Primary radiotherapy and deep inferior epigastric perforator flap reconstruction for patients with breast cancer (PRADA): a multicentre, prospective, non-randomised, feasibility study.

BACKGROUND: Radiotherapy before mastectomy and autologous free-flap breast reconstruction can avoid adverse radiation effects on healthy donor tissues and delays to adjuvant radiotherapy. However, evidence for this treatment sequence is sparse. We aimed to explore the feasibility of preoperative radiotherapy followed by skin-sparing mastectomy and deep inferior epigastric perforator (DIEP) flap reconstruction in patients with breast cancer requiring mastectomy. METHODS: We conducted a prospective, non-randomised, feasibility study at two National Health Service trusts in the UK. Eligible patients were women aged older than 18 years with a laboratory diagnosis of primary breast cancer requiring mastectomy and post-mastectomy radiotherapy, who were suitable for DIEP flap reconstruction. Preoperative radiotherapy started 3-4 weeks after neoadjuvant chemotherapy and was delivered to the breast, plus regional nodes as required, at 40 Gy in 15 fractions (over 3 weeks) or 42·72 Gy in 16 fractions (over 3·2 weeks). Adverse skin radiation toxicity was assessed preoperatively using the Radiation Therapy Oncology Group toxicity grading system. Skin-sparing mastectomy and DIEP flap reconstruction were planned for 2-6 weeks after completion of preoperative radiotherapy. The primary endpoint was the proportion of open breast wounds greater than 1 cm width requiring a dressing at 4 weeks after surgery, assessed in all participants. This study is registered with ClinicalTrials.gov, NCT02771938, and is closed to recruitment. FINDINGS: Between Jan 25, 2016, and Dec 11, 2017, 33 patients were enrolled. At 4 weeks after surgery, four (12·1%, 95% CI 3·4-28·2) of 33 patients had an open breast wound greater than 1 cm. One (3%) patient had confluent moist desquamation (grade 3). There were no serious treatment-related adverse events and no treatment-related deaths. INTERPRETATION: Preoperative radiotherapy followed by skin-sparing mastectomy and immediate DIEP flap reconstruction is feasible and technically safe, with rates of breast open wounds similar to those reported with post-mastectomy radiotherapy. A randomised trial comparing preoperative radiotherapy with post-mastectomy radiotherapy is required to precisely determine and compare surgical, oncological, and breast reconstruction outcomes, including quality of life. FUNDING: Cancer Research UK, National Institute for Health Research.

Ureterorenoscopy training on cadavers embalmed by Thiel's method: simulation or a further step towards reality? Initial report.

INTRODUCTION: The technique of ureterorenoscopy has a significant learning curve. Cadavers embalmed by the Thiel method have been successfully used for simulation training in a number of surgical specialties. Here we present our experience of the first use of Thiel cadavers in a formal ureteroscopy training course. MATERIAL AND METHODS: The inaugural 'Masterclass in Flexible Ureterorenoscopy' was run with participants performing ureterorenoscopy on three Thiel cadavers under expert supervision. A qualitative questionnaire was delivered to the participants and faculty. Assessed domains were tissue characteristics of the cadaveric urinary tract, anatomical features and procedural aspects. A five-point Likert score was used to assess responses. Data regarding participant experience in endourology were also collected. RESULTS: 8 questionnaires were collected. All participants completed cadaveric ureterorenoscopy. Three-quarters reported the overall quality of tissue in the cadaveric bladder, ureters and pelvicalyceal system as high or excellent. Half reported the cadaveric bladder as being softer than in a live patient, whilst five out of eight thought that the cadaveric ureter was softer and more prone to trauma. Seven out of eight were satisfied with the overall quality of the cadaveric model. The quality of vision and irrigation in the upper urinary tracts was reported as high. CONCLUSIONS: Thiel cadavers have been shown to have excellent tissue characteristics, as well as being durable and reusable. We have described the first use of Thiel cadavers in a designated ureterorenoscopy course, with high levels of delegate satisfaction. Further work is required to develop the role of Thiel cadavers as part of an integrated, modular urology training.

Development and Validation of a Novel and Cost-Effective Animal Tissue Model for Training Transurethral Resection of the Prostate.

OBJECTIVES: To develop and validate a new and cost-effective animal tissue training model for practicing resection skills of transurethral resection of the prostate (TURP). METHODS AND MATERIALS: A porcine kidney was prepared and restructured to simulate the relevant anatomy of the human prostate. The restructured prostate was connected to an artificial urethra and bladder. Face, content, and construct validity of the model was carried out using a 5-point Likert scale questionnaire, and comparison in task performance between participants and experts was made using observational clinical human reliability analysis. RESULTS: A total of 24 participants and 11 experts who practiced TURP skills on this model from October 2014 to December 2015 were recruited. The mean score on specific feature of the anatomy and color, sensation of texture and feeling of resection, conductibility of current, and efficacy and safety of the model were 4.34 ± 0.37, 4.51 ± 0.63, 4.13 ± 0.53, and 4.35 ± 0.71, respectively, by participants whereas they were 4.22 ± 0.23, 4.30 ± 0.48, 4.11 ± 0.62, and 4.56 ± 0.77, respectively, by the experts on a scale of 1 (unrealistic) to 5 (very realistic). Participants committed more technical errors than the experts (11 vs 7, p < 0.001), produced more movements of the instruments (51 vs 33, p < 0.001), and required longer operating time (11.4 vs 6.2min, p < 0.001). CONCLUSIONS: A newly developed restructured animal tissue model for training TURP was reported. Validation study on the model demonstrates that this is a very realistic and effective model for skills training of TURP. Trainees committed more technical errors, more unproductive movements, and required longer operating time.

Cytochrome P450 Allele CYP3A7*1C Associates with Adverse Outcomes in Chronic Lymphocytic Leukemia, Breast, and Lung Cancer.

CYP3A enzymes metabolize endogenous hormones and chemotherapeutic agents used to treat cancer, thereby potentially affecting drug effectiveness. Here, we refined the genetic basis underlying the functional effects of a CYP3A haplotype on urinary estrone glucuronide (E1G) levels and tested for an association between CYP3A genotype and outcome in patients with chronic lymphocytic leukemia (CLL), breast, or lung cancers. The most significantly associated SNP was rs45446698, an SNP that tags the CYP3A7*1C allele; this SNP was associated with a 54% decrease in urinary E1G levels. Genotyping this SNP in 1,008 breast cancer, 1,128 lung cancer, and 347 CLL patients, we found that rs45446698 was associated with breast cancer mortality (HR, 1.74; P = 0.03), all-cause mortality in lung cancer patients (HR, 1.43; P = 0.009), and CLL progression (HR, 1.62; P = 0.03). We also found borderline evidence of a statistical interaction between the CYP3A7*1C allele, treatment of patients with a cytotoxic agent that is a CYP3A substrate, and clinical outcome (Pinteraction = 0.06). The CYP3A7*1C allele, which results in adult expression of the fetal CYP3A7 gene, is likely to be the functional allele influencing levels of circulating endogenous sex hormones and outcome in these various malignancies. Further studies confirming these associations and determining the mechanism by which CYP3A7*1C influences outcome are required. One possibility is that standard chemotherapy regimens that include CYP3A substrates may not be optimal for the approximately 8% of cancer patients who are CYP3A7*1C carriers.

Is IORT ready for roll-out?

Two large randomised controlled trials of intraoperative radiotherapy (IORT) in breast-conserving surgery (TARGIT-A and ELIOT) have been published 14 years after their launch. Neither the TARGIT-A trial nor the ELIOT trial results have changed the current clinical practice for the use of IORT. The in-breast local recurrence rate (LRR) after IORT met the pre-specified non-inferiority margins in both trials and was 3.3% in TARGIT-A and 4.4% in the ELIOT trial. In both trials, the pre-specified estimates for local recurrence (LR) with external beam radiation therapy (EBRT) significantly overestimated actual LRR. In the TARGIT-A trial, LR with EBRT was estimated at the outset to be 6%, and in the ELIOT trial, it was estimated to be 3%. Surprisingly, LRR in the EBRT groups has been found to be significantly lower, 1.3% in the EBRT arm of the TARGIT-A and 0.4% in the EBRT arm of the ELIOT trial, respectively. Median follow-up was 2.4 years for the TARGIT-A trial and 5.8 years for the ELIOT trial. However, the initial cohort of patients in the TARGIT-A trial (reported in 2010) now have a median follow-up of 3.8 years and data on LR were available at 5 years follow-up on 35% of patients (18% who received IORT). Although further follow-up will increase confidence with the data, it will also further delay clinical implementation. By carefully weighing the risks and benefits of a single-fraction radiation treatment with patients, IORT should be offered within agreed and strict protocols. Patients deemed at low risk of LR or those deemed suitable for partial breast irradiation, according to the GEC-ESTRO and ASTRO recommendations, could be considered as candidates for IORT. These guidelines apply to all partial breast irradiation techniques, and more specific guidelines for IORT would assist clinicians.

The physician scientist: balancing clinical and research duties.

Physician scientists bridge the gap between biomedical research and clinical practice. However, the continuing decrease in number of people who choose this career path poses a threat to the advancement of biomedical science and the translation of research findings to clinical practice.

Genetic predisposition to in situ and invasive lobular carcinoma of the breast.

Invasive lobular breast cancer (ILC) accounts for 10-15% of all invasive breast carcinomas. It is generally ER positive (ER+) and often associated with lobular carcinoma in situ (LCIS). Genome-wide association studies have identified more than 70 common polymorphisms that predispose to breast cancer, but these studies included predominantly ductal (IDC) carcinomas. To identify novel common polymorphisms that predispose to ILC and LCIS, we pooled data from 6,023 cases (5,622 ILC, 401 pure LCIS) and 34,271 controls from 36 studies genotyped using the iCOGS chip. Six novel SNPs most strongly associated with ILC/LCIS in the pooled analysis were genotyped in a further 516 lobular cases (482 ILC, 36 LCIS) and 1,467 controls. These analyses identified a lobular-specific SNP at 7q34 (rs11977670, OR (95%CI) for ILC = 1.13 (1.09-1.18), P = 6.0 × 10(-10); P-het for ILC vs IDC ER+ tumors = 1.8 × 10(-4)). Of the 75 known breast cancer polymorphisms that were genotyped, 56 were associated with ILC and 15 with LCIS at P<0.05. Two SNPs showed significantly stronger associations for ILC than LCIS (rs2981579/10q26/FGFR2, P-het = 0.04 and rs889312/5q11/MAP3K1, P-het = 0.03); and two showed stronger associations for LCIS than ILC (rs6678914/1q32/LGR6, P-het = 0.001 and rs1752911/6q14, P-het = 0.04). In addition, seven of the 75 known loci showed significant differences between ER+ tumors with IDC and ILC histology, three of these showing stronger associations for ILC (rs11249433/1p11, rs2981579/10q26/FGFR2 and rs10995190/10q21/ZNF365) and four associated only with IDC (5p12/rs10941679; rs2588809/14q24/RAD51L1, rs6472903/8q21 and rs1550623/2q31/CDCA7). In conclusion, we have identified one novel lobular breast cancer specific predisposition polymorphism at 7q34, and shown for the first time that common breast cancer polymorphisms predispose to LCIS. We have shown that many of the ER+ breast cancer predisposition loci also predispose to ILC, although there is some heterogeneity between ER+ lobular and ER+ IDC tumors. These data provide evidence for overlapping, but distinct etiological pathways within ER+ breast cancer between morphological subtypes.

CYP3A variation, premenopausal estrone levels, and breast cancer risk.

BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer.

Development and use of a restructured animal tissue model for training in laparoscopic salpingostomy and salpingectomy.

Ectopic pregnancy is commonly managed via either laparoscopic salpingostomy or salpingectomy. However, there is a proficiency gain curve in mastering these 2 surgical procedures, and an effective simulated model is essential for training students of gynecology. The objective of this study was to develop and evaluate a restructured animal tissue model that can be used in the surgical training of gynecologists in laparoscopic salpingostomy and salpingectomy. Since 2005, a hands-on laparoscopic training course for gynecologic students has been developed and conducted at the Cushieri Skills Centre, University of Dundee. A restructured animal tissue model of ectopic pregnancy was developed and used for practicing laparoscopic salpingostomy and salpingectomy. At the end of each course, data were collected using a standardized anonymous questionnaire using a Likert scale (1= strongly disagree; 2 = disagree; 3 = neither agree nor disagree; 4 = agree; and 5 = strongly agree). Feedback on the ectopic pregnancy model from course participants was obtained insofar as the realism of the anatomical condition of the model, quality of the tissue and organ color, quality of organ consistency, and operative tactile properties during dissection. Over the last 6 years, from June 2005 to September 2010, 96 gynecologic trainees have practiced using this phantom. The mean (SD) overall satisfaction rate for the training phantom for laparoscopic salpingostomy and salpingectomy was 4.9 (0.1) on a scale of 1(unrealistic/poor) to 5 (very realistic/useful). Compared with real operating conditions, quality assessment of the model for anatomical condition was 4.9 (0.2), for quality of tissue and organ color was 4.9 (0.4), for organ consistency was 4.8 (0.3), and for operative tactility was 4.8 (0.6). It was concluded that the restructured animal tissue model of laparoscopic salpingostomy and salpingectomy in ectopic pregnancy is realistic, cost-effective, and simple enough to be produced for use in laboratory-based surgical training courses.

Novel breast cancer susceptibility locus at 9q31.2: results of a genome-wide association study.

BACKGROUND: Genome-wide association studies have identified several common genetic variants associated with breast cancer risk. It is likely, however, that a substantial proportion of such loci have not yet been discovered. METHODS: We compared 296,114 tagging single-nucleotide polymorphisms in 1694 breast cancer case subjects (92% with two primary cancers or at least two affected first-degree relatives) and 2365 control subjects, with validation in three independent series totaling 11,880 case subjects and 12,487 control subjects. Odds ratios (ORs) and associated 95% confidence intervals (CIs) in each stage and all stages combined were calculated using unconditional logistic regression. Heterogeneity was evaluated with Cochran Q and I(2) statistics. All statistical tests were two-sided. RESULTS: We identified a novel risk locus for breast cancer at 9q31.2 (rs865686: OR = 0.89, 95% CI = 0.85 to 0.92, P = 1.75 × 10(-10)). This single-nucleotide polymorphism maps to a gene desert, the nearest genes being Kruppel-like factor 4 (KLF4, 636 kb centromeric), RAD23 homolog B (RAD23B, 794 kb centromeric), and actin-like 7A (ACTL7A, 736 kb telomeric). We also identified two variants (rs3734805 and rs9383938) mapping to 6q25.1 estrogen receptor 1 (ESR1), which were associated with breast cancer in subjects of northern European ancestry (rs3734805: OR = 1.19, 95% CI = 1.11 to 1.27, P = 1.35 × 10(-7); rs9383938: OR = 1.18, 95% CI = 1.11 to 1.26, P = 1.41 × 10(-7)). A variant mapping to 10q26.13, approximately 300 kb telomeric to the established risk locus within the second intron of FGFR2, was also associated with breast cancer risk, although not at genome-wide statistical significance (rs10510102: OR = 1.12, 95% CI = 1.07 to 1.17, P = 1.58 × 10(-6)). CONCLUSIONS: These findings provide further evidence on the role of genetic variation in the etiology of breast cancer. Fine mapping will be needed to identify causal variants and to determine their functional effects.

Genome-wide association study identifies five new breast cancer susceptibility loci.

Breast cancer is the most common cancer in women in developed countries. To identify common breast cancer susceptibility alleles, we conducted a genome-wide association study in which 582,886 SNPs were genotyped in 3,659 cases with a family history of the disease and 4,897 controls. Promising associations were evaluated in a second stage, comprising 12,576 cases and 12,223 controls. We identified five new susceptibility loci, on chromosomes 9, 10 and 11 (P = 4.6 x 10(-7) to P = 3.2 x 10(-15)). We also identified SNPs in the 6q25.1 (rs3757318, P = 2.9 x 10(-6)), 8q24 (rs1562430, P = 5.8 x 10(-7)) and LSP1 (rs909116, P = 7.3 x 10(-7)) regions that showed more significant association with risk than those reported previously. Previously identified breast cancer susceptibility loci were also found to show larger effect sizes in this study of familial breast cancer cases than in previous population-based studies, consistent with polygenic susceptibility to the disease.

HER2 significance and treatment outcomes after radiotherapy for brain metastases in breast cancer patients.

The aim of this retrospective study was to examine the influence of HER2 status on outcome in breast cancer patients following whole brain radiotherapy (WBRT) for cerebral metastases. One hundred and eighty one patients with recordable HER2 status, who received WBRT at single institution were identified and stratified according to HER2 status. Eighty eight were HER2 positive (HER2+) (49%) and 93 HER2 negative (HER2-) (51%). A total of 72 (82%) HER2+ group developed brain metastases whilst on chemotherapy compared with 45 (48%) in HER2- group. Median survival after WBRT was 8 months (1-38) for HER2+ patients and 4 (1-64) for HER2- patients p=0.01. On brain metastasis progression, 18 (20%) of HER2+ patients received further local therapy compared with 6 (6%) in HER2- group. This study shows superior survival in HER2+ group following WBRT as compared to HER2- group and more aggressive management on disease progression in HER2+ group.

Accelerated partial breast irradiation: technically feasible but who will benefit?

Modern breast cancer radiotherapy aims to increase uncomplicated cure rates. A priority is reduction of late effects which include chronic chest wall or breast pain, poor cosmesis, and cardiac toxicity. As breast screening detects early cancers we may be able to safely restrict irradiation postlumpectomy to the tumour bed with a margin, defining a 'partial breast' target volume for treatment. Differing technical approaches to partial breast irradiation are being evaluated in phase III studies with standard whole breast irradiation. These include intra-operative single doses, hypo-fractionated accelerated brachytherapy, and LINAC (linear accelerator)-based three-dimensional external beam therapy.

Surgical wound care: current views on minimising dressing-related pain.

Managing surgical wounds healing by primary intention is likely to become less problematic with the development of more effective advanced wound dressings; increasingly effective methods of medicated pain management; education; and advances in minimal access surgical (MAS) techniques. Future research is likely to focus on management of patients with surgical wounds healing by secondary intention. If so, management of surgical wound pain must become an integral part of assessment. Theatre practitioners, clinical nurses and surgical practitioners, working as part of the multidisciplinary team, are ideally placed to undertake this work and to include multimodal, holistic approaches to caring for surgical wounds and controlling surgical wound pain (Gould, 1999). Patient support and education is likely to become an increasing priority, particularly in view of the significant move from inpatient care to short-stay and day-case surgery.

Breast cancer in women after treatment for Hodgkin's disease.

Although substantial progress has been made in the management of Hodgkin's lymphoma during the past 30 years, the development of secondary malignant diseases has emerged as a serious consequence of treatment. In particular, extended follow-up of patients with Hodgkin's disease has revealed an increased risk of breast cancer. We have systematically reviewed all published literature on breast cancer after treatment for Hodgkin's disease and show that high risk is particularly associated with treatment at a young age, mantle radiotherapy, and chemotherapy. Breast cancers in this context differ from sporadic disease because they develop in younger women, are associated with a high incidence of bilateral disease, and are generally located near the midline of the body. The risk of breast cancer is lower in patients who receive newer, combined modality treatments for Hodgkin's disease. In this review we discuss a protocol for formal follow-up and screening of patients who have recovered from Hodgkin's disease to aid early diagnosis and ensure the possibility of effective management.

Effects of the aromatase inhibitor letrozole on normal breast epithelial cell proliferation and metabolic indices in postmenopausal women: a pilot study for breast cancer prevention.

The aromatase enzyme converts androgens to estrogens and is the therapeutic target for aromatase inhibitors in postmenopausal patients with estrogen receptor-positive metastatic breast cancer. Third-generation inhibitors such as letrozole are being considered as potential prophylactic agents for breast cancer. The rationale for their preventive application would be aided by knowledge of their effects on the normal breast and on other estrogen-dependent processes such as bone and lipid metabolism. Thirty-two women without active breast disease were recruited to 3-month treatment with letrozole (2.5 mg/day). Core-cut biopsies from the breast and blood samples were collected before and at the end of treatment. Plasma estradiol levels were markedly suppressed in all but two patients, who were excluded from the efficacy assessment. There was no significant change in the proliferation marker Ki67 (mean change, -23%; 95% confidence interval, -50% to +23%) or estrogen receptor in breast epithelial cells with treatment. Similarly, there were no significant changes in plasma levels of insulin-like growth factor I or lipid profiles. However, there was a significant increase (25%) in the levels of the bone resorption marker C-telopeptide crosslinks (CTx). We conclude that any prophylactic effect of letrozole is not likely to be dependent on antiproliferative effects on normal breast. Studies in healthy patients will need to recognize the potential for enhanced bone resorption.

Variation in the manganese superoxide dismutase gene (SOD2) is not a major cause of radiotherapy complications in breast cancer patients.

BACKGROUND AND PURPOSE: Small proportions of patients receiving radiotherapy develop marked long-term radiation damage. It is thought that this is due, at least in part, to intrinsic differences in cellular radiosensitivity, but the underlying mechanism is unknown. Reactive oxygen species are involved in cellular radiation damage, hence inter-individual differences in free radical detoxification may be related to radiosensitivity. Within mitochondria manganese superoxide dismutase (MnSOD) provides a major defence against oxidative damage by reactive oxygen species. MnSOD has been linked to expression of malignant phenotype and apoptosis and polymorphic variation in the gene, SOD2 to risk of breast cancer. MATERIALS AND METHODS: Forty-one breast cancer patients developing marked changes in breast appearance after radiotherapy and 39 patients who showed no clinically detectable reaction after radiotherapy were analyzed for germline sequence variation in SOD2. RESULTS: The Ala-9Val polymorphism was detected, but no other sequence variants were detected in SOD2. Both alleles of the Ala-9Val polymorphism were equally distributed between the two patient groups. CONCLUSIONS: Sequence variation in SOD2 is not the major cause of radiotherapy complications in women with breast cancer.

Disruption of Brca2 increases the spontaneous mutation rate in vivo: synergism with ionizing radiation.

The breast cancer predisposition gene BRCA2 encodes a protein involved in the repair of DNA double-strand breaks, which arise spontaneously and following exposure to ionizing radiation (IR). To develop a mouse model that examines the effect of BRCA2 mutation and IR exposure on in vivo somatic mutation acquisition, we crossed mice with targeted disruption of Brca2 with a LacZ transgenic mutation reporter strain. Loss of both wild-type Brca2 alleles caused a 2.3-fold increase, equivalent to an extra 100 mutations per cell, in the in vivo acquisition of spontaneous somatic mutation by 2 weeks gestation. IR (4 Gy) had a disproportionate effect on animals homozygous for Brca2 disruption, inducing 3.4-fold more mutations compared with wild-type animals. These data provide the first evidence that loss of Brca2 increases in vivo somatic mutation acquisition and synergizes with IR exposure, with potential attendant implications for mammographic screening and therapeutic IR in mutation carriers.