Unprovoked venous thromboembolism in women over 40: is screening for occult malignancy with mammography and abdominopelvic CT of benefit?

AIM: To determine imaging and pathological outcomes in cases of unprovoked venous thromboembolism (VTE) referred for mammogram. A secondary objective was to elucidate outcomes of abdominopelvic computed tomography (CT) imaging performed in this cohort. MATERIALS AND METHODS: A retrospective review of mammograms performed in cases of unprovoked VTE was undertaken from January 2016 to September 2019. Patient notes and imaging were reviewed to establish patient demographics, additional imaging required, biopsies performed, pathology findings, and eventual outcomes. Cases were reviewed to determine if concurrent CT abdomen/pelvis was performed to screen for malignancy. Outcomes of CT were recorded. RESULTS: One hundred and thirty-nine women attended for screening mammogram following unprovoked VTE during the study period. Mean patient age was 68 years (range 42-89 years). Fourteen women (10%) were recalled for further breast imaging, with two cases of confirmed malignancy (1.4%). Of the 139 women, 118 also underwent CT imaging, with 18 patients (15%) recalled for further investigations. Two (1.7%) cases of malignancy (lung and ovarian) were identified. CONCLUSION: A low cancer detection rate was demonstrated in women undergoing mammography or CT following unprovoked VTE. In addition, the high number of false-positive findings and need for additional investigations questions the value of screening in this setting. Based on these findings, Cambridge Breast Unit has ceased mammographic and abdominopelvic CT imaging in women with unprovoked VTE, anticipating the newly updated National Institute for Health and Care Excellence (NICE) guidelines.

Professionalism and non-technical skills in Radiology in the UK: a review of the national curriculum.

OBJECTIVE: To drive quality and safe clinical practice, professional values and non-technical skills need to be explicit in all postgraduate medical curricula and appropriate assessment tools should be available for teachers to apply. We interrogate a national Radiology curriculum for content on professionalism and assessment tools, comparing it with the Royal College of Physicians' 2005 document. RESULTS: We found that whilst the knowledge for practising with professional values is embedded in the curriculum, the skills that have to be acquired have not been comprehensively developed. This is reflected in the restricted assessment tools that are mapped to each generic area. The terminology used in the Radiology curriculum was varied and the most frequently used descriptor for professionalism or behaviours pertaining to non-technical aspects was Good Medical Practice; a term used by our regulator, the General Medical Council, and to which our curriculum is mapped. If terminology is to be standardized in Britain collaboration with our regulator is key. We need standardized terminology to permit effective research and sharing of best practice. The Radiology curriculum encompasses all the values set out in the seminal document produced by the Royal College of Physicians in 2005, Doctors in society: medical professionalism in a changing world.

Relationship between human tumour angiogenic profile and combretastatin-induced vascular shutdown: an exploratory study.

Combretastatin-A4-phosphate (CA4P) acts most effectively against immature tumour vasculature. We investigated whether histological angiogenic profile can explain the differential sensitivity of human tumours to CA4P, by correlating the kinetic changes demonstrated by dynamic MRI (DCE-MRI) in response to CA4P, with tumour immunohistochemical angiogenic markers. Tissue was received from 24 patients (mean age 59, range 32-73, 18 women, 6 men). An angiogenic profile was performed using standard immunohistochemical techniques. Dynamic MRI data were obtained for the same patients before and 4 h after CA4P. Three patients showed a statistically significant fall in K(trans) following CA4P, and one a statistically significant fall in IAUGC(60). No statistically significant correlations were seen between the continuous or categorical variables and the DCE-MRI kinetic parameters other than between ang-2 and K(trans) (P=0.044). In conclusion, we found no strong relationships between changes in DCE-MRI kinetic variables following CA4P and the immunohistochemical angiogenic profile.

The relationship of the neo-angiogenic marker, endoglin, with response to neoadjuvant chemotherapy in breast cancer.

Endoglin (CD105) is upregulated in endothelial cells of tissues undergoing neovascularisation. A greater number of CD105-positive vessels predicts poor survival in breast cancer. We examine whether CD105 expression predicts response to neoadjuvant chemotherapy. Fifty-seven women (median age 50 years, range 29-70) received neoadjuvant chemotherapy for operable breast cancer. Immunohistochemical staining using monoclonal antibodies to CD105 and CD34 was performed on pretreatment biopsies and post-treatment surgical specimens. Individual microvessels were counted in 10 random fields at x 200 magnification. Median counts were correlated with clinical and pathological response using the Mann-Whitney U-test. Forty-five out of fifty-seven patients (79%) responded clinically, 22 (39%) responded pathologically. On pretreatment biopsies, clinical responders had significantly lower median CD105-positive vessel counts than nonresponders (median counts 5 and 9.3/high-power field (hpf), median difference=4.0/hpf, 95% CI 0.5-8.0/hpf, P=0.02). For pathological responders and nonresponders, median counts were 4.8 and 5.5/hpf (median difference -0.5/hpf, 95% CI=-2.5-2.0/hpf, P=0.77). CD34 expression (total microvessel density) did not correlate with response. Pretreatment CD105 expression predicts for clinical response to chemotherapy, with a lower initial count being favourable. Patients with high baseline new vessel counts or increased counts after conventional therapy may benefit from additional antiangiogenic therapy.

The impact of surgically induced ischaemia on protein levels in patients undergoing rectal cancer surgery.

The goal of targeted therapy has driven a search for markers of prognosis and response to adjuvant therapy. The surgical resection of a solid tumour induces tissue ischaemia and acidosis, both potent mediators of gene expression. This study investigated the impact of colorectal cancer (CRC) surgery on prognostic and predictive marker levels. Tumour expression of thymidylate synthase, thymidine phosphorylase, cyclin A, vascular endothelial growth factor (VEGF), carbonic anhydrase-9, hypoxia inducible factor-1alpha, and glucose transporter-1 (GLUT-1) proteins was determined before and after rectal cancer surgery. Spectral imaging of tissue sections stained by immunohistochemistry provided quantitative data. Surgery altered thymidylate synthase protein expression (P=0.02), and this correlated with the change in the proliferation marker cyclin A. The expression of hypoxia inducible factor-1alpha, VEGF, and GLUT-1 proteins was also different following surgery. Colorectal cancer surgery significantly impacts on intratumoral gene expression, suggesting archival specimens may not accurately reflect in situ marker levels. Although rectal cancer was the studied model, the results may be applicable to any solid tumour undergoing extirpation in which molecular markers have been proposed to guide patient therapy.

Dynamic contrast-enhanced magnetic resonance imaging is a poor measure of rectal cancer angiogenesis.

BACKGROUND: The aim of this study was to investigate the use of magnetic resonance imaging (MRI) for non-invasive measurement of rectal cancer angiogenesis and hypoxia. METHODS: Fifteen patients with rectal adenocarcinoma underwent preoperative dynamic contrast-enhanced (DCE) and blood oxygenation level-dependent (BOLD) MRI. Microvessel density (CD31 level), and expression of vascular endothelial growth factor (VEGF) and carbonic anhydrase (CA) 9 were measured immunohistochemically in histological tumour sections from 12 patients. Serum VEGF levels were also measured in 14 patients. Correlations between quantitative imaging indices and immunohistochemical variables were examined. RESULTS: There was good correlation between circulating VEGF and CD31 expression (r(S) = 0.88, P < 0.001). CD31 expression did not correlate with any dynamic MRI parameter, except transfer constant, with which it correlated inversely (r(S) = -0.65, P = 0.022). Tissue and circulating VEGF levels did not correlate, and neither correlated with any tumour DCE MRI parameter. No relationship was seen between BOLD MRI and CA-9 expression. CONCLUSION: The negative correlation between transfer constant (reflecting tumour blood flow and microvessel permeability) with CD31 expression is paradoxical. DCE MRI methods for assessing tissue vascularity correlate poorly with histological markers of angiogenesis and hypoxia, suggesting that DCE MRI does not simply reflect static histological vascular properties in patients with rectal cancer.

The effect of surgically induced ischaemia on gene expression in a colorectal cancer xenograft model.

Delays in tissue fixation following tumour vascular clamping and extirpation may adversely affect subsequent protein and mRNA analysis. This study investigated the effect of surgically induced ischaemia in a xenograft model of a colorectal cancer on the expression of a range of prognostic, predictive, and hypoxic markers, with a particular emphasis on thymidylate synthase. Vascular occlusion of human tumour xenografts by D-shaped metal clamps permitted defined periods of tumour ischaemia. Alterations in protein expression were measured by immunohistochemistry and spectral imaging, and changes in mRNA were measured by reverse transcriptase-polymerase chain reaction. Thymidylate synthase expression decreased following vascular occlusion, and this correlated with cyclin A expression. A similar reduction in dihydropyrimidine dehydrogenase was also seen. There were significant changes in the expression of several hypoxic markers, with carbonic anhydrase-9 showing the greatest response. Gene transcriptional levels were also noted to change following tumour clamping. In this xenograft model, surgically induced tumour ischaemia considerably altered the gene expression profiles of several prognostic and hypoxic markers, suggesting that the degree of tumour ischaemia should be minimised prior to tissue fixation.

Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer.

Primary systemic therapy (PST) for operable breast cancer enables the identification of in vivo biological markers that predict response to treatment. A total of 118 patients with T2-4 N0-1 M0 primary breast cancer received six cycles of anthracycline-based PST. Clinical and radiological response was assessed before and after treatment using UICC criteria. A grading system to score pathological response was devised. Diagnostic biopsies and postchemotherapy surgical specimens were stained for oestrogen (ER) and progesterone (PgR) receptor, HER-2 and cell proliferation (Ki-67). Clinical, radiological and pathological response rates were 78, 72 and 38%, respectively. There was a strong correlation between ER and PgR staining (P < 0.0001). Higher Ki-67 proliferation indices were associated with PgR- tumours (median 28.3%, PgR+ 22.9%; P = 0.042). There was no relationship between HER-2 and other biological markers. No single pretreatment or postchemotherapy biological parameter predicted response by any modality of assessment. In all, 10 tumours changed hormone receptor classification after chemotherapy (three ER, seven PgR); HER-2 staining changed in nine cases. Median Ki-67 index was 24.9% before and 18.1% after treatment (P = 0.02); the median reduction in Ki-67 index after treatment was 21.2%. Tumours displaying >75% reduction in Ki-67 after chemotherapy were more likely to achieve a pathological response (77.8 vs 26.7%, P = 0.004).

GLUT1 and CAIX as intrinsic markers of hypoxia in bladder cancer: relationship with vascularity and proliferation as predictors of outcome of ARCON.

Glucose transporter-1 protein (GLUT1) and carbonic anhydrase IX (CAIX) are regulated by hypoxia inducible factor-1 (HIF-1) and have been studied as putative intrinsic cellular markers for hypoxia. This study directly compares CAIX and GLUT1 with pimonidazole binding in a prospective series of bladder cancer patients and also studies the prognostic significance of the markers, in combination with vascularity and proliferation, in a retrospective series of bladder cancer patients treated in a phase II trial of radical radiotherapy with carbogen and nicotinamide (ARCON). A total of 21 patients with a diagnosis of transitional cell carcinoma of the bladder received 0.5 g m(-2) pimonidazole. Serial tumour sections were stained for pimonidazole, GLUT1 and CAIX and compared. Tissue sections obtained from a series of 64 patients previously treated for invasive bladder cancer using ARCON were stained for GLUT1 and CAIX together with Ki-67 and CD31/34. There was a good geographical colocalisation of both intrinsic markers with pimonidazole and a highly significant agreement in individual patients; correlation coefficients were 0.82 (P=0.0001) for GLUT1 and 0.74 (P<0.0001) for CAIX. In both series of patients, the intrinsic hypoxia markers were highly correlated with each other and a correlation with proliferation was also evident in the retrospective study. In univariate and multivariate analyses, GLUT1 and CAIX were independent predictors for overall and cause specific survival. The hypoxia markers did not predict for local control or metastases-free survival although higher Ki-67 indices showed a trend towards local failure. The data suggest that both hypoxia modification and accelerated treatment may be valid treatment options in bladder cancer.

bcl-2 expression in head and neck cancer: an enigmatic prognostic marker.

PURPOSE: The role of bcl-2 overexpression in cancer presents a paradox. In some tumor types, it is associated with favorable outcome, whereas in others the reverse is true. The purpose of this study was to explore the influence of bcl-2 in a large series of head and neck cancer patients treated in the CHART randomized trial. METHODS AND MATERIALS: Histologic material was obtained from 400 patients; bcl-2 expression was assessed by immunohistochemistry as either positive or negative cytoplasmic staining. RESULTS: Positivity of bcl-2 was recorded in 12.8% (9.5-16.5%, 95% confidence limits) of tumors. There were significant differences in positive tumors within different sites with nasopharynx showing the highest incidence (46.2%). A multivariate logistic regression analysis showed that bcl-2 was strongly associated with histologic dedifferentiation, as well as increasing N stage and female gender. In univariate analyses, bcl-2 positive patients had a lower locoregional relapse rate (RR 0.57, p = 0.02) and improved survival (RR 0.49, p = 0.004) compared to bcl-2 negative patients; this became more significant in multivariate analysis. CONCLUSION: These data demonstrate that bcl-2 overexpression is a marker of what is considered to be more advanced and aggressive disease yet it is associated with a more favorable outcome irrespective of the treatment schedule.

Aberrant expression of cyclin A in head and neck cancer.

Cyclin A expression was studied in a series of 65 squamous cell carcinomas of the head and neck (HNSCC) and compared with known markers of proliferation, iododeoxyuridine (IdUrd) and Ki-67, to assess whether aberrant expression was prevalent. Patients had previously been administered IdUrd to study cell kinetics in relation to outcome of radiotherapy. The data showed that all three parameters were highly correlated although the absolute values were different. The median labelling indices (LI) for IdUrd, cyclin A and Ki-67 were 10.7, 17.1 and 30.8% respectively, reflecting the known pattern of differential cell cycle expression. However, there were a significant number of cases in which an unexpected relationship between cyclin A and either IdUrd or Ki-67 was present. Some of these were attributable to overexpression but others indicated underexpression. Although the greater variability and range of cyclin A expression, coupled with its more closely associated role in cell cycle regulation, might suggest that it may be a more informative marker for cell proliferation than Ki-67, the aberrant expression seen in over one third of cases would indicate that caution should be exercised in interpreting cyclin A as a surrogate marker of proliferation in HNSCC.

Cellular proliferation characteristics do not account for the behaviour of horrifying basal cell carcinoma. A comparison of the growth fraction of horrifying and non horrifying tumours.

This study compared the clinical features, histological subtype, growth fraction (by Ki67 immunohistochemistry) and proliferation pattern of 22 clinically defined horrifying basal cell carcinoma compared to 81 non horrifying lesions. Late presentation was associated with half of the horrifying tumours. The other half developed horrifying tumours despite early intervention. The horrifying tumours exhibited a variety of histological growth patterns. A total of 50% were infiltrative, 23% nodular and 18% micronodular. There was no difference in the growth fraction or proliferation pattern between horrifying and non horrifying tumours of similar growth pattern (P = ns), although infiltrative tumours in either group exhibited a significantly higher growth fraction than nodular tumours (P < 0.01). This suggests that there is no intrinsic biological difference between horrifying and non horrifying tumours to account for their behaviour. We conclude that late presentation, failed or inadequate early management especially of infiltrative tumours (and other subtypes) determines the development of horrifying tumours.

Cellular proliferation characteristics of basal cell carcinoma: relationship to clinical subtype and histopathology.

This study investigates the proliferation characteristics of 81 primary basal cell carcinomas (BCC) using detection of the Ki-67 antigen by immunohistochemistry. The tumours were classified into distinct sub-types based on their histological growth pattern and differentiation status. The mean Ki-67 growth fraction was 0.293 and this was found to vary between the different growth patterns, with morpheic, infiltrating and superficial tumours showing the highest levels of proliferation at 0.373, 0.351 and 0.335, respectively; the nodular and micronodular growth patterns were significantly lower at 0.248 and 0.232, respectively. No overall association was seen between proliferation and differentiation status although certain histological growth patterns such as nodular showed a greater propensity to differentiate. Proliferation was related to tumour size, with larger lesions exhibiting higher growth fractions although this may have also been related to tumour subtype as infiltrating and morpheic tumours tended to present with larger tumour diameters. The spatial distribution of proliferating cells by Ki-67 labelling was not related to tumour subtype, differentiation or growth fraction. These studies have shown BCC to possess proliferative characteristics akin to other solid tumours commonly regarded as more rapidly dividing. There was an association between growth fraction and tumour subtype consistent with higher proliferation in the lesions considered to be more aggressive.

Bcl-2 expression correlates with favourable outcome in head and neck cancer treated by accelerated radiotherapy.

The aim of this study was to investigate bcl-2 expression in head and neck cancer patients and to investigate its correlation with biological and clinical characteristics and outcome of accelerated radiotherapy. A series of 93 patients with squamous cell carcinoma of the head and neck who had been uniformly treated with continuous hyperfractionated accelerated radiation treatment (CHART) were investigated. These patients had also been injected with bromodeoxyuridine (BrdUrd) to measure cell kinetic parameters using flow cytometry (FCM) and their p53 protein status had also previously been described. Bcl-2 expression was assessed using immunohistochemistry. Sixteen of the 93 (17.2%) patients stained positively for bcl-2 proto-oncogene. The percentage of positive tumour cells within the specimens was highly variable, ranging from a few percent to complete positivity. Bcl-2 positivity was correlated with improved local control (p > 0.0016) and survival (p > 0.012) in comparison with non-expressing tumours. There was no correlation between bcl-2 expression and histological grade, T stage or site but overexpressors were almost exclusively node negative. The significance of bcl-2 was reduced when node negative tumours were analysed alone. There was no correlation of bcl-2 with p53 expression but there was a trend for overexpression to be associated with diploidy and rapidly proliferating tumours. These data suggest that bcl-2 expression in head and neck cancer is not associated with disease progression.

Direct comparison of bromodeoxyuridine and Ki-67 labelling indices in human tumours.

Direct comparison of bromodeoxyuridine (BrdUrd) and Ki-67 labelling indices was achieved by selecting similar areas from serial sections of human tumours. Fifteen patients were selected who had been administered BrdUrd in vivo and both proliferation markers were assessed by immunohistochemistry. The data show a good correlation between both BrdUrd LI and MIB-1 LI and Tpot (calculated using the flow cytometry derived duration of S phase) and MIB-1 LI. The contribution of BrdUrd LI to growth fraction varied as a function of proliferation characteristics. In tumours with a high LI, the number of DNA synthesizing cells represented half the growth fraction, whilst in tumours with lower LI's ( < 10%) the ratio of DNA precursor labelled cells as a function of growth fraction fell to between 10% and 20%. Tpot showed a linear correlation with MIB-1/BrdUrd ratio with a slope approaching unity. It was apparent that both intra- and interpatient variation in proliferation index was greater for BrdUrd labelling than for MIB-1 expression.

Clinical and cytogenetic findings in seven cases of inverted duplication of 8p with evidence of a telomeric deletion using fluorescence in situ hybridization.

We report on the clinical and cytogenetic findings in 7 cases of inverted duplication of region 8p11.2p23. The phenotype of inv dup (8p) compiled from this series and the literature (N = 29) consists of severe mental retardation (100%), minor facial alterations (97%), agenesis of the corpus callosum (80%), hypotonia (66%), orthopedic abnormalities (58%), scoliosis/kyphosis (40%), and congenital heart defect (26%). A telomeric deletion of region 8p23.3-pter was confirmed in 3 of our cases studied using fluorescent in situ hybridization with a telomeric probe for 8p. Thus, these karyotypes are inv dup del(8) (qter-->p23.1::p23.1-->p11.2:). Our findings suggest that most cases of inv dup(8p) probably have a telomeric deletion.

p53 status of head and neck cancer: relation to biological characteristics and outcome of radiotherapy.

p53 status was investigated in 99 patients with squamous cell carcinoma of the head and neck region uniformly treated with accelerated radiotherapy and in whom tumour cell proliferation and DNA aneuploidy were assessed using bromodeoxyuridine (BrdUrd) incorporation and flow cytometry (FCM). Seventy-six percent of tumours were immunohistochemically positive for p53 protein, but heterogeneity was noticed both in the percentage of cells positive for p53 and in their level of expression. However, tumours which were either essentially all positive or all negative or showed sporadic positivity for p53 protein showed no differences in their level of aneuploidy, proliferation rate, tissue organisation or outcome with radiotherapy. There was a trend for those p53-positive tumours with the strongest expression to have more DNA aneuploidy and deregulation of proliferation organisation than weaker expressors; but there were no differences in proliferation rate or outcome of radiotherapy. These studies suggest that p53 protein stabilisation as assessed by immunohistochemistry does not have any major relationship with the biological characteristics and outcome of squamous cell cancer treated by accelerated radiotherapy.

Evaluating false positives in two hospital discharge data sets of the Birth Defects Monitoring Program.

The principal goal in this study was to quantify false positives in the hospital discharge data of the Birth Defects Monitoring Program conducted by the Centers of Disease Control and Prevention. The two hospital data processing agencies which contribute data to the Birth Defects Monitoring Program, the Commission on Professional and Hospital Activities and the McDonnell Douglas Health Information Systems, had respective levels of false positives of 13.2 percent and 8.5 percent, levels which were statistically different from each other. These false positive levels should be considered minimal because these data bases do not include information on sick babies who may be transferred into or out of member hospitals, and who may have their initial diagnoses significantly modified. Potential correlates of false positives were evaluated, including hospital size, diagnostic certainty, race, sex, and insurance source. Two-thirds of all false positives were due to the miscoding of correctly diagnosed anomalies, and another quarter were clearly contradicted in notes easily available before the patients were discharged. The authors hope that this study of false positives will enhance the interpretation of the Birth Defects Monitoring Program data and lead to improved understanding of data collection and processing.

The relationship between registration and dental health benefit in 8- and 9-year-old children in Cheshire.

The dental treatment needs of 8- and 9-year-old children registered with a GDP for at least 6 months were compared with the dental treatment needs of children from a similar social background who were neither registered nor regularly attending the Community Dental Service. The children were examined by one of the authors without prior knowledge of registration status for evidence of treatment need. Unequivocal treatment need was defined as untreated dental caries in permanent teeth, sepsis associated with deciduous teeth, instanding maxillary incisors, and untreated permanent teeth fractured into dentine; untreated caries in the deciduous teeth was also recorded. Registration status of the children was subsequently obtained from the Dental Practice Board. Sixty-three per cent of the children had been registered with a GDP for at least 6 months at the time of the survey, 6% had been registered for less than 6 months and 31% had never been registered under the new dental contract. Of the children who had been registered for more than 6 months, 18.5% had unequivocal treatment need as against 17.5% in the unregistered group; 40.4% of the registered children had decay in their deciduous teeth, as against 36.5% of the unregistered children. Comparison of the dental treatment needs of registered and unregistered children showed no significant difference between the two groups.