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Biomedical subjects

John F Thompson

Publications and source records attributed to John F Thompson.

At least 73 records · Page 4Linked to original sources
PubMed2004

Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes.

Various drugs are reported to prolong the QT-interval on the surface ECG, thereby increasing the risk of developing a potentially fatal arrhythmia known as Torsades de Pointes (TdP). TdP case reports for these drugs have often been associated with risk factors such as overdosing, concomitant drugs and/or existing pathophysiological conditions. A few cases appear to be devoid of these factors. To determine what role genetic variation in the hERG gene plays in drug-induced arrhythmias, we screened DNA samples collected from 105 atrial-fibrillation patients treated with dofetilide for polymorphisms, seven of whom developed TdP. An uncommon missense change, R1047L, was identified in two of seven patients who experienced TdP as compared with five of 98 individuals who were free of TdP. Included in the affected individuals was the only subject homozygous for this SNP. Cellular electrophysiological studies revealed a 10-mV positive shift in the steady-state activation curve of the 1047L hERG channel stably expressed in HEK-293 cells as compared with the wild-type (WT) channel. The activation and inactivation kinetics of the 1047L current were significantly slower than the WT (P < 0.05) at given membrane potentials. A computer simulation using a rabbit ventricular myocyte model indicated that same extent of changes in the I(Kr) channel may result in an approximately 15% prolongation in the action potential duration. Our study suggests that 1047L leads to a functional impairment of the hERG channel, which may contribute to the higher incidence of TdP in 1047L carriers when challenged with a channel blocker.

Animals↗
PubMed2004

Antimony concentrations in nodal tissue can confirm sentinel node identity.

The sentinel node biopsy procedure is a highly accurate method of staging patients with cutaneous melanoma and the tumor-harboring status of sentinel nodes is the most important prognostic factor. For the procedure to provide accurate prognostic information, however, it is essential that 'true' sentinel nodes are removed and examined thoroughly. A technique to confirm sentinel node identity may reduce the false-negative rate of the procedure. We have found that antimony (originating from the antimony sulfide colloid used for preoperative lymphoscintigraphy in our institution) can be measured in tissue sections of sentinel nodes using inductively coupled plasma mass spectrometry. The aims of this study were to determine whether antimony concentrations can be used to confirm that removed sentinel nodes are 'true' sentinel nodes and to differentiate sentinel nodes from nonsentinel nodes. In all, 24 patients who had both a tumor-positive sentinel node and a tumor-negative nonsentinel node removed from one regional node field during the same operation, were identified. Tissue sections (50 microm) thick were cut from archival paraffin blocks of each of the sentinel nodes and nonsentinel nodes. Antimony concentrations in the tissue sections were measured using inductively coupled plasma mass spectrometry. The median and mean concentrations of antimony in parts per billion were 0.526 and 1.198, respectively (range 0.020-7.596) in the sentinel nodes, and 0.043 and 0.123 (range 0-0.800) in the nonsentinel nodes (P = 0.004). In four of the 24 pairs, both the presumed sentinel nodes and the nonsentinel nodes had very low antimony levels (less than 0.18 parts per billion), suggesting that nodes designated as sentinel nodes may not have been 'true' sentinel nodes. It is concluded that determination of antimony concentrations within sentinel nodes using the highly sensitive method of inductively coupled plasma mass spectrometry can confirm the identity of sentinel nodes and validate the sentinel node technique.

Antimony↗
PubMed2004

Teaching points on lymphatic mapping for melanoma from the Sydney Melanoma Unit.

If incorrect or misleading information is obtained from a sentinel node (SN) biopsy procedure for melanoma, inappropriate management decisions may be made, and the patient's outcome compromised as a result. As well, misleading prognostic indications may be provided to the patient. It is therefore important to correctly identify all SNs in every patient and to remove them all for examination. To reduce the likelihood of error, a high-quality preoperative lymphoscintigraphy (LSG) is the first prerequisite. The surgical procedure must then be undertaken with great care to remove all of the SNs that have been identified by the LSG. This will involve both blue dye mapping and use of a gamma probe. A thorough knowledge and understanding of common and uncommon sites at which SNs can be located, as outlined here, will not only make the surgery simpler and quicker, but will reduce the possibility of error by diminishing the risk of overlooking possible locations at which SNs may be found.

Coloring Agents↗
PubMed2004

Nuclear medicine aspects of melanoma and breast lymphatic mapping.

A successful sentinel lymph node biopsy (SLNB) procedure in melanoma or breast cancer patients requires an accurate map of the pattern of lymphatic drainage from the primary site. Lymphoscintigraphy (LS) can provide such a map in each patient. This requires an understanding of lymphatic physiology, an appropriate small particle radiocolloid, high resolution collimators, and imaging protocols that detect all sentinel nodes (SNs) in every patient regardless of their location. The SN is not always found in the nearest node field and is best defined as "any lymph node receiving direct lymphatic drainage from a primary tumor site." Patterns of lymphatic drainage from the skin are not clinically predictable and unexpected drainage has been found from the skin of the back to SNs in the triangular intermuscular space or through the posterior body wall to SNs in the paraaortic, paravertebral, and retroperitoneal areas. Drainage from the head and neck is to unexpected nodes in 30% of patients. Upper limb drainage can be to SNs above the axilla. Interval nodes are not uncommon as SNs, especially on the trunk. Lymphatic drainage may involve SNs in multiple node fields and drainage across the midline of the body is quite common. In the breast, although 94% of patients have a SN in the ipsilateral axilla, 46% also have SNs outside the axilla, especially in the internal mammary chain (40%). Failure to biopsy all SNs in each patient thus has the potential to understage a significant number of patients with breast cancer. Micrometastatic disease can be present in any SN regardless of its location, and for the SLNB technique to be accurate a biopsy most be performed on all true SNs in every patient. LS is an important first step to ensure this goal is achieved.

Breast Neoplasms↗
PubMed2004

Histological expression of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) in human primary melanoma.

AIMS: Tumour necrosis factor-related apoptosis ligand (TRAIL) appears to selectively induce apoptosis in a wide range of cultured malignant cells, including melanoma. This study was designed to attempt to clarify the role of TRAIL in the biology of human melanoma. METHODS: Tissue sections cut from formalin-fixed, paraffin-embedded tissue blocks of 45 primary cutaneous melanomas were tested for expression of TRAIL using immunohistochemistry. The intensity, pattern of staining and percentage of positively stained tumour cells were evaluated in each melanoma. Breslow thickness, ulcerative state, dermal mitotic rate and the presence of tumour infiltrating lymphocytes were measured/determined in each case. Median follow up for the cohort of patients was 10 months (range 1-18). Survival analysis was conducted using the Kaplan-Meier method. The level of expression of TRAIL was compared with the various histological determinants using the two-tailed Fisher's exact test and the chi2-test. RESULTS: Overall and disease-free survival were 72 and 48%, respectively, and did not correlate with TRAIL expression. Among the pathological prognostic determinants, only mitotic rate showed a statistically significant correlation with TRAIL expression using the chi2-test (P=0.04). CONCLUSION: We conclude that TRAIL expression in melanoma defines a more aggressive/proliferative phenotype, either through selection of apoptotic resistant cells or by secondary induction of other factors enhancing proliferation of more malignant cells. Analysis of a larger group of patients with longer follow-up is required to determine whether TRAIL expression correlates with survival of patients.

Adult↗
PubMed2004

Combined naevus: a benign lesion frequently misdiagnosed both clinically and pathologically as melanoma.

BACKGROUND: Combined naevi are characterised pathologically by the presence of two or more different types of melanocytic naevi in a single lesion. They are prone to clinical and pathological misdiagnosis as melanoma. Misdiagnosis may result in inappropriate treatment, patient anxiety and medicolegal consequences. AIMS: With the aim of reducing the incidence of misdiagnosis, this study documents the clinical and pathological features of a large series of combined naevi and describes how to distinguish them from melanoma. PATIENTS AND METHODS: The slides of skin lesions from 220 patients that were coded as combined naevus between 1990 and 2001 were retrieved from the archival files of the Department of Anatomical Pathology, Royal Prince Alfred Hospital, Sydney, Australia. The clinical notes, letters from referring pathologists (for consultation cases) and slides were reviewed and for each lesion clinical and pathological features were assessed. Thirty-eight cases were excluded either because they included only one naevus component or because there were atypical pathological features in the slides available for review. The remaining 182 cases formed the study population. RESULTS: The patients included 92 females and 87 males (1.1:1). In three cases the gender was not known. Mean and median patient ages were 29.6 and 28 years, respectively. The anatomical site of involvement was the trunk in 64 cases (35.2%), head and neck region in 43 cases (23.6%), upper extremity in 40 cases (22.0%), lower extremity in 18 cases (9.9%) and perineum and buttock region in eight cases (4.4%). In nine cases the site of involvement was not known. A pre-operative clinical diagnosis was recorded in 126 cases; of these, melanoma was suspected clinically in 33 cases (26.2%) while combined naevus was diagnosed clinically in only three cases (2.4%). Histologically, 180 cases included two different naevus components, and in two cases three different naevus components were present. The most common combination was a common acquired naevus of compound type associated with a blue naevus of deep penetrating naevus type; this occurred in 57 cases (31.3%). The referring pathologist recorded a preferred diagnosis in 88 of 122 consultation cases; of these, melanoma was suspected in 23 cases (26.1%) and in 23 cases combined naevus was favoured (26.1%). CONCLUSIONS: Combined naevus is an uncommon type of melanocytic naevus that is frequently misdiagnosed both clinically and pathologically. Knowledge and recognition of the pathological features of combined naevi and the important features that distinguish them from melanomas should reduce the frequency of misdiagnosis.

Adolescent↗
PubMed2004

Cooperation between surgical oncologists and pathologists: a key element of multidisciplinary care for patients with cancer.

For patients with cancer it is essential to reach a definite diagnosis, obtain accurate staging and provide appropriate initial treatment if a successful outcome is to be achieved. These fundamental first steps in multidisciplinary care require close cooperation between surgical oncologists and pathologists. The most important aspect of this cooperation is clear and free exchange of information between them. The surgeon should provide the pathologist not only with an adequate tissue sample for examination, but also with clinical details that will assist in establishing a diagnosis. The location and orientation of specimens, and areas of particular concern, should always be indicated. Operative digital photographs may assist this process. The pathologist, in return, should provide the surgeon with a report containing sufficient information to allow an evidence-based management plan to be made for the patient, and to permit an accurate indication of prognosis to be determined. Use of a disease-specific synoptic report format will ensure that potentially important information is not overlooked. When there is diagnostic uncertainty, the pathologist should make this clear, but provide a preferred diagnosis. Further opinions may be helpful. If doubt exists, medico-legal considerations should not encourage a pathologist to issue a report with a diagnosis of malignancy. The pathologist should refrain from making management recommendations, because there may be valid reasons for the surgeon not providing this management. By cooperating fully and communicating freely with each other, surgical oncologists and pathologists can ensure high standards of initial and subsequent care for cancer patients.

Aged↗
PubMed2004

Spitz naevus: diagnostic problems and their management implications.

Spitz naevus is an uncommon, benign melanocytic neoplasm that shares many clinical and histological features with melanoma. While Spitz naevi typically occur in children and melanomas typically occur in adults, either tumour can occur in a patient of any age. In cases displaying all or most of the classical histological features, particularly when occurring in a young patient, it is possible to make a confident diagnosis of Spitz naevus. However, for those lesions with atypical features it may be difficult to predict the biological behaviour with certainty from the histopathological appearance. Hence, such tumours have been referred to by a variety of names including atypical Spitz naevus, atypical Spitz tumour and spitzoid tumours of uncertain malignant potential. However, even acknowledged experts in dermatopathology have a low concordance in distinguishing Spitz naevus with atypical features from melanoma. In this article, we highlight the histopathological features of Spitz naevi and those that may be useful in distinguishing Spitz naevi from melanomas. A suggested practical guide to clinical management of such lesions is provided.

Adult↗
PubMed2004

Cytoplasmic expression of nm23 predicts the potential for cerebral metastasis in patients with primary cutaneous melanoma.

The nm23 gene is a putative tumour and metastasis suppressor gene. A number of studies have found that reduction of its expression is associated with increased metastatic potential in several human malignancies. Similarly, clinical studies have shown correlation between reduced nm23 protein expression and a poor prognosis. The aim of this study was to determine if a relationship exists between nm23 expression in primary cutaneous melanomas with or without cerebral metastases. Paraffin-embedded tissues were retrieved from 21 patients with primary cutaneous melanomas (n=21) and who subsequently developed cerebral metastases (n=24). Primary cutaneous melanomas with no regional or organ metastases within a 10 year period were used as control cases (n=34). Nm23 staining was localized in the cytoplasm of the tumour cells. Most of the control cases showed strong expression, whereas the majority of the primary melanomas with cerebral metastases showed no or weak expression of nm23. The cerebral metastases mostly showed strong expression. In summary, the results of this study may have significant prognostic implications for patients presenting with cutaneous melanoma. Patients with cutaneous melanomas with a low expression of nm23 appear to be more at risk of developing brain metastases.

Biomarkers, Tumor↗
PubMed2004

Immunohistochemical stains fail to increase the detection rate of micrometastatic melanoma in completion regional lymph node dissection specimens.

In melanoma patients, examination of tissue sections stained for immunohistochemical markers as an adjunct to examination of haematoxylin and eosin (H&E)-stained sections has been shown to increase the detection rate of micrometastatic disease in sentinel lymph nodes (SLNs). However, immunohistochemical stains are not routinely performed on completion regional lymph node dissection (CLND) specimens in most centres and it is not known whether their use would increase the detection of micrometastatic disease in these specimens. This study was performed to determine whether the application of immunohistochemical stains for S100 and HMB45 (in addition to H&E stains) increases the detection of micrometastatic disease in CLND specimens of melanoma patients and whether their use would be cost-effective in routine pathological practice. Forty-nine CLND specimens from patients with a prior positive SLN biopsy were examined by performing H&E stains and immunohistochemical stains for S100 protein and HMB-45 on each node, and the detection rate of melanoma metastases using H&E-stained sections was compared with that using immunohistochemically stained sections. The number of nodes in the CLND specimens ranged from 4 to 37 (median 14, mean 14.7). Nodal deposits of melanoma cells were detected in 12 of 49 cases (24%). Among these 12 positive cases, the mean number of positive nodes per CLND specimen was 2.2 (range, 1-14). The total number of positive nodes in the 12 CLND specimens was 27, accounting for 3.8% of the 720 nodes removed in the study group of 49 cases. Melanoma cells in all 27 positive nodes were identified both on the H&E-stained slides and the slides stained immunohistochemically for S100. The melanoma cells were positive for HMB45 in 24 of the 27 lymph nodes that contained metastatic melanoma (the metastatic melanoma cells were negative for HMB45 in three positive nodes from one specimen). No further positive lymph nodes were detected with the immunostains that had not been identified on the H&E-stained sections. This study suggests that the use of immunostains does not increase the detection rate of metastatic melanoma in CLND specimens, and that their routine use would not be cost-effective. We therefore recommend only H&E staining on sections of all lymph nodes in CLND specimens from melanoma patients.

Humans↗
PubMed2004

Correlation between preoperative lymphoscintigraphy and metastatic nodal disease sites in 362 patients with cutaneous melanomas of the head and neck.

OBJECTIVE: Lymphoscintigraphy for head and neck melanomas demonstrates a wide variation in lymphatic drainage pathways, and sentinel nodes (SNs) are reported in sites that are not clinically predicted (discordant). To assess the clinical relevance of these discordant node fields, the lymphoscintigrams of patients with head and neck melanomas were analyzed and correlated with the sites of metastatic nodal disease. METHODS: In 362 patients with head and neck melanomas who underwent lymphoscintigraphy, the locations of the SNs were compared with the locations of the primary tumors. The SNs were removed and examined in 136 patients and an elective or therapeutic regional lymph node dissection was performed in 40 patients. RESULTS: Lymphoscintigraphy identified a total of 918 SNs (mean 2.5 per patient). One or more SNs was located in a discordant site in 114 patients (31.5%). Lymph node metastases developed in 16 patients with nonoperated SNs, all underneath the tattoo spots on the skin used to mark the position of the SNs. In 14 patients SN biopsy revealed metastatic melanoma. After a negative SN biopsy procedure 11 patients developed regional lymph node metastases during follow-up. Elective and therapeutic neck dissections demonstrated 10 patients with nodal metastases, all located in predicted node fields. Of the 51 patients with involved lymph nodes, 7 had positive nodes in discordant sites (13.7%). CONCLUSIONS: Metastases from head and neck melanomas can occur in any SN demonstrated by lymphoscintigraphy. SNs in discordant as well as predicted node fields should be removed and examined to optimize the accuracy of staging.

Head and Neck Neoplasms↗
PubMed2004

Lymphedema after complete axillary node dissection for melanoma: assessment using a new, objective definition.

OBJECTIVES: The objectives of this study were to define appropriate criteria for assessing the presence of lymphedema, and to report the prevalence and risk factors for development of upper limb lymphedema after level I-III axillary dissection for melanoma. SUMMARY BACKGROUND DATA: The lack of a consistent and reliable objective definition for lymphedema remains a significant barrier to appreciating its prevalence after axillary dissection for melanoma (or breast carcinoma). METHODS: Lymphedema was assessed in 107 patients (82 male, 25 female) who had previously undergone complete level I-III axillary dissection. Of the 107 patients, 17 had also received postoperative axillary radiotherapy. Arm volume was measured using a water displacement technique. Change in volume of the arm on the side of the dissection was referenced to the volume of the other (control) arm. Volume measurements were corrected for the effect of handedness using corrections derived from a control group. Classification and regression tree (CART) analysis was used to determine a threshold fractional arm volume increase above which volume changes were considered to indicate lymphedema. RESULTS: Based on the CART analysis results, lymphedema was defined as an increase in arm volume greater than 16% of the volume of the control arm. Using this definition, lymphedema prevalence for patients in the present study was 10% after complete level I-III axillary dissection for melanoma and 53% after additional axillary radiotherapy. Radiotherapy and wound complications were independent risk factors for the development of lymphedema. CONCLUSIONS: A suggested objective definition for arm lymphedema after axillary dissection is an arm volume increase of greater than 16% of the volume of the control arm.

Adult↗
PubMed2004

An analysis of the association between serum citrulline and acute rejection among 26 recipients of intestinal transplant.

Small preliminary studies suggest that serum citrulline levels may act as a marker for acute cellular rejection in small intestinal transplant recipients. The results comparing serum citrulline concentrations with biopsy-based grades of rejection are summarized here for an expanded group of 26 isolated intestinal and multivisceral transplant recipients. Other factors considered included patient and donor age and sex, ischemia time, serum creatinine, and type of transplant. Straight-line fits reasonably described how each patient's citrulline levels changed over time. Among 21 patients who demonstrated increasing citrulline levels over time, the estimated median time-to-achieve normal citrulline (>or=30 micromol/L) was 79 days post-transplant. Using stepwise linear regression, two characteristics were associated with a significantly higher maximum grade of rejection after 14 d post-transplant: longer time-to-achieve normal citrulline (using ranks, p < 0.00001) and the patient not receiving a multivisceral transplant (p = 0.0005). Only the latter characteristic was significantly associated with maximum grade of rejection during the first 14 d post-transplant (p = 0.01). Clearly, time-to-normalization of citrulline was delayed by the incidence of rejection, and in some cases with moderate-to-severe rejection, normalization of citrulline levels never occurred. We plan to further examine the use of citrulline as a marker for rejection in larger prospective studies.

Adult↗
PubMed2004

Application of pooled genotyping to scan candidate regions for association with HDL cholesterol levels.

Association studies are used to identify genetic determinants of complex human traits of medical interest. With the large number of validated single nucleotide polymorphisms (SNPs) currently available, two limiting factors in association studies are genotyping capability and costs. Pooled DNA genotyping has been proposed as an efficient means of screening SNPs for allele frequency differences in case-control studies and for prioritising them for subsequent individual genotyping analysis. Here, we apply quantitative pooled genotyping followed by individual genotyping and replication to identify associations with human serum high-density lipoprotein (HDL) cholesterol levels. The DNA from individuals with low and high HDL cholesterol levels was pooled separately, each pool was amplified by polymerase chain reaction in triplicate and each amplified product was separately hybridised to a high-density oligonucleotide array. Allele frequency differences between case and control groups with low and high HDL cholesterol levels were estimated for 7,283 SNPs distributed across 71 candidate gene regions spanning a total of 17.1 megabases. A novel method was developed to take advantage of independently derived haplotype map information to improve the pooled estimates of allele frequency differences. A subset of SNPs with the largest estimated allele frequency differences between low and high HDL cholesterol groups was chosen for individual genotyping in the study population, as well as in a separate replication population. Four SNPs in a single haplotype block within the cholesteryl ester transfer protein (CETP) gene interval were significantly associated with HDL cholesterol levels in both populations. Our study is among the first to demonstrate the application of pooled genotyping followed by confirmation with individual genotyping to identify genetic determinants of a complex trait.

Case-Control Studies↗