Signalling input from divergent pathways subverts B cell transformation.

Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer1. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5)2-4 or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK)5-8. STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10-16). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.

IFITM3 functions as a PIP3 scaffold to amplify PI3K signalling in B cells.

Interferon-induced transmembrane protein 3 (IFITM3) has previously been identified as an endosomal protein that blocks viral infection1-3. Here we studied clinical cohorts of patients with B cell leukaemia and lymphoma, and identified IFITM3 as a strong predictor of poor outcome. In normal resting B cells, IFITM3 was minimally expressed and mainly localized in endosomes. However, engagement of the B cell receptor (BCR) induced both expression of IFITM3 and phosphorylation of this protein at Tyr20, which resulted in the accumulation of IFITM3 at the cell surface. In B cell leukaemia, oncogenic kinases phosphorylate IFITM3 at Tyr20, which causes constitutive localization of this protein at the plasma membrane. In a mouse model, Ifitm3-/- naive B cells developed in normal numbers; however, the formation of germinal centres and the production of antigen-specific antibodies were compromised. Oncogenes that induce the development of leukaemia and lymphoma did not transform Ifitm3-/- B cells. Conversely, the phosphomimetic IFITM3(Y20E) mutant induced oncogenic PI3K signalling and initiated the transformation of premalignant B cells. Mechanistic experiments revealed that IFITM3 functions as a PIP3 scaffold and central amplifier of PI3K signalling. The amplification of PI3K signals depends on IFITM3 using two lysine residues (Lys83 and Lys104) in its conserved intracellular loop as a scaffold for the accumulation of PIP3. In Ifitm3-/- B cells, lipid rafts were depleted of PIP3, which resulted in the defective expression of over 60 lipid-raft-associated surface receptors, and impaired BCR signalling and cellular adhesion. We conclude that the phosphorylation of IFITM3 that occurs after B cells encounter antigen induces a dynamic switch from antiviral effector functions in endosomes to a PI3K amplification loop at the cell surface. IFITM3-dependent amplification of PI3K signalling, which in part acts downstream of the BCR, is critical for the rapid expansion of B cells with high affinity to antigen. In addition, multiple oncogenes depend on IFITM3 to assemble PIP3-dependent signalling complexes and amplify PI3K signalling for malignant transformation.

Synergistic immunomodulatory effect of synbiotics pre- and postoperative resection of pancreatic ductal adenocarcinoma: a randomized controlled study.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a highly immunosuppressive microenvironment. This single-blind, randomized study aimed to evaluate the synergistic immunomodulatory effects of synbiotics (probiotics and inulin prebiotics), as well as their impact on postoperative complications and outcomes, compared to the use of probiotics alone. Ninety patients diagnosed with PDAC were enrolled and randomly assigned into three groups: the placebo group, the probiotics group (receiving a mixture of ten strains of Lactobacillus, Bifidobacterium, and Streptococcus bacteria at a dose of 25 billion CFUs), and the synbiotics group (the same probiotics along with inulin prebiotics). The interventions were administered for 14 days before the surgery and continued for one month postoperatively. Tumor tissue infiltration of CD8 + T cells and the expression of IFN γ were assessed by immunohistochemistry (IHC). Inflammatory cytokines concentrations, including Il 1 B, IL 6, and IL 10, were evaluated as well by ELISA at various time points pre- and postoperative. Furthermore, patients were followed up after the surgery to assess postoperative short-term outcomes. Our results showed a significant elevation of CD8 + T cell proportion and IFN γ expression in the synbiotics group compared to the probiotics group (p = 0.049, p = 0.013, respectively). Inflammatory cytokines showed a significant gradual decrease in the synbiotics group compared to placebo and probiotics-treated groups (p = 0.000 for both). Administration of synbiotics and probiotics significantly decreased the rate of postoperative complications including anastomotic leakage, diarrhea, and abdominal distension (p = 0.032, p = 0.044, p = 0.042, respectively), with a remarkable reduction in bacteremia in the synbiotics group. These results revealed that this synbiotics formulation potentially enhances the immune response and reduces complications associated with surgery.Clinical trial identification: NCT06199752 (27-12-2023).

Percutaneous decannulation of venoarterial extracorporeal membrane oxygenation using the Manta vascular closure device: A systematic review and meta-analysis.

OBJECTIVES: To perform a systematic review and meta-analysis of the techniques and outcomes associated with percutaneous decannulation of venoarterial extracorporeal membrane oxygenation (VA-ECMO) using the Manta vascular closure device. BACKGROUND: Peripheral VA-ECMO can be used to treat critically ill patients with conditions such as refractory cardiogenic shock. After percutaneous implantation of VA-ECMO, VA-ECMO can also be decannulated completely percutaneously by using a vascular closure device. The Manta vascular closure device is a dedicated device used in the closure of large-bore arteriotomies by sandwiching the arteriotomy with an intra-arterial toggle and an extraluminal collagen plug. METHODS: We performed a thorough literature search using various electronic databases. We included studies that reported outcomes after peripheral femorofemoral VA-ECMO decannulation with the Manta vascular closure device. We performed a meta-analysis of proportions on outcome measures, including technical success, bleeding complications, vascular complications, wound complications, major amputation, and procedural-related deaths. RESULTS: We included seven studies with a total of 116 patients. The overall technical success of percutaneous decannulation of VA-ECMO with the Manta vascular closure device was 93.7%. The overall incidence of bleeding, vascular and wound complications was 1.7%, 13.8%, and 3.4%, respectively. No patient required lower limb amputation or died due to VA-ECMO decannulation. CONCLUSION: Percutaneous decannulation with the Manta vascular closure device is an effective and safe procedure that should be considered in suitable patients on VA-ECMO.

Enabling Remote Elderly Care: Design and Implementation of a Smart Energy Data System with Activity Recognition.

Seniors face many challenges as they age, such as dementia, cognitive and memory disorders, vision and hearing impairment, among others. Although most of them would like to stay in their own homes, as they feel comfortable and safe, in some cases, older people are taken to special institutions, such as nursing homes. In order to provide serious and quality care to elderly people at home, continuous remote monitoring is perceived as a solution to keep them connected to healthcare service providers. The new trend in medical health services, in general, is to move from 'hospital-centric' services to 'home-centric' services with the aim of reducing the costs of medical treatments and improving the recovery experience of patients, among other benefits for both patients and medical centers. Smart energy data captured from electrical home appliance sensors open a new opportunity for remote healthcare monitoring, linking the patient's health-state/health-condition with routine behaviors and activities over time. It is known that deviation from the normal routine can indicate abnormal conditions such as sleep disturbance, confusion, or memory problems. This work proposes the development and deployment of a smart energy data with activity recognition (SEDAR) system that uses machine learning (ML) techniques to identify appliance usage and behavior patterns oriented to older people living alone. The proposed system opens the door to a range of applications that go beyond healthcare, such as energy management strategies, load balancing techniques, and appliance-specific optimizations. This solution impacts on the massive adoption of telehealth in third-world economies where access to smart meters is still limited.

Relaxin does not prevent development of hypoxia-induced pulmonary edema in rats.

Acute hypoxia impairs left ventricular (LV) inotropic function and induces development of pulmonary edema (PE). Enhanced and uneven hypoxic pulmonary vasoconstriction is an important pathogenic factor of hypoxic PE. We hypothesized that the potent vasodilator relaxin might reduce hypoxic pulmonary vasoconstriction and prevent PE formation. Furthermore, as relaxin has shown beneficial effects in acute heart failure, we expected that relaxin might also improve LV inotropic function in hypoxia. Forty-two rats were exposed over 24 h to normoxia or hypoxia (10% N2 in O2). They were infused with either 0.9% NaCl solution (normoxic/hypoxic controls) or relaxin at two doses (15 and 75 µg kg-1 day-1). After 24 h, hemodynamic measurements and bronchoalveolar lavage were performed. Lung tissue was obtained for histological and immunohistochemical analyses. Hypoxic control rats presented significant depression of LV systolic pressure by 19% and of left and right ventricular contractility by about 40%. Relaxin did not prevent the hypoxic decrease in LV inotropic function, but re-increased right ventricular contractility. Moreover, hypoxia induced moderate interstitial PE and inflammation in the lung. Contrasting to our hypothesis, relaxin did not prevent hypoxia-induced pulmonary edema and inflammation. In hypoxic control rats, PE was similarly distributed in the apical and basal lung lobes. In relaxin-treated rats, PE index was 35-40% higher in the apical than in the basal lobe, which is probably due to gravity effects. We suggest that relaxin induced exaggerated vasodilation, and hence pulmonary overperfusion. In conclusion, the results show that relaxin does not prevent but rather may aggravate PE formation.

The prevalence and phenotypic manifestations of polycystic ovary syndrome (PCOS) among infertile Sudanese women: a cross-sectional study.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a global health problem associated with significant morbidity during reproductive age. Only a few published studies that address the clinical manifestations and phenotypic presentation of the disease have been conducted in Africa, including Sudan. Thus, this study aimed to evaluate the clinical and biochemical presentation of the different PCOS phenotypes among infertile Sudanese women. METHODS: A cross-sectional, descriptive study was conducted from January to December 2019. A total of 368 infertile women with PCOS (based on the Rotterdam criteria) were recruited from a fertility center in Khartoum, Sudan. Clinical, hormonal, and ultrasonographic characteristics were described and compared between the four phenotypes of PCOS. RESULTS: Majority (321 [87.2%]) of the women had oligo/anovulation (OA). Polycystic ovary morphology on ultrasound appeared in 236 (64.1%) women, acne in 171 (46.5%) women, acanthosis nigricans in 81 (22.0%) women, and hirsutism in 101 (27.4%) women. Phenotype D was the most prevalent among infertile Sudanese women (51.6%), followed by phenotype B (22.6%), phenotype C (18.2%), and phenotype A (7.6%). No statistical differences in the body mass index and hormonal profile between the four phenotypes were noted. Women with phenotype A were older and had high mean blood pressure, and a higher waist/hip ratio was observed among women with phenotype D. CONCLUSION: Unlike the global distribution of PCOS phenotypes, Sudanese women uniquely expressed phenotype D as the most prevalent. More epidemiological studies are needed in the region due to geographical, ethnic, and genetic variations.

Polycystic ovary syndrome (PCOS) is a global health problem associated with significant drawbacks during reproductive life. Few published studies have been conducted in Africa (including Sudan) addressing the clinical manifestations and phenotypic presentation of the disease. Therefore, we aimed to evaluate the clinical and biochemical presentation of the different PCOS phenotypes among infertile Sudanese women. A total of 368 infertile women with PCOS from a fertility center in Khartoum, Sudan, participated in the study. Clinical, hormonal, and ultrasonographic characteristics were described and compared between the four phenotype groups of PCOS. In this regard, Sudanese women uniquely expressed phenotype D as the most prevalent, and this does not match with the global distribution of PCOS phenotypes. Moreover, women with phenotype A were older and had high mean blood pressure, and a higher waist/hip ratio was observed among women with phenotype D. More epidemiological studies on this subject are needed in the region due to geographical, ethnic, and genetic variations.

Design and Implementation of a Cloud-IoT-Based Home Energy Management System.

The advances in the Internet of Things (IoT) and cloud computing opened new opportunities for developing various smart grid applications and services. The rapidly increasing adoption of IoT devices has enabled the development of applications and solutions to manage energy consumption efficiently. This work presents the design and implementation of a home energy management system (HEMS), which allows collecting and storing energy consumption data from appliances and the main load of the home. Two scenarios are designed and implemented: a local HEMS isolated from the Internet and relies on its processing and storage duties using an edge device and a Cloud HEMS using AWS IoT Core to manage incoming data messages and provide data-driven services and applications. A testbed was carried out in a real house in the city of Valparaiso, Chile, over a one-year period, where four appliances were used to collect energy consumption using smart plugs, as well as collecting the main energy load of the house through a data logger acting as a smart meter. To the best of our knowledge, this is the first electrical energy dataset with a 10-second sampling rate from a real household in Valparaiso, Chile. Results show that both implementations perform the baseline tasks (collecting, storing, and controlling) for a HEMS. This work contributes by providing a detailed technical implementation of HEMS that enables researchers and engineers to develop and implement HEMS solutions to support different smart home applications.

LoRa Based IoT Platform for Remote Monitoring of Large-Scale Agriculture Farms in Chile.

Nowadays, conventional agriculture farms lack high-level automated management due to the limited number of installed sensor nodes and measuring devices. Recent progress of the Internet of Things (IoT) technologies will play an essential role in future smart farming by enabling automated operations with minimum human intervention. The main objective of this work is to design and implement a flexible IoT-based platform for remote monitoring of agriculture farms of different scales, enabling continuous data collection from various IoT devices (sensors, actuators, meteorological masts, and drones). Such data will be available for end-users to improve decision-making and for training and validating advanced prediction algorithms. Unlike related works that concentrate on specific applications or evaluate technical aspects of specific layers of the IoT stack, this work considers a versatile approach and technical aspects at four layers: farm perception layer, sensors and actuators layer, communication layer, and application layer. The proposed solutions have been designed, implemented, and assessed for remote monitoring of plants, soil, and environmental conditions based on LoRaWAN technology. Results collected through both simulation and experimental validation show that the platform can be used to obtain valuable analytics of real-time monitoring that enable decisions and actions such as, for example, controlling the irrigation system or generating alarms. The contribution of this article relies on proposing a flexible hardware and software platform oriented on monitoring agriculture farms of different scales, based on LoRaWAN technology. Even though previous work can be found using similar technologies, they focus on specific applications or evaluate technical aspects of specific layers of the IoT stack.

Toward an Intelligent Campus: IoT Platform for Remote Monitoring and Control of Smart Buildings.

With the growing need to obtain information about power consumption in buildings, it is necessary to investigate how to collect, store, and visualize such information using low-cost solutions. Currently, the available building management solutions are expensive and challenging to support small and medium-sized buildings. Unfortunately, not all buildings are intelligent, making it difficult to obtain such data from energy measurement devices and appliances or access such information. The internet of things (IoT) opens new opportunities to support real-time monitoring and control to achieve future smart buildings. This work proposes an IoT platform for remote monitoring and control of smart buildings, which consists of four-layer architecture: power layer, data acquisition layer, communication network layer, and application layer. The proposed platform allows data collection for energy consumption, data storage, and visualization. Various sensor nodes and measurement devices are considered to collect information on energy use from different building spaces. The proposed solution has been designed, implemented, and tested on a university campus considering three scenarios: an office, a classroom, and a laboratory. This work provides a guideline for future implementation of intelligent buildings using low-cost open-source solutions to enable building automation, minimize power consumption costs, and guarantee end-user comfort.

CaWRKY30 Positively Regulates Pepper Immunity by Targeting CaWRKY40 against Ralstonia solanacearum Inoculation through Modulating Defense-Related Genes.

The WRKY transcription factors (TFs) network is composed of WRKY TFs' subset, which performs a critical role in immunity regulation of plants. However, functions of WRKY TFs' network remain unclear, particularly in non-model plants such as pepper (Capsicum annuum L.). This study functionally characterized CaWRKY30-a member of group III Pepper WRKY protein-for immunity of pepper against Ralstonia solanacearum infection. The CaWRKY30 was detected in nucleus, and its transcriptional expression levels were significantly upregulated by R. solanacearum inoculation (RSI), and foliar application ethylene (ET), abscisic acid (ABA), and salicylic acid (SA). Virus induced gene silencing (VIGS) of CaWRKY30 amplified pepper's vulnerability to RSI. Additionally, the silencing of CaWRKY30 by VIGS compromised HR-like cell death triggered by RSI and downregulated defense-associated marker genes, like CaPR1, CaNPR1, CaDEF1, CaABR1, CaHIR1, and CaWRKY40. Conversely, transient over-expression of CaWRKY30 in pepper leaves instigated HR-like cell death and upregulated defense-related maker genes. Furthermore, transient over-expression of CaWRKY30 upregulated transcriptional levels of CaWRKY6, CaWRKY22, CaWRKY27, and CaWRKY40. On the other hand, transient over-expression of CaWRKY6, CaWRKY22, CaWRKY27, and CaWRKY40 upregulated transcriptional expression levels of CaWRKY30. The results recommend that newly characterized CaWRKY30 positively regulates pepper's immunity against Ralstonia attack, which is governed by synergistically mediated signaling by phytohormones like ET, ABA, and SA, and transcriptionally assimilating into WRKY TFs networks, consisting of CaWRKY6, CaWRKY22, CaWRKY27, and CaWRKY40. Collectively, our data will facilitate to explicate the underlying mechanism of crosstalk between pepper's immunity and response to RSI.

Hepatitis B infection and preeclampsia among pregnant Sudanese women.

BACKGROUND: Previous published studies have reported conflicting results of association between hepatitis B virus (HBV) infection and preeclampsia. There was no published data on HBV and preeclampsia in Africa including Sudan. The aim of the present study was to investigate the association between HBsAg seropositivity and preeclampsia. METHODS: A case -controls study (200 women in each arm) was conducted at Saad Abualila Maternity Hospital, Khartoum, Sudan. The cases were women with preeclampsia and the controls were healthy pregnant women. Socio-demographic characteristics were gathered using questionnaire and HBsAg was investigated using an ELISA. RESULTS: There was no significant difference between the cases and the controls in their age, parity, residence, education and blood groups. The majority of the cases were mild preeclampsia (159; 79.5%). In comparison with the controls, a significantly higher number of the cases were HBsAg seropositive [30 (15.0%) vs.12 (6.0%), P = 0.005]. In binary regression women with HBsAg seropositive were at higher risk of preeclampsia than women who were HBsAg seronegative (OR = 2.86, 95%, CI = 1.41-5.79, P = 0.003). CONCLUSION: In the current study HBsAg seropositivity is associated with preeclampsia. Preventive measure should be implemented.

Effect of female genital cutting performed by health care professionals on labor complications in Egyptian women: a prospective cohort study.

AIM: To examine the effect of the degree of female genital cutting (FGC) performed by health-care professionals on perineal scarring; delivery mode; duration of second stage of labor; incidence of perineal tears and episiotomy in a cohort of uncircumcised versus circumcised (types I and II) women. METHODS: A prospective cohort study included 450 primigravida women in active labor attending the Faculty of Medicine Cairo University Hospital between January 2013 and August 2014. Women were divided into three groups based on medical examination upon admission. Group I (Control) included 150 uncut women, Group II included 150 women with type I FGC and Group III included 150 women with type II FGC. A structured questionnaire elicited the information on women's socio-demographic characteristics including age, residence, occupation, educational level, age of marriage and FGC circumstances. Association between FGC and labor complications was examined. MAIN OUTCOMES: risk of perineal scarring; delivery mode; duration of second stage of labor; incidence of perineal tears and episiotomy. RESULTS: Family history of genitally cut mother/sister was the most significant socio-demographic factor associated with FGC. FGC especially type II was associated with significantly higher incidence of vulvar scar (P<0.0002), perineal tears (P<0.0001) and increased likelihood of additional vaginal and perineal trauma [odds ratio (OR): 1.85, 95% CI: 0.60-5.65. P≤0.001]. There was insignificant difference in risks of cesarean section (CS), instrumental delivery, episiotomy and short-term neonatal outcomes. CONCLUSION: The study strengthens the evidence that FGC increases the risk of tears in spite of medicalization of the practice.

Diagnostic concordance of breast pathologists: lessons from the National Health Service Breast Screening Programme Pathology External Quality Assurance Scheme.

AIMS: Previous concordance studies examining accuracy of breast diagnosis by pathologists, typically targeting difficult, histologically challenging breast lesions using artificial and restrictive environments, have reported aberrantly high levels of diagnostic discordance. The results of these studies may be misinterpreted by non-pathologists and raise concerns relating to routine practice. This study aims to assess the diagnostic agreement among UK breast pathologists. METHODS: Two hundred and forty consecutive breast lesions, submitted by participants from their routine practice, included in the UK National Health Service Breast Screening Programme (NHSBSP) breast pathology EQA scheme during the last 10 years were reviewed. An average of approximately 600 participants viewed each case. Data on diagnostic categories (benign, atypical, in-situ malignant and invasive malignant) were collected. In this study, benign and atypical diagnoses were grouped together. RESULTS: The overall diagnostic agreement level was in the almost perfect range. Thirty-five cases (14.6%) showed diagnostic concordance of ≤95%. Reasons for discordance included one or more of: (1) scheme methodology limitations such as: (i) miscoding of certain lesions (e.g. phyllodes tumours and lobular neoplasia) (n = 7) and (ii) variable representation of the index lesion on glass slides (n = 18); and (2) diagnostically challenging cases that may be interpreted more easily using immunohistochemistry (n = 28). These latter included benign and malignant papillary lesions (n = 12), complex sclerosing lesions (n = 7), intraductal epithelial proliferative lesions (n = 6) and an unusual special tumour type (n = 1). Further review identified pathologists' misinterpretation in 13 cases (5.4%), with an average discordance rate of only 4.2%. CONCLUSIONS: The performance of breast pathologists is high. Exclusion of the effect of the scheme methodology limitations highlights further the high performance rate and identifies true diagnostically challenging entities. These difficult cases may benefit from additional diagnostic work-up and second opinions.

Restoration of resident sleep and wellness with block scheduling.

CONTEXT: Block scheduling during residency is an innovative model in which in-patient and ambulatory rotations are separated. We hypothesised that this format may have a positive impact on resident sleep and wellness in comparison with a traditional format. METHODS: We performed a single-centre, cross-sectional, observational study of residents rotating in the medical intensive care unit (MICU). Residents were observed for 4 weeks at a time: internal medicine (IM) residents were observed for 3 weeks in the MICU followed by 1 week in an ambulatory context, and non-IM residents were observed for 4 weeks in the MICU. We monitored daily total sleep time (TST) utilising actigraphy, and wellness measures with weekly Epworth Sleepiness Scale (ESS) and Perceived Stress Scale (PSS) questionnaires. RESULTS: A total of 64 of 110 (58%) eligible residents participated; data for 49 of 110 (45%) were included in the final analysis. Mean ± standard deviation (SD) daily TST in the entire cohort was 6.53 ± 0.78 hours. Residents slept significantly longer during the ambulatory block than during the MICU block (mean ± SD TST 6.97 ± 1.00 hours and 6.43 ± 0.78 hours, respectively; p < 0.0005). Sleep duration during night call was significantly shorter than during day shift (mean ± SD TST 6.07 ± 1.16 hours and 6.50 ± 0.73 hours, respectively; p < 0.0005). A total of 390 of 490 (80%) ESS and PSS questionnaires were completed; scores significantly declined during rotations in the MICU. Internal medicine residents showed significant improvements in TST, and in ESS and PSS scores (p < 0.05) at the end of the ambulatory week. Non-IM residents, who remained in the MICU for a fourth week, continued a trend that showed a decline in perceived wellness. CONCLUSIONS: Despite duty hour restrictions, residents obtain inadequate sleep. As MICU days accumulate, measures of resident wellness decline. Residents in a block schedule experienced improvements in all measured parameters during the ambulatory week, whereas residents in a traditional schedule continued a downward trend. Block scheduling may have the previously unrecognised benefits of repaying sleep debt, correcting circadian misalignment and improving wellness.

Management strategies and outcomes for very elderly patients with diffuse large B-cell lymphoma.

BACKGROUND: The number of elderly patients with diffuse large B-cell lymphoma (DLBCL) in our aging society continues to rise, although the optimal management of very elderly patients with DLBCL is unknown. METHODS: This study evaluated 207 patients who were 80 years old or older at the diagnosis of DLBCL from 2002 to 2014 at The University of Texas MD Anderson Cancer Center. Analyzed features included clinical characteristics, treatment outcomes, and tolerability of therapy. Cox proportional hazards models examined relations between the treatment regimen and survival. RESULTS: The median age was 83 years (range, 80-96 years). Fifty-four percent of the patients had intermediate- to high-risk or high-risk International Prognostic Index scores. Fifteen percent had scores of 4 or higher on the Charlson Comorbidity Index (CCI). The initial therapies included rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 70%); rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin (R-EPOCH; 6%); and non-anthracycline-based therapies, including rituximab, cyclophosphamide, etoposide, vincristine, and prednisone (R-CEOP) and rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP; 10%). With a median follow-up of 38.1 months, the 3-year failure-free survival (FFS) and overall survival (OS) rates were 55% and 54%, respectively. Eighty-eight patients experienced relapse during the follow-up, but only 3 patients (3.4%) experienced relapse beyond 3 years. Patients who received R-CHOP or R-EPOCH had significantly longer FFS than those who received R-CEOP or R-CVP, with 3-year FFS rates of 63% for R-CHOP, 74% for R-EPOCH, and 23% for R-CEOP and R-CVP. Male sex, a monocyte count ≥ 500 × 107 /L, and a CCI score ≥ 4 were significantly associated with inferior OS. Extranodal disease (≥2) and a higher CCI score were associated with a high risk of treatment-related mortality. CONCLUSIONS: With anthracycline-based regimens such as R-CHOP and R-EPOCH, very elderly patients with DLBCL had superior outcomes similar to those achieved for younger patients with DLBCL. Cancer 2016;122:3145-51. © 2016 American Cancer Society.

Papillary carcinoma of the breast: diagnostic agreement and management implications.

AIMS: Papillary carcinoma (PC), which is a rare type of breast cancer, comprises a heterogeneous group of tumours. The diagnostic categorization of PC as in-situ and invasive disease remains a matter of debate with respect to interpretation of its overlapping histological features, and with respect to the uncertainty in clinical behaviour that this dilemma raises. The aim of this study was to assess the diagnostic agreement regarding PC among reporting breast pathologists. METHODS AND RESULTS: Six cases of PC included in the UK National Health Service Breast Screening Programme breast pathology interpretive external quality assurance scheme in the last 10 years were reviewed. In this scheme, one representative haematoxylin and eosin-stained slide from each case is circulated to an average of 600 participants. Data on diagnostic categories were collected and slides were reviewed according to the World Health Organization (WHO) diagnostic criteria. The number of final diagnoses of malignancy (in situ or invasive) was highest for invasive PC (99% of the participants diagnosed it as malignant), followed by solid PC (94% and 95%, respectively), encapsulated PC (92% and 92%, respectively), and papillary ductal carcinoma in situ (DCIS) (88%). Most cases of papillary DCIS were correctly classified as in-situ disease (77%), but 28% of the participants classified invasive PC cases as in-situ disease. Of the participants, 24% reported encapsulated PC as invasive disease. Of the two solid PC cases, one showed some features consistent with the WHO description of invasive solid PC, whereas the other showed features of classic (non-invasive) solid PC. Both cases were reported as invasive by 75% and 77% of participants, respectively. Breast specialists more frequently classified PC as an in-situ carcinoma than did non-specialist participants, and the difference was significant (P = 0.013). CONCLUSIONS: Recognition of PC as a malignant entity (in situ or invasive) is high, but concordance of its classification into in-situ and invasive disease is low. Histological features that can define invasion in PC should be better defined. These rare lesions require additional diagnostic work-up, and difficult cases should trigger consensus opinion or expert referral.

Trimester-specific thyroid hormone reference ranges in Sudanese women.

BACKGROUND: Trimester-specific reference ranges for T3, T4, and TSH need to be established in different communities. Neither Sudan nor other African countries have established trimester-specific reference ranges for TSH, free T3 (FT3), and free T4 (FT4) in healthy pregnant women. This study aimed to establish trimester-specific reference ranges for TSH, FT3, and FT4 in healthy pregnant Sudanese women. RESULTS: We performed a longitudinal study, which included 63 women with singleton pregnancies who were followed since early pregnancy until the third trimester. The study was performed in Saad Abu-Alela Hospital, Khartoum, Sudan, during January to October 2014. An equal number of age- and parity-matched non-pregnant women were enrolled as a control group. Basic clinical and obstetrics data were gathered using questionnaires. TSH, FT3, and FT4 levels were measured. Median (5th-95th centile) values of TSH, FT3, and FT4 were 1.164 IU/ml (0.079-2.177 IU/ml), 4.639 nmol/l (3.843-6.562 nmol/l), and 16.86 pmol/l (13.02-31.48 pmol/l) in the first trimester. Median values of TSH, FT3, and FT4 were 1.364 IU/ml (0.540-2.521 IU/ml), 4.347 nmol/l (3.425-5.447 nmol/l), and 13.51 pmol/l (11.04-31.07 pmol/l) in the second trimester. These values were 1.445 IU/ml (0.588-2.460 IU/ml), 4.132 nmol/l (3.176-5.164 nmol/l), and 12.87 pmol/l (9.807-23.78 pmol/l) in the third trimester, respectively. TSH levels increased throughout the trimesters. FT3 and FT4 levels were significantly higher in the first trimester compared with the second and third trimesters. TSH, FT3, and FT4 levels were significantly lower in pregnant women compared with non-pregnant women (P < 0.001). CONCLUSIONS: The present study is the first to establish trimester-specific reference ranges of TSH, FT3, and FT4 in Sudanese women with normal pregnancies. Our results suggest that pregnancy is likely to suppress TSH, T3, and T4 levels in healthy women.