Biology of primary breast cancer in older women beyond routine biomarkers.

PURPOSE: There are numerous biomarkers which may have potential predictive and prognostic significance in breast cancer. This is extremely important in older adults, who may opt for less aggressive therapy. This work outlines the literature on biological assessment outside of standard biomarkers (defined as ER, PgR, HER2, Ki67) in women ≥ 65 years with primary operable invasive breast cancer, to determine which additional biomarkers are relevant to outcome in older women. METHODS: Medline and Embase databases were searched. Studies were eligible if included ≥ 50 patients aged ≥ 65 years; stratified results by age; measured a biomarker outside of standard assay and reported patient data. RESULTS: A total of 12 studies were appraised involving 5000 patients, measuring 28 biomarkers. The studies were extremely varied in methodology and outcome but three themes emerged: 1. Differences in biomarker expression between younger and older women, indicating that breast cancer in older women is generally less aggressive compared to younger women; 2. Relationship of biomarker expression with survival, suggesting biomarkers which may exclusively predict response to primary treatment in older women; 3. Association of biomarker with chemotherapy, suggesting that older patients should not be declined chemotherapy based on age alone. CONCLUSION: There is evidence to support further investigation of B-cell lymphoma (BCL2), liver kinase (LK)B1, epidermal growth factor receptor (EGFR), cytoplasmic cyclin-E, mucin (MUC)1 and cytokeratins (CKs) as potential predictive or prognostic markers in older women with breast cancer undergoing surgery. Studies exploring these biomarkers in larger cohorts and in women undergoing non-operative therapies are required.

The impact of breast cancer surgery on functional status in older women - A systematic review of the literature.

Primary endocrine therapy as treatment of breast cancer is only recommended in older women with limited life expectancy. However, many older women opt for endocrine therapy due to concerns regarding frailty and potential decline in function after surgery. A decline in functional status after surgery is documented in some cancer types, such as colorectal, however, the full impact of breast cancer surgery is less understood. A systematic review was performed to examine the evidence for impact of breast cancer surgery on functional status in older women. PubMed and Embase databases were searched. Studies were eligible if performed within the last 10 years; included patients over the age of 65 years undergoing breast cancer surgery; included stratification of results by age; measured functional status pre-operatively and at least six months following surgery. A total of 11 studies including 12 030 women were appraised. Two studies represented level-II and nine level-IV evidence. Overall, physical activity level was negatively impacted by breast cancer surgery and this was compounded by the extent of surgery. Evidence for impact of breast cancer surgery on quality of life, fatigue and cognition, was conflicting. The possibility of decline in functional status after breast cancer surgery should be discussed in all older women considering surgery. A structured exercise program may improve the negative effects of surgery on physical activity. Further work is required in the areas of quality of life, fatigability and cognition.

Patterns of biomarker expression in patients treated with primary endocrine therapy - a unique insight using core needle biopsy tissue microarray.

PURPOSE: Prediction of response to primary endocrine therapy (PET) in older women is based on measurement of oestrogen receptor (ER), progesterone receptor (PgR) and human epidermal growth factor (HER)-2. This study uses a unique method for construction of core needle biopsy (CNB) tissue microarray (TMA), to correlate expression of a panel of 17 biomarkers with clinical outcome, in patients receiving PET. METHODS: Over 37 years (1973-2010), 1758 older (≥ 70 years) women with operable primary breast cancer were managed in a single institution. Of these, 693 had sufficient good-quality CNB to construct TMA, of which 334 had ER-positive tumours treated by PET with a minimum of 6-month follow-up. A panel of biomarkers was measured by immunohistochemistry (ER, PgR, HER2, Ki-67, p53, CK5/6, CK 7/8, EGFR, BCL-2, MUC1, VEGF, LKB1, BRCA1, HER3, HER4, PTEN and AIB1). Expression of each biomarker was dichotomised into 'low' or 'high' based on breast cancer-specific survival (BCSS). RESULTS: From the panel of biomarkers, multivariate analysis showed: High ER (p = 0.003) and PgR (p = 0.002) were associated with clinical benefit of PET at 6 months, as opposed to progressive disease. High ER (p = 0.0023), PgR (p < 0.001) and BCL-2 (p = 0.043) and low LKB1 (p = 0.022) were associated with longer time to progression. High PgR (p < 0.001) and low MUC1 (p = 0.021) were associated with better BCSS. Expression of other biomarkers did not show any significant correlation. CONCLUSIONS: In addition to ER and PgR; MUC1, BCL-2 and LKB1 are important in determining the outcome of PET in this cohort.

Effect of day of the week on short- and long-term mortality after emergency general surgery.

BACKGROUND: The effect of day of the week on outcome after surgery is the subject of debate. The aim was to determine whether day of the week of emergency general surgery alters short- and long-term mortality. METHODS: This was an observational study of all patients undergoing emergency general surgery in Scotland between 1 January 2005 and 31 December 2007, followed to 2012. Multilevel logistic and Cox proportional hazards regression were used to assess the effect of day of the week of surgery on outcome after adjustment for case mix and risk factors. The primary outcome was perioperative mortality; the secondary outcome was overall survival. RESULTS: A total of 50 844 patients were identified, of whom 31 499 had an emergency procedure on Monday to Thursday and 19 345 on Friday to Sunday. Patients undergoing surgery at the weekend were younger (mean 45·9 versus 47·5 years; P < 0·001) and had fewer co-morbidities, but underwent riskier and/or more complex procedures (P < 0·001). Patients who had surgery at the weekend were more likely to have been operated on sooner than those who had weekday surgery (mean time from admission to operation 1·2 versus 1·6 days; P < 0·001). No difference in perioperative mortality (odds ratio 1·00, 95 per cent c.i. 0·89 to 1·13; P = 0·989) or overall survival (hazard ratio 1·01, 0·97 to 1·06; P = 0·583) was observed when surgery was performed at the weekend. There was no difference in overall survival after surgery undertaken on any particular day compared with Wednesday; a borderline reduction in perioperative mortality was seen on Tuesday. CONCLUSION: There was no difference in short- or long-term mortality following emergency general surgery at the weekend, compared with mid-week.

Axillary reverse mapping in N0 patients requiring sentinel lymph node biopsy - A systematic review of the literature and necessity of a randomised study.

OBJECTIVES: Axillary reverse mapping (ARM) is a technique to map and preserve arm lymphatics which may be damaged during surgery, resulting in lymphoedema. This work systematically reviews the incidence of lymphoedema following sentinel lymph node biopsy (SLNB) + ARM, compared to SLNB alone, for clinically node negative disease, as well as recurrence rate, other morbidity and the feasibility and difficulties of ARM. MATERIALS AND METHODS: The following databases were searched: PubMed, Embase, Cochrane Library. Abstracts submitted to recognised societies dedicated to research in oncology were included. Studies were eligible if performed within the last 10 years; ARM was used in any form; ARM performed during SLNB ± axillary lymph node dissection (ALND). Studies were analysed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: No studies were found meeting the initial inclusion criteria. Therefore, studies reporting use of SLNB + ARM (i.e. no comparison to SLNB) were reviewed. A second search was performed to identify studies reporting outcome following SLNB alone. Twelve studies reported data on patients undergoing SLNB + ARM and 23 studies on patients undergoing SLNB. Incidence of lymphoedema following SLNB + ARM was quoted between 0-4% and 0-63.4% following SLNB. Few studies commented on recurrence rate. Studies included were of mainly low level of evidence. CONCLUSION: Evidence is beginning to emerge for the use of ARM in order to reduce lymphoedema following axillary surgery. However, data regarding oncological safety of ARM is not clear and randomised controlled trials, with adequate follow-up, need to be performed to determine this.

Time to CT and Surgery for HPB Trauma in Scotland Prior to the Introduction of Major Trauma Centres.

AIMS: To assess the time taken to CT and emergency surgery for trauma patients with an injury to liver, spleen or pancreas prior to the introduction of major trauma centres (MTCs) in Scotland. METHODS: A search was performed of the Scottish Trauma Audit Group database for any patient with relevant injuries over a 2-year period. Primary outcome measures were time to CT and emergency surgery. Patient demographics were also recorded. RESULTS: A total of 211 patients were identified of whom 23 had more than one organ affected. There were a total of 234 injuries (123 liver, 99 splenic and 12 pancreatic) in these patients. A total of 160 injuries (75.8%) suffered blunt trauma. Of 211 patients, 157 underwent emergency CT with a median time to scan of 73 min (range 4-474). Hospitals provisionally designated as MTCs were 9 min faster than non-MTCs in time to CT. There was no difference in time of day. Ninety-nine patients had surgery within 24 h at a median time of 200 min. Twenty-five patients with hypotension on presentation took a median time of 130 min. Only 44 patients (27%) had a CT or emergency surgery within the expected MTC target of 1 h. Thirty-nine patients required transfer to another centre. CONCLUSIONS: Current management of patients with abdominal trauma and haemodynamic instability remains sub-optimal in Scotland when compared to recognized performance indicators of CT and emergency surgery within 1 h. Implementation of a major trauma network in Scotland should improve access to emergency radiology and surgery and efforts to shorten current timelines should improve patient outcomes.

Intensive care utilization and outcomes after high-risk surgery in Scotland: a population-based cohort study.

BACKGROUND: The optimal perioperative use of intensive care unit (ICU) resources is not yet defined. We sought to determine the effect of ICU admission on perioperative (30 day) and long-term mortality. METHODS: This was an observational study of all surgical patients in Scotland during 2005-7 followed up until 2012. Patient, operative, and care process factors were extracted. The primary outcome was perioperative mortality; secondary outcomes were 1 and 4 yr mortality. Multivariable regression was used to construct a risk prediction model to allow standard-risk and high-risk groups to be defined based on deciles of predicted perioperative mortality risk, and to determine the effect of ICU admission (direct from theatre; indirect after initial care on ward; no ICU admission) on outcome adjusted for confounders. RESULTS: There were 572 598 patients included. The risk model performed well (c-index 0.92). Perioperative mortality occurred in 1125 (0.2%) in the standard-risk group (n=510 979) and in 3636 (6.4%) in the high-risk group (n=56 785). Patients with no ICU admission within 7 days of surgery had the lowest perioperative mortality (whole cohort 0.7%; high-risk cohort 5.3%). Indirect ICU admission was associated with a higher risk of perioperative mortality when compared with direct admission for the whole cohort (20.9 vs 12.1%; adjusted odds ratio 2.39, 95% confidence interval 2.01-2.84; P<0.01) and for high-risk patients (26.2 vs 17.8%; adjusted odds ratio 1.64, 95% confidence interval 1.37-1.96; P<0.01). Compared with direct ICU admission, indirectly admitted patients had higher severity of illness on admission, required more organ support, and had an increased duration of ICU stay. CONCLUSIONS: Indirect ICU admission was associated with increased mortality and increased requirement for organ support. TRIAL REGISTRATION: UKCRN registry no. 15761.

Spinal Muscular Atrophy: More than a Disease of Motor Neurons?

Spinal muscular atrophy (SMA) is the most common genetically inherited neurodegenerative disease resulting in infant mortality. SMA is caused by genetic deletion or mutation in the survival of motor neuron 1 (SMN1) gene, which results in reduced levels of the survival of motor neuron (SMN) protein. SMN protein deficiency preferentially affects α- motor neurons, leading to their degeneration and subsequent atrophy of limb and trunk muscles, progressing to death in severe forms of the disease. More recent studies have shown that SMN protein depletion is detrimental to the functioning of other tissues including skeletal muscle, heart, autonomic and enteric nervous systems, metabolic/endocrine (e.g. pancreas), lymphatic, bone and reproductive system. In this review, we summarize studies discussing SMN protein's function in various cell and tissue types and their involvement in the context of SMA disease etiology. Taken together, these studies indicate that SMA is a multi-organ disease, which suggests that truly effective disease intervention may require body-wide correction of SMN protein levels.

Expression of the fusogenic p14 FAST protein from a replication-defective adenovirus vector does not provide a therapeutic benefit in an immunocompetent mouse model of cancer.

When injected directly into a tumor mass, adenovirus (Ad) vectors only transduce cells immediately along the injection tract. Expression of fusogenic proteins from the Ad vector can lead to syncytium formation, which efficiently spreads the therapeutic effect. Fusogenic proteins can also cause cancer cell death directly, and enhance the release of exosome-like particles containing tumor-associated antigens, which boosts the anti-tumor immune response. In this study, we have examined whether delivery of an early region 1 (E1)-deleted, replication-defective Ad vector encoding the reptilian reovirus p14 fusion-associated small transmembrane (FAST) protein can provide therapeutic efficacy in an immunocompetent mouse tumor model. A high multiplicity of infection of AdFAST is required to induce cell fusion in mouse mammary carcinoma 4T1 cells in vitro, and FAST protein expression caused a modest reduction in cell membrane integrity and metabolic activity compared with cells infected with a control vector. Cells expressing FAST protein released significantly higher quantities of exosomes. In immunocompetent Balb/C mice harboring subcutaneous 4T1 tumors, AdFAST did not induce detectable cancer cell fusion, promote tumor regression or prolong mouse survival compared with untreated mice. This study suggests that in the context of the 4T1 model, Ad-mediated FAST protein expression did not elicit a therapeutic effect.

Retinal transduction profiles by high-capacity viral vectors.

Retinal gene therapy with adeno-associated viral (AAV) vectors is safe and effective in humans. However, the limited cargo capacity of AAV prevents their use for therapy of those inherited retinopathies (IRs) due to mutations in large (>5 kb) genes. Viral vectors derived from adenovirus (Ad), lentivirus (LV) and herpes virus (HV) can package large DNA sequences, but do not target efficiently retinal photoreceptors (PRs) where the majority of genes responsible for IRs are expressed. Here, we have evaluated the mouse retinal transduction profiles of vectors derived from 16 different Ad serotypes, 7 LV pseudotypes and from a bovine HV. Most of the vectors tested transduced efficiently the retinal pigment epithelium. We found that LV-GP64 tends to transduce more PRs than the canonical LV-VSVG, albeit this was restricted to a narrow region. We observed more extensive PR transduction with HdAd1, 2 and 5/F35++ than with LV, although none of them outperformed the canonical HdAd5 or matched the extension of PR transduction achieved with AAV2/8.

Surgery for colorectal liver metastases.

Half of all patients with colorectal cancer develop metastatic disease. The liver is the principal site for metastases, and surgical resection is the only modality that offers the potential for long-term cure. Appropriate patient selection for surgery and improvements in perioperative care have resulted in low morbidity and mortality rates, resulting in this being the therapy of choice for suitable patients. Modern management of colorectal liver metastases is multimodal incorporating open and laparoscopic surgery, ablative therapies such as radiofrequency ablation or microwave ablation and (neo)adjuvant chemotherapy. The majority of patients with hepatic metastases should be considered for resectional surgery, if all disease can be resected, as this offers the only opportunity for prolonged survival.

At the "junction" of spinal muscular atrophy pathogenesis: the role of neuromuscular junction dysfunction in SMA disease progression.

Spinal muscular atrophy (SMA) is caused by mutations that reduce the level of the survival motor neuron protein (SMN) resulting in death of alpha-motor neurons, yet it is unclear why these cells are preferentially affected by a reduction in this ubiquitously-expressed protein. In mouse models of SMA, one of the earliest events detected is defects at the neuromuscular junction (NMJ). Although NMJs are established at a normal frequency, there are structural as well as functional perturbations and a lack of maturation of the primitive synapse. These early defects are followed by loss of the NMJ, denervation of the muscle and onset of muscle atrophy. In this review, we discuss our current understanding of the contribution of NMJ dysfunction in SMA disease pathogenesis, and also provide an overview of therapies currently under preclinical and clinical development for treatment of SMA.

Transarticular fusion for treatment of cystic lesion arising from an odontoid fracture.

INTRODUCTION: Odontoid fractures are the most common upper cervical spine fracture. There are two mechanisms in which odontoid fractures occur, most commonly hyperflexion of the neck resulting in displacement of the dens anteriorly and hyperextension resulting in posterior dens displacement. Type 2 fractures are the most common and are associated with significant non-union rates after treatment. One possible consequence of an odontoid fracture is a synovial cyst, resulting in spinal cord compression, presenting as myelopathy or radiculopathy. Synovial cysts as a result of spinal fracture, usually of the facet joint, are most common in the lumbar region, followed by the thoracic and then cervical region; cervical cysts are rare. Fracture and subsequent cyst formation is thought to be related to hyper-motion or trauma of the spine. This is reinforced by the appearance of spinal synovial cysts most commonly at the level of L4/5; this being the region with the biggest weight-bearing function. The most common site of cervical cyst formation is at the level of C7/T1; this is a transitional joint subjected to unique stress and mechanical forces not present at higher levels. Treatment of a cervical synovial cyst at the level of the odontoid is challenging with little information available in the literature. The majority of cases appear to implement posterior surgical resection of the cyst, with fusion of adjacent cervical vertebrae to stabilise the fracture, resulting in restricted range of movement. CASE PRESENTATION: We describe a case concerning a 39-year-old female who presented with uncertain cause of odontoid fracture, resulting in a cystic lesion compressing the upper cervical spinal cord. OUTCOME: Minimal invasive surgery of C1/C2 transarticular fusion was successfully performed resulting in significant improvement of neurological symptoms in this patient. At 1-year follow-up, the cyst had resolved without surgical removal and this was confirmed by radiological measures.

Hepatic cytokine response can be modulated using the Kupffer cell blocker gadolinium chloride in obstructive jaundice.

INTRODUCTION: Depletion of Kupffer cells by gadolinium chloride (GdCl(3)) reduces the systemic response during sepsis. The study aim was to investigate the effect of this depletion on hepatic proinflammatory cytokine response to portal endotoxaemia. METHODS: Sixteen Wistar rats were randomised to receive either saline IV (n = 8) or GdCl(3) (10 mg/kg IV, n = 8) six days after bile duct ligation (BDL). 24 h later the animals were perfused for 2 h, using isolated hepatic perfusion. Aliquots of effluent perfusate were collected at 20-min intervals for cytokine analysis. Sections of liver were sampled and the hepatic Kupffer cell number of each group was measured using ED1 immunohistochemistry. RESULTS: Pre-treatment with GdCl(3) resulted in significantly reduced serum bilirubin concentrations but significantly elevated serum ALP and AST levels compared to the control group. It was also associated with a significant reduction in Kupffer cell numbers and a corresponding significant reduction in hepatic TNFα and IL-6 production in response to portal endotoxaemia. CONCLUSIONS: Pre-treatment with GdCl(3) in jaundiced animals reduced Kupffer cell numbers, attenuated liver enzyme abnormalities and reduced TNFα and IL-6 in response to portal endotoxaemia. Hepatic Kupffer cells, therefore, play a significant role in the development of an exaggerated inflammatory response in obstructive jaundice.

Traumatic injury to the colon and rectum in Scotland: demographics and outcome.

AIM: An analysis of a multi-centred database of trauma patients was performed. METHOD: The study used data from a prospective multi-centre trauma database containing details of 52 887 trauma patients admitted to participating Scottish Hospitals over an 11-year period. RESULTS: Three hundred and forty (0.64%) of 52 887 trauma patients (284 male) with colorectal injuries were identified; 43.9% of colorectal injuries occurred following blunt trauma and 56.1% following penetrating injury. Patients in the latter group were younger, had less haemodynamic compromise and were less likely to die than those with blunt trauma (P < 0.01). The overall mortality rate was 25.6% and after rectal injury it was 21.2% (P > 0.05). Female gender, increased age, road traffic accidents and those admitted as a result of a blunt traumatic injury were associated with increased mortality. Age > 65 years (P = 0.01), increasing injury severity score (ISS) at presentation (P < 0.001), haemodynamic compromise (P = 0.045) and decreased Glasgow Coma Score (GCS) (P < 0.001) had the strongest independent associations with mortality. CONCLUSION: Colorectal injury after trauma has a high morbidity. Clinical features associated with death allow stratification of mortality risk.