Significantly reducing implant loss rates in immediate implant-based breast reconstruction: A protocol and completed audit of quality assurance.

INTRODUCTION: Immediate implant-based breast reconstruction (IBR) rates have increased considerably with the advent of acellular dermal matrices. Implant loss is a significant complication and is costly to patients and the NHS. National Mastectomy and Breast Reconstruction Audit and Implant-Based Breast Reconstruction Audit data have demonstrated national implant loss rate of 9% at 3 months. National Oncoplastic Guidelines for Best Practice cite a < 5% target. We aimed to reduce implant loss by introducing a protocol with pre-, intra- and post-operative interventions. METHODS: Audit of IBR at a single oncoplastic breast unit was commenced and implant loss at 3 months was recorded (May 2012-July 2014). Patients were identified from a prospectively maintained database, and case notes were examined by identifying factors associated with implant loss. A team involving microbiology, theatre staff, infection control and surgeons was established. A novel, evidence-based intervention bundle, including more than 25 protocol changes, was introduced. Prospective re-audit of IBR (April 2015-December 2017) was completed following introduction of the new protocol and implant loss was recorded at 3 months. RESULTS: The first retrospective audit of 77 reconstructions (54 patients) demonstrated 11 implant losses at 3 months (14%). Re-audit, post-intervention, comprised 129 reconstructions (106 patients) with no implant loss at 3 months. Fisher's exact analysis revealed statistically significant reduction in implant loss rate (P < 0.00001) following protocol introduction. CONCLUSIONS: Implant loss rate following IBR can be reduced to an exceptionally low level, well below national targets, by adhering to this evidence-based intervention bundle. Our protocol could improve outcomes nationally.

Posttransplant Lymphoproliferative Disorders in Neuronal Xenotransplanted Macaques.

Posttransplant lymphoproliferative disorders (PTLDs) are a heterogeneous group of lymphoid proliferations that occur in the setting of depressed T-cell function due to immunosuppressive therapy used following solid organ transplantation, hematopoietic stem cell transplantation, and also xenotransplantation. In the present study, 28 immunosuppressed parkinsonian Macaca fascicularis were intracerebrally injected with wild-type or CTLA4-Ig transgenic porcine xenografts to identify a suitable strategy to enable long-term cell survival, maturation, and differentiation. Nine of 28 (32%) immunosuppressed primates developed masses compatible with PTLD, located mainly in the gastrointestinal tract and/or nasal cavity. The masses were classified as monomorphic PTLD according to the World Health Organization classification. Immunohistochemistry and polymerase chain reaction (PCR) analyses revealed that the PTLDs were associated with macaca lymphocryptovirus as confirmed by double-labeling immunohistochemistry for CD20 and Epstein-Barr nuclear antigen 2 (EBNA-2), where the viral protein was located within the CD20+ neoplastic B cells. In sera from 3 distinct phases of the experimental life of the primates, testing by quantitative PCR revealed a progression of the viral load that paralleled the PTLD progression and no evidence of zoonotic transmission of porcine lymphotropic herpesvirus through xenoneuronal grafts. These data suggest that monitoring the variation of macaca lymphocryptovirus DNA in primates could be used as a possible early diagnostic tool for PTLD progression, allowing preemptive treatment such as immunosuppression therapy reduction.

Systematic analysis of missed colorectal cancer cases and common pitfalls in diagnosis.

BACKGROUND: Missed colorectal cancer on endoscopic or radiological investigations may delay diagnosis and impact outcome. This study audits incidence of previous investigations in patients with colorectal cancer, considers outcome in 'missed' cancer cases and examines the diagnostic pathway in the derived case series to identify common pitfalls in diagnosis. METHODS: Patients diagnosed with colorectal cancer in 2011 at a single National Health Service (NHS) Trust were reviewed. Incidence of endoscopic and radiological investigations in the 3 years preceding diagnosis and outcome data were collected. Cases of prior investigation not leading to diagnosis were considered 'missed' cancers and survival compared with 'detected' cases. The diagnostic pathway in each 'missed' case was reviewed. RESULTS: 395 colorectal cancer cases were studied. Eighteen (4.6%) patients underwent previous investigation including colonoscopy (n=4), flexible sigmoidoscopy (n=5), barium enema (n=5) and diagnostic abdominal CT scan (n=12), median 708 days prior to diagnosis. Previous investigation predicted reduced overall and disease-free survival (HR 2.07, p=0.04 and HR 2.66, p<0.0001), after age and gender adjustment. Ten different categories termed 'pitfalls' were derived from analysis of the diagnostic pathway. These included CT scanning for abdominal pain without further investigation (n=7), rectosigmoid cancer following a previous diagnosis of diverticular disease (n=4) and incomplete diagnostic investigations without adequate follow-up (n=3). CONCLUSIONS: A proportion of patients diagnosed with colorectal cancer have previously been investigated for gastrointestinal symptoms and survival appears reduced in these patients. Regular audit and analysis of previous investigations can identify common pitfalls in diagnosis, which should be used to inform training and improve practice.

Immunohistochemical Characterization of Large Intestinal Adenocarcinoma in the Rhesus Macaque (Macaca mulatta).

In rhesus macaques, adenocarcinomas of either the ileocecal junction or colon are common spontaneous tumors in aging populations. The macaque tumors have similar gross and histologic characteristics compared with their human counterpart, but little is known regarding the immunohistochemical expression of proteins that are commonly implicated in the pathogenesis of these tumors in humans. We performed a retrospective review of 22 cases of large intestinal carcinoma in the rhesus macaque and evaluated the expression pattern of a panel of potentially prognostically significant proteins identified from human studies. Histologic characteristics of the tumors included abundant mucin deposition, transmural spread, and lymphatic invasion. All rhesus adenocarcinomas displayed altered expression of 1 or more of CD10, ß-catenin, sirtuin 1, cytokeratin 17, and p53 compared with age-matched controls. Zymographic analysis of active matrix metalloproteinases 2 and 9 in the serum from 5 animals failed to reveal statistically significant differences between adenocarcinoma cases and controls. Based on the data presented herein, large intestinal carcinomas in the macaque share many histomorphologic and immunohistochemical similarities to large intestinal tumors in humans. Further validation of this animal model is considered important for the development of novel therapeutics and a better understanding of the pathogenesis.

Polioencephalomalacia secondary to hypernatremia in squirrel monkeys (Saimiri sciureus).

Squirrel monkeys (Saimiri spp) are one of the most consistently used New World primates in biomedical research and are increasingly being used in neuroscience research, including models of drug abuse and addiction. Spontaneous neurologic disease in the squirrel monkey is uncommonly reported but includes various infectious diseases as well as cerebral amyloidosis. Hypernatremia is an extremely serious condition of hyperosmolarity that occurs as a result of water loss, adipsia, or excess sodium intake. Neurologic effects of hypernatremia reflect the cellular dehydration produced by the shift of water from the intracellular fluid space into the hypertonic extracellular fluid space. Severe hypernatremia may result in cerebrocortical laminar necrosis (polioencephalomalacia) in human patients as well as in a number of domestic species, including pigs, poultry, and ruminants. We report the clinical, histopathologic, and immunohistochemical findings of polioencephalomalacia in 13 squirrel monkeys. Polioencephalomalacia in these animals was associated with hypernatremia that was confirmed by serum levels of sodium greater than 180 mmol/L (reference range, 134.0-154.0 mmol/L [mEq/L]). All animals had concurrent diseases or experimental manipulation that predisposed to adipsia. Immunohistochemical investigation using antibodies to neuronal nuclei (NeuN), CNPase, Iba-1, and CD31 revealed necrosis of predominantly cerebral cortical layers 3, 4, and 5 characterized by neuronal degeneration and loss, oligodendrocytic loss, microglial proliferation, and vascular reactivity. The squirrel monkey is exquisitely sensitive to hyperosmolar metabolic disruption and it is associated with laminar cortical necrosis.

Implementation of the INTERGROWTH-21st Project in the United States.

The North American site in the INTERGROWTH-21(st) Project was North Seattle, Washington State, USA. The majority of the data were collected from within Seattle City, which has approximately 12 300 births per year. The sample for the Newborn Cross-Sectional Study (NCSS) was drawn from two hospitals (Swedish Medical Center and the University of Washington) covering almost 80% of deliveries within the target population. The Fetal Growth Longitudinal Study (FGLS) sample was recruited from several antenatal clinics serving the University of Washington Medical Center and Providence Everett Medical Center. Special activities to encourage participation and raise awareness of the studies included furnishing the recruitment sites with fliers designed by the Project Coordinating Unit, and presenting the studies to clinical staff to encourage providers to refer appropriate patients. One of the major challenges at this site was the low recruitment rate in the early phase of the FGLS because of the high rates of smoking, maternal age >35 years and body mass index >30 years. This was remedied by the inclusion of other ancillary clinics, as well as increased advertising among the general public.

Implementation of the INTERGROWTH-21st Project in the UK.

There are approximately 10,000 births per year in the county of Oxfordshire in the UK, which is one of the two European sites for the International Fetal and Newborn Growth Consortium for the 21(st) Century (INTERGROWTH-21(st) ) Project. The samples for both components of the project--the Fetal Growth Longitudinal Study (FGLS) and Newborn Cross-Sectional Study (NCSS)--were drawn from the John Radcliffe Hospital, a major university hospital with a large regional role that covers more than 75% of deliveries in the county. Special activities to encourage participation in this population included the formation of a research coalition to streamline recruitment in the Maternity Unit and the distribution of study information leaflets to women using the hospital's antenatal care service. This was a demanding project and several challenges were overcome to reach recruitment targets and to maintain high standards of data quality. Amongst the major challenges for FGLS at this study site was the level of ineligibility because of maternal age, smoking and body mass index (BMI) ≥ 30. The major challenge for the NCSS field teams was to ensure that all anthropometric data were collected before the early discharge of uncomplicated deliveries, often within 6 hours of birth. It is evident from our experience in implementing this project that, when large-scale clinical studies are meticulously planned and avoid major disruption to routine clinical care, they are well received by hospital staff and can contribute to the improvement of the overall standard of clinical care.

Mesenchymoproliferative enteropathy associated with dual simian polyomavirus and rhesus cytomegalovirus infection in a simian immunodeficiency virus-infected rhesus macaque (Macaca mulatta).

Opportunistic viral infections are common in simian immunodeficiency virus-infected rhesus macaques and include simian polyomavirus 40 (SV40), which causes interstitial nephritis, pneumonia, meningoencephalitis, and progressive multifocal leukoencephalopathy and rhesus cytomegalovirus (Macacine herpesvirus-3), which is associated with many pathologic manifestations, including the formation of neutrophil-rich gastrointestinal masses. Herein we report the findings of a simian immunodeficiency virus-infected rhesus macaque that presented to necropsy with multiple nodular masses restricted to the proximal jejunum. Histologically, the masses within the lamina propria were composed of abundant, loosely organized, mesenchymal tissue forming broad interlacing whorls and sheets admixed with variable numbers of neutrophils. Cells within the mesenchymoproliferative nodules contained numerous basophilic, intranuclear inclusion bodies with only scattered cytomegalic cells. Immunohistochemistry for rhesus cytomegalovirus and SV40 demonstrated variable numbers of immunopositive cells within the affected nodules. This report is the first description of SV40-associated pathology in the small intestine of a rhesus macaque and highlights the role that opportunistic viral infections can have on gastrointestinal pathology in immunosuppressed rhesus macaques.

Images of the terminal ileum are more convincing than cecal images for verifying the extent of colonoscopy.

BACKGROUND AND STUDY AIMS: Independent verification of colonoscopy completion is important for quality assurance. Cecal photographs aimed at showing key landmarks, including the ileocecal valve (ICV) and appendiceal orifice are the currently recommended standard, but are often perceived as unreliable. Images of the terminal ileum demonstrating villi may provide more robust evidence of completion. We sought to prospectively evaluate the ease of routine intubation of the terminal ileum and to compare the effectiveness of terminal ileum and cecal photographs in convincing independent reviewers that total colonoscopy had been accomplished. PATIENTS AND METHODS: A prospective, observational study evaluated 216 consecutively completed colonoscopies performed in routine clinical practice. Cecal and terminal ileum photographs were evaluated and scored by independent reviewers. Frequency of terminal ileum intubation, time required, and safety parameters were recorded. RESULTS: The terminal ileum was intubated and photographed in 188/216 (87%) of cases. Median time taken to intubate, or attempt to intubate the terminal ileum was 1 min 24 s, and was achieved without complications or requirement for additional sedation. Terminal ileum images were significantly more likely to be considered convincing than cecal images ( P<0.0001 for all reviewers). There was excellent interobserver agreement amongst the opinion of reviewers regarding terminal ileum photographs (kappa=0.91). CONCLUSION: Terminal ileum intubation is achievable rapidly and safely in the majority of patients undergoing colonoscopy. Terminal ileum images provide more convincing evidence of complete examination of the colon than cecal images, even when attempts to capture images specifically of the ICV and appendiceal orifice are made.

Small intestinal adenocarcinoma in common marmosets (Callithrix jacchus).

Small intestinal adenocarcinomas are uncommon neoplasms that are rarely reported in nonhuman primates. These neoplasms are also rare in humans, although they are thought to share a similar pathogenesis with the more common colorectal carcinoma. Herein the authors report the clinical, histologic, immunohistochemical, and molecular characteristics of small intestinal adenocarcinoma in 10 common marmosets (Callithrix jacchus). Retrospective analysis of necropsy records revealed small intestinal carcinoma to be the most common neoplastic cause of morbidity and mortality in aged common marmosets. The average age of affected animals was 6.6 years old, and there was no sex predilection. Nine of 10 (90%) tumors arose within the proximal small intestine near the interface with the duodenum. All cases were characterized by disorganization, loss of polarity, and proliferation of neoplastic epithelial cells along the crypt to midvillous interface. Two of 10 (20%) were defined as carcinoma in situ. Eight of 10 (80%) had some degree of invasion, with lymphatic invasion and lymph node metastasis present in 6 of 10 (60%) animals. Immunohistochemically, 10 of 10 (100%) expressed cytokeratin; 7 of 9 (77%) expressed E-cadherin; and 8 of 9 (88%) expressed beta-catenin. The expression of E-cadherin and beta-catenin was decreased in the cell membrane and increased in the cytoplasm. No Helicobacter-like bacteria were observed via silver stain, and callitrichine herpesvirus 3 was detected by polymerase chain reaction with equal frequency from neoplastic and nonneoplastic intestinal sections. The tumors described in this population illustrate comparable features to human cases of small intestine carcinoma and may serve as a potential animal model for small intestinal carcinomas.

Ovarian pathology in rhesus macaques: a 12-year retrospective.

BACKGROUND: Ovarian pathology is an important cause of decreased fertility and reproductive capability and may impact multiple systems, particularly in aging rhesus macaques. METHODS: Retrospective histopathologic and immunohistochemical analysis of 458 female rhesus macaque necropsies over 12 years at the New England Primate Research Center in Southborough, MA. RESULTS: Degenerative and inflammatory changes in the ovaries included mineralization, infiltration by lymphocytes, macrophages and multinucleated giant cells, endometriosis, and arteriopathy. Cystic changes included follicular cysts, cystic rete, and mesonephric duct cysts with cystic rete the most common. Neoplasms included granulosa cell tumors, cystadenoma, cystadenocarcinoma, and teratoma. CONCLUSIONS: Ovarian lesions of the rhesus macaque are similar to those of cynomolgus macaques and humans. These lesions are frequently incidental findings but may impact metabolic and neurocognitive studies.

Centralization of services: standard setting and outcomes.

OBJECTIVE: To test specific standards set in the newly established cleft lip and palate service in three regions of the U.K. The standards relate to record collection and outcomes. DESIGN: Retrospective analysis. PATIENTS: Records of 31 children, 5 years of age, who were born in 1997 with complete unilateral clefts of lip and palate and were treated by surgeons in three regions. MAIN OUTCOME MEASURES: Record collection standards were measured by collecting dental study models. Outcomes were measured with the 5-Year-Old Index. RESULTS: Of the 31 subjects, 52% had excellent and good outcomes. The 31 cases represented 62% of the total records collected. CONCLUSIONS: The three regions examined fell short of the standards set, but the outcomes were improved compared with previous national outcomes. The failings in record collection need to be rectified. This study provides baseline data for further development of cleft services within three regions.

Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brains of macaques: implications for the neuropathogenesis of AIDS.

The macrophage is well established as a target of HIV and simian immunodeficiency virus (SIV) infection and a major contributor to the neuropathogenesis of AIDS. However, the identification of distinct subpopulations of monocyte/macrophages that carry virus to the brain and that sustain infection within the central nervous system (CNS) has not been examined. We demonstrate that the perivascular macrophage and not the parenchymal microglia is the primary cell productively infected by SIV. We further demonstrate that although productive viral infection of the CNS occurs early, thereafter it is not easily detectable until terminal AIDS. The biology of perivascular macrophages, including their rate of turnover and replacement by peripheral blood monocytes, may explain the timing of neuroinvasion, disappearance, and reappearance of virus in the CNS, and questions the ability of the brain to function as a reservoir for productive infection by HIV/SIV.

Local anaesthesia for vitreoretinal surgery: an audit of patient and surgical experience.

PURPOSE: Local anaesthesia for vitreoretinal surgery is little used as these procedures are deemed to be too long and uncomfortable for patients to tolerate. In this unit anterior intraconal local anaesthesia is used for most routine surgery. We undertook an audit to ensure that surgical standards and patient acceptability were not compromised. METHODS: A prospective observational audit was performed. Audit data included: Grade of anaesthetist and surgeon; details of anaesthetic and operation; compliance of patient; operating conditions and pain scores. Anaesthesia was provided with a combined peribulbar and intraconal anaesthetic, using bicarbonate buffered lignocaine and bupivacaine 50:50 mixture. RESULTS: 135 (76%) had local anaesthesia alone, 13 (7%) had local anaesthesia with sedation and 29 (16%) had general anaesthesia. 96.4% of patients were compliant and 98.8% of operating conditions were good or excellent. The mean perioperative pain score was 0.1 (range of 0-1), 97% said they would choose local anaesthesia again. CONCLUSIONS: LA for vitreoretinal surgery is a useful and flexible method of anaesthesia, which has been shown to have excellent patient tolerance.

Neuropathogenesis of simian immunodeficiency virus in neonatal rhesus macaques.

Neonatal human immunodeficiency virus (HIV) infection usually occurs intrapartum or postpartum and results in a higher incidence of neurological dysfunction than is seen in adults. To explore the neuropathogenesis of neonatal HIV infection, we infected neonatal macaques with simian immunodeficiency virus (SIV) and followed the course of infection focusing on early time points. Infected neonates had decreased brain growth and mild histological changes in brain that resembled those seen in pediatric AIDS, including perivascular infiltrates of mononuclear cells, mineralization of vessels in the basal ganglia, and gliosis. The perivascular lesions and gliosis were associated with the presence of occasional infected cells that required in situ hybridization with radiolabeled riboprobes for detection. Using this technique, SIV-infected cells were detected in the brain parenchyma within 7 days of infection. These findings were confirmed by nested PCR for SIVgag DNA in brain and RT-PCR for viral RNA in cerebrospinal fluid. Together, these techniques revealed SIV infection of the CNS in 12 of 13 neonates infected with SIVmac239, 3 of 3 infected with SIVmac251, and 2 of 2 infected with SIVmac239/316. The prevalence of CNS infection was indistinguishable from that of older animals infected with the same dose and stock of virus, but neonates appeared to have fewer infected cells in the CNS and detecting them required more sensitive techniques. This observation was true regardless of inoculum and despite the fact that neonates had equal or greater viral loads in the periphery compared with older animals. These data suggest that maturation-dependent host factors have a major impact on the neuropathogenesis of pediatric AIDS.

Induced hypothermia as salvage treatment for refractory cardiac failure following paediatric cardiac surgery.

OBJECTIVE: Following corrective cardiac surgery in infants and children for congenital heart disease, a persistent low cardiac output refractory to conventional modes of treatment is associated with a mortality approaching 100%. We advocate the use of whole body hypothermia to reduce tissue oxygen demand and provide a degree of cellular protection against ischaemia allowing time for recovery. We describe our experience. METHODS: Between July 1986 and December 1995, 1885 infants and children underwent surgery (operative mortality, 6%), 1302 requiring cardiopulmonary bypass. Fifty-seven patients had a persistent low cardiac output, impaired respiratory function, decreased urine output and acidosis despite maximal intensive care treatment. Cooling to 32-33 degrees C was therefore started using a thermostatically controlled water filled cooling blanket. RESULTS: Following cooling, there was a fall in heart rate (P<0.001), a rise in mean arterial pressure (P<0.001) and a fall in mean atrial pressure (P<0.001). Significant (P<0.001) increases in pH and urine output were also recorded. Thirty-one (54%) of the 57 patients treated with cooling survived to leave hospital. No long-term sequelae have been noted in these patients. CONCLUSION: Induced hypothermia is a useful salvage treatment, in children following corrective cardiac surgery when all conventional treatment has been tried and failed.

Association of simian virus 40 with a central nervous system lesion distinct from progressive multifocal leukoencephalopathy in macaques with AIDS.

The primate polyomavirus SV40 is known to cause interstitial nephritis in primary infections and progressive multifocal leukoencephalopathy (PML) upon reactivation of a latent infection in SIV-infected macaques. We now describe a second central nervous system manifestation of SV40: a meningoencephalitis affecting cerebral gray matter, without demyelination, distinct from PML. Meningoencephalitis appears also to be a primary manifestation of SV40 infection and can be seen in conjunction with SV40-induced interstitial nephritis and pneumonitis. The difference in the lesions of meningoencephalitis and PML does not appear to be due to cellular tropism, as both oligodendrocytes and astrocytes are infected in PML and meningoencephalitis, as determined by in situ hybridization or immunohistochemistry for SV40 coupled with immunohistochemistry for cellular determinants. This is further supported by examination of SV40 nucleic acid sequences from the ori-enhancer and large-T-antigen regions, which reveals no tissue-or lesion-specific variation in SV40 sequences.

Induced hypothermia in the postoperative management of refractory cardiac failure following paediatric cardiac surgery.

Postoperative low cardiac output states are a major cause of postoperative mortality in infants and children following corrective cardiac surgery for congenital heart defects. In this unit, whole body hypothermia has been used since 1979 in the management of these low output states when they are refractory to conventional modes of therapy. Twenty cases treated in this way between July 1986 and June 1990 were reviewed in 1992. The current report reviews the 50 further cases treated with moderate hypothermia between July 1990 and December 1995. The median (range) age of patients was 8 months (0 days-16 years) with a median weight of 4.1 kg (2.5-33 kg). Following cooling, there was a decrease in heart rate (p < 0.001), an increase in mean arterial pressure (p < 0.001) and a decrease in mean atrial pressure (p < 0.001). Significant increases in pH and urine output were also noticed, the increase in urine output being greater in the surviving group (p = 0.02). A decrease in platelet count occurred (p < 0.001) but white blood cell count remained unchanged (p = 0.18). Twenty-five of the 50 patients survived to leave hospital. Induced hypothermia does not appear to be associated with any complications and after the failure of all conventional treatment, it seems likely that the technique may have been beneficial to outcome in some patients.

Characterization of the cutaneous exanthem in macaques infected with a Nef gene variant of SIVmac239.

The molecularly cloned viruses known as SIVmac239/R17Y and SIVmac239/YEnef cause extensive lymphocyte activation and induce an acute disease syndrome in macaque monkeys. One manifestation of this syndrome is a severe diffuse cutaneous maculopapular exanthem that is similar to the exanthem associated with HIV-1 infection. To examine the pathogenesis of this exanthem, biopsies obtained throughout the course of clinically evident rash were examined for the presence of virus by in situ hybridization and immunohistochemistry, and the cellular infiltrate was characterized with respect to cellular immunophenotype and chemokine receptor expression. The onset of rash was associated with abundant simian immunodeficiency virus nucleic acid and protein within perivascular dermal infiltrates and occasionally within intraepithelial cells. Analysis of cellular infiltrates showed that biopsies, obtained on the day of rash onset, were composed of equal numbers of CD4+ and CD8+ lymphocytes and abundant alphaEbeta7 positive cells surrounding vessels with upregulated endothelial E-selectin. Moreover, by examining virus expression in sequential skin biopsies from the same animal, the clearance of virus and the resolution of rash were associated with an increase in the percentage of cells expressing CD8, the chemokine receptor CXCR3, and GMP-17, a marker of cytotoxic granules. These results suggest that activated cytotoxic T cells are trafficking to sites of inflammation in the skin and directly or indirectly affect levels of viral replication at these sites.