Clinical utility of MRI in the neoadjuvant management of early-stage breast cancer.

BACKGROUND: With the increasing use of neoadjuvant treatment (NAT) for patients with early-stage breast cancer (ESBC), adequate clinical staging is essential to inform treatment. While the use of MRI with NAT has been proposed to help with accuracy of pre-treatment clinical staging, its impact in clinical practice remains controversial. METHODS: A prospective institutional database of patients with ESBC treated with NAT between May 2012 and December 2020 was analyzed in order to compare the management of patients who received an MRI prior to NAT to those who did not. The indications for MRI and correlation of MRI findings to conventional breast imaging were evaluated. The impact of MRI on management was compared between the MRI and non-MRI groups. RESULTS: A total of 530 patients met inclusion criteria. Of these, 186 (35.1%) had an MRI and 344 (64.9%) did not. The most frequent indication for MRI was the determination of disease extent (54.5%). Patients who had an MRI prior to neoadjuvant treatment were significantly more likely to be younger (47 years versus 57 years; p < 0.001) and have multifocal disease (32.3% versus 22.1%; p < 0.05). When compared to conventional imaging, MRI reported a greater extent of disease in the breast (37.6%), more nodal involvement (18.8%), and multifocal disease (15.1%). Additional diagnostic interventions were advised in 52.2% of patients who underwent MRI. Rates of mastectomies were greater in the MRI group (80.0% versus 58.9%; p < 0.05) in addition to more axillary dissections (28.0% versus 17.4%; p < 0.01). Rates of locoregional recurrences were low in both groups, with similar disease-free survival outcomes at 5 years. CONCLUSION: MRI identified significantly more disease in contrast to conventional imaging and lead to more aggressive surgical management. Prospective studies evaluating the role of MRI before NAT and its impact on long-term outcomes are needed.

Burkitt Lymphoma/Leukaemia in Children & Young Adolescents.

Aims Burkitt Lymphoma (BL) accounts for approximately 40% of childhood non-Hodgkin Lymphoma (NHL) in the developed world. Survival rates have improved dramatically in recent years, a success attributed to better use of poly-chemotherapy and targeted immunotherapy. Nevertheless, relapse is unpredictable and carries a dismal prognosis. We report on event-free survival (EFS) and overall survival (OS) rates in the Republic of Ireland (ROI) during 2000-2017, and evaluate novel predictors of outcome. Methods Data was collected by retrospective review of patient medical records. Results Thirty-three patients were identified (twenty-five [76%] males, eight [24%] females), fourteen [42%] having stage III disease at presentation. Six [18%] had stage IV disease. Five [15%] had refractory disease; one salvaged with allogeneic stem cell transplantation. Of the four [12%] who died; two [50%] had weights >99th centile, one [25%] >90th centile. One died during induction from refractory lactic acidosis, one from early relapse. Discussion EFS and OS was 85% and 89% respectively; in keeping with the best international standards. Obesity appears to be a poor predictor of outcome in our cohort.

Leptomeningeal Relapse of Embryonal Rhabdomyosarcoma after 15 years.

Aim Rhabdomyosarcoma (RMS) is the most common malignant soft tissue tumour of childhood. We present the case of a late relapse of RMS to the leptomeninges after 15 years. Methods A 20 year old male presented with a 3 week history of headaches and nausea. He previously had RMS of his right ear diagnosed at age 5 years which was treated with concurrent chemoradiotherapy. An MRI Brain and Spine confirmed extensive leptomeningeal disease and CSF analysis confirmed the presence of recurrent embryonal RMS. Results He completed two cycles of cyclophosphamide and topotecan followed by 45Gy/25Fr of craniospinal radiotherapy. Conclusion Late relapses beyond five years can be seen in up to 9% of patients, however very late recurrences (>10 years) are exceedingly rare. Molecular based methods such as gene expression profiling can aid risk stratification and survivorship clinics may become increasingly useful in following patients with high risk features.

Pulmonary aspiration in preschool children with cystic fibrosis.

Pulmonary aspiration of gastric refluxate (PAGR) has been demonstrated in association with pulmonary inflammation in school aged children with Cystic Fibrosis (CF). We sought to determine if similar findings were present in preschool children. Pepsin was measured in Broncho-alveolar lavage (BAL) fluid collected from clinically stable preschool children with CF and controls. Elevated pepsin levels were found in a subgroup of children with CF, but this was not found to be associated with pulmonary infection, pulmonary inflammation or respiratory or gastrointestinal symptoms.

Use of whole genome sequencing to complement characterisation of a typhoid fever outbreak among a Marshallese community: Oklahoma, 2015.

Typhoid fever is an illness caused by Salmonella enterica serotype Typhi. In developing regions, it affects an estimated 20 million people annually, causing 200 000 deaths. Although uncommon, cases occur in the USA each year, predominantly due to international travel. During February 2015, the Oklahoma State Department of Health (OSDH) detected an outbreak of typhoid fever among residents of northwestern Oklahoma. OSDH conducted case-patient interviews to identify the source and symptomatic contacts. Whole genome sequencing (WGS) was performed to characterise the genetic relatedness of isolates among the four outbreak-associated pulsed-field gel electrophoresis (PFGE) patterns. We identified 38 cases, 25 confirmed and 13 probable, in two states. WGS revealed a 0-10 single-nucleotide polymorphism variation between isolates. Although we were unable to determine the source, almost all case-patients were members of the Marshallese community that attended a common event in Oklahoma, or were contacts to a confirmed case. This is the largest outbreak of typhoid fever in the USA since 1989, and first to apply WGS to complement interpretation of PFGE results during a typhoid fever outbreak investigation. This investigation illustrates the potential risk of outbreaks among communities comprised of international populations from regions where typhoid fever remains endemic.

The Theory of Planned Behaviour and dietary patterns: A systematic review and meta-analysis.

OBJECTIVE: Promoting adherence to healthy dietary patterns is a critical public health issue. Models of behaviour, such as the Theory of Planned Behaviour (TPB) allow programme designers to identify antecedents of dietary patterns and design effective interventions. The primary aim of this study was to examine the association between TPB variables and dietary patterns. METHODS: A systematic literature search was conducted to identify relevant studies. Random-effects meta-analysis was used to calculate average correlations. Meta-regression was used to test the impact of moderator variables. RESULTS: In total, 22 reports met the inclusion criteria. Attitudes had the strongest association with intention (r+=0.61) followed by perceived behavioural control (PBC, r+=0.46) and subjective norm (r+=0.35). The association between intention and behaviour was r+=0.47, and between PBC and behaviour r+=0.32. Moderator analyses revealed that younger participants had stronger PBC-behaviour associations than older participants had, and studies recording participants' perceptions of behaviour reported significantly higher intention-behaviour associations than did those using less subjective measures. CONCLUSIONS: TPB variables were found to have medium to large associations with both intention and behaviour that were robust to the influence of key moderators. Recommendations for future research include further examination of the moderation of TPB variables by age and gender and the use of more valid measures of eating behaviour.

Pro-angiogenic cellular and genomic expression patterns within glioblastoma influences dynamic susceptibility weighted perfusion MRI.

AIM: To investigate whether quantitative dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion magnetic resonance imaging (MRI) metrics are influenced by cellular and genomic expression patterns of glioblastoma angiogenesis. MATERIALS AND METHODS: Twenty-five stereotactic neurosurgical tissue samples were prospectively obtained from enhancing and non-enhancing tumour regions from 10 patients with treatment-naïve glioblastoma. Using monoclonal antibodies, histopathological features of angiogenesis were examined: total microvascular density, vascular morphology, and hypoxia. Angiogenic expression patterns of tissue samples were investigated using RNA microarrays. DSC perfusion MRI metrics were measured from the tissue sampling sites. MRI and histopathological variables were compared using Pearson's correlations. Microarray analysis was performed using false discovery rate (FDR) statistics. RESULTS: Thirteen enhancing and 12 non-enhancing MR image-guided tissue specimens were prospectively obtained. Enhancing tumour regions demonstrated a significant difference in DSC perfusion and histopathological metrics of angiogenesis when compared to non-enhancing regions. Four angiogenic pathways (vascular endothelial growth factor [VEGF], hypoxia inducible factor [HIF], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF]; 25 individual genes) were significantly up-regulated within enhancing regions when compared to non-enhancing regions (adjusted p<0.05, FDR <0.05). A statistically significant correlation was observed between VEGF-A expression, microvascular density, microvascular morphology, and DSC perfusion MRI metrics (p<0.05). CONCLUSION: Pro-angiogenic genomic and cellular expression patterns of treatment-naïve primary glioblastoma significantly influences morphological and physiological DSC perfusion metrics suggesting that expression levels of therapeutically relevant genetic signatures can be quantified using MRI.

Delayed neurological deficit following resection of tuberculum sellae meningioma: report of two cases, one with permanent and one with reversible visual impairment.

The most common presentation of patients with tuberculum sellae meningiomas is visual loss, and surgical resection is the main mode of treatment. Preservation of vision is not only the main objective of the surgery; loss of vision is also its main risk. Visual deterioration following surgery is usually apparent immediately post-operatively. Here we present two cases of patients who underwent resection of tuberculum sellae meningioma and whose vision following surgery was initially unchanged until the postoperative day two when dramatic visual deterioration occurred. In the first case this resulted in blindness, whereas in the second case vision recovered back to the preoperative state. The possible mechanisms of visual deterioration and modes of treatment are discussed.

Congenital-infantile fibrosarcoma of the foot--avoidance of amputation.

Congenital-infantile fibrosarcoma is a rare entity with a five year survival rate of over 90%. Surgery is still the most common treatment modality with amputation often necessary. There have been reports supporting the use of neoadjuvant chemotherapy to debulk the tumour in an effort to facilitate limb sparing surgery. We report a case of a newborn who presented with a life threatening haemorrhage from a fibrosarcoma of the foot, successfully treated with Vincristine, Actinomycin and Cyclophosphamide (VAC) chemotherapy alone.

The wide world of non-mammalian phospholipase D enzymes.

Phospholipase D (PLD) hydrolyses phosphatidylcholine (PtdCho) to produce free choline and the critically important lipid signaling molecule phosphatidic acid (PtdOH). Since the initial discovery of PLD activities in plants and bacteria, PLDs have been identified in a diverse range of organisms spanning the taxa. While widespread interest in these proteins grew following the discovery of mammalian isoforms, research into the PLDs of non-mammalian organisms has revealed a fascinating array of functions ranging from roles in microbial pathogenesis, to the stress responses of plants and the developmental patterning of flies. Furthermore, studies in non-mammalian model systems have aided our understanding of the entire PLD superfamily, with translational relevance to human biology and health. Increasingly, the promise for utilization of non-mammalian PLDs in biotechnology is also being recognized, with widespread potential applications ranging from roles in lipid synthesis, to their exploitation for agricultural and pharmaceutical applications.

Treatment rates and healthcare costs of patients with fragility fracture by site of care: a real-world data analysis.

In a characterization of treatment rates and healthcare costs among patients with an osteoporotic-related fragility fracture overall and by site of care, costs were high and treatment rates were low. PURPOSE: Osteoporotic fractures can be debilitating, even fatal, among older adults. The cost of osteoporosis and related fractures is projected to increase to more than $25 billion by 2025. The objective of this analysis is to characterize disease-related treatment rates and healthcare costs of patients with an osteoporotic fragility fracture overall and by site of fracture diagnosis. METHODS: In this retrospective analysis, individuals with fragility fractures were identified in the Merative MarketScan® Commercial and Medicare Databases among women 50 years of age or older and diagnosed with fragility fracture between 1/1/2013 and 6/30/2018 (earliest fracture diagnosis = index). Cohorts were categorized by clinical site of care where the diagnosis of fragility fracture was made and were continuously followed for 12 months prior to and following index. Sites of care were inpatient admission, outpatient office, outpatient hospital, emergency room hospital, and urgent care. RESULTS: Of the 108,965 eligible patients with fragility fracture (mean age 68.8), most were diagnosed during an inpatient admission or outpatient office visit (42.7%, 31.9%). The mean annual healthcare costs among patients with fragility fracture were $44,311 (± $67,427) and were highest for those diagnosed in an inpatient setting ($71,561 ± $84,072). Compared with other sites of care at fracture diagnosis, patients diagnosed during an inpatient admission also had highest proportion of subsequent fractures (33.2%), osteoporosis diagnosis (27.7%), and osteoporosis therapy (17.2%) during follow-up. CONCLUSION: The site of care for diagnosis of fragility fracture affects treatment rates and healthcare costs. Further studies are needed to determine how attitude or knowledge about osteoporosis treatment or healthcare experiences differ at various clinical sites of care in the medical management of osteoporosis.

Differential effects of infliximab on absolute circulating blood leucocyte counts of innate immune cells in early and late rheumatoid arthritis patients.

Anti-tumour necrosis factor (TNF) biologics have revolutionized therapy of rheumatoid arthritis (RA). We compared the effects of infliximab on numbers of circulating leucocyte subsets in early RA (disease/symptom duration of ≤1 year) and late RA patients (>1 year). A control group consisted of early RA patients treated with a combination of methotrexate (MTX) and methylprednisolone. Blood samples were obtained at baseline (pre-therapy) from all RA patients, divided into three groups: (i) late RA receiving infliximab/MTX, (ii) early RA-infliximab/MTX, (iii) early RA-steroid/MTX, and also from follow-up patients at 2 and 14 weeks. Significant differences in absolute counts of monocytes and granulocytes were observed between healthy controls and RA patients. At baseline CD14(bright) monocytes and CD16(+) granulocytes were increased in both early RA and late RA patients. CD4(+) T cells, CD8(+) T cells and B cells were all increased at baseline in early RA, but not in late RA. At 2 weeks following infliximab treatment decreased granulocytes were observed in both early and late RA and decreased natural killer (NK) cells in late RA. CD16(+) granulocytes and NK cells were also decreased at 14 weeks post-infliximab in early RA. Biotinylated infliximab was used to detect membrane-associated TNF (mTNF)-expressing leucocytes in RA patients. CD16(+) granulocytes, NK cells and CD14(dim) monocytes all expressed higher levels of mTNF in RA patients. In summary infliximab is associated with decreased CD16(+) granulocyte and NK cell counts, possibly through binding of mTNF. Differential effects of infliximab between early and late RA suggest that pathogenic mechanisms change as disease progresses.

Epidemiology of a large restaurant-associated outbreak of Shiga toxin-producing Escherichia coli O111:NM.

In August 2008, a large outbreak of Shiga toxin-producing Escherichia coli (STEC) O111:NM infections associated with a buffet-style restaurant in rural Oklahoma was identified. A case-control study of restaurant patrons and a retrospective cohort study of catered event attendees were conducted coupled with an environmental investigation to determine the outbreak's source and mode of transmission. Of 1823 persons interviewed, 341 (18·7%) met the outbreak case definition; 70 (20·5%) were hospitalized, 25 (7·3%) developed haemolytic uraemic syndrome, and one died. Multiple food items were significantly associated with illness by both bivariate and multivariate analyses, but none stood out as a predominant transmission vehicle. All water, food, and restaurant surface swabs, and stool cultures from nine ill employees were negative for the presence of Shiga toxin and E. coli O111:NM although epidemiological evidence suggested the outbreak resulted from cross-contamination of restaurant food from food preparation equipment or surfaces, or from an unidentified infected food handler.

Reversible infantile respiratory chain deficiency is a unique, genetically heterogenous mitochondrial disease.

OBJECTIVES: Homoplasmic maternally inherited, m.14674T>C or m. 14674T>G mt-tRNA(Glu) mutations have recently been identified in reversible infantile cytochrome c oxidase deficiency (or 'benign COX deficiency'). This study sought other genetic defects that may give rise to similar presentations. PATIENTS: Eight patients from seven families with clinicopathological features of infantile reversible cytochrome c oxidase deficiency were investigated. METHODS: The study reviewed the diagnostic features and performed molecular genetic analyses of mitochondrial DNA and nuclear encoded candidate genes. RESULTS: Patients presented with subacute onset of profound hypotonia, feeding difficulties and lactic acidosis within the first months of life. Although recovery was remarkable, a mild myopathy persisted into adulthood. Histopathological findings in muscle included increased lipid and/or glycogen content, ragged-red and COX negative fibres. Biochemical studies suggested more generalised abnormalities than pure COX deficiency. Clinical improvement was reflected by normalisation of lactic acidosis and histopathological abnormalities. The m.14674T>C mt-tRNA(Glu) mutation was identified in four families, but none had the m. 14674T>G mutation. Furthermore, in two families pathogenic mutations were also found in the nuclear TRMU gene which has not previously been associated with this phenotype. In one family, the genetic aetiology still remains unknown. CONCLUSIONS: Benign COX deficiency is better described as 'reversible infantile respiratory chain deficiency'. It is genetically heterogeneous, and patients not carrying the m.14674T>C or T>G mt-tRNA(Glu) mutations may have mutations in the TRMU gene. Diagnosing this disorder at the molecular level is a significant advance for paediatric neurologists and intensive care paediatricians, enabling them to select children with an excellent prognosis for continuing respiratory support from those with severe mitochondrial presentation in infancy.

Outcome measures in placebo-controlled trials of osteoarthritis: responsiveness to treatment effects in the REPORT database.

INTRODUCTION: Treatment response in randomized clinical trials (RCT) of osteoarthritis (OA) has been assessed by multiple primary and secondary outcomes, including pain, function, patient and clinician global measures of status and response to treatment, and various composite and responder measures. Identifying outcome measures with greater responsiveness to treatment is important to increase the assay sensitivity of RCTs. OBJECTIVE: To assess and compare the responsiveness of different outcome measures used in placebo-controlled RCTs of OA. SEARCH STRATEGY: The Resource for Evaluating Procedures and Outcomes of Randomized Trials database includes placebo-controlled clinical trials of pharmacologic treatments (oral, topical, or transdermal) for OA identified from a systematic literature search of RCTs published or publicly available before August 5, 2009, which was conducted using PubMed, the Cochrane collaboration, publicly-available websites, and reference lists of retrieved publications. DATA COLLECTION AND ANALYSIS: Data collected included: (1) pain assessed with single-item ratings and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale; (2) patient and clinician global measures of status, improvement, and treatment response; (3) function assessed by the WOMAC function subscale; (4) stiffness assessed by the WOMAC stiffness subscale; and (5) the WOMAC and Lequesne Algofunctional Index composite outcomes. Measures were grouped according to the total number of response categories (i.e., <10 categories or ≥10 categories). The treatment effect (difference in mean change from baseline between the placebo and active therapy arms) and standardized effect size (SES) were estimated for each measure in a meta-analysis using a random effects model. RESULTS: There were 125 RCTs with data to compute the treatment effect for at least one measure; the majority evaluated non-steroidal anti-inflammatory drugs (NSAIDs), followed by opioids, glucosamine and/or chondroitin, and acetaminophen. In general, the patient-reported pain outcome measures had comparable responsiveness to treatment as shown by the estimates of treatment effects and SES. Treatment effects and SESs were generally higher for patient-reported global measures compared with clinician-rated global measures but generally similar for the WOMAC and Lequesne composite measures. CONCLUSIONS: Comparing different outcome measures using meta-analysis and selecting those that have the greatest ability to identify efficacious treatments may increase the efficiency of clinical trials of treatments for OA. Improvements in the quality of the reporting of clinical trial results are needed to facilitate meta-analyses to evaluate the responsiveness of outcome measures and to also address other issues related to assay sensitivity.

Mammalian phospholipase D: Function, and therapeutics.

Despite being discovered over 60 years ago, the precise role of phospholipase D (PLD) is still being elucidated. PLD enzymes catalyze the hydrolysis of the phosphodiester bond of glycerophospholipids producing phosphatidic acid and the free headgroup. PLD family members are found in organisms ranging from viruses, and bacteria to plants, and mammals. They display a range of substrate specificities, are regulated by a diverse range of molecules, and have been implicated in a broad range of cellular processes including receptor signaling, cytoskeletal regulation and membrane trafficking. Recent technological advances including: the development of PLD knockout mice, isoform-specific antibodies, and specific inhibitors are finally permitting a thorough analysis of the in vivo role of mammalian PLDs. These studies are facilitating increased recognition of PLD's role in disease states including cancers and Alzheimer's disease, offering potential as a target for therapeutic intervention.

A molecular basis for MHC class II--associated autoimmunity.

Class II major histocompatibility (MHC) molecules have an immunoregulatory role. These cell-surface glycoproteins present fragments of protein antigens (or peptides) to thymus-derived lymphocytes (T cells). Nucleotide sequence polymorphism in the genes that encode the class II MHC products determines the specificity of the immune response and is correlated with the development of autoimmune diseases. This study identifies certain class II polymorphic amino acid residues that are strongly associated with susceptibility to insulin-dependent diabetes mellitus, rheumatoid arthritis, and pemphigus vulgaris. These findings implicate particular class II MHC isotypes in susceptibility to each disease and suggest new prophylactic and therapeutic strategies.

Dramatic spontaneous regression of a medium-sized congenital melanocytic naevus.

We report a case of a 6-month-old girl who was referred for evaluation of a congenital melanocytic naevus (CMN) on her right thigh. The lesion was consistent with a medium-sized CMN and was managed conservatively. A halo of depigmentation, which coincided with occlusion of the lesion during a holiday in a sunny climate, was noted soon after her fourth birthday and the CNM regressed completely over a 4-month period. A residual patch of leucoderma still remained at the original CMN site > 2 years after its total involution. The process has been documented with photographs and a skin biopsy during the resolving phase.