In vivo assignment of methylmalonic acid in breast tissue using 2D MRS and relationship with breast density, menopausal status and cancer risk.

BACKGROUND: Methylmalonic acid (MMA) is linked to progression and aggressiveness of tumours. A recent study showed that high levels of circulatory MMA directed genetic programs promoting cancer progression. PURPOSE: To evaluate in vivo two-dimensional correlated spectroscopy (2D COSY) data from women at elevated risk of breast cancer to determine if resonances consistent with MMA are present, and if so to correlate levels with breast density, menopausal status and risk categories. MATERIALS AND METHODS: With institutional review board approval, 106 women at elevated risk (mean age 47), including 46 participants at medium risk, 43 at high risk with no known mutation and 17 BRCA-mutation carriers, were recruited. Breast density was assessed using a T2 sequence. A T1 sequence was used to place the voxel for the 2D COSY data. Peak volumes were normalized to the methylene peak at (1.30, 1.30) ppm. Chi-squared and Mann-Whitney tests were used. RESULTS: Two resonances are assigned on the diagonal at 3.15 ppm and 3.19 ppm consistent with and denoted MMA1 and MMA2 respectively. MMA1 and MMA2 increased in parallel with increased risk. BRCA-mutation carriers recorded an increase in mean MMA1 of 120% (p = 0.033) and MMA2 of 127% (p = 0.020) in comparison with participants with no known mutation. BRCA-mutation carriers with dense breasts recorded a significant increase in mean MMA1 of 137% (p = 0.002) and in mean MMA2 of 143% (p = 0.004) compared with BRCA-mutation participants with low-density breast tissue. MMA1 and MMA2 were higher in premenopausal women with dense breasts compared with those with low-density tissue. The highest values of MMA were recorded in BRCA-mutation carriers. CONCLUSION: Two tentative assignments are made for MMA in breast tissue of women at elevated risk for cancer. BRCA-mutation carriers exhibited higher values of MMA than those with no known mutation. Premenopausal women with BRCA mutation and dense breasts recorded the highest levels of MMA compared with other categories.

Breast Tissue Chemistry Measured In Vivo In Healthy Women Correlate with Breast Density and Breast Cancer Risk.

BACKGROUND: The relationship of tissue chemistry to breast density and cancer risk has not been documented despite breast density being a known risk factor. PURPOSE: To investigate whether distinct chemical profiles associated with breast density and cancer risk are identified in healthy breast tissue using in vivo two-dimensional correlated spectroscopy (2D COSY). STUDY TYPE: Prospective. POPULATION: One-hundred-seven participants including 55 at low risk and 52 at high risk of developing breast cancer. FIELD STRENGTH/SEQUENCE: 3 T/ axial/ T1, T2, 2D COSY. ASSESSMENT: Two radiologists defined breast density on T2. Interobserver variability assessed. Peak volumes normalized to methylene at (1.30, 1.30) ppm as internal shift reference. STATISTICAL TESTS: Chi-squared/Mann-Whitney/Kappa statistics/Kruskal Wallis/pairwise analyses. Significance level 0.05. RESULTS: Ten percentage were fatty breasts, 39% scattered fibroglandular, 35% heterogeneously dense, and 16% extremely dense. Interobserver variability was excellent (kappa = 0.817). Sixty percentage (64/107) were premenopausal. Four distinct tissue chemistry categories were identified: low-density (LD)/premenopausal, high-density (HD)/premenopausal, LD/postmenopausal, and HD/postmenopausal. Compared to LD, HD breast chemistry showed significant increases of cholesterol (235%) and lipid unsaturation (33%). In the low-risk category, postmenopausal women with dense breasts recorded the largest significant changes including cholesterol methyl 540%, lipid unsaturation 207%, glutamine/glutamate 900%, and choline/phosphocholine 800%. In the high-risk cohort, premenopausal women with HD recorded a more active chemical profile with significant increases in choline/phosphocholine 1100%, taurine/glucose 550% and cholesterol sterol 250%. DATA CONCLUSION: Four distinct chemical profiles were identified in healthy breast tissue based on breast density and menopausal status in participants at low and high risk. Gradual increase in neutral lipid content and metabolites was noted in both risk groups across categories in different order. In low risk, the HD postmenopausal category exhibited the highest metabolic activity, while women at high risk exhibited the highest lipid content and metabolic activity in the HD premenopausal category. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY STAGE: 3.

Author Correction: Post-traumatic stress disorder affects fucose-α(1-2)-glycans in the human brain: preliminary findings of neuro deregulation using in vivo two-dimensional neuro MR spectroscopy.

The original article contained errors in the Fig. 1 caption. The incorrect sentence, "The region highlighted by the white box is expanded in Fig. 3" was corrected to, "The region highlighted by the white box is expanded in Fig. 2." This has been corrected in the HTML and PDF of the article.

Post-traumatic stress disorder affects fucose-α(1-2)-glycans in the human brain: preliminary findings of neuro deregulation using in vivo two-dimensional neuro MR spectroscopy.

Post-traumatic stress disorder (PTSD) is triggered by experiencing terrifying event(s) for which there is currently no objective test for a definitive diagnosis. We report a pilot study where two-dimensional (2D) neuro magnetic resonance spectroscopy (MRS), collected at 3 T in a clinical scanner with a 64-channel head coil, identifies neuro deregulation in the PTSD cohort. The control subjects (n = 10) were compared with PTSD participants with minimal co-morbidities (n = 10). The 2D MRS identified statistically significant increases in the total spectral region containing both free substrate fucose and fucosylated glycans of 31% (P = 0.0013), two of multiple fucosylated glycans (Fuc IV and VI) were elevated by 48% (P = 0.002), and 41% (P = 0.02), respectively, imidazole was increased by 12% (P = 0.002), and lipid saturation was increased by 12.5% (P = 0.009). This is the first evidence of fucosylated glycans, reported in animals to be involved in learning and memory, to be affected in humans with PTSD.

Lipid and Metabolite Deregulation in the Breast Tissue of Women Carrying BRCA1 and BRCA2 Genetic Mutations.

PURPOSE: To use localized correlated spectroscopy (COSY) to assess for an altered biochemical state or states in breast tissue of women with BRCA gene mutations that potentially constitute preinvasive conditions. MATERIALS AND METHODS: Institutional review board approval was obtained. Participants provided written informed consent. In vivo localized COSY images were recorded at 3 T in the breast tissue of women carrying BRCA1 (n = 9) or BRCA2 (n = 14) gene mutations and were compared with images in healthy control subjects with no family history of breast cancer (n = 10). All participants underwent contrast material-enhanced MR imaging and ultrasonography (US). Statistical significance was calculated with the Mann-Whitney two-sided nonparametric test. RESULTS: No abnormality was recorded with MR imaging or US. Metabolite levels in the BRCA1 cohort were reduced by 79% (P = .014) when compared with triglycerides level, and there was a 19% increase in lipid unsaturation and triglyceride levels (P = .027 and P = .086, respectively) when compared with cellular cholesterol level. Cholesterol level was reduced by 47% (P = .027) when compared with diallylic lipid level. Metabolite levels in the BRCA2 cohort showed increased unsaturation of 21% (P = .030) relative to triglycerides level. Comparison of the BRCA1 and BRCA2 cohorts showed a 47% (P = .002) increase in cholesterol level in the BRCA2 cohort when compared with diallylic lipid level and a 52% (P = .003) increase when compared with triglycerides level. Levels of diallylic lipid, unsaturated lipid, triglycerides, and terminal methyl on the acyl chain are reduced by 46% (P = .002), 57% (P = .003), 66% (P = .003), and 29% (P = .010), respectively, when compared with cholesterol level. CONCLUSION: Localized COSY recorded significant changes in women with BRCA1 and BRCA2 gene mutations when compared with control subjects. If these changes are ultimately proven to be a premalignant stage, this method may prove useful in screening.

Clinician-performed ultrasound in assessing potentially malignant thyroid nodules.

BACKGROUND: Ultrasound (US) is used in the workup of thyroid nodules. Ultrasonographic characteristics, such as an ill-defined margin, hypoechoicity or fine calcifications, are known to be associated with malignant thyroid lesions. The association between these characteristics and the risk of malignancy has been reported predominantly from series published where US is performed in radiology departments. Clinician-performed ultrasound (CPU) is increasingly being used as a modality, although there is little published literature validating this practice. METHOD: A prospectively collected database of known ultrasonographic characteristics of malignancy as determined by CPU on thyroid nodules is reported and correlated against adequate cytology or operative histopathology. RESULTS: In total, 157 thyroid nodules (28 malignant, 129 benign) were included and characteristics of poorly defined capsule (sensitivity 46%, specificity 91%), absence of halo (sensitivity 54%, specificity 80%), hypoechoicity (sensitivity 79%, specificity 54%), heterogeneity (sensitivity 64%, specificity 68%), fine calcifications (sensitivity 36%, specificity 95%) and central blood supply (sensitivity 71%, specificity 69%) were found to be associated with malignant thyroid nodules. Negative-predictive values (NPVs) for these characteristics were consistently high (89%, 89%, 92%, 90%, 87% and 94%, respectively). DISCUSSION: These results are consistent with the previously published datasets of ultrasonographic characteristics of malignancy and validate the use of CPU. The consistently high NPV suggests that the absence of ultrasonographic characteristics of malignancy correlates well with benign lesions. CPU is a reliable and useful tool in the hands of surgeons assessing and following potentially malignancy thyroid nodules.

Survival from breast cancer: an analysis of Australian data by surgeon case load, treatment centre location, and health insurance status.

OBJECTIVE: Early invasive breast cancer data from the Australian National Breast Cancer Audit were used to compare case fatality by surgeon case load, treatment centre location and health insurance status. METHOD: Deaths were traced to 31 December 2007, for cancers diagnosed in 1998-2005. Risk of breast cancer death was compared using Cox proportional hazards regression. RESULTS: When adjustment was made for age and clinical risk factors: (i) the relative risk of breast cancer death (95% confidence limit) was lower when surgeons' annual case loads exceeded 20 cases, at 0.87 (0.76, 0.995) for 21-100 cases and 0.83 (0.72, 0.97) for higher case loads. These relative risks were not statistically significant when also adjusting for treatment centre location (P ≥ 0.15); and (ii) compared with major city centres, inner regional centres had a relative risk of 1.32 (1.18, 1.48), but the risk was not elevated for more remote sites at 0.95 (0.74, 1.22). Risk of death was not related to private insurance status. CONCLUSION: Higher breast cancer mortality in patients treated in inner regional than major city centres and in those treated by surgeons with lower case loads requires further study.

Age effects on survival from early breast cancer in clinical settings in Australia.

BACKGROUND: The study aim was to determine whether age is an independent risk factor for survival from early invasive breast cancer in contemporary Australian clinical settings. METHODS: The study included 31 493 breast cancers diagnosed in 1998-2005. Risk of death from breast cancer was compared by age, without and with adjustment for clinical risk factors, using Cox proportional hazard regression. RESULTS: Risk of breast cancer death was elevated for cancers of larger size, higher grade, positive nodal status, oestrogen receptor negative status, vascular invasion and multiple foci. Ductal lesions presented a higher risk than other lesions. Adjusting for these factors, the relative risk of breast cancer death (95% confidence limits) was lower for 40-49-year-olds at 0.80 (0.66, 0.96) than for the reference category under 40 years, but higher for 70-79-year-olds at 1.64 (1.36, 1.98) and women aged 80 years or more at 2.19 (1.79, 2.69). The risk for 50-69-year-olds and women under 40 years was similar. Risk-factor adjustment reduced the difference in risk between the reference category under 40 years and 40-49-year-olds, largely eliminated the lower relative risk for 50-69-year-olds, and increased the relative risks for women aged 70-79 years and older. DISCUSSION: Survivals in women under 40 and over 70 years of age are poorer than for 40-69-year-olds. Research is needed into the best treatment modalities for younger women and older women with co-morbidity.

Survival from synchronous bilateral breast cancer: the experience of surgeons participating in the breast audit of the Society of Breast Surgeons of Australia and New Zealand.

BACKGROUND: Previous studies generally indicate that synchronous bilateral breast cancers (SBBC) have an equivalent or moderately poorer survival compared with unilateral cases. The prognostic characteristics of SBBC would be relevant when planning adjuvant therapies and follow-up medical surveillance. The frequency of SBBC among early breast cancers in clinical settings in Australia and New Zealand were investigated, plus their prognostic significance, using the Breast Cancer Audit Database of the Society of Breast Surgeons of Australia and New Zealand, which covered an estimated 60% of early invasive lesions in those countries. DESIGN: Rate ratios (95% confidence limits) of SBBC were investigated among 35,370 female breast cancer cases by age of woman, histology type, grade, tumour diameter, nodal status, lymphatic/vascular invasion and oestrogen receptor status. Univariate and multivariable disease-specific survival analyses were undertaken. RESULTS: 2.3% of cases were found to be SBBC (i.e., diagnoses occurring within 3 months). The figure increased from 1.4% in women less than 40 years to 4.1% in those aged 80 years or more. Disease-specific survivals did not vary by SBBC status (p=0.206). After adjusting for age, histology type, diameter, grade, nodal status, lymphatic/vascular invasion, and oestrogen receptor status, the relative risk of breast cancer death for SBBC was 1.17 (95% CL: 0.91, 1.51). After adjusting for favourable prognostic factors more common in SBBC cases (i.e., histology type, grade, lymphatic/ vascular invasion, and oestrogen receptor status), the relative risk of breast cancer death for SBBC was 1.42 (95% CL: 1.10, 1.82). After adjusting for unfavourable prognostic factors more common in SBBC cases (i.e., older age and large tumour diameter), the relative risk of breast cancer death for SBBC was 0.98 (95% CL: 0.76, 1.26). CONCLUSIONS: Results confirm previous findings of an equivalent or moderately poorer survival for SBBC but indicate that SBBC status is likely to be an important prognostic indicator for some cases.

Long-term symptom relief from primary hyperparathyroidism following minimally invasive parathyroidectomy.

BACKGROUND: The affect of the surgical approach for primary hyperparathyroidism (1HPT) on long-term symptom relief has not been studied. This study compares the long-term relief of symptoms assessed by the Parathyroidectomy Assessment of Symptoms (PAS) score in patients undergoing bilateral neck exploration (BNE) and minimally invasive parathyroidectomy (MIP). METHODS: In this case-control study, patients with 1HPT who had followed a protocol to assess symptoms before and after parathyroid surgery between 1999 and 2008 were contacted by letter and had blood taken to assess calcium, ionized calcium, and parathyroid hormone (PTH). The main aim was to assess symptoms at long-term follow-up using the PAS score. The incidence of persistent or recurrent 1HPT at long-term follow-up after MIP and BNE was also compared. RESULTS: Two hundred and forty-six patients underwent parathyroid surgery and 142 responded to our correspondence, of which 64 underwent MIP and 78 BNE. Follow-up after BNE was longer than MIP (61 vs. 41 months). At long-term follow-up, the mean PAS score fell by 125 and 175 in the MIP and BNE groups, respectively. There was no statistically significant difference in the decline of the PAS score between the MIP and BNE groups. Six patients developed persistent or recurrent 1HPT following MIP compared to three after BNE; this difference was not statistically significant. CONCLUSIONS: This study is the first to report on long-term symptom relief from 1HPT after MIP, and demonstrates that both MIP and BNE can achieve this. In order to establish whether the long-term outcomes from these procedures are equivalent, further adequately powered studies are required.

Proton MRS of the breast in the clinical setting.

Information for determining whether a primary breast lesion is invasive and its receptor status and grade can be obtained before surgery by performing proton MRS on a fine-needle aspiration biopsy (FNAB) specimen and analyzing the MRS information by a pattern recognition method. Two-dimensional MRS, on either specimens or cells, allows the unambiguous assignment of most resonances. When correlated with the spectral regions selected by the pattern recognition method, there are strong indications for the biochemical markers responsible for prognostic information of invasive capacity and metastatic spread. Spectral assignments and biological correlations can be made using cell models. In vivo MRS can distinguish invasive from benign lesions. This pathological distinction can be made from the presence of resonances at discrete frequencies. To achieve this level of spectral resolution and signal-to-noise ratio, there are stringent requirements when acquiring and processing the data. The challenge now is to implement two-dimensional MRS in vivo. Until this is realized, the combination of in vivo MR, for diagnosis and spatial location, and MRS, for image-guided biopsy to provide information on tumor spread, promises to provide a higher level of preoperative diagnosis than previously achieved.

Oncoplastic breast surgery: a global perspective on practice, availability, and training.

Oncoplastic surgery is the seamless joining of the extirpative and reconstructive aspects of breast surgery that is performed by a single surgeon. A symposium was held at ISW 2007 in Montreal with a prearranged aim to publish an article on the current and historical record of the developing specialty of oncoplastic breast surgery. The presenters and authors are well-known breast surgeons from Australia, Croatia, India, Sweden, and South Africa.

Minimally invasive parathyroidectomy using surgeon-performed ultrasound and sestamibi.

BACKGROUND: Surgeon-performed ultrasound (SPU) and (99m)Tc-sestamibi (SM) scanning can be used alone or in combination in patients with primary hyperparathyroidism to select cases suitable for minimally invasive parathyroidectomy (MIP). The aim of the study was to evaluate SPU and SM and to determine the reliability they provide the surgeon in planning and carrying out MIP. METHODS: The study was a prospective analysis of 130 patients with primary hyperparathyroidism who had preoperative localization with SPU and SM at a tertiary referral centre between 2003 and 2006. All ultrasound scans were carried out by one surgeon, followed by correlative sestamibi scan and a further 'on operating table' ultrasound to reassess the lesion and mark the operative site. Selection criteria for MIP were a positive SPU and SM, although a positive SPU or SM allowed the surgeon to focus on the nominated side. SPU and SM localizations were correlated to the operative findings. RESULTS: One hundred and thirty patients underwent both SPU and SM. There were 97 women and 33 men, with a mean age of 59 years. SPU alone identified the abnormal parathyroid in 103 cases (sensitivity 82%; positive predictive value 96.3%). SM alone identified the abnormal gland in 102 cases (sensitivity 79%; positive predictive value 99%). In 88 patients, the SPU and SM were concordant, and 94% had successful MIP. SPU and SM were both negative in 13 patients, and all these patients had bilateral neck exploration. CONCLUSION: SPU in the hands of an experienced surgeon in association with sestamibi is a reliable tool for the preoperative localization of parathyroid adenomas and facilitates a minimally invasive procedure.

Proton spectroscopy provides accurate pathology on biopsy and in vivo.

In the last 25 years, MR spectroscopy (MRS) has moved from being a basic research tool into routine clinical use. The spectroscopy method reports on those chemicals that are mobile on the MR time scale. Many of these chemicals reflect specific pathological processes but are complicated by the fact that many chemicals change at one time. There are currently two clinical applications for spectroscopy. The first is in the pathology laboratory, where it can be an adjunct to, and in some cases replacement, for difficult pathologies like Barrett's esophagus and follicular adenoma of the thyroid. The spectroscopy method on a breast biopsy can also report on prognostic indicators, including the potential for spread, from information present in the primary tumor alone. The second application for spectroscopy is in vivo to provide a preoperative diagnosis and this is now achievable for several organs including the prostate. The development of spectroscopy for clinical purposes has relied heavily on the serially-sectioned histopathology to confirm the high accuracy of the method. The combination of in vivo MRI, in vivo MRS, and ex vivo MRS on biopsy samples offers a modality of very high accuracy for preoperative diagnosis and provision of prognostic information for human cancers.

Large retrosternal goitre: a diagnostic and management dilemma.

A substernal goitre is of clinical significance because its growth between the sternum anteriorly and vertebral bodies posteriorly leads to impingement on the surrounding structures and compressive symptoms. The incidence of substernal goitre is documented to vary between .02 and .5%. It accounts for 3-12% of mediastinal masses and is the most common superior mediastinal mass. This condition is important because it presents a diagnostic dilemma as its size and compressive symptoms mimic malignant disease, and an operative dilemma for the approach to its management. We present one of the largest reported retrosternal goitre cases in the literature.

Psychological impact and cosmetic outcome of surgical breast cancer strategies.

BACKGROUND: Current surgical treatment modalities for breast cancer include breast conserving surgery, mastectomy alone and mastectomy with breast reconstruction. There are recognized benefits of breast conservation and breast reconstruction over mastectomy but there are few studies assessing this area in Australia. The aim of the present study was to compare the various surgical strategies for breast cancer treatment in terms of quality of life, cosmesis and patient satisfaction. METHODS: A chart analysis was conducted of all patients who underwent Breast Cancer Reconstruction at the Royal Adelaide Hospital Breast Unit between 1990 and 2002. Patients were then traced and asked to take part in an interview. Mastectomy and breast conservation patients who attended outpatient clinic for follow up were also approached. All three groups were interviewed and self-assessment quality of life questionnaires (Functional Assessment of Cancer Therapy-Breast, body image) were administered. The breast conservation and reconstruction groups also underwent assessment of satisfaction and cosmesis. RESULTS: A total of 78 mastectomy, 109 breast conservation and 123 breast reconstruction patients were interviewed. Quality of life assessment was similar between the three groups but the breast conservation and reconstruction patients' body image scores were superior to the mastectomy group. Patient satisfaction was higher in the reconstruction group than the breast conservation group of patients, while cosmesis was similar. CONCLUSION: While little difference was seen on quality of life assessment, body image is improved with the use of breast conservation and reconstruction. The high satisfaction and cosmesis scores in the breast reconstruction group are an indication of the superior results that can be achieved with breast reconstruction.

Specificity of choline metabolites for in vivo diagnosis of breast cancer using 1H MRS at 1.5 T.

The purpose was to determine if in vivo proton magnetic resonance spectroscopy ((1)H MRS) at 1.5 T can accurately provide the correct pathology of breast disease. Forty-three asymptomatic volunteers including three lactating mothers were examined and compared with 21 breast cancer patients. Examinations were undertaken at 1.5 T using a purpose-built transmit-receive single breast coil. Single voxel spectroscopy was undertaken using echo times of 135 and 350 ms. The broad composite resonance at 3.2 ppm, which includes contributions from choline, phosphocholine (PC), glycerophosphocholine (GPC), myo-inositol and taurine, was found not to be a unique marker for malignancy providing a diagnostic sensitivity and specificity of 80.0 and 86.0%, respectively. This was due to three of the asymptomatic volunteers and all of the lactating mothers also generating the broad composite resonance at 3.2 ppm. Optimised post-acquisitional processing of the spectra resolved a resonance at 3.22 ppm, consistent with PC, in patients with cancer. In contrast the spectra recorded for three false-positive volunteers, and the three lactating mothers had a resonance centred at 3.28 ppm (possibly taurine, myo-inositol or GPC). This improved the specificity of the test to 100%. Careful referencing of the spectra and post-acquisitional processing intended to optimise spectral resolution of in vivo MR proton spectra from human breast tissue resolves the composite choline resonance. This allows the distinction of patients with malignant disease from volunteers with a sensitivity of 80% and specificity of 100%. Therefore, resolution of the composite choline resonance into its constituent components improves the specificity of the in vivo (1)H MRS method, but does not overcome the problem of 20% false-negatives.