Malcolm R. Kell

Effect of Margin Status on Local Recurrence After Breast Conservation and Radiation Therapy for Ductal Carcinoma In Situ

PURPOSE There is no consensus on what constitutes an adequate surgical margin in patients receiving breast-conserving surgery (BCS) and postoperative radiation therapy (RT) for ductal carcinoma in situ (DCIS). Inadequate margins may result in high local recurrence, and excessively large resections may lead to poor cosmetic outcome without oncologic benefit. METHODS A comprehensive search for published trials that examined outcomes after adjuvant RT after BCS for DCIS was performed using MEDLINE and cross referencing available data. Reviews of each study were conducted, and data were extracted. Primary outcome was ipsilateral breast tumor recurrence (IBTR) related to surgical margins. RESULTS A total of 4,660 patients were identified from trials examining BCS and RT for DCIS. Patients with negative margins were significantly less likely to experience recurrence than patients with positive margins after RT (odds ratio [OR] = 0.36; 95% CI, 0.27 to 0.47). A negative margin significantly reduced the risk of IBTR when compared with a close (OR = 0.59; 95% CI, 0.42 to 0.83) or unknown margin (OR = 0.56; 95% CI, 0.36 to 0.87). When specific margin thresholds were examined, a 2-mm margin was superior to a margin less than 2 mm (OR = 0.53; 95% CI, 0.26 to 0.96); however, we saw no significant difference in the rate of IBTR with margins between 2 mm and more than 5 mm (OR = 1.51; 95% CI, 0.51 to 5.0; P > .05). CONCLUSION Surgical margins negative for DCIS should be obtained after BCS for DCIS. A margin threshold of 2 mm seems to be as good as a larger margin when BCS for DCIS is combined with RT.

Sentinel lymph node biopsy

Is now an established and widely available technique for breast cancer and melanoma Sentinel lymph node biopsy has developed over the past decade as a minimally invasive technique to assess regional lymph node status in patients with malignancy. This technique allows us to find out the status of a lymph node basin by removing only a small number of nodes. These nodes stand sentry to the rest of the nodal basin: if malignant disease is going to affect a nodal region it must first pass through the sentinel node. Therefore the nodal basin will contain malignant cells only if the sentinel node is first involved. The specific and limited removal of the sentinel node reduces surgical insult and morbidity compared with conventional lymphatic clearance. Sentinel lymph node biopsy is now widely available, and most cancer surgeons offer this as part of their diagnostic protocol for patients. Sentinel lymph node biopsy was initially developed to detect lymphatic metastasis in parotid carcinoma.1 As this technique has developed it has been used in the management of penile carcinoma, but it is now predominantly used in the diagnosis of lymphatic metastasis from breast cancer and melanoma.2–4 It can also be used to detect …

Surgical Aspects of Inflammatory Breast Cancer

Mastectomy alone as a treatment for inflammatory breast cancer results in local recurrence in 20% of cases and a median survival of only 2 years. Current management of inflammatory cancer employs initial chemotherapy with surgery reserved for patients who have complete resolution of inflammatory changes. The combination of chemotherapy, mastectomy, and radiotherapy results in local control in 80% of patients. Breast conserving surgery and sentinel node biopsy are contraindicated in inflammatory cancer.

The fate of chemoresistance in triple negative breast cancer (TNBC)

Background Treatment options for women presenting with triple negative breast cancer (TNBC) are limited due to the lack of a therapeutic target and as a result, are managed with standard chemotherapy such as paclitaxel (Taxol®). Following chemotherapy, the ideal tumour response is apoptotic cell death. Post-chemotherapy, cells can maintain viability by undergoing viable cellular responses such as cellular senescence, generating secretomes which can directly enhance the malignant phenotype. Scope of Review How tumour cells retain viability in response to chemotherapeutic engagement is discussed. In addition we discuss the implications of this retained tumour cell viability in the context of the development of recurrent and metastatic TNBC disease. Current adjuvant and neo-adjuvant treatments available and the novel potential therapies that are being researched are also reviewed. Major conclusions Cellular senescence and cytoprotective autophagy are potential mechanisms of chemoresistance in TNBC. These two non-apoptotic outcomes in response to chemotherapy are inextricably linked and are neglected outcomes of investigation in the chemotherapeutic arena. Cellular fate assessments may therefore have the potential to predict TNBC patient outcome. General Significance Focusing on the fact that cancer cells can bypass the desired cellular apoptotic response to chemotherapy through cellular senescence and cytoprotective autophagy will highlight the importance of targeting non-apoptotic survival pathways to enhance chemotherapeutic efficacy.

Bacterial Lipoprotein Delays Apoptosis in Human Neutrophils through Inhibition of Caspase-3 Activity: Regulatory Roles for CD14 and TLR-2

The human sepsis syndrome resulting from bacterial infection continues to account for a significant proportion of hospital mortality. Neutralizing strategies aimed at individual bacterial wall products (such as LPS) have enjoyed limited success in this arena. Bacterial lipoprotein (BLP) is a major constituent of the wall of diverse bacterial forms and profoundly influences cellular function in vivo and in vitro, and has been implicated in the etiology of human sepsis. Delayed polymorphonuclear cell (PMN) apoptosis is a characteristic feature of human sepsis arising from Gram-negative or Gram-positive bacterial infection. Bacterial wall product ligation and subsequent receptor-mediated events upstream of caspase inhibition in neutrophils remain incompletely understood. BLP has been shown to exert its cellular effects primarily through TLR-2, and it is now widely accepted that lateral associations with the TLRs represent the means by which CD14 communicates intracellular messages. In this study, we demonstrate that BLP inhibits neutrophil mitochondrial membrane depolarization with a subsequent reduction in caspase-3 processing, ultimately leading to a significant delay in PMN apoptosis. Pretreatment of PMNs with an anti-TLR-2 mAb or anti-CD14 mAb prevented BLP from delaying PMN apoptosis to such a marked degree. Combination blockade using both mAbs completely prevented the effects of BLP (in 1 and 10 ng/ml concentrations) on PMN apoptosis. At higher concentrations of BLP, the antiapoptotic effects were observed, but were not as pronounced. Our findings therefore provide the first evidence of a crucial role for both CD14 and TLR-2 in delayed PMN apoptosis arising from bacterial infection.

FDG-PET/CT in the staging of local/regional metastases in breast cancer

Breast cancer is the commonest female malignancy in the Western world and the most reliable predictor for survival is axillary lymph node metastases. Conventional staging techniques employed in breast cancer include mammography, ultrasonography, isotope bone scanning, sentinel lymph node biopsy, axillary lymph node dissection and magnetic resonance imaging. More recently FDG-PET and FDG-PET/CT have been used to complement the above methods. This review assesses the role of FDG-PET/CT in axillary staging in patients with primary breast cancer. A PubMed search was conducted and all articles containing relevant or new information were included. Relevant studies examined identified that FDG-PET/CT has a sensitivity of 60% and a specificity of 97% in detecting lymphatic metastasis. Although positive axillary FDG-PET/CT is a good predictor of axillary disease and correlates well with SLNB, the relatively poor sensitivity (60%) must be considered for treatment planning.

Injury primes the immune system for an enhanced and lethal T-cell response against bacterial superantigen.

We previously reported the high lethality of CD4+ T-cell activation in burn-injured T-cell receptor (TCR) transgenic mice. This suggested to us that T-cells may play a role in the development of the systemic inflammatory response syndrome (SIRS) which can occur after severe injury. In this study, we sought a more clinically relevant model to test the hypothesis that naturally produced bacterial toxins that are known to act as potent polyclonal T-cell activating agents may induce a similar lethal shock-like response in injured, non-TCR transgenic mice. Accordingly, sham- or burn-injured mice were treated with various doses of staphylococcal enterotoxin A (SEA), then observed for 48-hour mortality. We observed 94% and 56% 48-h mortality when burn-injured mice were given 15 microg and 10 microg of SEA, respectively, while neither SEA dose caused mortality in sham-injured mice. The assessment of serum cytokine levels demonstrated significantly elevated interleukin 2 (IL-2) and tumor necrosis factor alpha (TNFalpha) levels when compared to sham mice (P < 0.01). In vitro studies confirmed our in vivo results and also demonstrated elevated levels of interferon gamma (IFNgamma) (P < 0.01). We also observed a novel injury-dependent switch from CD4+ to CD8+ T-cells as the dominant T-cell type producing TNFalpha and IFNgamma in response to SEA stimulation in vitro. Taken together, our findings indicate that injury primes the immune system for an augmented early T-cell response that can result in a lethal shock-like syndrome.

Overexpression of the microRNA miR-433 promotes resistance to paclitaxel through the induction of cellular senescence in ovarian cancer cells

Annually, ovarian cancer (OC) affects 240,000 women worldwide and is the most lethal gynecological malignancy. High‐grade serous OC (HGSOC) is the most common and aggressive OC subtype, characterized by widespread genome changes and chromosomal instability and is consequently poorly responsive to chemotherapy treatment. The objective of this study was to investigate the role of the microRNA miR‐433 in the cellular response of OC cells to paclitaxel treatment. We show that stable miR‐433 expression in A2780 OC cells results in the induction of cellular senescence demonstrated by morphological changes, downregulation of phosphorylated retinoblastoma (p‐Rb), and an increase in β‐galactosidase activity. Furthermore, in silico analysis identified four possible miR‐433 target genes associated with cellular senescence: cyclin‐dependent kinase 6 (CDK6), MAPK14, E2F3, and CDKN2A. Mechanistically, we demonstrate that downregulation of p‐Rb is attributable to a miR‐433‐dependent downregulation of CDK6, establishing it as a novel miR‐433 associated gene. Interestingly, we show that high miR‐433 expressing cells release miR‐433 into the growth media via exosomes which in turn can induce a senescence bystander effect. Furthermore, in relation to a chemotherapeutic response, quantitative real‐time polymerase chain reaction (qRT‐PCR) analysis revealed that only PEO1 and PEO4 OC cells with the highest miR‐433 expression survive paclitaxel treatment. Our data highlight how the aberrant expression of miR‐433 can adversely affect intracellular signaling to mediate chemoresistance in OC cells by driving cellular senescence.

Meta-analysis of the effect of central neuraxial regional anesthesia compared with general anesthesia on postoperative natural killer T lymphocyte function

STUDY OBJECTIVE To compare the effect of central neuraxial (spinal or epidural) anesthesia with general anesthesia on postoperative natural killer (NK) T lymphocyte function. DESIGN Meta-analysis. SETTING University-affiliated hospital. MEASUREMENTS A systematic search of the medical literature from 1966 to 2009 yielded 5 eligible studies with a total of 184 patients who received neuraxial blockade. Natural killer T lymphocyte function was studied. MAIN RESULTS There was significant heterogeneity between the studies [I(2) = 94.4% (95% CI= 90.3-96.2%)]. Overall fixed-effect odds ratio was 0.86 (0.66-1.14, P = 0.25). The random-effect odds ratio was 1.13 (0.26-4.92, P = 0.79). CONCLUSION Anesthetic technique does not appear to significantly affect postoperative NK T lymphocyte function. Given the heterogeneity observed, further clinical studies in cancer patients of the effect of anesthetic technique on immune function in general, and NK T lymphocyte function in particular, are needed.

A characterization of anaerobic colonization and associated mucosal adaptations in the undiseased ileal pouch.

Introduction  The resolution of pouchitis with metronidazole points to an anaerobic aetiology. Pouchitis is mainly seen in patients with ulcerative colitis pouches (UCP). We have recently found that sulphate reducing bacteria (SRB), a species of strict anaerobe, colonize UCP exclusively. Herein, we aimed to correlate levels of different bacterial species (including SRB) with mucosal inflammation and morphology.