Meta-analysis to determine the clinical impact of axillary lymph node dissection in the treatment of invasive breast cancer.

There are divergent opinions regarding the optimum surgical management of the axilla in patients with invasive breast cancer. Guidelines mandate axillary lymph node dissection (ALND) in the setting of positive sentinel lymph nodes. However, recent studies have questioned the true benefits of this procedure. Therefore, a meta-analysis of relevant randomized trials was performed in order to clarify the oncological benefit of axillary lymph node dissection. A comprehensive search of published randomized trials that compared patients with primary operable breast cancer with/without ALND was performed using MEDLINE, and available data were cross-referenced. Reviews of each study were conducted, and data were extracted. Primary outcomes were overall survival and recurrent axillary disease. A total of 7347 patients with operable primary breast cancer were identified from 8 randomised controlled trials comparing axillary recurrence in patients with or without ALND. Six of these trials provided data on overall survival on 6895 patients. Overall survival favours patients having ALND (OR = 1.22 (95% CI 1.03-1.44, p = 0.02). Similarly, patients undergoing ALND had increased recurrence-free survival (OR = 2.25 (95% CI 1.28-3.94, p = 0.0047). ALND appears to positively impact on overall and recurrence-free survival from breast cancer. These data highlight the enduring benefits of ALND in an era where adjuvant therapies are being promoted to manage regionally advanced/metastatic disease.

Radiotherapy and breast reconstruction: a meta-analysis.

The optimum sequencing of breast reconstruction (BR) in patients receiving postmastectomy radiation therapy (PMRT) is controversial. A comprehensive search of published studies that examined postoperative morbidity following immediate or delayed BR with combined radiotherapy was performed. Medical (MEDLINE & EMBASE) databases were searched and cross-referenced for appropriate studies where morbidity following BR was the primary outcome measured. A total of 1,105 patients were identified from 11 appropriately selected studies. Patients undergoing PMRT and BR are more likely to suffer morbidity compared with patients not receiving PMRT (OR = 4.2; 95% CI, 2.4-7.2 [no PMRT vs. PMRT]). Reconstruction technique was also examined with outcome when PMRT was delivered after BR, and this demonstrated that autologous reconstruction is associated with less morbidity in this setting (OR = 0.21; 95% CI, 0.1-0.4 [autologous vs. implant-based]). Delaying BR until after PMRT had no significant effect on outcome (OR = 0.87; 95% CI, 0.47-1.62 [delayed vs. immediate]). PMRT has a detrimental effect on BR outcome. These results suggest that where immediate reconstruction is undertaken with the necessity of PMRT, an autologous flap results in less morbidity when compared with implant-based reconstruction.

Health-related quality of life following breast reconstruction compared to total mastectomy and breast-conserving surgery among breast cancer survivors: a systematic review and meta-analysis.

The present review evaluated health-related quality of life (HR-QoL) outcomes in surgical breast cancer survivors who received breast reconstruction (BR), breast-conservation surgery (BCS) or mastectomy (M), and whether HR-QoL domains across generic and disease/surgery-specific questionnaires are compatible. Six electronic databases were searched for appropriate observational studies. Standardized scores for different HR-QoL domains in the BR, BCS, and M treatment groups were extracted from each study for the purpose of a meta-analysis. Using Stata version 14.0, a random-effects meta-analysis model was adopted for each outcome variable to estimate the effect size, 95% CI-confidence intervals, and statistical significance. Sixteen of the 18 eligible studies with BR (n = 1474) and BCS (n = 2612) or M (n = 1458) groups were included in the meta-analysis. The BR group exhibited a better physical health (k = 12; 0.1, 95% CI 0.04, 0.24) and body image (k = 12; 0.50, 95% CI 0.10, 0.89) than the M group. However, the two groups exhibited comparable social health (k = 13; 0.1, 95% CI -0.07, 0.37), emotional health (k = 13; -0.08, 95% CI - 0.41, 0.25), global health (k = 7; 0.1, 95% CI - 0.01, 0.27), and sexual health (k =11; 0.2, 95% CI - 0.02,0.57). There was no clear evidence of the superiority of BR to BCS for all the six domains. These results suggest that HR-QoL outcomes in BR and BCS groups are better than the M group. Therefore, women opting for BR or BCS are likely to report fairly better HR-QoL outcomes than M. However, due to the significant heterogeneity observed in most BR versus BCS outcomes, developing a unified questionnaire incorporating both breast/surgery-specific and generic HR-QoL domains is warranted.

PET CT imaging in patients undergoing sentinel node biopsy for melanoma.

AIMS: Sentinel lymph node biopsy (SLNB) has been adopted in the surgical treatment of melanoma to reduce morbidity and enhance staging. Positron emission tomography with computerised tomography (PET/CT) has been utilised in the staging of patients with malignancy though the role of this imaging modality in early stage melanoma is unclear. This study examined the preoperative value of PET/CT in patients undergoing SLNB for malignant melanoma. METHODS: Patients presenting with primary melanoma without evidence of either locoregional or systemic metastasis were considered candidates for SLNB. Selected patients underwent preoperative PET/CT followed by definitive surgical therapy including SLNB with regional lymphadenectomy, where indicated. RESULTS: During a 12-month period 83 patients were identified as having undergone SLNB for melanoma, of which 37 (45%) had preoperative PET/CT. Mean melanoma thickness 1.9 mm and 2.4 mm (PET/CT vs. no PET/CT, p>0.05). 13 (15.6%) patients were found to have lymphatic metastasis at SLNB; nine of these patients underwent PET/CT, only two of these scans were suggestive of lymphatic metastasis (positive predictive value 24%, negative predictive value 76%). PET/CT revealed no unheralded metastatic disease but did identify a second occult malignancy in 4 (10.8%) patients undergoing therapy for melanoma. CONCLUSIONS: The results of this study do not support the use of PET/CT in patients undergoing SLNB for melanoma. SLNB appears to be a more sensitive staging modality in the detection of lymphatic metastasis; however PET/CT may have a future role as a screening tool for malignancy.

The clinical and pathological differences in prevalent round screen-detected and symptomatic invasive breast cancer.

The potential benefits of breast cancer screening include the detection of cancers at a more favourable stage, however, cancers detected during the prevalent round of screening may differ from true screen-detected cancers. These differences are poorly defined. This study prospectively assessed all women between 50 and 64 years of age undergoing curative surgery for breast cancer, both screen-detected and symptomatic, in one screening centre during the prevalent round of the national breast cancer-screening programme. Four hundred and thirty seven patients (364 screen-detected and 73 symptomatic patients) underwent surgery for breast cancer. Symptomatic breast cancers were of a higher grade (p < 0.0001; Chi2) and less likely to be oestrogen receptor positive (49% versus 88%; p < 0.0001; Fisher's exact test); however there was no difference in size of tumour or axillary nodal positivity. This study suggests that tumours detected by screening during the prevalent round of a screening programme are of a more prognostically favourable type than symptomatic breast cancers in the same age group.

Breast cancer detection among Irish BRCA1 & BRCA2 mutation carriers: a population-based study.

BACKGROUND: High-risk breast cancer screening for BRCA1/2 mutation carriers with clinical breast exam, mammography and MRI has reported sensitivity of 100 %, but BRCA1/2 mutation carriers still present with interval cancers. AIMS: We investigated the presentation and screening patterns of an Irish cohort of BRCA1/2 mutation carriers with breast cancer. MATERIALS AND METHODS: BRCA1/2 mutation carriers with breast cancer were identified in this retrospective cohort study. Records were reviewed for BRCA1/2 mutation status, demographics, screening regimen, screening modality, stage and histology at diagnosis. RESULTS: Fifty-three cases of breast cancer were diagnosed between 1968 and 2010 among 60 Irish hereditary breast ovarian cancer (HBOC) families. In 50 of 53 women, the diagnosis of breast cancer predated the identification of BRCA1/2 mutations. Breast cancer detection method was identified in 47 % of patients (n = 25): 80 % (n = 20) by clinical breast exam (CBE), 12 % by mammography (n = 3), 8 % by MRI (n = 2). Fourteen women (26 %) developed a second breast cancer. Ten of these patients (71 %) were involved in regular screening; 50 % were detected by screening mammography, 20 % by MRI and 30 % by CBE alone. Six patients (43 %) had a change in morphology from first to second breast cancers. There was no change in hormone receptor status between first and second breast cancers. CONCLUSION: In this cohort of Irish BRCA1/2 mutation carriers, compliance with screening was inconsistent. There was a 30 % incidence of interval cancers occurring in women in high-risk screening. Preventive surgery may be a more effective risk reduction strategy for certain high-risk women.

The role of sentinel lymph node biopsy in ductal carcinoma in situ.

AIM: To review the role of sentinel lymph node (SLN) biopsy in the surgical management of patients with ductal carcinoma in situ (DCIS). METHODS: A search was conducted of Medline and the National Library of Medicine to identify key articles concerning DCIS, SLN biopsy (SLNB) and axillary dissection. Further relevant articles were obtained from the references cited in the literature. RESULTS: Up to 20% of patients with a core biopsy diagnosis of DCIS will be later up-staged based on an invasive component identified on the excision specimen. Quality assurance in breast screening programmes requires minimally invasive pre-operative diagnosis and also axillary sampling in the case of documented invasive disease. As an effective and validated procedure, SLNB represents a paradigm shift in the surgical management of the axilla for patients with invasive breast cancer. It remains undefined which, if any, subgroups of patients with DCIS should undergo SLNB. CONCLUSION: Axillary lymphadenectomy is an overtreatment for patients with DCIS. Performing a SLNB during the initial procedure may avoid a second operation in some DCIS patients who are diagnosed with occult invasive disease at their definitive operation. When predictors of hidden invasive disease are clarified by further study, SLNB may be used in the management of selected high-risk DCIS patients.

Surgical management of lobular carcinoma from a national screening program: a retrospective analysis.

OBJECTIVE: To compare the surgical outcomes of women diagnosed with invasive ductal and lobular carcinoma of the breast. BACKGROUND: The role of Breast Conserving Surgery (BCS) for invasive cancers of the breast is well established; however its role for invasive lobular carcinoma is less well defined. Concerns exist regarding the need for re-excision of margins and the eventual need for mastectomy in women with Invasive Lobular Carcinoma (ILC) compared with Ductal Carcinoma (IDC). In this study we compare the surgical results of these two groups examining BCS from a national breast cancer screening program. METHODS: Analysis of mammographically detected ILC and IDC tumours obtained from the national breast cancer screening program of the Republic of Ireland (BreastCheck) was performed. BreastCheck offers biannual screening mammograms to women throughout the Republic of Ireland between 50 and 65 years of age. We examined and pooled the data across 4 screening zones from 2005 to 2010. CONCLUSIONS: We observed similar success rates and trends in both the ILC and IDC groups where BCS was attempted. Patients selected for BCS with ILC were statistically more likely to have successful surgery compared with IDC as tumour size increased. There however was no statistical difference in a pooled analysis of successful treatment across all tumour sizes in comparing the two groups. We conclude that BCS is an appropriate and acceptable treatment option for women diagnosed with ILC.

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.

Circulating granulocyte macrophage colony-stimulating factor in plasma of patients with the systemic inflammatory response syndrome delays neutrophil apoptosis through inhibition of spontaneous reactive oxygen species generation.

In the normal resolution of an acute inflammatory response apoptosis of neutrophils is essential to maintain immune homeostasis and limit inappropriate host tissue damage by decreasing neutrophil tissue load, function, and release of phlogistic reactive oxygen species and proteases. The systemic inflammatory response syndrome (SIRS), a massive pro-inflammatory immune state, is associated with delayed neutrophil apoptosis, however, the systemic circulating factors and intracellular signal transduction pathways important in regulating neutrophil apoptosis in SIRS are poorly described. Neutrophils isolated from patients with SIRS on admission to the intensive care unit showed significantly (p<.01) delayed spontaneous neutrophil apoptosis compared with healthy neutrophils as quantified using annexin V-FITC and terminal deoxyuridine triphosphate (dUTD) nick end labeling (TUNEL) flow cytometry methods. Plasma from SIRS patients markedly (41.5+/-7.2%, p<.01) inhibited apoptosis of healthy neutrophils compared with controls (69.7+/-4.8%) indicating the presence of soluble circulating factors that can modify the expression of neutrophil apoptosis. Various pro-inflammatory (IL-6, granulocyte macrophage colony-simulating factor, interleukin (IL)-1beta, tumor necrosis factor-alpha) mediators, known to modulate neutrophil apoptosis in vitro, were elevated in the plasma of our cohort of SIRS patients compared with controls. However, the anti-apoptotic effect of SIRS plasma was specifically attenuated (75.5%, p<.01) by neutralizing SIRS plasma of granulocyte macrophage-colony-stimulating factor, but not IL-6, IL-1beta, tumor necrosis factor-alpha. Although the anti-inflammatory cytokine IL-10 was elevated in SIRS plasma (median level 7.2 pg/mL), further boosting SIRS plasma with recombinant human IL-10 (10 ng/mL, levels found in septic shock patients) significantly countered (63.8%, p<.01) the inhibitory effect of SIRS plasma on neutrophil apoptosis. Suppression of neutrophil apoptosis was concomitant with delayed spontaneous elevation of reactive oxygen species, quantified as peroxide production, and reversed by addition of neutralizing antibodies to GM-CSF, and recombinant human IL-10 to SIRS plasma. These results identify circulating GM-CSF as a significant inhibitor of neutrophil apoptosis in patients with SIRS, and that this effect can be countered by boosting SIRS plasma with IL-10. GM-CSF and IL-10 appear to modulate neutrophil apoptosis by altering reactive oxygen species generation in neutrophils.

A central role for CD95 (Fas) in T-cell reactivity after injury.

BACKGROUND: Recent findings indicate that severe injury primes the immune system for an enhanced and lethal proinflammatory cytokine response against bacterial-derived superantigens. This study asked whether this response to injury involves the CD95 (Fas) signaling pathway. METHODS: To assess superantigen-mediated mortality, wild-type (WT) C57BL/6 and Fas-deficient C57BL/6 lpr (-/-) (lpr) mice underwent burn or sham injury and were challenged 2 hours later with staphylococcal enterotoxin B (SEB). Spleen cells from sham and burn WT or lpr mice were stimulated in vitro with SEB to assess injury effects on IL-2, TNF-alpha, and IFN-gamma production. RESULTS: Lpr burn mice survived the SEB challenge (100% survival), while WT burn mice showed a high mortality (17% survival, P < 001, analysis of variance [ANOVA]). Sham lpr or WT mice suffered no mortality to the SEB challenge. In vitro studies demonstrated that burn lpr mice produced significantly less TNF-alpha, IFN-gamma, IL-2 than burn WT mice (P <.01, ANOVA). Burn injury markedly enhanced SEB-stimulated IFN-gamma production by WT spleen cells and CD8+ T cells, while this did not occur in SEB-stimulated lpr spleen cells. CONCLUSIONS: These findings support the hypothesis that the CD95 (Fas) signaling pathway plays an integral role in the injury-induced enhanced and lethal T-cell reactivity against bacterial superantigens.

Interleukin 10 is not essential for survival or for modulating T-cell function after injury.

BACKGROUND: Interleukin 10 (IL-10) is thought to be protective in injury and sepsis. However, we recently reported that IL-10 antagonism can be beneficial after burn injury. This study used IL-10-deficient (IL-10 [-/-]) mice to further define the role of IL-10 after injury. METHODS: Wild-type (WT) C57BL/6 or IL-10 (-/-) mice were anesthetized, sham or burn injured, and immunized subcutaneously with a T-cell-dependent protein antigen. Ten days later antigen-specific serum antibody isotype formation was measured by enzyme-linked immunosorbent assay. In addition, antigen-stimulated splenic T-cell proliferation and cytokine production (interleukin 2, interferon gamma, and tumor necrosis factor-alpha) were measured. RESULTS: Burn-injured IL-10 (-/-) mice survival (80%) was equivalent to that of burn-injured WT mice (74%). An injury-dependent loss of T-helper 1 (Th1)-type antibody isotype (IgG2a) formation occurred in both WT and IL-10 (-/-) mice. In vitro studies indicated that burn injury caused reduced antigen-stimulated splenic T-cell proliferation and Th1-type (interleukin 2 and interferon gamma) cytokine production in WT and IL-10 (-/-) mice, whereas burn-injured IL-10 (-/-) mice produced high levels of antigen-stimulated tumor necrosis factor-alpha. CONCLUSIONS: IL-10 is not essential for survival after burn injury or for several injury-induced changes in adaptive immune function, including Th1-type antibody isotype formation, T-cell proliferation, and Th1-type cytokine production.

Tumor lysis syndrome following endoscopic radiofrequency interstitial thermal ablation of colorectal liver metastases.

Radiofrequency interstitial thermal ablation (RITA) provides a palliative option for patients suffering from metastatic liver disease. This procedure can be performed using a laparoscopic approach with laparoscopic ultrasound used to position the RITA probe. We describe a case of laparoscopic RITA performed for colorectal liver metastasis that was complicated by tumor lysis syndrome (TLS) following treatment. We consider RITA to be a safe procedure, as supported by the literature, but where intracorporal tumor lysis is the treatment goal we believe that the systemic release of tumor products can overwhelm the excretory capacity; therefore, TLS is an inevitable consequence in some patients.

Minimally invasive parathyroidectomy with operative ultrasound localization of the adenoma.

BACKGROUND: Minimally invasive parathyroidectomy is the procedure of choice for primary hyperparathyroidism due to parathyroid adenoma. Adequate perioperative adenoma localization is essential for this operation. We describe a technique using ultrasound to perform minimally invasive parathyroidectomy. METHODS: 99mTc sestamibi scanning was performed on patients with primary hyperparathyroidism to localize parathyroid adenomas; no intraoperative gamma probe was used. We also performed pre- and intraoperative ultrasound scanning to localize these adenomas. RESULTS: All patients underwent successful localization and removal of their parathyroid adenomas. At follow-up, all patients were well, with calcium within normal limits. CONCLUSION: The use of intraoperative ultrasound facilitates minimally invasive parathyroidectomy and may obviate the need for intraoperative 99mTc sestamibi scanning.

Predicting outcome after appendicectomy.

AIM: To validate an intraoperative appendicitis severity score (IASS) and examine outcome following emergency appendectomy. METHODS: A prospective study was undertaken, enrolling consecutive patients undergoing emergency appendicectomy. Data were obtained independently on preoperative Alvarado scores, IASS (0-3: 0 no inflammation, 1 engorged appendix/no peritonitis, 2 peritoneal reaction/exudate or 3 evidence of perforation/abscess) and postoperative outcome parameters. RESULTS: There were 149 patients identified with a mean age of 20.7 years. There was no association between Alvarado score and length of hospital stay, septic complication, patient sex or duration of symptoms (p>0.05). IASS was found to be an independent risk factor for septic complication, wound infection (p<0.05) and length of hospital stay (p<0.001). There was no correlation between preoperative duration of symptoms or time until surgery and intraoperative score. CONCLUSIONS: This simple scoring system can identify patients more likely to suffer morbidity following emergency appendicectomy. Specifically, this system identifies patients who have a high risk of sepsis and therefore could be of use when comparing healthcare performance.

Re-evaluating the role of axillary lymph node dissection in screen-detected breast cancer patients.

INTRODUCTION: The American College of Surgeons Oncology Group (ACOSOG), Z0011 trial, demonstrated that there was no therapeutic benefit from completion lymphadenectomy in early stage breast cancer patients with positive sentinel node (SLN) biopsy. Patients with asymptomatic screen-detected tumors may represent a subgroup where completion axillary dissection with its attendant morbidities is unacceptable. Therefore, the aim of this study was to evaluate the role of ALND in an asymptomatic screen-detected breast cancer cohort. METHODS: Patients were recruited from the national screening program which offers women (aged 50 to 65) biannual digital mammography. Over a 1 year period 519 screen-detected breast cancer patients were recruited of which 110 had a positive SLN. RESULTS: Of 519 patients in a national screening program that were clinically/radiologically identified as axillary node negative, 110 (21.2%) had a positive SLN. All 110 (T1 = 68, T2 = 42) patients proceeded to have an axillary clearance. 68 (59%) had T1 tumors and of these 40 (60%), despite a positive SLN, had no metastatic nodes on final pathological analysis of their axilla. In addition, 21 (50%) patients with T2 tumors had no metastatic nodes except for a positive SNB. Furthermore, only 6 (8.8%) of T1 tumors with a positive SLN had 4 or more metastatic axillary lymph nodes. CONCLUSION: 55.45% of patients with a screen-detected T1/T2 tumor had negative completion lymphadectomy. These findings compel us to re-evaluate the role of axillary dissection in the screen-detected asymptomatic breast cancer population to avoid unnecessary ALND with its attendant morbidities.