Performance of four published risk models to predict sentinel lymph-node involvement in Australian women with early breast cancer.

BACKGROUND: Sentinel lymph-node biopsy has reduced the need for extensive axillary surgery for staging. It still exposes women to associated morbidity. Risk models that use clinical and pathology information of the primary tumour to predict sentinel lymph-node metastasis may allow further improvements in care. This study assessed the performance of four published risk models for predicting sentinel lymph-node metastasis in Australian women with early breast cancer; including one model developed in an Australian population. METHODS: The Sentinel Node Biopsy Versus Axillary Clearance (SNAC) trial dataset was used to assess model discrimination by calculating the area under the receiver-operating-characteristic curve (AUC) and the false-negative rate for sentinel lymph-node metastasis using model-predicted risk cut-points of 10%, 20%, 30%, and calibration using Hosmer-Lemeshow tests and calibration plots. RESULTS: The sentinel node was positive in 248 of 982 (25.2%) women (158 macrometastasis, 90 micrometastasis). The AUCs of risk models ranged from 0.70 to 0.74 for prediction of any sentinel-node metastasis; 0.72 to 0.75 for macrometastasis. Calibration was poor for the three models developed outside of Australia (lack-of-fit statistics, P < 0.001). For women with a model-predicted risk of sentinel lymph-node metastasis ≤10%, observed risk was 0-13% (three models <10%), false-negative rate 0-9%; 1-17% of women were classified in this range. CONCLUSION: All four models showed good discrimination for predicting sentinel lymph-node metastasis, in particular for macrometastasis. With further development such risk models could have a role in the provision of reassurance to low risk women with normal nodes sonographicaally for whom no axillary surgery is contemplated.

Contemporary indications for diagnostic open biopsy in women assessed for screen-detected breast lesions: A ten-year, single institution series of 814 consecutive cases.

PURPOSE: In contemporary practice, 5% of women with non-malignant needle biopsies of screen-detected lesions still require diagnostic open biopsy (OBx). Our aims are to (i) capture a snapshot of the contemporary indications for OBx in screen-detected lesions; (ii) determine upgrade rates to malignancy (DCIS or invasive cancer); (iii) identify indications with sufficiently low upgrades to justify avoidance of OBx and (iv) propose plausible non-surgical alternatives. METHODS: Between Jan 2005 and Dec 2014, women assessed for a screen-detected lesion and recommended for OBx are included. We retrieved patient, imaging, biopsy and final pathology or follow-up data. RESULTS: 814 lesions, mean diameter 16.7 mm, microcalcifications in 353 (43.4%) cases, lesions other than calcifications in 461 (56.6%), mean patient age 58.4 yrs, are included. Surgery was performed in 98.2% cases. Imaging follow-up (1-6.5 yrs) is available in 13 of 15 remaining cases. 27 indications for OBx were identified, with a prevalence of 0.3-13.9%. Borderline lesions (BL) comprised 64% of OBx indications, amongst which atypical ductal hyperplasia was the most prevalent at 13.9%, followed by papillary lesions, radial scars, flat epithelial atypia and lobular neoplasia. Imaging factors contributed 26.3% of OBx. In 9.8% of cases, NCB was not performed due to client, technical or cytologic factors. Overall, 261(32.1%) lesions were malignant at OBx. Upgrade rates varied from 0 to 100%, depending on the specific indication for OBx. CONCLUSIONS: Surgical biopsy remains a valuable method of last resort for breast cancer diagnosis but strategies to limit benign breast surgery merit attention as a public health issue.

Effectiveness of core biopsy for screen-detected breast lesions under 10 mm: implications for surgical management.

BACKGROUND: Technical advances have improved the detection of small mammographic lesions. In the context of mammographic screening, accurate sampling of these lesions by percutaneous biopsy is crucial in limiting diagnostic surgical biopsies, many of which show benign results. METHODS: Women undergoing core biopsy between January 1997 and December 2007 for <10-mm lesions are included. Patient demographics, imaging features and final histology were tabulated. Performance indices were evaluated. RESULTS: This audit includes 803 lesions <10 mm. Based on core histology, 345 women (43.0%) were immediately cleared of malignancy and 300 (37.4%) were referred for definitive cancer treatment. A further 157 women (19.6%) required diagnostic surgical biopsy because of indefinite or inadequate core results or radiological-pathological discordance, and one woman (0.1%) needed further imaging in 12 months. The open biopsies were malignant in 46 (29.3%) cases. The positive predictive value of malignant core biopsy was 100%. The negative predictive value for benign core results was 97.7%, and the false-negative rate was 2.6%. The lesion could not be visualized after core biopsy in 5.1% of women and in 4.0% of women with malignant core biopsies excision specimens did not contain residual malignancy. Excessive delays in surgery because of complications of core biopsy were not reported. CONCLUSION: Even at this small size range, core biopsy evaluation of screen-detected breast lesions is highly effective and accurate. A lesion miss rate of 3.1% and under-representation of lesions on core samples highlight the continued need for multidisciplinary collaboration and selective use of diagnostic surgical biopsy.

Phyllodes tumour among participants in screening mammography.

BACKGROUND: In screening, the distinction between phyllodes tumour (PT) and fibroadenoma (FA) is imprecise, often needing surgery. METHODS: In this retrospective cohort study and literature review, we wished to (i) present our experience with PT diagnosed among screening participants; (ii) identify discriminating features between FA and PT; (iii) assess the efficacy of cancer screening in identifying PT; and (iv) for women diagnosed with PT, determine appropriate breast cancer screening schedules. RESULTS: During a 23.7 years time frame, PT was diagnosed in 30 women, reflecting an incidence of 2.53 per 100 000 women screened. Only 22 (73.3%) PT were found by screening. The remaining eight (26.7%) presented as interval tumours. Thirteen PT were benign, eight borderline and nine malignant. Six of eight (75%) malignant PT were symptomatic. A circumscribed mass, mean diameter 34.7 mm, was the dominant finding. Enlargement (14 imaging, seven clinical) was documented in 21 (70%) cases. Diagnostic open biopsy was required in 67.9%. Follow-up of at least 12 months is available in 20 cases. Only two developed recurrence. One woman died of metastatic PT and one PT recurred locally. CONCLUSION: The extreme rarity of PT in screening contrasts with the prevalence of FAs. The peak incidence of PT in women is 40-50, whereas screening is targeted at women 50-74. Two yearly screening mammography is not designed to detect PT reliably. In particular, malignant PT grows rapidly and becomes symptomatic. Women with benign PT can continue with screening. Women with borderline and malignant PT should resume screening after 5 years of specialist surveillance.

Cancer Detection in Human Tissue Samples Using a Fiber-Tip pH Probe.

Intraoperative detection of tumorous tissue is an important unresolved issue for cancer surgery. Difficulty in differentiating between tissue types commonly results in the requirement for additional surgeries to excise unremoved cancer tissue or alternatively in the removal of excess amounts of healthy tissue. Although pathologic methods exist to determine tissue type during surgery, these methods can compromise postoperative pathology, have a lag of minutes to hours before the surgeon receives the results of the tissue analysis, and are restricted to excised tissue. In this work, we report the development of an optical fiber probe that could potentially find use as an aid for margin detection during surgery. A fluorophore-doped polymer coating is deposited on the tip of an optical fiber, which can then be used to record the pH by monitoring the emission spectra from this dye. By measuring the tissue pH and comparing with the values from regular tissue, the tissue type can be determined quickly and accurately. The use of a novel lift-and-measure technique allows for these measurements to be performed without influence from the inherent autofluorescence that commonly affects fluorescence-based measurements on biological samples. The probe developed here shows strong potential for use during surgery, as the probe design can be readily adapted to a low-cost portable configuration, which could find use in the operating theater. Use of this probe in surgery either on excised or in vivo tissue has the potential to improve success rates for complete removal of cancers. Cancer Res; 76(23); 6795-801. ©2016 AACR.

Review of the role of sentinel node biopsy in cutaneous head and neck melanoma.

Sentinel node biopsy (SNB) is recommended for selected melanoma patients in many parts of the world. This review examines the evidence surrounding the accuracy and prognostic value of SNB and completion neck dissection in head and neck melanoma. Sentinel nodes were identified in an average of 94.7% of head and neck cases compared with 95.3-100% in all melanoma cases. More false-negative sentinel nodes were found in head and neck cases. A positive sentinel node was associated with both lower disease-free survival (53.4 versus 83.2%) and overall survival (40 versus 84%). We conclude that SNB should be offered to all patients with intermediate and high-risk melanomas in the head and neck area. To date, evidence does not exist to demonstrate the safety of avoiding completion lymph node dissection in sentinel node-positive patients with head and neck melanoma.

A comparison of vitamin D activity in paired non-malignant and malignant human breast tissues.

Links between a low vitamin D status and an increased risk of breast cancer have been observed in epidemiological studies. These links have been investigated in human tissue homogenates and cultured cell lines. We have used non-malignant, malignant and normal reduction mammoplasty breast tissues to investigate the biological and metabolic consequences of the application of vitamin D to intact ex vivo human breast tissue. Tissues were exposed to 1α,25(OH)(2)D(3) (1,25D; active metabolite) and 25(OH)D (25D; pre-metabolite). Changes in mRNA expression and protein expression after vitamin D exposure were analysed. Results indicate that while responses in normal and non-malignant breast tissues are similar between individuals, different tumour tissues are highly variable with regards to their gene expression and biological response. Collectively, malignant breast tissue responds well to active 1,25D, but not to the inactive pre-metabolite 25D. This may have consequences for the recommendation of vitamin D supplementation in breast cancer patients.

Diagnostic value of an initial C-reactive protein level in acute surgical patients.

BACKGROUND: In surgical patients, C-reactive protein (CRP) levels are often measured as a marker of inflammation and infection. However, the diagnostic and prognostic value of a single initial CRP measurement in the acute presentation has not been well established. This study was performed to investigate the usefulness of measuring CRP in such a setting. METHODS: CRP levels were measured retrospectively in 473 surgical patients who presented to the Royal Adelaide Hospital emergency department. This was correlated with patient outcomes, defined by the need for imaging tests and/or surgical interventions, the length of hospital stay and 30-day mortality. Spearman's rank correlation and one-way analysis of variance were used for statistical analysis. RESULTS: Of 473 patients, 42% had a CRP test in the emergency department within 24 h of admission. Approximately 80% of patients required imaging for diagnosis and 40% required surgery, regardless of the initial CRP level. No correlation was evident between initial CRP level and length of hospital stay (r= 0.06). One-way analysis of variance revealed no variation in levels between patients who required imaging or had surgery compared to those who did not, with P-values of 0.76 and 0.85, respectively. Two patients died within 30 days of presentation. CONCLUSIONS: CRP has poor diagnostic and prognostic capabilities as a single initial measurement in acute surgical patients. The statistical analyses imply that CRP levels are unable to accurately predict outcomes of such patients. Therefore, we suggest that CRP should not be used as a routine screening tool.

Predictors of malignancy in screen-detected breast masses with indeterminate/equivocal (grade 3) imaging features.

BACKGROUND: The mammographic grading system used by BreastScreen Australia accredited programs requires needle biopsy of lesions with indeterminate features (grade 3). We wished to determine the predictors of malignancy for these common lesions, so as to reduce surgery for benign lesions. DESIGN: Grade 3 masses assessed between Jan 1996-Dec 2005 are included. New or changing lesions were identified through film review. Imaging, demographic and final outcome data were tabulated. Statistical analysis was performed to determine the predictors of malignancy. RESULTS: 1181 lesions, including 623 new or changing masses are assessed. Of these 98 (8.3%) were malignant. Malignancy was found in 3% first round masses versus 13% of new or changing lesions. Withholding needle biopsy results, interval change (OR 2.85, p = 0.0001), increasing age (p = 0.0001) and diameter were independent predictors of malignancy, lesion diameter having an inverse relationship with malignancy. Once needle biopsy results were included, this parameter became the sole predictor of malignancy as other factors lost significance in a multivariate model. CONCLUSION: Surgical biopsy is not indicated in well-sampled grade 3 masses with benign needle biopsy results. Surgery is valuable for diagnosis or treatment of the remaining such masses without benign needle biopsy results.

Comparing patients' and clinicians' assessment of outcomes in a randomised trial of sentinel node biopsy for breast cancer (the RACS SNAC trial).

The RACS sentinel node biopsy versus axillary clearance (SNAC) trial compared sentinel-node-based management (SNBM) and axillary lymph-node dissection (ALND) for breast cancer. In this sub study, we sought to determine whether patient ratings of arm swelling, symptoms, function and disability or clinicians' measurements were most efficient at detecting differences between randomized groups, and therefore, which of these outcome measures would minimise the required sample sizes in future clinical trials. 324 women randomised to SNBM and 319 randomised to ALND were included. The primary endpoint of the trial was percentage increase in arm volume calculated from clinicians' measurements of arm circumference at 10 cm intervals. Secondary endpoints included reductions in range of motion and sensation (both measured by clinicians); and, patients' ratings of arm swelling, symptoms and quality of life, using the European Organisation for Research and Treatment of Cancer Breast Cancer Module (EORTC QLM-BR23), the body image after breast cancer questionnaire (BIBC) and the SNAC study specific scales (SSSS). The relative efficiency (RE, the squared ratio of the test statistics, with 95% confidence intervals calculated by bootstrapping) was used to compare these measures in detecting differences between the treatment groups. Patients' self-ratings of arm swelling were generally more efficient than clinicians' measurements of arm volume in detecting differences between treatment groups. The SSSS arm symptoms scale was the most efficient (RE = 7.1) The entire SSSS was slightly less so (RE = 4.6). Patients' ratings on single items were 3-5 times more efficient than clinicians' measurements. Primary endpoints based on patient-rated outcome measures could reduce the required sample size in future surgical trials.

Atypical presentations of screen-detected DCIS Implications for pre-operative assessment and surgical intervention.

Few series are published on DCIS that forms parenchymal lesions on screening mammograms. The implications of these unusual presentations for pre-operative assessment and surgical intervention are of interest. In the setting of a large, population-based breast cancer screening program, the diagnostic and management implications of DCIS presenting as parenchymal lesions on screening mammograms are investigated. A total of 125 lesions (20.1% of all DCIS) presented as a mass (n=99) or microcalcifications with an associated parenchymal lesion (n=26). Cytology was positive in 47.1% of cases. Core biopsy diagnosed DCIS in 68.4% of cases. Breast surgery after a definite preoperative diagnosis achieved negative initial margins in 69.4% case, versus 54.7% without a pre-operative malignant diagnosis. The mastectomy rate was 26.4%. Axillary surgery was carried out in 32.8% cases, including axillary clearance in 26.4% of cases. One in five cases of DCIS detected during mammographic screening has features other than pure microcalcifications. This has implications for pre-operative assessment and surgical management.

Participation in the RACS sentinel node biopsy versus axillary clearance trial.

BACKGROUND: The Royal Australasian College of Surgeons (RACS) SNAC trial is a randomized controlled trial of sentinel node biopsy (SNB) versus axillary clearance (AC). It opened in May 2001 and is recruiting rapidly with good acceptance by consumers. METHODS: A study of eligibility and treatment choices was conducted between November 2001 and September 2002 for women presenting with early breast cancer to 10 centres participating in the trial. RESULTS: More than half of the 622 women (54%) were ineligible for trial entry because they had large (> 3 cm) or multicentric cancers. Participation was offered to 92% of eligible women and was taken up by 63%. The commonest reason for not participating was the desire to choose treatment rather than have it randomly allocated. Despite this there is a great acceptance of clinical trials because very few women (4% of those eligible) gave 'lack of interest in clinical trials' as the reason for non-participation. Few women who declined trial participation chose to have SNB alone (4.5% of those eligible). CONCLUSION: Sentinel node biopsy may become the standard of care for managing small breast cancers, but a significant number of patients will still require or choose axillary dissection. Results from large randomized trials are needed to determine the relative benefits and harms of SNB compared with AC. Surgeons must carefully discuss options for management with their patients.

A decision aid for predicting non-sentinel node involvement in women with breast cancer and at least one positive sentinel node.

BACKGROUND: Several clinical trials are re-evaluating the management of the axilla after sentinel node (SN) biopsy. Approximately 50-70% of patients with positive SN have no further nodal involvement. Estimates of the risk of non-sentinel node (NSN) involvement would aid decisions regarding further axillary surgery. METHODS: Clinical and pathological variables for 82 breast cancer patients with metastasis to at least one SN, were used to find independent predictors of the status of NSNs. RESULTS: NSN metastases were found in 46.3% of patients. In a regression model patient age, proportion of SN replaced by metastasis and number of SNs were independent predictors of NSN status. CONCLUSION: Data available after SN biopsy allow estimation of the risk of NSN metastases among patients with positive SNs. Individualised estimates of the risk of NSN involvement may facilitate discussions regarding the trade off between the likely benefits of further axillary surgery and the morbidity of this procedure.

Breast volume replacement using the latissimus dorsi miniflap.

BACKGROUND: Mastectomy is often recommended to women with early breast cancer who have large tumours or where the breast volume requiring resection to achieve adequate tumour clearance is too great to allow for a satisfactory cosmetic result after breast conservation surgery. The use of a latissimus dorsi muscular flap (latissimus dorsi miniflap (LDMF)) to replace the volume loss after major breast sector resection is an option where the tumour to breast volume ratio is large. The present study describes the technique and evaluates the experience of the LDMF at Royal Adelaide Hospital, Adelaide, Australia. METHODS: Between August 1997 and April 2002, 18 women aged 37-64 years underwent wide local excision for primary breast cancer with LDMF reconstruction. Tumour characteristics, breast specimen weight and postoperative sequelae were assessed. Quality of life measurements and objective assessments of aesthetic outcome were evaluated. RESULTS: Tumour diameter ranged from 13 to 80 mm (median 30 mm). Nine patients had multifocal or extensive intraductal component positive tumours. The weight of the resected specimens ranged from 75 to 395 g (median 130 g). There were no major postoperative complications, with a range of inpatient stay of 3-10 days. Seromas were aspirated in 14 patients but did not delay adjuvant treatment. Quality of Life results showed high patient satisfaction in all but one patient. A satisfactory cosmetic result was achieved in all but one patient who subsequently required mastectomy. CONCLUSION: The LDMF procedure allows breast conservation to be achieved in women with large tumour to breast volume ratios, with satisfactory resection margins and good cosmetic and functional results. In the present experience standard oncological adjuvant treatment is not compromised.

Implication of intraoperative sentinel node imprint cytology for consent in the SNAC Trial.

BACKGROUND: Women randomized into the sentinel node biopsy-only arm of the Sentinel Node versus Axillary Clearance Trial require axillary clearance if the sentinel node is unable to be identified, or if the sentinel node contains metastases. The aim of the present study was to determine the likelihood of immediate and delayed axillary clearance in patients in the trial when nodes were subjected to intraoperative imprint cytology. METHODS: A prospective database for 400 patients with operable breast cancer was analysed to determine the likelihood of lymph node involvement according to tumour size. The ability to successfully remove a sentinel node and the accuracy of intraoperative imprint cytology of sentinel nodes was investigated. These data were used to predict the likelihood of patients proceeding to immediate or delayed axillary clearance. RESULTS: The rate of lymph node involvement was 0%, 10%, 30%, and 53% in tumours measuring <5 mm, 6-10 mm, 11-20 mm and 21-30 mm, respectively. A sentinel node was identified in 95% of cases. In a series of 79 consecutive cases using intraoperative imprint cytology, 37% of sentinel nodes containing metastases were identified intraoperatively. The estimated likelihood of undergoing immediate axillary clearance therefore ranges from 5% for tumours <5 mm, up to 24% for tumours 21-30 mm. Similarly the likelihood of delayed clearance ranges from 0% to 32% depending on tumour size. CONCLUSIONS: It is possible to give detailed and accurate information to patients undergoing sentinel node biopsy about both the risk of lymph node involvement and the likelihood of requiring immediate or secondary axillary clearance.

Sentinel lymph node dissection and lymphatic mapping for local subcutaneous recurrence in melanoma treatment: longer-term follow-up results.

Lymphatic mapping and sentinel lymph node dissection (LM/SLND) for surgical staging of cutaneous primary melanoma is currently being evaluated, but the role of these techniques in recurrent (secondary) melanoma is largely unexplored. Our experience with 12 patients indicates the potential usefulness of LM/SLND in the management of locally recurrent melanoma at subcutaneous sites. We have even used mapping to localize the sentinel node draining a subcutaneous local recurrence after previous LM/SLND for primary melanoma. The application of LM/SLND may therefore be extended beyond primary melanoma management as we understand more about the technical issues and appropriate selection of patients.

Sentinel lymph node biopsy versus axillary clearance in operable breast cancer: The RACS SNAC trial, a multicenter randomized trial of the Royal Australian College of Surgeons (RACS) Section of Breast Surgery, in collaboration with the National Health and Medical Research Council Clinical Trials Center.

The aim of the SNAC trial is to determine if sentinel node biopsy (SNB) produces less morbidity and equivalent cancer-related outcomes in comparison with immediate axillary clearance (AC) in women with early breast cancer. The intervention is SNB followed by immediate AC, or SNB followed by AC only if the SNB specimen is positive. This is a multicenter, centrally randomized phase III trial of 1000 women stratified according to age, tumor palpability, lymphatic mapping technique, and center. Accrual rate is 26 women per month; 789 women have been randomized to date. Analysis of the first 150 women indicates good compliance with study treatment and acceptable surgical technique.

Intraoperative imprint cytologic assessment of the sentinel node for early breast cancer.

An increasing number of patients are undergoing sentinel node biopsy alone for axillary staging of early breast cancer. A reliable method for evaluating the status of the sentinel node intraoperatively would allow patients with sentinel node metastases to undergo immediate rather than delayed axillary clearance. Sentinel nodes in 53 consecutive patients were examined by intraoperative imprint cytology. When compared with subsequent analysis by hematoxylin-eosin staining and immunohistochemistry, the accuracy of imprint cytology for the detecting nodal metastases was 81.1%; the false negative rate was 47.0%, and there were no false positives. Results were made available to the operating surgeon within a mean time of 25 minutes. All but one of the false negatives involved micrometastatic deposits of less than 0.1 mm. Intraoperative imprint cytologic examination of the sentinel node is a useful technique that can be performed efficiently and without loss of nodal tissue for subsequent analysis. With the use of this technique, more than 50% of lymph node-positive patients would potentially be spared a second operation.

Adjuvant immunotherapy of patients with high-risk melanoma using vaccinia viral lysates of melanoma: results of a randomized trial.

PURPOSE: Patients with high-risk melanoma treated by immunotherapy with vaccinia viral lysates were found in phase II studies to have improved survival compared with historical controls. We therefore elected to test this therapy in a phase III study. PATIENTS AND METHODS: A prospective, randomized, multicenter trial to determine whether immunotherapy with a vaccine prepared from vaccinia melanoma cell lysates (VMCL) over a 2-year period after definitive surgery would improve relapse-free survival (RFS) and overall survival (OS) in patients with American Joint Committee on Cancer stage IIB and III melanoma compared with a control group treated only with surgery. RESULTS: A total of 700 patients were randomized: 353 to VMCL and 347 to no immunotherapy. Seventy-seven percent had lymph node (LN) metastases and 66% had clinically detected LN metastases. Analysis on the basis of all eligible, randomized patients (n = 675) found, after a median follow-up period of 8 years, a median OS of 88 months in the control versus 151 months in the treated group (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.64 to 1.02; P =.068 by stratified univariate Cox analysis). At 5 and 10 years, survival rates for control and treated patients were 54.8% v 60.6% and 41% v 53.4%, respectively. Median RFS was 43 months in the control group compared with 83 months in the treated group (HR, 0.86; 95% CI, 0.7 to 1.07; P =.17). RFS at 5 years was 50.9% for the treated group and 46.8% for the control group. There were no selective benefits from the vaccine for particular subsets of patients. CONCLUSION: Immunotherapy with VMCL was not associated with a statistically significant improvement in OS or RFS, with CIs not ruling out important gains from such treatment.