Physical resolution of tubal ectopic pregnancy on ultrasound imaging following successful expectant management

RESEARCH QUESTION What is the time required for complete physical resolution of tubal ectopic pregnancies diagnosed on ultrasound imaging in women undergoing successful expectant management? DESIGN A prospective observational cohort study of 177 women who had successful expectant management of tubal ectopic pregnancy, who attended a single Early Pregnancy Unit between January 2014 and December 2018. All participants were monitored until their serum β-hCG dropped to non-pregnant levels and with two-weekly follow-up ultrasound scans until resolution of the pregnancy. RESULTS 112/177 (63.8%, 95% CI 56.3-70.9) of tubal ectopic pregnancies were indiscernible on ultrasound 2 weeks after serum β-hCG had returned to non-pregnant levels. In 8/177 (4.5%, 95% CI 2.0-8.7) physical resolution took longer than 78 days. There was a positive correlation between biochemical and physical resolution of tubal ectopic pregnancy (r=0.21, p=0.006). CONCLUSIONS Physical resolution of tubal ectopic pregnancy is often prolonged and is positively correlated with initial and maximum β-hCG levels. Our results indicate that β-hCG resolution cannot be used as the end-point of expectant management of tubal ectopic pregnancy, which should be considered when counselling women and planning for future pregnancies. KEY MESSAGE In a significant proportion, physical resolution of tubal ectopic pregnancy takes several weeks following the return of serum β-hCG to non-pregnant levels. Women should be advised to delay trying for another pregnancy for three months, to avoid resolving pregnancies being misdiagnosed as new ones and to reduce the theoretical risk of recurrent ectopic, due to temporary tubal blockage by the resolving trophoblast

Impact of location on placentation in live tubal and cesarean scar ectopic pregnancies

INTRODUCTION: The objective of this study was to evaluate the impact of implantation outside the normal intra-uterine endometrium on development of the gestational sac. METHODS: We reviewed and compared the ultrasound measurements and vascularity score around the gestational sac in 69 women diagnosed with a live tubal ectopic pregnancy (TEP) and 54 with a cesarean scar ectopic pregnancy (CSP) at 6-11 weeks of gestation who were certain of their last menstrual period. RESULTS: The rate of a fetus with a cardiac activity in the study population was significantly (P < 0.001) higher in CSPs than in TEPs. The median maternal age, gravidity and parity were significantly (P =.005; P < 0.001 and P < 0.001, respectively) lower in the TEP than in the CSP group. The number of gestational sac size <5th centile for gestational age was significantly (P < 0.001) higher in the TEP than in the CSP group. There were no differences between the groups for the other ultrasound measurements. In cases matched for gestational age, the gestational sac size was significantly (P < 0.001) smaller in the TEP compared to the CSP group. There was a significant (P < 0.001) difference in the distribution of blood flow score with CSP presenting with higher incidence of moderate and high vascularity than TEP. DISCUSSION: Both TEP and CSP are associated with a higher rate of miscarriage than intrauterine pregnancies and the slow development of the gestation sac is more pronounced in TEPs probably as a consequence of a limited access to decidual gland secretions

Magnitude of Alloresponses to MHC Class I/II Expressing Human Cardiac Myocytes is Limited by their Intrinsic Ability to Process and Present Antigenic Peptides

In this investigation we have explored the relationship between the weak allogenicity of cardiac myocytes and their capacity to present allo-antigens by examining the ability of a human cardiac myocyte cell line (W-1) to process and present nominal antigens. W-1 cells (HLA-A*0201 and HLA-DR β1*0301) pulsed with the influenza A matrix 1 (58-66) peptide (M1) were able to serve as targets for the HLA-A*0201 restricted CTL line PG, specific for M1-peptide. However, PG-CTLs were unable to lyse W-1 target cells infected with a recombinant vaccinia virus expressing the M1 protein (M1-VAC). Pretreatment of these M1-VAC targets with IFN-γ partially restored their ability to process and present the M1 peptide. However, parallel studies demonstrated that IFN-γ pretreated W-1's could not process tetanus toxin (TT) or present the TT(830-843) peptide to HLA-DR3 restricted TT-primed T cells. Semi-quantitative RT-PCR measurements revealed significantly lower constitutive levels of expression for MHC class I, TAP-1/2, and LMP-2/7 genes in W-1s that could be elevated by pretreatment with IFN-γ to values equal to or greater than those expressed in EBV-PBLs. However, mRNA levels for the genes encoding MHC class II, Ii, CIITA, and DMA/B were markedly lower in both untreated and IFN-γ pretreated W-1s relative to EBV-PBLs. Furthermore, pulse-chase analysis of the corresponding genes revealed significantly lower protein levels and longer half-life expression in W-1s relative to EBV-PBLs. These results suggest that weak allogenicity of cardiac myocytes may be governed by their limited expression of MHC genes and gene products critical for antigen processing and presentation

Maintaining high bandwidth under dynamic network conditions

The need to distribute large files across multiple wide-area sites is becoming increasingly common, for instance, in support of scientific computing, configuring distributed systems, distributing software updates such as open source ISOs or Windows patches, or disseminating multimedia content. Recently a number of techniques have been proposed for simultaneously retrieving portions of a file from multiple remote sites with the twin goals of filling the client's pipe and overcoming any performance bottlenecks between the client and any individual server. While there are a number of interesting tradeoffs in locating appropriate download sites in the face of dynamically changing network conditions, to date there has been no systematic evaluation of the merits of different protocols. This paper explores the design space of file distribution protocols and conducts a detailed performance evaluation of a number of competing systems running in both controlled emulation environments and live across the Internet. Based on our experience with these systems under a variety of conditions, we propose, implement and evaluate Bullet' (Bullet prime), a mesh based high bandwidth data dissemination system that outperforms previous techniques under both static and dynamic condition

Magnetization steps in a diluted Heisenberg antiferromagnetic chain: Theory and experiments on TMMC:Cd

A theory for the equilibrium low-temperature magnetization M of a diluted Heisenberg antiferromagnetic chain is presented. The magnetization curve, M versus B, is calculated using the exact contributions of finite chains with 1 to 5 spins, and the "rise and ramp approximation" for longer chains. Some non-equilibrium effects that occur in a rapidly changing B, are also considered. Specific non-equilibrium models based on earlier treatments of the phonon bottleneck, and of spin flips associated with cross relaxation and with level crossings, are discussed. Magnetization data on powders of TMMC diluted with cadmium [i.e., (CH_3)_4NMn_xCd_(1-x)Cl_3, with 0.16<=x<=0.50 were measured at 0.55 K in 18 T superconducting magnets. The field B_1 at the first MST from pairs is used to determine the NN exchange constant, J, which changes from -5.9 K to -6.5 K as x increases from 0.16 to 0.50. The magnetization curves obtained in the superconducting magnets are compared with simulations based on the equilibrium theory. Data for the differential susceptibility, dM/dB, were taken in pulsed magnetic fields (7.4 ms duration) up to 50 T, with the powder samples in a 1.5 K liquid-helium bath. Non-equilibrium effects, which became more severe as x decreased, were observed. The non-equilibrium effects are tentatively interpreted using the "Inadequate Heat Flow Scenario," or to cross-relaxation, and crossings of energy levels, including those of excited states.Comment: 16 pages, 14 figure

Metastatic squamous cell carcinoma of an unknown primary localized to the neck. Advantages of an aggressive treatment.

Treatment of patients with squamous cell carcinoma (SCC) of an unknown primary localized to the neck is still controversial, particularly regarding advanced disease. We reviewed 41 such patients treated with surgery and/or radiotherapy (RT) (n = 25) or with combined modality treatment including chemotherapy (CH) (n = 16). The male to female ratio was 28 to 13, and the median age was 58 years (range, 32 to 94 years). There were 27 (66%) patients with poorly differentiated SCC and 8 with moderately differentiated or well-differentiated cancer. Twenty-three (56%) patients had N3 disease, 16 (39%) had N2, and 2 had N1. The majority of N3 patients have been treated with CH and RT (n = 12) or with RT alone (n = 9). The combined CH-RT was well tolerated, with no life-threatening toxicity. The complete response (CR) to CH-RT was 81% (11 patients have no evidence of disease [NED] currently). The median survival time of this group was 37+ months. Of the 25 patients who had surgery and/or RT as their first planned treatment, 7 (28%) have NED currently. The median survival time of this group was 24 months. Patients with N3 disease who received CH had a higher CR rate and a longer survival time as compared with those treated with surgery and/or RT, despite a higher (N3) stage of disease. These findings warrant further investigation in randomized cooperative studies

CheckMate-032 study: efficacy and safety of nivolumab and nivolumab plus ipilimumab in patients with metastatic esophagogastric cancer

Purpose: Metastatic esophagogastric cancer treatments after failure of second-line chemotherapy are limited. Nivolumab demonstrated superior overall survival (OS) versus placebo in Asian patients with advanced gastric or gastroesophageal junction cancers. We assessed the safety and efficacy of nivolumab and nivolumab plus ipilimumab in Western patients with chemotherapy-refractory esophagogastric cancers. Patients and Methods: Patients with locally advanced or metastatic chemotherapy–refractory gastric, esophageal, or gastroesophageal junction cancer from centers in the United States and Europe received nivolumab or nivolumab plus ipilimumab. The primary end point was objective response rate. The association of tumor programmed death-ligand 1 status with response and survival was also evaluated. Results: Of 160 treated patients (59 with nivolumab 3 mg/kg, 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/kg, 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), 79% had received two or more prior therapies. At the data cutoff, investigator-assessed objective response rates were 12% (95% CI, 5% to 23%), 24% (95% CI, 13% to 39%), and 8% (95% CI, 2% to 19%) in the three groups, respectively. Responses were observed regardless of tumor programmed death-ligand 1 status. With a median follow-up of 28, 24, and 22 months across the three groups, 12-month progression-free survival rates were 8%, 17%, and 10%, respectively; 12-month OS rates were 39%, 35%, and 24%, respectively. Treatment-related grade 3/4 adverse events were reported in 17%, 47%, and 27% of patients in the three groups, respectively. Conclusion: Nivolumab and nivolumab plus ipilimumab demonstrated clinically meaningful antitumor activity, durable responses, encouraging long-term OS, and a manageable safety profile in patients with chemotherapy-refractory esophagogastric cancer. Phase III studies evaluating nivolumab or nivolumab plus ipilimumab in earlier lines of therapy for esophagogastric cancers are underway

A phase 1 study of mTORC1/2 inhibitor BI 860585 as a single agent or with exemestane or paclitaxel in patients with advanced solid tumors

This phase 1 trial (NCT01938846) determined the maximum tolerated dose (MTD) of the mTOR serine/threonine kinase inhibitor, BI 860585, as monotherapy and with exemestane or paclitaxel in patients with advanced solid tumors. This 3+3 dose-escalation study assessed BI 860585 monotherapy (5–300 mg/day; Arm A), BI 860585 (40–220 mg/day; Arm B) with 25 mg/day exemestane, and BI 860585 (80–220 mg/day; Arm C) with 60–80 mg/m2 /week paclitaxel, in 28-day cycles. Primary endpoints were the number of patients with dose-limiting toxicities (DLTs) in cycle 1 and the MTD. Forty-one, 25, and 24 patients were treated (Arms A, B, and C). DLTs were observed in four (rash (n = 2), elevated alanine aminotransferase/aspartate aminotransferase, diarrhea), four (rash (n = 3), stomatitis, and increased gamma-glutamyl transferase), and two (diarrhea, increased blood creatine phosphokinase) patients in cycle 1. The BI 860585 MTD was 220 mg/day (Arm A) and 160 mg/day (Arms B and C). Nine patients achieved an objective response (Arm B: Four partial responses (PRs); Arm C: Four PRs; one complete response). The disease control rate was 20%, 28%, and 58% (Arms A, B, and C). The most frequent treatment-related adverse events (AEs) were hyperglycemia (54%) and diarrhea (39%) (Arm A); diarrhea (40%) and stomatitis (40%) (Arm B); fatigue (58%) and diarrhea (58%) (Arm C). The MTD was determined in all arms. Antitumor activity was observed with BI 860585 monotherapy and in combination with exemestane or paclitaxel

ceritinib plus nivolumab in patients with advanced alk rearranged non small cell lung cancer results of an open label multicenter phase 1b study

Abstract Introduction Induction of programmed death ligand 1 (PD-L1) expression due to constitutive oncogenic signaling has been reported in NSCLC models harboring echinoderm microtubule associated protein like 4 gene (EML4)–ALK receptor tyrosine kinase gene (ALK) rearrangements. We assessed the safety and activity of ceritinib plus nivolumab in these patients. Methods In this open-label, phase 1B, multicenter, dose escalation and expansion study, previously treated (with ALK receptor tyrosine kinase [ALK] inhibitor [ALKI]/chemotherapy) or treatment-naive patients with stage IIIB or IV ALK-rearranged NSCLC received nivolumab, 3 mg/kg intravenously every 2 weeks, plus ceritinib, 450 mg/300 mg daily, with a low-fat meal. Results In total, 36 patients were treated (a 450-mg cohort [n=14] and a 300-mg cohort [n=22]). In the 450-mg cohort, four patients experienced dose-limiting toxicities. In the 300-mg cohort, two patients experienced dose-limiting toxicities. Among ALKI-naive patients, the overall response rate (ORR) was 83% (95% confidence interval [CI]: 35.9–99.6) in the 450-mg cohort and 60% (95% CI: 26.2–87.8) in the 300-mg cohort. Among ALKI-pretreated patients, the ORR was 50% (95% CI: 15.7–84.3) in the 450-mg cohort and 25% (95% CI: 5.5–57.2) in the 300-mg cohort. The ORR point estimate was observed to be greater in patients who were positive for PD-L1 than in those who were negative for PD-L1, with overlapping CIs (e.g., at a cutoff ≥1% PD-L1, 64% of patients [95% CI: 35.1–87.2] had confirmed responses as compared with those with negative PD-L1 staining (31% [95% CI: 11.0–58.7]). The most frequently reported grade 3 or 4 adverse events were increased alanine aminotransferase level (25%), increased gamma-glutamyl transferase level (22%), increased amylase level (14%), increased lipase level (11%), and maculopapular rash (11%). The incidence of all-grade rash (grouped term) was 64% in both cohorts; grade 3 rash was reported in 29% and 14% of patients in the 450-mg and 300-mg cohorts, respectively; no grade 4 rash was reported. Conclusion Ceritinib plus nivolumab has activity; ORR appears to correlate with PD-L1 at baseline. Toxicity, especially rash, is more common than with either single agent

Genome sequencing of the extinct Eurasian wild aurochs, Bos primigenius, illuminates the phylogeography and evolution of cattle

Background Domestication of the now-extinct wild aurochs, Bos primigenius, gave rise to the two major domestic extant cattle taxa, B. taurus and B. indicus. While previous genetic studies have shed some light on the evolutionary relationships between European aurochs and modern cattle, important questions remain unanswered, including the phylogenetic status of aurochs, whether gene flow from aurochs into early domestic populations occurred, and which genomic regions were subject to selection processes during and after domestication. Here, we address these questions using whole-genome sequencing data generated from an approximately 6,750-year-old British aurochs bone and genome sequence data from 81 additional cattle plus genome-wide single nucleotide polymorphism data from a diverse panel of 1,225 modern animals. Results Phylogenomic analyses place the aurochs as a distinct outgroup to the domestic B. taurus lineage, supporting the predominant Near Eastern origin of European cattle. Conversely, traditional British and Irish breeds share more genetic variants with this aurochs specimen than other European populations, supporting localized gene flow from aurochs into the ancestors of modern British and Irish cattle, perhaps through purposeful restocking by early herders in Britain. Finally, the functions of genes showing evidence for positive selection in B. taurus are enriched for neurobiology, growth, metabolism and immunobiology, suggesting that these biological processes have been important in the domestication of cattle. Conclusions This work provides important new information regarding the origins and functional evolution of modern cattle, revealing that the interface between early European domestic populations and wild aurochs was significantly more complex than previously thought