biopsy specimens were stained and morphological and immunohistochemical features graded. The polymerase chain reaction was used to determine mucosal cytokine expression. The immunoglobulin G antibody response to endotoxin and serum interleukin 6 were measured by enzyme linked immunosorbent assay. RESULTS: There was a significant increase in intestinal permeability in the malnourished patients in association with phenotypic and molecular evidence of activation of lamina propria mononuclear cells and enterocytes, and a heightened acute phase response. CONCLUSIONS: Intestinal barrier function is significantly compromised in malnourished patients, but the clinical significance is unclear.

Aged↗

PubMed1997

Stage-specific serine and metallo-proteinase release by adult and larval Trichostrongylus vitrinus.

Proteinases were released in a stage-specific manner during in vitro culture by 4th larval stage and adult Trichostrongylus vitrinus. Substrate gel analyses and inhibitor studies revealed the presence of serine and metallo-proteinases, active over a broad pH range, which degraded proteins such as fibrinogen, plasminogen and fibronectin but not immunoglobulin. The adult proteinases were partially inhibited (43%) by immunoglobulin from immune lamb lymph compared to controls, indicating their relevance to parasite immunobiology in vivo.

Animals↗

PubMed1996

Association between sarcoidosis and lymphoma revisited.

AIMS: To investigate the relation between sarcoidosis and lymphoma. METHODS: The hospital notes of five patients with sarcoidosis and a lymphoproliferative disorder were reviewed. Histological material on which the diagnoses of sarcoidosis and lymphoma were made was re-analysed. RESULTS: Four of the five patients had well documented sarcoidosis preceding the development of lymphoma by 18 months to 28 years; the fifth patient had lymphoplasmacytic lymphoma with a reactive granuloma reaction. Two patients had chronic sarcoidosis and three were treated with prednisolone. The types of lymphoma were: Hodgkin's disease (n = 1), B cell lymphoma (n = 2) (mantle cell and lymphoplasmacytic/local plasmacytoma) and large granular lymphocyte leukaemia (T cell) (n = 1). CONCLUSIONS: The association between sarcoidosis and lymphoma is confirmed, suggesting that sarcoidosis may be a predisposing factor for the development of a lymphoid malignancy due to disturbance of the immune system. All types of lymphoma may develop. The first case of T cell granular lymphocytic leukaemia in a patient with sarcoidosis has been documented.

Adult↗

PubMed1995

The histological and immunohistochemical changes in the skin of patients with melanoma who develop changes in skin pigmentation following immunotherapy.

The histological and immunocytochemical appearances of skin with altered pigmentation from two patients receiving chemoimmunotherapy for melanoma were examined. In both patients, there was a clinical response to treatment coincident with depigmentation of skin and hair. Skin biopsies showed extensive infiltration with CD8+ and CD4+ lymphocytes rather than CD57+ in the depigmented areas suggestive of a specific MHC-related cytotoxic T-cell activity against melanocytes. In keeping with this, MHCII expression was markedly up-regulated. These observations suggest the development of a simultaneous anti-tumour and anti-melanocyte immune response stimulated by chemoimmunotherapy, possibly against the same or similar antigens.

Adult↗

PubMed1994

Immunohistochemical and biochemical analysis of the oestrogen regulated protein pS2, and its relation with oestrogen receptor and progesterone receptor in breast cancer.

AIMS: (i) To assess the validity of an immunocytochemical technique for detecting pS2 protein in paraffin wax embedded tissue; (ii) to provide further data on the relation between pS2 protein and oestrogen receptor (ER) and progesterone receptor (PgR). METHODS: Breast cancer excision biopsy specimens were obtained from 35 previously untreated patients. An immunoradiometric assay was compared with an immunohistochemical method for measuring pS2 protein. ER and PgR were measured in cytosol fractions by enzyme immunoassay and the relation between the presence of these receptors and pS2 protein was assessed before and after subdivision of the women into groups of over or under 50 years of age. RESULTS: A good correlation was seen between the immunoradiometric and immunohistochemical methods for pS2 protein measurement (r = 0.84; p = 0.0001). Log-transformed data showed a significant correlation between increasing values of ER and pS2 protein (r = 0.45; p = 0.006) and to a lesser extent between pS2 protein and PgR (r = 0.38; p = 0.03). Correlations were also shown between pS2+ and PgR+ status (p = 0.01), and between ER and PgR positivity (p = 0.05; Fisher's exact test). pS2+ protein status was only associated with ER+ status in patients aged 50 years or less. CONCLUSIONS: The two methods for pS2 analysis are virtually interchangeable. This provides strong support for using immunohistochemistry for pS2 in paraffin wax embedded tissue. The association with ER positivity and pS2+ protein status only in the premenopausal patients may be due to the higher levels of oestrogenic stimuli in that group.

Adult↗

PubMed1994

The role of pentostatin in the treatment of T-cell malignancies: analysis of response rate in 145 patients according to disease subtype.

PURPOSE: To assess the results of treatment with the purine analog 2'deoxycoformycin (pentostatin [DCF]) in patients with postthymic T-cell malignancies. PATIENTS AND METHODS: One hundred forty-five patients with postthymic T-cell malignancies were given DCF intravenously at 4 mg/m2/wk for the first 4 weeks and then every 2 weeks until maximal response; the last 30 patients received weekly injections until maximal response. RESULTS: The overall response rate was 32% (complete responses [CRs] plus partial responses [PRs]), with marked variation according to diagnosis. The best responses occurred in patients with Sézary syndrome (62%) and T-prolymphocytic leukemia (T-PLL) (45%), with CRs in three of 16 Sézary syndrome and five of 55 T-PLL patients. In contrast, no responses (NRs) were documented in 13 patients with other types of cutaneous T-cell lymphoma, including five mycosis fungoides. Two of five patients with large granular lymphocyte (LGL) leukemia had a CR and two of four with Sézary cell leukaemia had a PR. A low response rate was observed in 27 patients with peripheral T-non-Hodgkin's lymphoma (T-NHL) (19%) and in 25 with adult T-cell leukemia/lymphoma (ATLL) (12%). The latter included two CRs and one PR. Toxicity was low and DCF was generally well tolerated. No significant differences were observed when results were analyzed according to previous treatment. Disease subtype was the most important factor to influence results. CONCLUSION: We conclude that DCF is effective as a single agent in T-PLL, Sézary syndrome, and LGL leukemia, but has low activity in other T-cell disorders.

Adult↗

PubMed1993

Immune changes in peripheral blood resulting from locally directed interleukin-2 therapy in squamous cell carcinoma of the head and neck.

Interleukin-2 (IL-2) was administered locally by constant intra-arterial infusion in four escalating doses from 3 x 10(4)-3 x 10(7) IU/day to 12 patients with squamous cell carcinoma of the head and neck (SCCHN) in a phase I trial. Lymphocyte phenotypic markers and serum cytokine concentrations were measured over the course of treatment. Serum IL-1-alpha, -beta and IL-6 were not induced at any dose level. Tumour necrosis factor (TNF)-alpha was induced in the 2 patients who showed a clinical response (at the lowest dose) as well as in 4/10 of the non-responders. In addition TNF-beta was induced in 3/10 and IFN-gamma in 5/10 non-responders. Soluble IL-2 receptor concentrations were increased at the two higher doses. The highest dose of IL-2 produced a lymphocytosis after day 5 until the end of administration reflected by a general rise in lymphocyte phenotypic markers. CD25, CD3/HLA-DR and CD56 showed an additional upregulation not accounted for by the lymphocytosis with a suggestion of a bell-shaped dose-response curve for CD25 and CD3/HLA-DR. Administration of IL-2 in this manner has been shown to be well tolerated and has some anti-tumour activity at low doses, with little toxicity.

Adult↗