The Z0011 Trial: Is this the end of axillary ultrasound in the pre-operative assessment of breast cancer patients?

OBJECTIVES: The Z0011 trial questioned the role of axillary ultrasound (AxUS) in preoperative staging of breast cancer in patients with ≤2 positive sentinel lymph nodes (SLN). The purpose of this study was to correlate the number of abnormal nodes on AxUS with final nodal burden and determine the utility of AxUS with sampling (AxUS + S) in preoperative staging. METHODS: Six hundred and seventy-nine patients underwent pre-operative AxUS. Suspicious nodes were sampled. Negative axillae proceeded to SLN biopsy. The number of abnormal nodes identified on ultrasound and final histology as well as sensitivity and specificity for AxUS + S were calculated. Subgroup analysis was performed on Z0011 eligible patients. RESULTS: Two hundred and ninety-six patients had positive axillary nodes on final histology with 169 detected by AxUS + S (sensitivity 86.2%, specificity 100%, PPV 100 %, NPV 71.9%). Patients with nodal metastases identified by AxUS had a mean burden of 7.3 nodes on histology (1 node on AxUS = 5.2 nodes on histology, 2 nodes on AxUS = 7.5 nodes, >2 nodes = 10.1 nodes). Patients diagnosed on SLNB had a mean burden of 2.2 nodes. CONCLUSION: A single nodal metastasis detected on AxUS + S correlated with a mean of 5.2 nodes on final histology highlighting that AxUS remains essential in guiding appropriate management of the axilla in breast cancer. KEY POINTS: • Axillary ultrasound +/- sampling is an essential technique in preoperative axillary staging. • Axillary ultrasound findings correlate with final histological axillary node disease burden. • Axillary ultrasound can help triage patients who require axillary lymph node dissection. • The role of axillary ultrasound in breast cancer staging continues to evolve.

The effect of aerobic exercise on metabolic and inflammatory markers in breast cancer survivors--a pilot study.

PURPOSE: Physical activity is associated with a reduced risk of breast cancer development and recurrence. There are several hypothesised mechanisms for this including positive effects on metabolic and inflammatory biomarkers and favourable changes in anthropometric variables. This pilot study examined the effect of an 8-week aerobic exercise intervention on several of these outcomes, including body composition, the metabolic syndrome, C-reactive protein (CRP) and physical activity, in breast cancer survivors 2-6 months post-chemotherapy. METHODS: Assessments were completed at baseline, at 8-weeks and 3-months post-intervention. Measures taken following a 12-h fast included body composition (bioimpedance analysis), metabolic syndrome (waist circumference, blood pressure, high-density lipoprotein cholesterol, triglycerides and fasting glucose), insulin resistance (homeostatic model assessment), CRP and physical activity (accelerometry and questionnaire). Participants were randomized to either an 8-week moderate-intensity aerobic exercise group or a usual-care control group. Analysis was completed using repeated-measures analysis of variance (ANOVA) (p = 0.05). RESULTS: Twenty-six breast cancer survivors participated (mean (standard deviation) age 48.1 (8.8) years, exercise group; n = 16, control group; n = 10). At baseline, 13 participants were overweight, 6 were obese and 19 centrally obese. Intention-to-treat analysis revealed no significant differences between the exercise and control groups in any of the outcomes measures; however, analysis of those who adhered to >90 % of the supervised exercise class showed a significant decrease in waist circumference (p = 0.05) and a significant increase in subjectively reported "total weekly" (p = 0.005) activity. CONCLUSION: While this 8-week aerobic exercise pilot intervention did not elicit significant improvements in biomarkers of breast cancer risk, there was some suggestion of improvements in waist circumference and subjectively measured physical activity in participants with >90 % adherence to the programme. A trial of longer duration and greater subject numbers is warranted.

Perioperative diagnosis of the positive axilla in breast cancer: a safe, time efficient algorithm.

BACKGROUND: This study evaluates the combined role of axillary ultrasound (Ax US), fine needle aspiration (FNAC) and intraoperative frozen section analysis of the sentinel node (FS SN) in a practical, time efficient algorithm to reduce the requirement for reoperation for axillary clearance in breast cancer in a busy tertiary unit. METHODS: Between October 2007 and June 2009 188 women underwent Ax US as a first investigation for nodal status. Suspicious nodes were biopsied, negative axillae proceeded to FS SN at time of primary breast surgery. All confirmed positive cases proceeded to immediate axillary clearance. RESULTS: 93 women had positive axillary nodes at final histology. Ax US + FNAC identified 59 positive axillae and had a sensitivity of 63.4% and specificity of 100%. FS SN identified a further 26 cases with a sensitivity of 76.5% and specificity of 100%. Overall, only 8 women required reoperation for axillary clearance. Sensitivity for the combined procedures was 91.4%. Commencement of adjuvant therapy was significantly less in those women identified earlier compared to those requiring a second operation (23.3 days vs 49.0 days, p < 0.005). CONCLUSION: 95.7% of cases were diagnosed accurately in the perioperative period, preventing delay to triage to definitive oncological care and reducing requirement for costly reoperation.

Antimetastatic activity of a cyclooxygenase-2 inhibitor.

Cyclooxygenase-2 (COX-2) expression is increased in breast cancer and surgery has been shown to increase the growth of metastatic tumours. We investigated the effect of selective COX-2 inhibition on the growth of metastases in either an experimental metastasis model or following excision of a murine primary breast tumour. 50,000 4T1 mammary carcinoma cells were injected into the mammary fat pad of female BALB/c mice. When the mean TD reached 8+/-0.4 mm, tumours were excised and the mice were randomised into two groups (n=12 per group) to receive daily intraperitoneal injections of the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days. Alternatively, experimental metastases were established by tail-vein injection of 50,000 4T1 cells. Mice received either the selective COX-2 inhibitor, SC-236 or drug vehicle for 14 days (n=12 per group). SC-236 treatment significantly reduced tumour burden, the number and size of spontaneous metastases following primary tumour excision. SC-236 treatment also reduced tumour burden, the number and size of experimental metastases. Immunohistochemical staining demonstrated that COX-2 inhibition reduced microvessel density and increased apoptosis within both spontaneous and experimental metastases. These data clearly demonstrate that the selective COX-2 inhibitor, SC-236, has potent antimetastatic activity against both spontaneous metastases arising following primary tumour excision and experimental metastases.

Lack of prognostic effect of Cox-2 expression in primary breast cancer on short-term follow-up.

AIMS: Cyclo-oxygenase (Cox) catalyses the conversion of arachidonic acid into prostaglandins (PG) and other eciosanoids. The prostaglandins, especially PGE(2) are implicated in tumorigenesis via angiogenesis and suppression of immune reactivity. There are two known isoforms of the enzyme, Cox-1, which is constitutively expressed and the inducible isoform, Cox-2. Cox-2 is induced in response to inflammatory mediators, growth factors, oncogenes and mitogens. Non-selective Cox inhibitors may reduce the relative risk of colonic and breast carcinoma. METHODS: We studied the expression of Cox-2 by immunohistochemistry in 106 primary breast carcinoma specimens collected over a three-year period, using a commercially available polyclonal antibody on formalin-fixed, paraffin-embedded tissue. The slides were examined independently by two pathologists. Tumours were classified according to accepted criteria and an immunohistochemical score (IHS) was calculated for each specimen. The IHS combines the percentage of immunoreactive cells (quantity score) and an estimate of staining intensity (staining intensity score). RESULTS: All patients were female. The mean age was 53 years, range 28-86 years. Forty percent (n=42) of tumours were node negative and 60% (n=64) node positive. Forty-nine percent (n=52) of tumours were grade 3, a further 49% (n=52) grade 2 and 2% (n=2) grade 1. There was no statistically significant correlation between IHS and tumour size, grade, histology, nodal status, estrogen receptor or progesterone receptor positivity. A trend was observed showing an IHS of zero is associated with prolonged survival compared with an IHS of 9-12. CONCLUSION: Cox-2 expression in primary breast cancer does not correlate with accepted pathological or biochemical prognostic indicators.

Gastrointestinal stromal tumours.

BACKGROUND: Gastrointestinal stromal tumours (GISTs), previously classified as benign or malignant smooth muscle tumours, are the most common mesenchymal tumours of the gastrointestinal tract. GISTs express a growth factor receptor with tyrosine kinase activity, termed KIT. Mutations of KIT are common in malignant GISTs and lead to constitutional activation of tyrosine kinase function, which causes cellular proliferation and resistance to apoptosis. GISTs are notoriously unresponsive to chemotherapy and, until the recent introduction of the KIT inhibitor imatinib, there has been no effective therapy for advanced, metastatic disease. METHODS: A Medline literature search was preformed to locate all articles relating to gastrointestinal tumours, GISTs, KIT and imatinib. RESULTS AND CONCLUSIONS: The 5-year survival rate after complete resection of GISTs is approximately 50 per cent. The median duration of survival for patients with a metastatic GIST is approximately 20 months, and 9-12 months for patients with local recurrence. Phase II trials have investigated the effect of imatinib on irresectable or metastatic GISTs. In these trials more than 50 per cent of patients responded to imatinib within a few months and approximately 12 per cent had disease progression. Uptake of [(18)F]fluoro-2-deoxy-D-glucose demonstrated by positron emission tomography has been found to be reduced after starting imatinib. The potential for cure and the optimal length of treatment is currently unknown. Imatinib is the first effective systemic therapy for metastatic and locally irresectable GISTs. Large multi-institutional clinical trials to investigate the efficacy of imatinib as adjuvant or neoadjuvant therapy for GISTs are now required.

Pharmacological induction of HSP27 attenuates intimal hyperplasia in vivo.

OBJECTIVES: intimal hyperplasia (IH) is a major cause of re-stenosis post-vascular intervention. Induction of heat shock proteins (HSPs), by thermal pre-conditioning, reduces IH. Our aim was to investigate the effect of the pharmacological HSP inducer herbimycin A on IH in the rat carotid balloon injury model. MATERIALS AND METHODS: thirty male Sprague-Dawley rats were randomized into three groups. All groups underwent balloon injury to the left carotid artery. Stress proteins were induced 18 h pre-operatively by heat shock or herbimycin A. Two weeks post-operatively, animals were sacrificed and carotid intima/media area ratio (I/M ratio) calculated using computerized planimetry. Neo-intimal proliferation was assessed immunohistochemically with PCNA (proliferating cell nuclear antigen). Western blot and immunohistochemistry for arterial HSP70 and HSP27 were performed. RESULTS: heat stress and herbimycin significantly reduced the I/M ratio (p < 0.05 vs balloon injury alone). Neo-intimal proliferation was significantly reduced in the heat stress and herbimycin groups (p < 0.05 vs balloon injury alone). Heat stress induced arterial HSP70 and HSP27. Herbimycin A increased arterial HSP27. CONCLUSION: herbimycin A significantly attenuates IH after balloon injury. HSP27 may be the HSP involved in mediating this response. Pharmacological inducers of HSPs may have a therapeutic role to play in preventing re-stenosis post-vascular intervention.

A novel treatment for chronic pancreatitis.

BACKGROUND: Hereditary pancreatitis is an important cause of chronic pancreatitis, which may result in endocrine and exocrine failure. This may necessitate simultaneous pancreas and kidney transplant (SPK). Bladder drainage of the exocrine secretions may cause problems. AIM: To report one such case and its surgical correction. METHODS: A 20-year-old male with insulin-dependent diabetes mellitus secondary to idiopathic chronic pancreatitis had a SPK with bladder drainage. Urological and metabolic complications secondary to the drainage of pancreatic secretions, rich in proteolytic enzymes required convertion from bladder to enteric drainage. RESULTS: He was able to discontinue his pancreatic enzyme supplements, ceased to have steatorrhoea and gained weight. He was referred to the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC), hereditary pancreatitis was confirmed by genetic analysis. CONCLUSION: Enteric-drained pancreas transplantation is a successful treatment for exocrine as well as endocrine pancreatic failure and should be considered as a treatment option in patients with chronic pancreatitis.

Cyclo-oxygenase inhibition reduces tumour growth and metastasis in an orthotopic model of breast cancer.

The effect of selective and non-selective cyclo-oxygenase inhibition on tumour growth and metastasis in an orthotopic model of breast cancer was investigated. 4T1 mammary adenocarcinoma cells were injected into the mammary fat pad of female BALB/c mice. When tumours reached a mean tumour diameter of 8.4+/-0.4 mm, mice were randomised into three groups (n=6 per group) and received daily intraperitoneal injections of the selective cyclo-oxygenase-2 inhibitor, SC-236, the non selective cyclo-oxygenase inhibitor, Indomethacin, or drug vehicle. Tumour diameter was recorded on alternate days. From 8 days after initiation of treatment, tumour diameter in animals treated with either SC-236 or indomethacin was significantly reduced relative to controls. Both primary tumour weight and the number of lung metastases were significantly reduced in the SC-236 and indomethacin treated mice. Microvessel density was reduced and tumor cell apoptosis increased in the primary tumour of mice treated with either the selective or non-selective cyclo-oxygenase inhibitor. In vitro, cyclo-oxygenase inhibition decreased vascular endothelial growth factor production and increased apoptosis of tumour cells. Our results suggest that cyclo-oxygenase inhibitors will be of value in the treatment of both primary and metastatic breast cancer.

Enteric conversion after bladder-drained pancreatic transplantation; a simple and safe salvage procedure.

OBJECTIVE: To present our experience with conversion from bladder to enteric drainage after simultaneous pancreatic and renal transplants, so that new transplant centres know that it is both safe and effective. DESIGN: Retrospective study. SETTINGS: Teaching hospital, Republic of Ireland. SUBJECTS: Six patients who had simultaneous pancreatic and renal transplants for insulin-dependent diabetes and who subsequently developed complications of bladder drainage including recurrent episodes of dehydration and metabolic acidosis (n = 3), haematuria (n = 2), and urinary tract infections (n = 1). INTERVENTION: Conversion to enteric drainage. MAIN OUTCOME MEASURE: Resolution of symptoms. RESULTS: All symptoms resolved, but one patient each developed pulmonary oedema, haematuria, and prolonged ileus. All three complications resolved on conservative treatment. All patients are well with surviving grafts a mean of 40 months later (range 19-50). CONCLUSION: Conversion to enteric drainage is safe and effective in patients with refractory metabolic or urological complications of bladder drainage after simultaneous pancreatic and renal transplantation.

Randomized clinical trial of diathermy versus scalpel incision in elective midline laparotomy.

BACKGROUND: Electrocautery is used increasingly for tissue dissection, although fears of excessive scarring and poor wound healing have curtailed its widespread use for skin incision. This study compared electrosurgical incision with traditional scalpel incision. METHODS: One hundred patients requiring elective midline laparotomy were randomized prospectively to either scalpel or diathermy incision. Parameters measured included incision time, wound size, wound blood loss, total intraoperative blood loss and postoperative wound pain. All wound complications were recorded. RESULTS: The two groups did not differ significantly in relation to patient or wound characteristics. Laparotomy incisions using diathermy were significantly quicker than scalpel incisions (mean(s. e.m.) 6.1(0.4) versus 7.5(0.5) s/cm2; P < 0.04). There was significantly less blood loss in the diathermy group compared with the scalpel group (0.8(0.1) versus 1.7(0.3) ml/cm2; P = 0.002). Postoperative pain scores were significantly lower in the diathermy group for the first 48 h after operation (P < 0.05). Morphine requirements were also significantly lower over the first 5 postoperative days in the diathermy incision group (P < 0.04). There was no difference between groups in wound complications before discharge and at the 1-month follow-up. CONCLUSION: Electrosurgical midline incision in elective surgery has significant advantages over scalpel use on the basis of incision time, blood loss, early postoperative pain and analgesia requirements.

Complications relating to the urinary tract associated with bladder-drained pancreatic transplantation.

OBJECTIVE: To evaluate the incidence and management of the urological complications after bladder-drained pancreatic transplantation. PATIENTS AND METHODS: A retrospective study was carried out on 24 consecutive bladder-drained pancreatic transplants in 24 patients with type I insulin-dependent diabetes mellitus, 22 with simultaneous kidney transplants and two of pancreas alone, over a period of 53 months. RESULTS: All 24 patients were alive within a mean follow-up of 26.7 months: 22 patients have functioning pancreatic grafts and are insulin-independent. The overall incidence of urological complications was 83% (20 of 24 patients) and 14 patients had more than one complication. The major non-infective complication was haematuria (eleven), which was treated conservatively, with only two patients requiring enteric conversion. One patient developed a duodeno-vesical fistula and lost the functioning pancreatic graft as a consequence. Other non-infective complications were urethritis (one) and urethral stricture (one), which were managed with catheter drainage and internal urethrotomy, respectively, and vulval ulcers (one) and reflux pancreatitis (one) treated conservatively. The main infective complications were recurrent lower urinary tract infection (nine), asymptomatic persistent bacteriuria (nine), prostatitis and epididymitis (one), and pyelonephritis (one), all managed with appropriate antibiotics. Three patients developed septicaemia from urosepsis and were treated successfully with antibiotics. Two patients developed genital warts and were treated with laser vaporization. CONCLUSION: Although bladder drainage has significantly contributed to the increasing success of pancreatic transplantation, urological complications are frequent and can be serious and life-threatening. As more of these procedures are performed urologists need to be able to recognize and treat these problems.

Randomized, prospective trial of bilevel versus continuous positive airway pressure in acute pulmonary edema.

OBJECTIVE: To evaluate whether bilevel positive airway pressure, by actively assisting inhalation, more rapidly improves ventilation, acidemia, and dyspnea than continuous positive airway pressure (CPAP) in patients with acute pulmonary edema. DESIGN: Randomized, controlled, double-blind trial. SETTING: Emergency department in a university hospital. PATIENTS: Twenty-seven patients, presenting with acute pulmonary edema, characterized by dyspnea, tachypnea, tachycardia, accessory muscle use, bilateral rales, and typical findings of congestion on a chest radiograph. INTERVENTIONS: In addition to standard therapy, 13 patients were randomized to receive nasal CPAP (10 cm H2O), and 14 patients were randomized to receive nasal bilevel positive airway pressure (inspiratory and expiratory positive airway pressures of 15 and 5 cm H2O, respectively) in the spontaneous/timed mode that combines patient flow-triggering and backup time-triggering. MEASUREMENTS AND MAIN RESULTS: After 30 mins, significant reductions in breathing frequency (32 +/- 4 to 26 +/- 5 breaths/min), heart rate (110 +/- 21 to 97 +/- 20 beats/min), blood pressure (mean 117 +/- 28 to 92 +/- 18 mm Hg), and Paco2 (56 +/- 15 to 43 +/- 9 torr [7.5 +/- 2 to 5.7 +/- 1.2 kPa]) were observed in the bilevel positive airway pressure group, as were significant improvements in arterial pH and dyspnea scores (p < .05 for all of these parameters). Only breathing frequency improved significantly in the CPAP group (32 +/- 4 to 28 +/- 5 breaths/min, p < .05). At 30 mins; the bilevel positive airway pressure group had greater reductions in Paco2 (p = .057), systolic blood pressure (p = .005), and mean arterial pressure (p = .03) than the CPAP group. The myocardial infarction rate was higher in the bilevel positive airway pressure group (71%) compared with both the CPAP group (31%) and historically matched controls (38%) (p = .05). Duration of ventilator use, intensive care unit and hospital stays, and intubation and mortality rates were similar between the two groups. CONCLUSIONS: Bilevel positive airway pressure improves ventilation and vital signs more rapidly than CPAP in patients with acute pulmonary edema. The higher rate of myocardial infarctions associated with the use of bilevel positive airway pressure highlights the need for further studies to clarify its effects on hemodynamics and infarction rates, and to determine optimal pressure settings.