A modular microfluidic platform to enable complex and customisable in vitro models for neuroscience.

Disorders of the central nervous system (CNS) represent a global health challenge and an increased understanding of the CNS in both physiological and pathophysiological states is essential to tackle the problem. Modelling CNS conditions is difficult, as traditional in vitro models fail to recapitulate precise microenvironments and animal models of complex disease often have limited translational validity. Microfluidic and organ-on-chip technologies offer an opportunity to develop more physiologically relevant and complex in vitro models of the CNS. They can be developed to allow precise cellular patterning and enhanced experimental capabilities to study neuronal function and dysfunction. To improve ease-of-use of the technology and create new opportunities for novel in vitro studies, we introduce a modular platform consisting of multiple, individual microfluidic units that can be combined in several configurations to create bespoke culture environments. Here, we report proof-of-concept experiments creating complex in vitro models and performing functional analysis of neuronal activity across modular interfaces. This platform technology presents an opportunity to increase our understanding of CNS disease mechanisms and ultimately aid the development of novel therapies.

Dysregulation of the interleukin-17A pathway in endometrial tissue from women with unexplained infertility affects pregnancy outcome following assisted reproductive treatment.

STUDY QUESTION: Which transcriptomic alterations in mid-luteal endometrial scratch biopsies, taken prior to the assisted reproductive treatment (ART) treatment cycle are associated with unsuccessful pregnancy? SUMMARY ANSWER: Dysregulated interleukin-17 (IL-17) pathway components are demonstrated in women who fail to become pregnant after ART. WHAT IS KNOWN ALREADY: Implantation failure is now recognised as a critical factor in unexplained infertility and may be an important component of failed ART. STUDY DESIGN, SIZE, DURATION: Using a prospective longitudinal study design, 29 nulliparous women with unexplained infertility undergoing ART were recruited between October 2016 and February 2018. Mid-luteal stage endometrium and matched serum samples were collected, and patients underwent a single embryo transfer in the subsequent cycle. RNA-seq analysis of endometrial biopsies was performed on the discovery cohort (n = 20). PARTICIPANTS/MATERIALS, SETTING, METHODS: Gene set enrichment analysis of the differentially expressed genes (DEGs) was performed. Endometrium and serum were then prepared for IL-17A analysis by ELISA. MAIN RESULTS AND THE ROLE OF CHANCE: There were 204 differentially expressed protein-coding genes identified in tissue from women who became pregnant (n = 9) compared with tissue from women who failed to become pregnant (n = 11) (false discovery rate; P < 0.05). Of the 204 DEGs, 166 were decreased while 38 were increased in the pregnant compared to the non-pregnant groups. Gene set enrichment analysis of the DEGs identified an over-representation of IL-17 and Pl3K-Akt signalling pathways. All the DEGs within the IL-17 signalling pathway (MMP3, MMP1, IL1ß, LCN2, S100A9 and FOSL1) demonstrated decreased expression in the pregnant group. Serum IL-17 protein levels were increased in the non-pregnant discovery cohort (n = 11) and these findings were confirmed a validation cohort (n = 9). LIMITATIONS, REASONS FOR CAUTION: Limitations of our study include the cohort size and the lack of aneuploidy data for the embryos; however, all embryos transferred were single good or top-quality blastocysts. WIDER IMPLICATIONS OF THE FINDINGS: These findings demonstrate dysregulated IL-17 pathway components in women who fail to become pregnant after ART. Elevated serum levels of the pro-inflammatory cytokine IL-17 may predict failure of ART in women with unexplained infertility. Future trials of anti-IL-17 therapies in this cohort warrant further investigation. STUDY FUNDING/COMPETING INTEREST(S): Funding from the UCD Wellcome Institutional Strategic Support Fund, which was financed jointly by University College Dublin and the SFI-HRB-Wellcome Biomedical Research Partnership (ref 204844/Z/16/Z), is acknowledged. The authors have no competing interests. TRIAL REGISTRATION NUMBER: NA.

Intravesical chondroitin sulphate for interstitial cystitis/painful bladder syndrome.

INTRODUCTION: Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic inflammatory condition of the bladder. Bladder instillation is one avenue of treatment but evidence for its effectiveness is limited. Chondroitin sulphate solution 2.0% (Urocyst) is a glycosaminoglycan (GAG) replenishment therapy instilled for patients with IC/PBS. We assessed its effectiveness for treating IC/PBS in Northern Ireland. METHODS: Patients with IC/PBS were assessed with the O'Leary-Sant interstitial cystitis index score and global response assessment questionnaire prior to commencing treatment. Assessment with these questionnaires was performed after 6 treatments (10 weeks) and again after 10 treatments (24 weeks). Assessment end points were pain, urgency, symptom score and problem score. RESULTS: Data was collected on 10 patients, 9 female and 1 male. 6 patients had failed RIMSO-50 dimethyl sulphoxide (DMSO) 50% treatment prior. At baseline the mean pain score was 6.6, urgency score 7.00, symptom score 13.5 and problem score 12.5. After 24 weeks the mean pain score fell to 2.0, urgency score to 1.80, symptom score to 6.89 and problem score to 5.67. At 10 weeks the global response to treatment was 100%. Nocturia was the first symptom to improve with urgency and pain following. No side effects were noted during instillation and all patients tolerated the treatments. CONCLUSION: IC/PBS is a difficult disease to treat. It requires a multimodal approach. We found that intravesical chondroitin sulphate reduced pain, urgency and O'Leary-Sant symptom and problem scores in patients with IC/PBS. All patients tolerated the treatment and no side effects were reported.

Neonatal referrals to the coroner service: a short survey on current practice.

In Ireland, coroners are required by law to ascertain the details of potentially unexplained deaths. The Coroner's Acts (1962 and 2005) detail deaths which must be notified to the coroner. We surveyed current practice regarding the notification of the Coroner Service following neonatal deaths by telephone interview of senior clinical nurse managers of paediatric units with neonatal inpatients. Five of 21 units (23.8%) reported that all neonatal deaths would prompt contact with the Coroner Service, with four more units (19%) reporting that unexpected neonatal deaths would be referred. Nine units (42.9%) reported that referral was at the discretion of the consultant involved while three units (14.3%) do not refer neonatal deaths to the coroner.

Placental pathology associated with small for gestational age infants.

Infants with intrauterine growth restriction (IUGR) are at an increased risk of perinatal disease, including death. Many, but not all small for gestational age infants (SGA) have IUGR. Placental disease is an important cause of IUGR, and gross and microscopic examination is critical in explaining such cases. Reports of placentas from infants with a birth weight < 2SD from the mean (approx 3rd centile) born between Jan 2004-Dec 2011 were evaluated. The principal pathology was determined in each case. Where two or more pathologic findings were present, they were ranked as principal and co-existing in terms of severity. There were 69,493 deliveries over the study period. 461 SGA cases were identified. No placenta was available in 44 cases, and 21 cases of known anomalies were excluded, leaving a study group of 396 cases. Pathology potentially causing or contributing to SGA and/or IUGR was identified in 84.1% of cases. Significant co-existing pathology was seen in 88 cases (22%). Placental examination provides key information in understanding abnormal fetal growth.

Novel placental ultrasound assessment: potential role in pre-gestational diabetic pregnancy.

OBJECTIVES: Management of women with pre-gestational diabetes continues to be challenging for clinicians. This study aims to determine if 3D power Doppler (3DPD) analysis of placental volume and flow, and calculation of placental calcification using a novel software method, differ between pregnancies with type 1 or type 2 diabetes and normal controls, and if there is a relationship between these ultrasound placental parameters and clinical measures in diabetics. METHODS: This was a prospective cohort study of 50 women with diabetes and 250 controls (12-40 weeks gestation). 3DPD ultrasound was used to evaluate placental volume, vascularisation index (VI), flow index (FI) and vascularisation-flow index (VFI). Placental calcification was calculated by computer analysis. Results in diabetics were compared with control values, and correlated with early pregnancy HbA1c, Doppler results and placental histology. RESULTS: Placental calcification and volume increased with advancing gestation in pre-gestational diabetic placentae. Volume was also found to be significantly higher than in normal placentae. VI and VFI were significantly lower in diabetic pregnancies between 35 and 40 weeks gestation. A strong relationship was seen between a larger placental volume and both increasing umbilical artery pulsatility index and decreasing middle cerebral artery pulsatility index. FI was significantly lower in cases which had a booking HbA1c level ≥6.5%. Ultrasound assessed placental calcification was reduced with a histology finding of delayed villous maturation. No other correlation with placental histology was found. CONCLUSIONS: This study shows a potential role for 3D placental evaluation, and computer analysis of calcification, in monitoring pre-gestational diabetic pregnancies.

Reversible inhibition of the glycine transporter GlyT2 circumvents acute toxicity while preserving efficacy in the treatment of pain.

BACKGROUND AND PURPOSE: Available medications for chronic pain provide only partial relief and often cause unacceptable side effects. There is therefore a need for novel molecular targets to develop new therapeutics with improved efficacy and tolerability. Despite encouraging efficacy data in rodents with inhibitors of the neuronal glycine transporter-2 (GlyT2), there are also some reports of toxicity and their development was discontinued. EXPERIMENTAL APPROACH: In order to clarify the possibility of targeting GlyT2 for the treatment of pain, we have used an integrated approach comprising in vitro pharmacology, selectivity, bioavailability, in vivo efficacy and safety assessment to analyse the properties and efficacy of ALX-1393 and Org-25543, the two published GlyT2 inhibitors from which in vivo data are available. KEY RESULTS: We report that these compounds have a different set of undesirable properties that limit their usefulness as pharmacological tools. Importantly, we discover that inhibitors of GlyT2 can exert an apparent reversible or irreversible inhibition of the transporter and describe a new class of reversible GlyT2 inhibitors that preserves efficacy while avoiding acute toxicity. CONCLUSIONS AND IMPLICATIONS: Our pharmacological comparison of two closely related GlyT2 inhibitors with different modes of inhibition provides important insights into their safety and efficacy profiles, uncovering that in the presence of a GlyT2 mechanism-based toxicity, reversible inhibitors might allow a tolerable balance between efficacy and toxicity. These findings shed light into the drawbacks associated with the early GlyT2 inhibitors and describe a new mechanism that might serve as the starting point for new drug development.

Synchronous sigmoid and caecal cancers together with a primary renal cell carcinoma.

BACKGROUND: Multiple primary neoplasms, a common clinical entity, can be classified as synchronous or metachronous. Renal cell carcinoma, in particular, is associated with a high rate of multiple primary neoplasms. METHODS: We report a case of a 67-year-old Caucasian woman, who was admitted with history of bleeding per rectum. We conducted a literature review of metachronous and synchronous multiple primary neoplasms. RESULTS: Colonoscopy revealed a 3 cm tumour in the caecum and a small sigmoid tubulovillous polyp. Staging computed tomography showed a non-enhancing mass in the upper pole of the right kidney. Following a radical nephrectomy/right hemicolectomy, microscopy demonstrated a renal cell carcinoma. Follow-up colonoscopy visualised a mucosal irregularity at the site of the previous sigmoid polyp, with biopsies confirming invasive adenocarcinoma. Patient underwent a total colectomy with an ileo-rectal anastamosis. CONCLUSION: Multiple primary neoplasms are a well-recognised clinical entity. This report emphasises the need for a comprehensive evidence-based work-up in all cancer cases, especially when dealing with renal cell carcinoma, to look for coexisting metachronous/synchronous primary neoplasms.

Independent predictors of breast malignancy in screen-detected microcalcifications: biopsy results in 2545 cases.

BACKGROUND: Mammographic microcalcifications are associated with many benign lesions, ductal carcinoma in situ (DCIS) and invasive cancer. Careful assessment criteria are required to minimise benign biopsies while optimising cancer diagnosis. We wished to evaluate the assessment outcomes of microcalcifications biopsied in the setting of population-based breast cancer screening. METHODS: Between January 1992 and December 2007, cases biopsied in which microcalcifications were the only imaging abnormality were included. Patient demographics, imaging features and final histology were subjected to statistical analysis to determine independent predictors of malignancy. RESULTS: In all, 2545 lesions, with a mean diameter of 21.8 mm (s.d. 23.8 mm) and observed in patients with a mean age of 57.7 years (s.d. 8.4 years), were included. Using the grading system adopted by the RANZCR, the grade was 3 in 47.7%; 4 in 28.3% and 5 in 24.0%. After assessment, 1220 lesions (47.9%) were malignant (809 DCIS only, 411 DCIS with invasive cancer) and 1325 (52.1%) were non-malignant, including 122 (4.8%) premalignant lesions (lobular carcinoma in situ, atypical lobular hyperplasia and atypical ductal hyperplasia). Only 30.9% of the DCIS was of low grade.Mammographic extent of microcalcifications >15 mm, imaging grade, their pattern of distribution, presence of a palpable mass and detection after the first screening episode showed significant univariate associations with malignancy. On multivariate modeling imaging grade, mammographic extent of microcalcifications >15 mm, palpable mass and screening episode were retained as independent predictors of malignancy. Radiological grade had the largest effect with lesions of grade 4 and 5 being 2.2 and 3.3 times more likely to be malignant, respectively, than grade 3 lesions. CONCLUSION: The radiological grading scheme used throughout Australia and parts of Europe is validated as a useful system of stratifying microcalcifications into groups with significantly different risks of malignancy. Biopsy assessment of appropriately selected microcalcifications is an effective method of detecting invasive breast cancer and DCIS, particularly of non-low-grade subtypes.

Fisiopatología de la insuficiencia renal aguda durante la sepsis / Physiopathology of acute renal failure during sepsis

La insuficiencia renal aguda (IRA) es un factor de riesgo independiente asociado a mayor mortalidad durante la sepsis. Definiciones de con senso recientes han permitido estandarizarlos trabajos de investigación en el tema. La comprensión de la fisiopatología de la IRA durante la sepsis está limitada por la escasez de estudios histológicos y por la imposibilidad de medir los flujos microcirculatorios renales. Históricamente se ha considerado a la IRA séptica como una patología dependiente de la caída del flujo sanguíneo renal (FSR). Efectivamente, en las etapas precoces de la sepsis o en la sepsis acompañada de shock cardiogénico existe compromiso del FSR; sin embargo, estudios recientes han demostrado que en la sepsis reanimada, aquella en que característicamente se observa un gasto cardiaco normal o alto y vasodilatación sistémica, el FSR es normal o incluso aumentado y no existe evidencia histológica significativa denecrosis tubular. Otros factores, distintos al puramente hemodinámico, participan en la génesis de la IRA en la sepsis. Entre éstos están la apoptosis celular, los trastornos microcirculatorios glomerulares y medulares, los cambios celulares en respuestas a la cascada proinflamatoria propia de la sepsis, el estrés oxidativo, la disfunción mitocondrial y el daño a distancia inducido por ventilación mecánica, entre otros. En la actualidad, el tratamiento de la IRA en la sepsis es de soporte. En general, las terapias de reemplazo renal pueden ser clasificadas como intermitentes o continuas, y en las que buscan primariamente el reemplazo de la función renal deteriorada, frente a aquellas cuyo objetivo principal es lograr la estabilidad hemodinámica de los pacientes mediante la remoción de mediadores proinflamatorios (AU)

Acute renal failure (ARF) is an independent risk factor associated with increased mortality during sepsis. Recent consensus definitions have allowed the standardization of researchon the subject. The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows. Historically, ARF during sepsis has been considered to be a consequence of diminished renal bloodflow (RBF). Indeed, in early stages of sepsis or in sepsis associated to cardiogenic shock, RBF may decrease. However, recent studies have shown that in resuscitated sepsis, in which cardiacout put is characteristically normal or even elevated and there is systemic vasodilatation, RBF is normal or even increased, with no associated histological evidence of significant tubularnecrosis. Thus, other factors may participate in the genesis of ARF in sepsis. These includeapoptosis, glomerular and medullary microcirculatory disorders, cell changes in response to thepro-inflammatory cascade characteristic of sepsis, oxidative stress, mitochondrial dysfunction and damage induced by mechanical ventilation, among others. Sepsis associated ARF treatmentis supportive. In general, renal replacement therapies can be grouped as intermittent or continuous, and as those whose primary objective is the replacement of impaired renal function,versus those whose main objective is to secure hemodynamic stability through the clearing ofpro-inflammatory mediators (AU)

PEA3/ETV4-related transcription factors coupled with active ERK signalling are associated with poor prognosis in gastric adenocarcinoma.

BACKGROUND: Transcription factors often play important roles in tumourigenesis. Members of the PEA3 subfamily of ETS-domain transcription factors fulfil such a role and have been associated with tumour metastasis in several different cancers. Moreover, the activity of the PEA3 subfamily transcription factors is potentiated by Ras-ERK pathway signalling, which is itself often deregulated in tumour cells. METHODS: Immunohistochemical patterns of PEA3 expression and active ERK signalling were analysed and mRNA expression levels of PEA3, ER81, MMP-1 and MMP-7 were determined in gastric adenocarcinoma samples. RESULTS: Here, we have studied the expression of the PEA3 subfamily members PEA3/ETV4 and ER81/ETV1 in gastric adenocarcinomas. PEA3 is upregulated at the protein level in gastric adenocarcinomas and both PEA3/ETV4 and ER81/ETV1 are upregulated at the mRNA level in gastric adenocarcinoma tissues. This increased expression correlates with the expression of a target gene associated with metastasis, MMP-1. Enhanced ERK signalling is also more prevalent in late-stage gastric adenocarcinomas, and the co-association of ERK signalling and PEA3 expression also occurs in late-stage gastric adenocarcinomas. Furthermore, the co-association of ERK signalling and PEA3 expression correlates with decreased survival rates. CONCLUSIONS: This study shows that members of the PEA3 subfamily of transcription factors are upregulated in gastric adenocarcinomas and that the simultaneous upregulation of PEA3 expression and ERK pathway signalling is indicative of late-stage disease and a poor survival prognosis.

[Physiopathology of acute renal failure during sepsis]. / Fisiopatología de la insuficiencia renal aguda durante la sepsis.

Acute renal failure (ARF) is an independent risk factor associated with increased mortality during sepsis. Recent consensus definitions have allowed the standardization of research on the subject. The understanding of the physiopathology of ARF during sepsis is limited by the scarcity of histological studies and the inability to measure renal microcirculatory flows. Historically, ARF during sepsis has been considered to be a consequence of diminished renal blood flow (RBF). Indeed, in early stages of sepsis or in sepsis associated to cardiogenic shock, RBF may decrease. However, recent studies have shown that in resuscitated sepsis, in which cardiac output is characteristically normal or even elevated and there is systemic vasodilatation, RBF is normal or even increased, with no associated histological evidence of significant tubular necrosis. Thus, other factors may participate in the genesis of ARF in sepsis. These include apoptosis, glomerular and medullary microcirculatory disorders, cell changes in response to the pro-inflammatory cascade characteristic of sepsis, oxidative stress, mitochondrial dysfunction and damage induced by mechanical ventilation, among others. Sepsis associated ARF treatment is supportive. In general, renal replacement therapies can be grouped as intermittent or continuous, and as those whose primary objective is the replacement of impaired renal function, versus those whose main objective is to secure hemodynamic stability through the clearing of pro-inflammatory mediators.

Hemofiltración de alto volumen en shock séptico / High volume hemofiltration in septic shock

La sepsis grave y el shock séptico son entidades catastróficas asociadas a una elevada morbimortalidad. La liberación desproporcionada de mediadores proinflamatorios y antiinflamatorios, ocasionada por el insulto séptico, es la promotora de la disfunción orgánica múltiple. Las técnicas convencionales de hemodiálisis, hemofiltración o una combinación de ambas pueden ser una buena opción para suplir el deterioro de la función renal en pacientes críticos mediante la eliminación de compuestos nitrogenados (moléculas pequeñas). Sin embargo, esta dosis renal resulta insuficiente para la depuración de mediadores inflamatorios (moléculas medianas) y, por tanto, de escaso aporte en la estabilización cardiovascular de pacientes con shock séptico. En este escenario, una mayor dosis de ultrafiltración (>50ml/kg/h) o dosis séptica podría ser necesaria. En este artículo de revisión se analiza la fundamentación fisiopatológica y clínica para el empleo de la hemofiltración de alto volumen en pacientes con shock séptico (AU)

Severe sepsis and septic shock are conditions associated with high morbidity and mortality. The disproportionate release of pro-inflammatory and anti-inflammatory mediators caused by the septic insult is the promoter of multiple organ dysfunction. Conventional hemodialysis, hemofiltration or a combination of both can be a good option to replace the deteriorating renal function in critically ill patients by the removal of nitrogen compounds (small molecules). However, this «renal dose» is insufficient for the removal of inflammatory mediators (medium molecules), and therefore contributes little to the cardiovascular stabilization of patients with septic shock. In this setting, a higher dose of ultrafiltration (> 50ml/kg/h) or «septic dose» may be needed. In this review article, we have analyzed the clinical and pathophysiological rationale for the use of high volume hemofiltration in patients with septic shock (AU)

[High volume hemofiltration in septic shock]. / Hemofiltración de alto volumen en shock séptico.

Severe sepsis and septic shock are conditions associated with high morbidity and mortality. The disproportionate release of pro-inflammatory and anti-inflammatory mediators caused by the septic insult is the promoter of multiple organ dysfunction. Conventional hemodialysis, hemofiltration or a combination of both can be a good option to replace the deteriorating renal function in critically ill patients by the removal of nitrogen compounds (small molecules). However, this "renal dose" is insufficient for the removal of inflammatory mediators (medium molecules), and therefore contributes little to the cardiovascular stabilization of patients with septic shock. In this setting, a higher dose of ultrafiltration (> 50 ml/kg/h) or "septic dose" may be needed. In this review article, we have analyzed the clinical and pathophysiological rationale for the use of high volume hemofiltration in patients with septic shock.

Assessment of 1183 screen-detected, category 3B, circumscribed masses by cytology and core biopsy with long-term follow up data.

Discrete masses are commonly detected during mammographic screening and most such lesions are benign. For lesions without pathognomonically benign imaging features that are still regarded likely to be non-malignant (Tabar grade 3) reliable biopsy results would be a clinically useful alternative to mammographic surveillance. Appropriate institutional guidelines for ethical research were followed. Between Jan 1996--Dec 2005 grade 3B discrete masses detected in the setting of a large, population based, breast cancer screening programme are included. Patient demographics, fine needle aspiration biopsy (FNAB), core and surgical biopsy results are tabulated. The final pathology of excised lesions was obtained. Information regarding interval cancers was obtained from the State Cancer Registry records and also through long term follow-up of clients in subsequent rounds of screening. A total of 1183 lesions, mean diameter of 13.3 mm (+/-8.3 mm) and mean client age of 55.1 years (+/-8.8 years) are included. After diagnostic work up, 98 lesions (8.3%) were malignant, 1083 were non-malignant and a final histologic diagnosis was not established in two lesions. In the 27 months after assessment, no interval cancers were attributable to these lesions and during a mean follow up of 54.5 months, available in 84.9% of eligible women, only one cancer has developed in the same quadrant as the original lesion, although the two processes are believed to be unrelated. FNAB performed in 1149 cases was definitive in 80.5% cases (882 benign, 43 malignant) with a negative predictive value (NPV) of 99.8% (880 of 882) and a positive predictive value (PPV) of 95.2% (40 of 42, both intraductal papillomas). Core biopsy was performed in 178 lesions, mostly for indefinite cytology. Core biopsy was definitive in 79.8% cases (57% benign 22% malignant) with a PPV of 100% and NPV of 99.0%. In experienced hands FNAB is an accurate first line diagnostic modality for the assessment of 3B screen-detected discrete masses, providing definitive results in 80.5% of cases. When used as a second line modality, core biopsy had a similarly high rate of definitive diagnosis at 79.8%. The stepwise approach to the use of FNAB and core biopsy would reduce substantially the proportion of cases requiring surgical diagnostic biopsy. Given the low probability of malignancy and the imperative to limit the morbidity associated with cancer screening, the demonstration of the reliability of FNAB as a minimally invasive but highly accurate test for this particular subset of screen-detected lesions has significant clinical utility.

Population screening and intensity of screening are associated with reduced breast cancer mortality: evidence of efficacy of mammography screening in Australia.

BACKGROUND: Efficacy of breast screening may differ in practice from the results of randomized trials. We report one of the largest case-control evaluations of a screening service. METHODS: Subjects included 491 breast-cancer deaths affecting 45-80-year-old South Australian females during 2002-2005 (diagnosed after BreastScreen commencement) and 1,473 live controls (three per death) randomly selected from the State Electoral Roll after birth-date matching. Cancer Registry and BreastScreen records provided cancer and screening details. Risk estimates were calculated by BreastScreen participation, using conditional logistic regression. Interpretation was assisted by a population survey of risk factor prevalence by BreastScreen participation in 1,684 females aged > or =40 years. RESULTS: The relative odds (OR) (95% confidence limits) of breast-cancer death in BreastScreen participants compared with non-participants were 0.59 (0.47, 0.74). Compared with non-participants, the OR was 0.70 (0.47, 1.05) for women last screened through BreastScreen more than 3 years before diagnosis of the index case, and 0.57 (0.44, 0.72) for women screened more recently. The OR of 0.47 (0.34, 0.65) for women screened more frequently in the pre-diagnosis phase was lower than the 0.64 (0.50, 0.82) for other screened women. The overall OR of 0.59 approximated 0.70 when corrected for the screening self-selection bias observed in five randomized trials. However, multivariable analysis of survey data did not indicate a lower prevalence of breast-cancer risk factors among BreastScreen participants, suggesting that this correction may be inappropriate. CONCLUSIONS: Participation in screening was associated with a breast-cancer mortality reduction of between 30 and 41%, depending on assumptions about screening self-selection bias. A downward mortality risk by recency of last screen prior to cancer diagnosis, and frequency of recent screening, is consistent with a screening effect.

Long term disease-free survival in acute leukemia patients recovering with increased gammadelta T cells after partially mismatched related donor bone marrow transplantation.

Allogeneic stem cell transplantation (ASCT) has improved leukemia-free survival (LFS) in many but not all patients with acute leukemia. This is an eight-year follow-up to our previous study showing a survival advantage to patients with an increased gammadelta T cells following ASCT. gammadelta T cell levels were collected prospectively in 153 patients (acute lymphoblastic leukemia (ALL) n = 77; acute myelogenous leukemia (AML) n = 76) undergoing partially mismatched related donor ASCT. Median age was 22 years (1-59), and 62% of the patients were in relapse at transplant. Patient-donor human leukocyte antigen (HLA) disparity of three antigens was 37% in the graft-versus-host disease (GvHD) and 29% in the rejection directions. All patients received a partially T cell-depleted graft using T10B9 (n = 46) or OKT3 (n = 107). Five years LFS and overall survival (OS) of patients with increased gammadelta compared to those with normal/decreased numbers were 54.4 vs 19.1%; P < 0.0003, and 70.8 vs 19.6% P < 0.0001, respectively, with no difference in GvHD (P = 0.96). In a Cox multivariate analysis, normal/decreased gammadelta (hazard ratio (HR) 4.26, P = 0.0002) and sex mismatch (HR 1.45 P=0.049) were associated with inferior LFS. In conclusion, gammadelta T cells may facilitate a graft-versus-leukemia (GvL) effect, without causing GvHD. Further evaluations of this effect may lead to specific immunotherapy for patients with refractory leukemia.