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Notes: Abstract:  The changing trends in the diagnosis and management of women with invasive breast cancer have prompted an examination of the need for routine axillary lymph node dissection (ALND) in women with a clinically negative axilla. The objective of this study was to examine the value of information from an ALND in guiding the selection of adjuvant systemic therapy for women with clinically node-negative breast cancer. Between January 1996 and June 2000, 447 clinically node-negative women underwent an ALND as part of their treatment for invasive breast cancer at Westmead Hospital. Three categories of risk of recurrence were devised, based on the primary tumor characteristics alone, without information from an ALND. Recommendations for adjuvant systemic therapy with and without information from an ALND were compared, and the frequency of change was calculated. Overall, 12% of women had their treatment recommendation altered by their pathologic nodal status based on the model treatment algorithm. For women in the low-risk category (pathologic tumor size ≤10 mm, grade 1, lymphovascular invasion [LVI] negative, and estrogen receptor [ER] positive), 17% of those less than 50 years old and 14% of those 50–69 years old would have a shift in their treatment recommendations based on the pathologic nodal status. In addition, 13% of the women less than 50 years old and 10% of those 50–69 years old were recommended for more intensive chemotherapy on the basis of four or more involved nodes. For women in the high-risk category (pathologic tumor size greater than 20 mm or greater than 10 mm associated with any unfavorable prognostic factor [grade 3, LVI, or negative ER]), 19% of those less than 50 years old and 18% of those 50–69 years old were recommended for more intensive chemotherapy. Information from ALND did not alter the treatment recommendation for women ≥70 years old, as they were not recommended chemotherapy in the model algorithm. If women ≥70 years old who were node positive and had an ER-negative tumor were recommended chemotherapy, 14% in the high-risk category would have had their treatment recommendation altered as a result of the information from ALND. The continued utilization of ALND is appropriate in women less than 70 years old in the high-risk category. In other patients less than 70 years old, the pathologic nodal status is of value in guiding the selection of women for adjuvant systemic therapy. For women ≥70 years old, information from an ALND adds little to the selection of patients for adjuvant systemic therapy. However, in selected patients ≥70 years old who are classified as high risk on the basis of unfavorable primary tumor features, and are potential candidates for chemotherapy, an ALND would be appropriate. 

Notes: The purpose of this article was to review the patterns and morbidity of regional recurrence (RR) in patients with early breast cancer, efficacy of salvage therapy for RR, and complications of regional nodal treatment. A retrospective evaluation of 1,158 patients with stage I or stage II breast cancer treated with conservative surgery and radiotherapy (RT) between 1979 and 1994 was performed. Seven hundred fifty patients underwent axillary surgery, and 229 patients received RT as their only treatment of the regional lymphatics. Regional nodal RT was given to 168 patients who also had axillary surgery. The regional lymphatics of 11 patients were not treated. The patterns and morbidity of RR, relapse management, and complications related to regional nodal treatment were reviewed from the patients' records. With a median follow-up of 88 months, a total of 31 patients (2.7%) developed a RR. Nine of 31 patients (29%) with an RR experienced significant morbidity, including pain, fungating tumor, dysphagia, dyspnoea, and/or sensory motor changes at diagnosis. Nineteen patients (61%) had symptomatic residual or progressive regional disease after salvage therapy at last follow-up or death. Six of nine patients (67%) who developed an isolated axillary recurrence and underwent salvage surgery had no further axillary recurrence. The addition of regional nodal RT to breast irradiation significantly increased the incidence of symptomatic pneumonitis (1% without regional nodal RT and 4% with regional nodal RT, p 〈 0.001). Combined axillary dissection and nodal irradiation resulted in a significantly higher incidence of arm edema compared with either alone (9.5% with axillary dissection, 6.1% with RT to the axilla and supraclavicular fossa, and 31% with combined modality therapy, p 〈 0.001). Five of 380 patients (1%) who received RT to the axilla and/or supraclavicular fossa developed a transient brachial plexus neuropathy. Although RR was uncommon in patients treated with axillary surgery and/or regional nodal irradiation, salvage therapy failed to eradicate the recurrence in approximately two thirds of the patients with a RR. Ongoing research is essential to optimize regional control with an acceptable level of risk of treatment complications. Sentinel lymph node biopsy, if validated as an accurate method of staging the axilla in patients with breast cancer, would allow selective avoidance of regional nodal treatment and hence the associated morbidity.

Notes: Abstract:  This study was to determine if the use of regional radiotherapy (RT) changed in British Columbia after publication of new randomized trial data in 1997. Women with pathologic T1–3N1, nonmetastatic breast cancer treated with a mastectomy or breast-conserving surgery (BCS) were included. The use of regional RT was compared in two cohorts: cohort 1, July 1, 1995–June 30, 1997 (n = 834); and cohort 2, July 1, 1998–June 30, 2000 (n = 1072). All p-values were two-sided. Adjuvant systemic therapy was given to 96% and 95% of women in cohorts 1 and 2, respectively. Forty-five percent of cohort 1 and 48% of cohort 2 had BCS. Regional RT was received by 44% of cohort 1 and 66% of cohort 2 (p 〈 0.001). Eighty-eight percent and 90% of women with four or more positive nodes in cohorts 1 and 2 received regional RT, respectively. For women in cohorts 1 and 2 with one to three positive nodes, regional RT use increased from 32% to 54% after mastectomy, and from 23% to 59% after BCS, respectively (p 〈 0.001 for both). Publication of randomized trials and a coordinated guideline implementation process in British Columbia was associated with a significant increase in the use of regional RT in women with one to three positive nodes. 

Notes: The pathogenesis of various acute and chronic neurodegenerative disorders has been linked to excitotoxic processes and excess generation of nitric oxide. We investigated the deleterious effects of calpain activation in nitric oxide-elicited neuronal apoptosis. In this model, nitric oxide triggers apoptosis of murine cerebellar granule cells by an excitotoxic mechanism requiring glutamate exocytosis and receptor-mediated intracellular calcium overload. Here, we found that calcium-dependent cysteine proteases, calpains, were activated early in apoptosis of cerebellar granule cells exposed to nitric oxide. Release of the proapoptogenic factors cytochrome c and apoptosis-inducing factor from mitochondria preceded neuronal death. However, caspases-3 was not activated. We observed that procaspase-9 was cleaved by calpains to proteolytically inactive fragments. Inhibition of calpains by different synthetic calpain inhibitors or by adenovirally mediated expression of the calpastatin inhibitory domain prevented mitochondrial release of cytochrome c and apoptosis-inducing factor, calpain-specific proteolysis and neuronal apoptosis. We conclude that (i) signal transduction pathways exist that prevent the entry of neurons into a caspase-dependent death after mitochondrial release of cytochrome c and (ii) that calpain activation links nitric oxide-triggered excitotoxic events with the execution of caspase-independent apoptosis in neurons.

Notes: By mimicking the microstructure of human cortical bone, a variety of bioactive particlereinforced polymer composites have been developed for hard tissue repair. Apart from biologicalassessments, these composites must be fully evaluated in terms of their mechanical performancebefore they can be used in patients. The bioactive particles in these composites are normally hard(relative to matrix materials) and brittle bioceramics such as hydroxyapatite (HA), tricalciumphosphate (TCP), Bioglass, etc. The matrices can be either “biostable” polymers such as highdensity polyethylene (HDPE) and polysulfone (PSU) or biodegradable polymers such aspolyhydroxybutyrate (PHB) and poly(L-lactide) (PLLA). These polymers on their own possessdifferent mechanical properties and display different deformation behaviours. With the incorporationof various amounts of particulate HA, TCP or Bioglass, the bone analogue polymeric compositesexhibit a spectrum of deformation and fracture characteristics. In our systematic studies of HA/HDPE,Bioglass/HDPE, HA/PSU, HA/PHB, TCP/PHB and a few other bone analogues biomaterials overthe past fifteen years, mechanical tests were conducted under a variety of loading conditions (tension,compression, bending, torsion, etc.). Comparisons of deformation and fracture behaviours of thesecomposites were made and presented. The insights that have been gained are important for developingother bioactive ceramic-polymer composites