Efferent limb stimulation prior to loop ileostomy closure: a systematic review and meta-analysis.

BACKGROUND: Postoperative ileus (POI) remains a common phenomenon following loop ileostomy closure. Our aim was to determine whether preoperative physiological stimulation (PPS) of the efferent limb reduced POI incidence. METHODS: A PRISMA-compliant meta-analysis searching PubMed, EMBASE and CENTRAL databases was performed. The last search was carried out on 30 January 2023. All randomized studies comparing PPS versus no stimulation were included. The primary endpoint was POI incidence. Secondary endpoints included the time to first passage of flatus/stool, time to resume oral diet, need for nasogastric tube (NGT) placement postoperatively, length of stay (LOS) and other complications. Random effects models were used to calculate pooled effect size estimates. Trial sequential analyses (TSA) were also performed. RESULTS: Three randomized studies capturing 235 patients (116 PPS, 119 no stimulation) were included. On random effects analysis, PPS was associated with a quicker time to resume oral diet (MD - 1.47 days, 95% CI - 2.75 to - 0.19, p = 0.02), shorter LOS (MD - 1.47 days, 95% CI - 2.47 to - 0.46, p = 0.004) (MD - 1.41 days, 95% CI - 2.32 to - 0.50, p = 0.002, I2 = 56%) and fewer other complications (OR 0.42, 95% CI 0.18 to 1.01, p = 0.05). However, there was no difference in POI incidence (OR 0.35, 95% CI 0.10 to 1.21, p = 0.10), the requirement for NGT placement (OR 0.50, 95% CI 0.21 to 1.20, p = 0.12) or time to first passage of flatus/stool (MD - 0.60 days, 95% CI - 1.95 to 0.76, p = 0.39). TSA revealed imprecise estimates for all outcomes (except LOS) and further studies are warranted to meet the required information threshold. CONCLUSIONS: PPS prior to stoma closure may reduce LOS and postoperative complications albeit without a demonstrable beneficial effect on POI. Further high-powered studies are required to confirm or refute these findings.

Oncological outcomes of laparoscopic versus open rectal cancer resections: meta-analysis of randomized clinical trials.

BACKGROUND: The role of laparoscopic rectal cancer surgery has been questioned owing to conflicting reports on pathological outcomes from recent RCTs. However, it is unclear whether these pathological markers and the surgical approach have an impact on oncological outcomes. This study assessed oncological outcomes of laparoscopic and open rectal cancer resections. METHODS: A meta-analysis of RCTs was performed. Primary endpoints included oncological outcomes (disease-free survival (DFS), overall survival (OS), local recurrence). Secondary endpoints included surrogate markers for the quality of surgical resection. RESULTS: Twelve RCTs including 3744 patients (2133 laparoscopic, 1611 open) were included. There was no significant difference in OS (hazard ratio (HR) 0.87, 95 per cent c.i. 0.73 to 1.04; P = 0.12; I2 = 0 per cent) and DFS (HR 0.95, 0.81 to 1.11; P = 0.52; I2 = 0 per cent) between laparoscopic and open rectal resections. There was no significant difference in locoregional (odds ratio (OR) 1.03, 95 per cent c.i. 0.72 to 1.48; P = 0.86; I2 = 0 per cent) or distant (OR 0.87, 0.70 to 1.08; P = 0.20; I2 = 7 per cent) recurrence between the groups. Achieving a successful composite score (intact mesorectal excision, clear circumferential resection margin and distal margin) was significantly associated with improved DFS (OR 0.55, 0.33 to 0.74; P < 0.001; I2 = 0 per cent). An intact or acceptable mesorectal excision (intact mesorectal excision with or without superficial defects) had no impact on DFS. Finally, a positive CRM was associated with worse DFS. CONCLUSION: Well performed surgery (laparoscopic or open) achieves excellent oncological outcomes with very little difference between the two modalities. The advantage and benefit of minimally invasive surgery should be assessed on an individual basis.

Clinicopathological and prognostic significance of programmed cell death ligand 1 expression in patients diagnosed with breast cancer: meta-analysis.

BACKGROUND: Uncertainty exists regarding the clinical relevance of programmed cell death ligand 1 (PD-L1) expression in breast cancer. METHODS: A systematic review was performed in accordance with PRISMA guidelines. Observational studies that compared high versus low expression of PD-L1 on breast cancer cells were identified. Log hazard ratios (HRs) for disease-free and overall survival and their standard errors were calculated from Kaplan-Meier curves or Cox regression analyses, and pooled using the inverse-variance method. Dichotomous variables were pooled as odds ratios (ORs) using the Mantel-Haenszel method. RESULTS: Sixty-five studies with 19 870 patients were included; 14 404 patients were classified as having low and 4975 high PD-L1 expression. High PD-L1 was associated with achieving a pathological complete response following neoadjuvant chemotherapy (OR 3.30, 95 per cent confidence interval 1.19 to 9.16; P < 0.01; I2 = 85 per cent). Low PD-L1 expression was associated with human epidermal growth factor receptor 2 (OR 3.98, 1.81 to 8.75; P < 0.001; I2 = 96 per cent) and luminal (OR 14.93, 6.46 to 34.51; P < 0.001; I2 = 99 per cent) breast cancer subtypes. Those with low PD-L1 had favourable overall survival rates (HR 1.30, 1.05 to 1.61; P = 0.02; I2 = 85 per cent). CONCLUSION: Breast cancers with high PD-L1 expression are associated with aggressive clinicopathological and immunohistochemical characteristics and are more likely to achieve a pathological complete response following neoadjuvant chemotherapy. These breast cancers are, however, associated with worse overall survival outcomes.

Value of a 21-gene expression assay on core biopsy to predict neoadjuvant chemotherapy response in breast cancer: systematic review and meta-analysis.

BACKGROUND: A recurrence score based on a 21-gene expression assay predicts the benefit of adjuvant chemotherapy in oestrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. This systematic review aimed to determine whether the 21-gene expression assay performed on core biopsy at diagnosis predicted pathological complete response (pCR) to neoadjuvant chemotherapy. METHODS: The study was performed according to PRISMA guidelines. Relevant databases were searched to identify studies assessing the value of the 21-gene expression assay recurrence score in predicting response to neoadjuvant chemotherapy in patients with breast cancer. The Newcastle-Ottawa Scale was used to assess the quality of the studies. Results are reported as risk ratio (RR) with 95 per cent confidence interval using the Cochrane-Mantel-Haenszel method for meta-analysis. Sensitivity analyses were carried out where appropriate. RESULTS: Seven studies involving 1744 patients reported the correlation between pretreatment recurrence score and pCR. Of these, 777 patients (44.6 per cent) had a high recurrence score and 967 (55.4 per cent) a low-intermediate score. A pCR was achieved in 94 patients (5.4 per cent). The pCR rate was significantly higher in the group with a high recurrence score than in the group with a low-intermediate score (10.9 versus 1.1 per cent; RR 4.47, 95 per cent c.i. 2.76 to 7.21; P < 0.001). A significant risk difference was observed between the two groups (risk difference 0.10, 0.04 to 0.15; P = 0.001). CONCLUSION: A high recurrence score is associated with higher pCR rates and a low-intermediate recurrence score may indicate chemoresistance. Routine assessment of recurrence score by the 21-gene expression assay on core biopsy might be of value when considering neoadjuvant chemotherapy in patients with ER-positive, HER2-negative breast cancer.

Meta-analysis of the impact of progesterone receptor status on oncological outcomes in oestrogen receptor-positive breast cancer.

BACKGROUND: Assessment of the oestrogen receptor (ER) provides important prognostic information in breast cancer. The impact of progesterone receptor (PgR) status is less clear. Standardization of immunohistochemical analysis of these receptors has reduced interstudy heterogeneity. The aim of this meta-analysis was to evaluate the impact of PgR negativity on outcomes in ER-positive (ER+) breast cancer. METHODS: This study was performed according to PRISMA and MOOSE guidelines. PubMed, Embase and the Cochrane Library were searched systematically to identify studies comparing disease-free survival as the primary outcome and overall survival as secondary outcome between PgR-positive (PgR+) and PgR-negative (PgR-) status in ER+ breast cancer. A meta-analysis of time-to-effect measures from included studies was undertaken. RESULTS: Eight studies including 13 667 patients, 11 838 in the ER+PgR+ group and 1829 in the ER+PgR- group, met the inclusion criteria. Treatment characteristics did not differ significantly between the two groups. Patients in the ER+PgR- group had a higher risk of disease recurrence than those who had ER+PgR+ disease (hazard ratio (HR) 1·57, 95 per cent c.i. 1·38 to 1·79; P < 0·001). This hazard was increased in patients with human epidermal growth factor receptor 2-negative tumours (HR 1·62, 1·37 to 1·93; P < 0·001). A similar result was observed for overall survival (HR 1·69, 1·33 to 2·14; P < 0·001). CONCLUSION: PgR negativity is associated with significant reductions in disease-free and overall survival in ER+ breast cancer. Treatment and surveillance strategies in these patients should be tailored accordingly.

ANTECEDENTES: La evaluación del receptor de estrógenos (oestrogen receptor, ER) proporciona una importante información pronóstica en el cáncer de mama. El impacto de del estado del receptor de la progesterona (progesterone receptor, PgR) está menos claro. La estandarización del análisis inmunohistoquímico de estos receptores ha reducido la heterogeneidad entre los estudios. El objetivo de este metaanálisis fue evaluar el impacto de la negatividad de PgR (PgR-) en los resultados del cáncer de mama ER positivo (ER+). MÉTODOS: Este estudio se realizó de acuerdo con las directrices PRISMA/MOOSE. Se llevó a cabo una búsqueda sistemática en MEDLINE, PubMed y biblioteca Cochrane para identificar estudios que comparasen la supervivencia libre de enfermedad (disease free survival, DFS) como resultado primario y la supervivencia global (overall survival, OS) como resultado secundario entre los estados PgR+ y PgR- en el cáncer de mama ER+. Se realizó un metaanálisis de los estudios incluidos de las medidas de tiempo hasta el efecto. RESULTADOS: Ocho estudios que incluían 13.533 pacientes, 11.724 en el grupo ER+PgR+ y 1.809 en el grupo ER+PgR- cumplieron con los criterios de inclusión. Las características del tratamiento no diferían significativamente entre los dos grupos. Los pacientes en el grupo ER+PgR- presentaron un riesgo más elevado de recidiva de la enfermedad que aquellas que tenían enfermedad ER+PgR+ (DFS, cociente de riesgos instantáneos, hazard ratio, HR 1,57; i.c. del 95% 1,38-1,79; P < 0,001). Este riesgo se incrementó en pacientes que eran HER2 negativo (DFS HR 1,62; i.c. del 95% 1,37-1,93; P < 0,001). Un resultado similar se observó para la OS (HR 1,69; i.c. del 95% 1,33-2,14, P < 0,001). CONCLUSIÓN: La negatividad de PgR se asocia con disminuciones significativas de DFS y OS en el cáncer de mama ER+. En estas pacientes, las estrategias de tratamiento y seguimiento en deberán adecuarse a cada caso particular.

Meta-analysis of the effect of extending the interval after long-course chemoradiotherapy before surgery in locally advanced rectal cancer.

BACKGROUND: The current standard of care in locally advanced rectal cancer (LARC) is neoadjuvant long-course chemoradiotherapy (nCRT) followed by total mesorectal excision (TME). Surgery is conventionally performed approximately 6-8 weeks after nCRT. This study aimed to determine the effect on outcomes of extending this interval. METHODS: A systematic search was performed for studies reporting oncological results that compared the classical interval (less than 8 weeks) from the end of nCRT to TME with a minimum 8-week interval in patients with LARC. The primary endpoint was the rate of pathological complete response (pCR). Secondary endpoints were recurrence-free survival, local recurrence and distant metastasis rates, R0 resection rates, completeness of TME, margin positivity, sphincter preservation, stoma formation, anastomotic leak and other complications. A meta-analysis was performed using the Mantel-Haenszel method. RESULTS: Twenty-six publications, including four RCTs, with 25 445 patients were identified. A minimum 8-week interval was associated with increased odds of pCR (odds ratio (OR) 1·41, 95 per cent c.i. 1·30 to 1·52; P < 0·001) and tumour downstaging (OR 1·18, 1·05 to 1·32; P = 0·004). R0 resection rates, TME completeness, lymph node yield, sphincter preservation, stoma formation and complication rates were similar between the two groups. The increased rate of pCR translated to reduced distant metastasis (OR 0·71, 0·54 to 0·93; P = 0·01) and overall recurrence (OR 0·76, 0·58 to 0·98; P = 0·04), but not local recurrence (OR 0·83, 0·49 to 1·42; P = 0·50). CONCLUSION: A minimum 8-week interval from the end of nCRT to TME increases pCR and downstaging rates, and improves recurrence-free survival without compromising surgical morbidity.

ANTECEDENTES: El tratamiento estándar actual del cáncer de recto localmente avanzado (locally advanced rectal cancer, LARC) consiste en quimiorradioterapia neoadyuvante de ciclo largo (neoadjuvant, long-course chemoradiation, nCRT) seguida de exéresis total del mesorrecto (total mesorectal excision, TME). De forma convencional, la cirugía se realiza a las 6-8 semanas después de la nCRT. Este estudio tuvo como objetivo determinar el efecto sobre los resultados de ampliar este intervalo. MÉTODOS: Se realizó una búsqueda sistemática de los estudios que analizaban los resultados oncológicos, comparando el intervalo clásico (< 8 semanas) desde el final de la nCRT hasta la TME con un intervalo mínimo de 8 semanas, en pacientes con LARC. El criterio de valoración principal fue la tasa de respuesta patológica completa (pathologic complete response, pCR). Los criterios de valoración secundarios fueron las tasas de supervivencia sin recidiva (recurrence-free survival, RFS), recidiva local (local recurrence, LR) y metástasis a distancia (distant metastasis, DM), tasas de resección R0, integridad (completeness) del mesorrecto, afectación del margen de resección, preservación esfinteriana, formación de estoma, fuga anastomótica y otras complicaciones. Se realizó un metaanálisis utilizando el método de Mantel-Haenszel. RESULTADOS: Se identificaron 26 publicaciones, incluidos cuatro ensayos clínicos aleatorizados, con 17.220 pacientes. Un intervalo mínimo de 8 semanas se asoció con un aumento de la razón de oportunidades (odds ratio, OR) de pCR (OR, 1,68, i.c. del 95% 1,37-2,06, P < 0,001) y de disminución del estadio tumoral (OR 1,18, i.c. del 95% 1,05-1,32, P = 0,004). Los porcentajes de resección R0, integridad del mesorrecto, ganglios linfáticos identificados, preservación esfinteriana, formación de estoma y complicaciones fueron similares entre los dos grupos. El aumento del porcentaje de pCR se tradujo en una disminución de las DM (OR 0,71, i.c. del 95% 0,54-0,93, P = 0,01) y de la recidiva global (OR 0,76, i.c. del 95% 0,58-0,98, P = 0,04), pero no de la LR (OR 0,83, i.c. del 95% 0,49-1,42, P = 0,50). CONCLUSIÓN: Un intervalo mínimo de 8 semanas entre el final de la nCRT y la TME aumenta las tasas de pCR y la reducción del estadio tumoral, así como mejora la RFS sin comprometer la morbilidad quirúrgica.

Minimally invasive approaches to the management of anastomotic leakage following restorative rectal cancer resection.

AIM: Management of anastomotic leakage (AL) following rectal resection has evolved with increasing use of less invasive techniques. The aim of this study was to review the management of AL following restorative rectal cancer resection in a tertiary referral centre. METHOD: A retrospective review of a prospectively maintained database was performed. The primary outcome was successful management of AL. The secondary outcome was the impact of AL on oncological outcome. RESULTS: Five hundred and two restorative rectal cancer resections were performed during the study period. The incidence of AL was 9.9% (n = 50). AL occurred more commonly following neoadjuvant chemoradiotherapy (n = 31/252, 12.3%) than in those who did not receive neoadjuvant chemoradiotherapy (n = 19/250, 7.6%; P = 0.107); however, this was not statistically significant. Successful minimally invasive drainage was achieved in 28 patients (56%, radiological n = 24, surgical n = 4). Trans-rectal drainage was the most common drainage method (n = 14). The median duration of drainage was longer in the neoadjuvant group (27 vs 18 days). Surgical intervention was required in 11 patients, with anastomotic takedown and end-colostomy formation was most commonly required. Successful management of AL with drainage (maintenance of the anastomosis without the need for further intervention) was achieved in 26 of the 28 patients. There were no significant differences in overall or disease-free survival when patients with AL were compared with patients without AL (69.4% vs 72.6%, P = 0.99 and 78.7% vs 71.3%, P = 0.45, respectively). CONCLUSION: In selected patients, AL following restorative rectal resection can be effectively controlled using minimally invasive radiological or surgical drainage without the need for further intervention.

Altered expression of caspases-4 and -5 during inflammatory bowel disease and colorectal cancer: Diagnostic and therapeutic potential.

Caspases are a group of proteolytic enzymes involved in the co-ordination of cellular processes, including cellular homeostasis, inflammation and apoptosis. Altered activity of caspases, particularly caspase-1, has been implicated in the development of intestinal diseases, such as inflammatory bowel disease (IBD) and colorectal cancer (CRC). However, the involvement of two related inflammatory caspase members, caspases-4 and -5, during intestinal homeostasis and disease has not yet been established. This study demonstrates that caspases-4 and -5 are involved in IBD-associated intestinal inflammation. Furthermore, we found a clear correlation between stromal caspase-4 and -5 expression levels, inflammation and disease activity in ulcerative colitis patients. Deregulated intestinal inflammation in IBD patients is associated with an increased risk of developing CRC. We found robust expression of caspases-4 and -5 within intestinal epithelial cells, exclusively within neoplastic tissue, of colorectal tumours. An examination of adjacent normal, inflamed and tumour tissue from patients with colitis-associated CRC confirmed that stromal expression of caspases-4 and -5 is increased in inflamed and dysplastic tissue, while epithelial expression is restricted to neoplastic tissue. In addition to identifying caspases-4 and -5 as potential targets for limiting intestinal inflammation, this study has identified epithelial-expressed caspases-4 and -5 as biomarkers with diagnostic and therapeutic potential in CRC.

Tumour microenvironment of both early- and late-stage colorectal cancer is equally immunosuppressive.

BACKGROUND: Tumour microenvironment (TME) of advanced colorectal cancer (CRC) suppresses dendritic cell (DC) maturation. Here, our aim was to determine how the microenvironment of early-stage tumours influences DCs. METHODS: Tumour-conditioned media (TCM) was generated by culturing explant tumour tissue in vitro (n=50). Monocyte-derived DCs (MDDCs) of healthy donors or cancer patients were pretreated with TCM and stimulated with lipopolysaccharide (LPS). DC maturation was assessed by flow cytometry and cytokine production measured by ELISA. RESULTS: TCM from both early- and late-staged tumours abrogated LPS-induction of IL-12p70 secretion, while increasing IL-10. The profile of inflammatory mediators in TCM was similar across stages, and all increased pSTAT3 expression by DCs.CRC patient DCs (n=31) secreted low levels of IL-12p70 and failed to upregulate expression of maturation markers in response to LPS. Furthermore, in vitro culture of autologous DCs with TCM did not change the hypo-responsiveness of patient DCs. CONCLUSION: Our data demonstrates that the TME of all stages of CRC contains inflammatory mediators capable of suppressing local DCs. MDDCs obtained from CRC patients are hyporesponsive to stimuli such as LPS. Measures to reverse the negative influence of the TME on DCs will optimise cancer vaccines in both early- and late-stage CRC.

Factors affecting Naseptin treatment success - A prospective cohort study.

OBJECTIVE: To assess patient factors to predict treatment success of Naseptin for recurrent paediatric epistaxis. METHODS: This prospective cohort study of paediatric patients referred to a tertiary paediatric otolaryngology clinic with recurrent epistaxis treated with Naseptin cream and education. Patients with red flag symptoms and bleeding diathesis were omitted, along with patients with concurrent otolaryngology complaints. Statistical analysis included logistic regression analysis to assess for predictive factors contributing to treatment success. RESULTS: 125 of 210 patients on the waiting list met the inclusion criteria and were given a complete trial of Naseptin. 80.8% (n = 101) of patients found that the frequency and severity of epistaxis had reduced, with the remaining 19.2% (n = 24) reporting that the episodes of epistaxis remained the same and required further management (i.e., silver nitrate cautery). Five patients (4%) reported minor side effects (skin irritation etc.) with no significant adverse events reported. CONCLUSION: We found that Naseptin is a safe, well-tolerated treatment that should be trialled in most cases of recurrent paediatric epistaxis. Most children will benefit from it with complete epistaxis cessation or at least reduced frequency and severity.

Reef islands have continually adjusted to environmental change over the past two millennia.

Global environmental change is identified as a driver of physical transformation of coral reef islands over the past half-century, and next 100 years, posing major adaptation challenges to island nations. Here we resolve whether these recent documented changes in islands are unprecedented compared with the pre-industrial era. We utilise radiometric dating, geological, and remote sensing techniques to document the dynamics of a Maldivian reef island at millennial to decadal timescales. Results show the magnitude of island change over the past half-century (±40 m movement) is not unprecedented compared with paleo-dynamic evidence that reveals large-scale changes in island dimension, shape, beach levels, as well as positional changes of ±200 m since island formation ~1,500 years ago. Results highlight the value of a multi-temporal methodological approach to gain a deeper understanding of the dynamic trajectories of reef islands, to support development of adaptation strategies at timeframes relevant to human security.

The affect of chronic hepatitis C infection on dendritic cell function: a summary of the experimental evidence.

Chronic hepatitis C virus (HCV) infection occurs in patients who fail to mount an effective T-cell response against the virus. One hypothesis for poor anti-viral immunity in these patients is that the virus impedes the immune response by disabling dendritic cells (DCs), cells that play a key role in pathogen recognition and initiation of adaptive immunity. Initial studies in the 1990s supported this hypothesis, as they clearly demonstrated that monocyte-derived DCs obtained from patients with chronic HCV infection displayed a reduced ability to stimulate lymphocyte proliferation. However, over the last 20 years, the situation has become more ambiguous. Many studies support the initial observation of a DC defect, while others using different patient cohorts or technologies have clearly demonstrated intact DC function in patients with chronic HCV. It is likely that the true situation lies somewhere in between. Just as there is a spectrum of disease in patients with chronic HCV, DCs obtained from different patients may display different properties. It is important to reconcile these divergent findings, as a clearer understanding of how the virus affects DC function will facilitate the development of immunotherapy and therapeutic vaccination strategies for patients with chronic HCV infection.

Chronic hepatitis C infection blocks the ability of dendritic cells to secrete IFN-α and stimulate T-cell proliferation.

Dendritic cells (DCs) are likely to play a key role in the compromised T-cell function associated with hepatitis C Virus (HCV) infection. However, studies of DC function in HCV-infected patients to date have yielded conflicting findings possibly because of patient and virus heterogeneity. Here, we report the characterization of monocyte-derived DCs obtained from a homogenous cohort of women who were infected with HCV genotype 1b following exposure to contaminated anti-D immunoglobulin from a single donor source. Patients included in the study had not received anti-viral therapy and all had mild liver disease. We show that phenotypically normal monocyte-derived dendritic cells (MDDCs) (CD11c(+) HLA(-) DR(+) CD1a(+) CD14(lo) ) can be obtained from these patients. These cells respond to both Poly(I:C) and LPS, by up-regulating expression of CD86. They secrete high levels of IL-8 and CCL5 in response to LPS, an indication that the MyD88-dependent and MyD88-independent signalling pathways downstream of TLR4 ligation are functioning normally. However, these cells are poor stimulators of T-cell proliferation in allogeneic mixed lymphocyte reactions. Furthermore, patient MDDCs fail to secrete IFN-α in response to poly(I:C) or IFN-ß stimulation. Altered DC function may contribute to impaired cellular immune responses and chronicity of disease following HCV infection in this cohort. An effective therapeutic vaccine for chronic HCV infection will most likely need to target DCs to elicit an appropriate cellular response; therefore, it is important to resolve how the DCs of different patient cohorts respond to stimulation via TLRs.

Combined breast conservation therapy versus mastectomy for BRCA mutation carriers - A systematic review and meta-analysis.

BACKGROUND: The non-inferiority of combined breast conservation surgery (BCS) and radiotherapy (breast conservation therapy or BCT) compared to mastectomy in sporadic breast cancer cases is well recognised. Uncertainty remains regarding optimal surgical practice in BRCA mutation carriers. AIMS: To evaluate the oncological safety of combined BCT versus mastectomy in BRCA mutation carriers following breast cancer diagnosis. METHODS: A systematic review was performed as per PRISMA and MOOSE guidelines. Observational studies comparing BCS and mastectomy in BRCA carriers were identified. Dichotomous variables were pooled as odds ratios (OR) using the Mantel-Haenszel method. Log hazard ratios (lnHR) for locoregional recurrence (LRR), contralateral breast cancer, disease-free and overall survival and their standard errors were calculated from Kaplan-Meier or cox-regression analyses and pooled using the inverse variance method. RESULTS: Twenty three studies of 3807 patients met inclusion criteria; 2200 (57.7%) were BRCA1 and 1212 (31.8%) were BRCA2 carriers. Median age at diagnosis was 41 years with 96 months follow up. BCS was performed on 2157 (56.7%) while 1408 (41.5%) underwent mastectomy. An increased risk of LRR was observed in patients treated with BCS (HR:4.54, 95% Confidence Interval: 2.77-7.42, P < 0.001, heterogeneity (I2) = 0%). However, the risks of contralateral breast cancer (HR:1.51, 95%CI: 0.44-5.11, P = 0.510, I2 = 80%), disease recurrence (HR:1.16, 95%CI: 0.78-1.72, P = 0.470, I2 = 44%), disease-specific recurrence (HR:1.58, 95%CI: 0.79-3.15, P = 0.200, I2 = 38%) and death (HR:1.10, 95%CI: 0.72-1.69, P = 0.660, I2 = 38%) were equivalent for combined BCT and mastectomy. CONCLUSIONS: Survival outcomes following combined BCT is comparable to mastectomy in BRCA carriers. However, the risk of LRR is increased. Patient counselling should be tailored to incorporate these findings.

Clinical utility of the 21-gene assay in predicting response to neoadjuvant endocrine therapy in breast cancer: A systematic review and meta-analysis.

INTRODUCTION: OncotypeDX© Recurrence Score (RS) is a multigene panel used to aid therapeutic decision making in early-stage, estrogen receptor positive (ER+)/human epidermal growth factor receptor-2 negative (HER2-) breast cancer. AIM: To compare responses to neoadjuvant endocrine therapy (NET) in patients with ER+/HER2-breast cancer following substratification by RS testing. METHODS: This systematic review was performed in accordance to the PRISMA guidelines. Studies evaluating pathological complete response (pCR), partial response (PR), and successful conversion to breast conservation surgery (BCS) rates following NET guided by RS were retrieved. Dichotomous outcomes were reported as odds ratios (ORs) with 95% confidence intervals (CIs) following estimation by Mantel-Haenszel method. RESULTS: Eight prospective studies involving 691 patients were included. The mean age was 62.6 years (range 25-85) and the mean RS was 14.5 (range 0-68). Patients with RS < 25 (OR: 4.60, 95% CI: 2.53-8.37, P < 0.001) and RS < 30 (OR: 3.40, 95% CI: 1.96-5.91, P < 0.001) were more likely to achieve PR than their counterparts. NET prescription failed to increase BCS conversion rates for patients with RS < 18 (OR: 0.23, 95% CI: 0.04-1.47, P = 0.120) and RS > 30 (OR: 1.27, 95% CI: 0.64-2.49, P = 0.490) respectively. Only 22 patients achieved pCR (2.8%) and RS group failed to predict pCR following NET (P = 0.850). CONCLUSION: Estimations from this analysis indicate that those with low-intermediate RS on core biopsy are four times more likely to respond to NET than those with high-risk RS. Performing RS testing on diagnostic biopsy may be useful in guiding NET prescription.