Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer.

BACKGROUND: Approximately 80% of all breast cancers (BCs) are currently categorized as human epidermal growth factor receptor 2 (HER2)-negative [immunohistochemistry (IHC) 0, 1+, or 2+/in situ hybridization (ISH) negative]; approximately 60% of BCs traditionally categorized as HER2-negative express low levels of HER2. HER2-low (IHC 1+ or IHC 2+/ISH-) status became clinically actionable with approval of trastuzumab deruxtecan to treat unresectable/metastatic HER2-low BC. Greater understanding of patients with HER2-low disease is urgently needed. PATIENTS AND METHODS: This global, multicenter, retrospective study (NCT04807595) included tissue samples from patients with confirmed HER2-negative unresectable/metastatic BC [any hormone receptor (HR) status] diagnosed from 2014 to 2017. Pathologists rescored HER2 IHC-stained slides as HER2-low (IHC 1+ or IHC 2+/ISH-) or HER2 IHC 0 after training on low-end expression scoring using Ventana 4B5 and other assays at local laboratories (13 sites; 10 countries) blinded to historical scores. HER2-low prevalence and concordance between historical scores and rescores were assessed. Demographics, clinicopathological characteristics, treatments, and outcomes were examined. RESULTS: In rescored samples from 789 patients with HER2-negative unresectable/metastatic BC, the overall HER2-low prevalence was 67.2% (HR positive, 71.1%; HR negative, 52.8%). Concordance was moderate between historical and rescored HER2 statuses (81.3%; κ = 0.583); positive agreement was numerically higher for HER2-low (87.5%) than HER2 IHC 0 (69.9%). More than 30% of historical IHC 0 cases were rescored as HER2-low overall (all assays) and using Ventana 4B5. There were no notable differences between HER2-low and HER2 IHC 0 in patient characteristics, treatments received, or clinical outcomes. CONCLUSIONS: Approximately two-thirds of patients with historically HER2-negative unresectable/metastatic BC may benefit from HER2-low-directed treatments. Our data suggest that HER2 reassessment in patients with historical IHC 0 scores may be considered to help optimize selection of patients for treatment. Further, accurate identification of patients with HER2-low BC may be achieved with standardized pathologist training.

The potential of bacteriophage therapy in the treatment of paediatric respiratory infections.

The looming antibiotic resistance crisis is forcing clinicians to consider alternative approaches to treating bacterial infections. As the window of use for current antimicrobial agents becomes ever narrower, we consider if looking back will now be the way forward. Conceptually, phage therapy is simple and specific; a targeted treatment to control bacterial overgrowth. In this article we discuss bacteriophage and potential use in future therapy.

Socio-economic disadvantage and delusional-like experiences: a nationwide population-based study.

PURPOSE: Delusional-like experiences (DLE) have been associated with low income, suggesting that more broadly defined socio-economic disadvantage may be associated with these experiences. We had the opportunity to explore the association between DLE and both individual- and area-level measures of socio-economic disadvantage. METHOD: Subjects were drawn from the Australian National Survey of Mental Health and Wellbeing 2007. The Composite International Diagnostic Interview was used to identify DLE, common psychiatric disorders, and physical disorders. Individual-level and area-level socio-economic disadvantage measures were available based on variables including income, educational attainment, employment status, and housing. We examined the relationship between the variables of interest using logistic regression, adjusting for potential confounding factors. RESULTS: Of the 8773 subjects, 8.4% (n=776) positively endorsed one or more DLE. DLE screen items were more likely to be endorsed by those who were (a) younger, (b) never married, or widowed, separated or divorced status, (c) migrants, or (d) living in rented houses. There were significant associations between socio-economic disadvantage and increased DLE endorsement, and this was found for both individual-level and area-level measures of socio-economic disadvantage. In general, the associations remained significant after adjusting for a range of potential confounding factors and in planned sensitivity analyses. CONCLUSIONS: DLE are associated with socio-economic disadvantage in the general population. We speculate that the link between socio-economic disadvantage and DLE may be mediated by psychosocial stress and general psychological distress.

The heritability of delusional-like experiences.

OBJECTIVE: Delusional-like experiences (DLE) are common in the general community and are associated with a family history of mental illness. The aim of this study was to estimate the heritability of DLE. METHOD: The Peter's Delusional Inventory (PDI) was administered to a population-based cohort of mothers (n = 2861, aged 35-67 years) and their adult offspring (n = 3079, aged 18-23 years). Heritability of DLE was estimated from the sum scores of the 21 item PDI under the assumption that the covariance between mother-offspring scores is attributable to shared additive genetic factors. RESULTS: The means (medians and standard deviations) for the total PDI scores for the mothers and their offspring were 3.6 (3.0, 3.0) and 5.0 (4.0, 3.5), respectively. The Pearson correlation coefficient between mother and offspring PDI scores was 0.17 (P < 0.001). The heritability was estimated to be 0.35 (standard error 0.04). CONCLUSION: Heritable factors contribute to over a third of the variance of PDI scores in this population. In light of the association between a family history of a wide range of mental disorders and DLE, these experiences may represent a useful quantitative endophenotype for genetic studies of common mental disorders in population settings.

Social support and delusional-like experiences: a nationwide population-based study.

BACKGROUND: Population-based studies have identified that delusional-like experiences (DLEs) are common in the general population. While there is a large literature exploring the relationship between poor social support and risk of mental illness, there is a lack of empirical data examining the association of poor social support and DLEs. The aim of the study was to explore the association between social support and DLEs using a large, nationally representative community sample. METHODS: Subjects were drawn from a national multistage probability survey of 8841 adults aged between 16 and 85 years. The Composite International Diagnostic Interview was used to identify DLEs, common psychiatric disorders and physical disorders. Eight questions assessed various aspects of social support with spouse/partners and other family and friends. We examined the relationship between DLEs and social support using logistic regression, adjusting for potential confounding factors. RESULTS: Of the sample, 8.4% (n = 776) positively endorsed one or more DLEs. Individuals who (a) had the least contact with friends, or (b) could not rely on or confide in spouse/partner, family or friends were significantly more likely to endorse DLEs. The associations remained significant after adjusting for a range of potential confounding factors. CONCLUSIONS: DLEs are associated with impoverished social support in the general population. While we cannot exclude the possibility that the presence of isolated DLEs results in a reduction of social support, we speculate that poor social support may contribute in a causal fashion to the risk of DLEs.

Differential response of cancer cells to HDAC inhibitors trichostatin A and depsipeptide.

BACKGROUND: Over the last decade, several drugs that inhibit class I and/or class II histone deacetylases (HDACs) have been identified, including trichostatin A, the cyclic depsipeptide FR901228 and the antibiotic apicidin. These compounds have had immediate application in cancer research because of their ability to reactivate aberrantly silenced tumour suppressor genes and/or block tumour cell growth. Although a number of HDAC inhibitors are being evaluated in preclinical cancer models and in clinical trials, little is known about the differences in their specific mechanism of action and about the unique determinants of cancer cell sensitivity to each of these inhibitors. METHODS: Using a combination of cell viability assays, HDAC enzyme activity measurements, western blots for histone modifications, microarray gene expression analysis and qRT-PCR, we have characterised differences in trichostatin A vs depsipeptide-induced phenotypes in lung cancer, breast cancer and skin cancer cells and in normal cells and have then expanded these studies to other HDAC inhibitors. RESULTS: Cell viability profiles across panels of lung cancer, breast cancer and melanoma cell lines showed distinct sensitivities to the pan-inhibitor TSA compared with the class 1 selective inhibitor depsipeptide. In several instances, the cell lines most sensitive to one inhibitor were most resistant to the other inhibitor, demonstrating these drugs act on at least some non-overlapping cellular targets. These differences were not explained by the HDAC selectivity of these inhibitors alone since apicidin, which is a class 1 selective compound similar to depsipeptide, also showed a unique drug sensitivity profile of its own. TSA had greater specificity for cancer vs normal cells compared with other HDAC inhibitors. In addition, at concentrations that blocked cancer cell viability, TSA effectively inhibited purified recombinant HDACs 1, 2 and 5 and moderately inhibited HDAC8, while depsipeptide did not inhibit the activity of purified HDACs in vitro but did in cellular extracts, suggesting a potentially indirect action of this drug. Although both depsipeptide and TSA increased levels of histone acetylation in cancer cells, only depsipeptide decreased global levels of transcriptionally repressive histone methylation marks. Analysis of gene expression profiles of an isogenic cell line pair that showed discrepant sensitivity to depsipeptide, suggested that resistance to this inhibitor may be mediated by increased expression of multidrug resistance genes triggered by exposure to chemotherapy as was confirmed by verapamil studies. CONCLUSION: Although generally thought to have similar activities, the HDAC modulators trichostatin A and depsipeptide demonstrated distinct phenotypes in the inhibition of cancer cell viability and of HDAC activity, in their selectivity for cancer vs normal cells, and in their effects on histone modifications. These differences in mode of action may bear on the future therapeutic and research application of these inhibitors.

Cryopreservation of shoot tips of Trichilia emetica, a tropical recalcitrant-seeded species.

This paper reports the successful cryopreservation of shoot tips of Trichilia emetica, a tropical tree species producing recalcitrant seeds. Preculture of shoot tips on MS medium with 0.7 M sucrose or with 0.3 M sucrose + 0.5 M glycerol followed by cryoprotection with a mixture of glycerol and DMSO or with PVS2 was crucial for successful recovery following cryostorage. Three cooling rates were applied to assess the effects on post-thaw regrowth of shoot tips. Slow cooling of the shoot tips (WC 1.24 g/g DW) precultured on medium with 0.3 M sucrose + 0.5 M glycerol and cryoprotected with PVS2 resulted in high shoot production (71 percent). Subsequent to relatively faster cooling, only 38 percent of the shoot tips developed shoots. Ultra-rapid cooling with PVS2 resulted in callus formation with 55 percent regrowth. We report one of the very few successful attempts to cryopreserve explants alternative to zygotic axes of tropical tree species producing recalcitrant seeds.

Outcome of non-elective coronary artery bypass grafting without cardio-pulmonary bypass.

OBJECTIVES: There is limited experience in the use of beating heart coronary artery bypass grafting (CABG) in emergency and urgent cases. The aim of this study was to retrospectively assess the safety and efficacy of this technique when used in a non-elective setting. METHODS: We retrospectively reviewed all urgent and emergency cases of coronary artery bypass grafting performed without cardiopulmonary bypass (CPB) from July 1999 to February 2000. There were 35 patients in total. The mean age was 64.8+/-11.9. Twenty-six (74.3%) patients had Canadian Cardiovascular Society grade 4 angina. Twenty-six patients (74.3%) had triple vessel disease. Eleven patients (31.4%) were on preoperative IV nitrates and nine patients (25.7%) had a preoperative IABP (intra aortic balloon pump). Three patients (8.6%) had suffered a preoperative cardiac arrest during coronary angiography. Other associated significant risk factors were smoking (60%), hypertension (40%), hypercholesterolemia (57.1%) and previous Q wave myocardial infarction (31.4%). RESULTS: Twenty-two patients (62.9%) were classified as being urgent and 13 patients (37.1%) were classified as emergencies. The mean number of anastomoses performed were 2.8+/-0.8 (range 1-4) with 68.6% of patients under going triple or quadruple vessel grafting. All patients (100%) received at least one arterial graft. There was no conversion to cardiopulmonary bypass. The main postoperative complications were--supraventricular arrhythmias eight (22.9%), low cardiac output seven (20%) and postoperative HF/dialysis two (5.7%). The median postoperative intensive care unit (ICU) stay was 27.5 h. The mean postoperative hospital stay was 8.3+/-3.1 days. One patient died (2.9%) at the eighth day after surgery due to postoperative myocardial infarction, multi-organ failure secondary to the septicaemia and ventricular arrest. CONCLUSION: Non-elective CABG without CPB is feasible and safe with modern cardiac stabilization devices.

Repair of pulmonary vein rupture after deceleration injury.

Injuries to the major pulmonary vessels are uncommon and are extremely difficult to manage. We report a case of an isolated pulmonary vein injury following a road traffic accident that was repaired successfully.

Quality-of-life study on four patients who underwent esophageal resection and delayed reconstruction for Boerhaave's syndrome.

Boerhaave's syndrome is the condition of spontaneous rupture of the esophagus as a consequence of the strain of emesis with or without predisposing esophageal disease. It is a condition with high mortality. We describe four patients who underwent a transthoracic esophagectomy to remove the rupture of the intrathoracic esophagus, closure of the esophageal gastric junction, fashioning of a feeding gastrostomy, and formation of a left cervical esophagostomy. Three patients underwent reconstruction with subcutaneous colon. We suggest that this method of management may be considered where primary repair is impossible in those patients too ill for prolonged reconstruction or as a salvage procedure where other methods have failed. The poor quality of life after esophagectomy is improved by reconstruction. Other surgical options include covering the repaired opening with a circumferential wrap of pleura, chest wall muscle, or omentum or closing the repair around a T-tube of large caliber. Esophageal exclusion using absorbable staples is another approach.

Surgical training for the next millennium.

The Calman reforms in training have meant that surgical training now consists of a 2-year basic training period followed by a 6-year period of higher surgical training. This article addresses the problems faced by the new Calman surgical trainees and proposes some new measures which could be introduced for surgical training in the next millennium.

Improving senior house officer training in accident and emergency medicine: the benefits of a diploma.

Accident and emergency is a fascinating specialty providing exposure to a wide range of acute and chronic conditions from all branches of medicine. To ensure a minimal standard of training nationally we propose the introduction of a diploma for junior doctors.

An inexpensive and easily constructed laparoscopic simulator.

In this short article the authors describe a simple yet effective method to train surgical trainees in minimally invasive surgery. This method will allow trainees to freely practice and acquire the necessary basic skills required to both competently assist and perform laparoscopic surgery.