Sarah Vinnicombe

Risk and Clinical Implications of Transformation of Follicular Lymphoma to Diffuse Large B-Cell Lymphoma

PURPOSEnTo study the clinical significance of transformation to diffuse large B-cell lymphoma (DLBCL) in patients with follicular lymphoma (FL).nnnPATIENTS AND METHODSnFrom 1972 to 1999, 325 patients were diagnosed with FL at St Bartholomews Hospital (London, United Kingdom). With a median follow-up of 15 years, progression occurred in 186 patients and biopsy-proven transformation in 88 of the 325. The overall repeat biopsy rate was 70%.nnnRESULTSnThe risk of histologic transformation (HT) by 10 years was 28%, HT not yet having been observed after 16.2 years. The risk was higher in patients with advanced stage (P = .02), high-risk Follicular Lymphoma International Prognostic Index (FLIPI; P = .01), and International Prognostic Index (IPI; P = .04) scores at diagnosis. Expectant management (as opposed to treatment being initiated at diagnosis) also predicted for a higher risk of HT (P = .008). Older age (P = .005), low hemoglobin level (P = .03), high lactate dehydrogenase (P < .0001), and high-risk FLIPI (P = .01) or IPI (P = .003) score at the time of first recurrence were associated with the diagnosis of HT in a biopsy performed at that time. The median survival from transformation was 1.2 years. Patients with HT had a shorter overall survival (P < .0001) and a shorter survival from progression (P < .0001) than did those in whom it was not diagnosed.nnnCONCLUSIONnAdvanced stage and high-risk FLIPI and IPI scores at diagnosis correlate with an increased risk of HT. This event strongly influences the outcome of patients with FL by shortening their survival. There may be a subgroup of patients in whom HT does not occur.

Full-Field Digital versus Screen-Film Mammography: Comparison within the UK Breast Screening Program and Systematic Review of Published Data

PURPOSEnTo (a) compare the performance of full-field digital mammography (FFDM), using hard-copy image reading, with that of screen-film mammography (SFM) within a UK screening program (screening once every 3 years) for women aged 50 years or older and (b) conduct a meta-analysis of published findings along with the UK data.nnnMATERIALS AND METHODSnThe study complied with the UK National Health Service Central Office for Research Ethics Committee guidelines; informed patient consent was not required, since analysis was carried out retrospectively after data anonymization. Between January 2006 and June 2007, a London population-based screening center performed 8478 FFDM and 31 720 SFM screening examinations, with modality determined by the type of machine available at the screening site. Logistic regression was used to assess whether breast cancer detection rates and recall rates differed between screening modalities. For the meta-analysis, random-effects models were used to combine study-specific estimates, if appropriate.nnnRESULTSnA total of 263 breast cancers were detected. After adjustment for age, ethnicity, area of residence, and type of referral, there was no evidence of differences between FFDM and SFM in terms of detection rates (0.68 [95% confidence interval {CI}: 0.47, 0.89] vs 0.72 [95% CI: 0.58, 0.85], respectively, per 100 screening mammograms; P = .74), recall rates (3.2% [95% CI: 2.8, 3.6] vs 3.4% [95% CI: 3.1, 3.6]; P = .44), positive predictive value (PPV) of an abnormal mammogram, or characteristics of detected tumors. Meta-analysis of data from eight studies showed a slightly higher detection rate for FFDM, particularly at 60 years of age or younger (pooled FFDM-SFM difference: 0.11 [95% CI: 0.04, 0.18] per 100 screening mammograms), but no clear modality differences in recall rates or PPVs.nnnCONCLUSIONnWithin a routine screening program, FFDM with hard-copy image reading performed as well as SFM in terms of process indicators; the meta-analysis was consistent with FFDM yielding detection rates at least as high as those for SFM.

Tositumomab and Iodine I 131 Tositumomab for Recurrent Indolent and Transformed B-Cell Non-Hodgkin’s Lymphoma

PURPOSEnAn open-label phase II study was conducted at two centers to establish the efficacy and safety of tositumomab and iodine I 131 tositumomab at first or second recurrence of indolent or transformed indolent B-cell lymphoma.nnnPATIENTS AND METHODSnA single dosimetric dose was followed at 7 to 14 days by the patient-specific administered radioactivity required to deliver a total body dose of 0.75 Gy (reduced to 0.65 Gy for patients with platelets counts of 100 to 149 x 10(9)/L). Forty of 41 patients received both infusions.nnnRESULTSnThirty-one of 41 patients (76%) responded, with 20 patients (49%) achieving either a complete (CR) or unconfirmed complete remission [CR(u)] and 11 patients (27%) achieving a partial remission. Response rates were similar in both indolent (76%) and transformed disease (71%). The overall median duration of remission was 1.3 years. The median duration of remission has not yet been reached for those patients who achieved a CR or CR(u). Eleven patients continue in CR or CR(u) between 2.6+ and 5.2+ years after therapy. Therapy was well tolerated; hematologic toxicity was the principal adverse event. Grade 3 or 4 anemia, neutropenia, and thrombocytopenia were observed in 5%, 45%, and 32% of patients, respectively. Secondary myelodysplasia has occurred in one patient. Four patients developed human antimouse antibodies after therapy. Five of 38 assessable patients have developed an elevated thyroid-stimulating hormone; treatment with thyroxine has been initiated in one patient.nnnCONCLUSIONnHigh overall and CR rates were observed after a single dose of tositumomab and iodine I 131 tositumomab in this patient group. Toxicity was modest and easily managed.

Using MRI to plan breast-conserving surgery following neoadjuvant chemotherapy for early breast cancer

Contrast-enhanced magnetic resonance imaging (MRI) was used to monitor the response of patients undergoing neoadjuvant chemotherapy for breast cancer with the aim of undergoing breast-conserving surgery (BCS). Patients were prospectively recruited to undergo MRI as well as conventional methods of clinical examination, mammography (MM) and ultrasonography (USS) and response was assessed by each of these methods. Thirty-two patients with primary breast cancer were recruited. Magnetic resonance imaging correlation with histopathological size (r=0.71) was superior to USS (r=0.65) and to MM where tumour size was not measurable following chemotherapy in 71% of patients. Magnetic resonance imaging had 87.5% sensitivity (95% CI=68–97%) and 50% specificity (95% CI=16–84%) for a PPV (positive predictive value) of 99.8% and NPV (negative predictive value) of 80% for the detection of residual invasive cancer. Magnetic resonance imaging displayed 80% sensitivity (95% CI=28.4–99.5%) and 89% specificity (95% CI=71–98%) to detect pathological pCR in the breast. Eighty-four per cent of recruited patients were identified as potentially suitable candidates for BCS following chemotherapy and of those choosing to accept BCS, breast conservation was achieved in 90.5%, or 65.6% of all patients. Of those who proceeded to BCS, 9.5% required a re-do mastectomy because of positive margins; however, no residual tumour was found on histological examination of mastectomy specimens. Magnetic resonance imaging appears to be superior to conventional methods for assessing pathological response and the low rate of re-operation for positive margins indicates a valuable role in aiding the decision to undergo BCS or mastectomy.

Computerised tomography in the staging of Hodgkin's disease and non-Hodgkin's lymphoma.

The last 25 years have seen major changes in the imaging investigation and subsequent management of patients with Hodgkins disease (HD) and non-Hodgkins lymphoma (NHL); accurate staging is vital for prognostication and treatment in both, and particularly in HD. The choice of imaging modality for staging depends on its accuracy, impact on clinical decision-making, and availability. Modern CT scanners fulfil most of the desired criteria. The advent of CT scanning, along with the development of ever more effective chemotherapeutic regimens, has resulted in the virtual demise of bipedal lymphangiography (LAG) as a staging tool in patients with lymphoma. It has rendered superfluous a battery of other tests that were in routine use. This contribution reviews the evidence for the use of CT in preference to LAG. CT accurately depicts nodal enlargement above and below the diaphragm, has variable sensitivity for intra-abdominal visceral involvement and is generally outstanding in depicting the extent of disease, especially extranodal extension. Despite the advances in CT technology, there are still areas where CT performs less well (e.g. disease in normal-sized lymph nodes, splenic and bone marrow infiltration). The influence of technical factors, such as the use of intravenous contrast medium, is discussed. In some instances, CT is not the imaging modality of choice and the place of newer techniques such as MRI and endoscopic ultrasound will be reviewed.

Metastases to the breast revisited: radiological-histopathological correlation.

Metastases to the breast from extramammary tumours are infrequent. The main challenge in diagnosis is differentiating them from primary breast cancer. Radiologically this can be difficult as there are no specific imaging characteristics for metastases to the breast. Cytopathological evaluation, as well as full radiological assessment, is vital to avoid unnecessary surgery. Sources of primary tumours include a wide variety of cancers. In this pictorial review we illustrate a number of the commonest sources of primary tumours including lymphoma, lung, ovarian and cervical carcinoma, intestinal carcinoid and rare cases of Ewings sarcoma and malignant pigmented melanocytic schwannoma (low-grade malignant melanoma).

Life-course body size and perimenopausal mammographic parenchymal patterns in the MRC 1946 British birth cohort

Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01–1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.

Ethnic variations in mammographic density: a British multiethnic longitudinal study.

It is not known whether the 20-30% lower breast cancer incidence rates in first-generation South Asian and Afro-Caribbean women relative to Caucasian women in the United Kingdom are reflected in mammographic density. The authors conducted a United Kingdom population-based multiethnic study of mammographic density at ages 50-64 years in 645 women. Data on breast cancer risk factors were obtained using a questionnaire/telephone interview. Threshold percent density was assessed on 5,277 digitized mammograms taken in 1995-2004 and was analyzed using multilevel models. Both ethnic minorities were characterized by more protective breast cancer risk factor distributions than Caucasians, such as later menarche, shorter stature, higher parity, earlier age at first birth, and less use of hormone therapy, but they had a higher mean body mass index; the last four factors were associated with lower mammographic density. Age-adjusted percent mammographic densities in Afro-Caribbeans and South Asians were 5.6% (95% confidence interval (CI): 3.5, 7.5) and 5.9% (95% CI: 3.6, 8.0) lower, respectively, than in Caucasians. Lower densities were partly attributed to higher body mass index, less use of hormone therapy, and a protective reproductive history, but these factors did not account entirely for ethnic differences, since fully adjusted mean densities were 1.3% (95% CI: -1.3, 3.7) and 3.8% (95% CI: 1.1, 6.3) lower, respectively. Ethnic differences in mammographic density are consistent with those for breast cancer risk.

Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women

IntroductionSex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates.MethodsIn a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method.ResultsMean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m2 (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI.ConclusionsThese findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels.

Myositis, polyserositis with a large pericardial effusion and constrictive pericarditis as manifestations of chronic graft-versus-host disease after non-myeloablative peripheral stem cell transplantation and subsequent donor lymphocyte infusion

The clinical features of chronic graft-versus-host disease (cGVHD) following a non-myeloablative peripheral blood stem cell (PBSC) transplant may differ from those that occur after a conventional allograft. We describe a man with Hodgkins disease refractory to chemotherapy and radiotherapy who was transplanted from an HLA-identical brother, who developed cGVHD characterised, in particular, by polymyositis, polyserositis with a large pericardial effusion and constrictive pericarditis, 1 month after donor lymphocyte infusion for relapsed disease. Constrictive pericarditis has not been previously reported after a conventional allograft, and none of these features have been reported after a non-myeloablative transplant. The course of cGVHD necessitated potent immunosuppression leading to the presumed loss of graft-versus-lymphoma (GVL) effect. Bone Marrow Transplantation (2001) 27, 231–233.