A 30-year long-term experience in appendix neuroendocrine neoplasms—granting a positive outcome

Neuroendocrine neoplasms (NENs) are the most common tumor of the appendix and have an excellent prognosis. Appendiceal tumors diagnosed between 1989 and 2019 were reviewed, and clinical data were collected from patient files. Part of the series was immuno-profiled for markers related to cell cycle proliferation and/or senescence-type, apoptotic, and metastatic potential. Appendix NENs were detected in 74 patients, with 0.47% of incidence per appendectomy. The median age of the patients was 21.5 years, with two age peaks of incidence at 17.0 and 55.2 years. The median tumors size was 5.8 mm, and most were smaller than 10 mm. Lymphovascular and perineural invasion, as well as necrosis, was associated with larger tumor size. G1 tumors composed 96.0% of the cohort. The presence of moderate/strong p16 and the absent/low Bcl-2 expression was frequently observed and associated with a smaller size. This study represents one of the largest cohorts and with a long follow-up. For tumors smaller than 10 mm appendicectomy was sufficient as a curative procedure, as revealed by the good outcome. This series presented a 100% disease-free survival. The indolent phenotype of appendix NENs is supported by the expression of markers that point towards a strong inhibition of cell replication and growth inhibition.This study was supported by FCT—Fundação para a Ciência e a Tecnologia, Ministério da Ciência, Tecnologia e Ensino Superior by a research contract to João Vinagre (CEECIND/00201/2017). Further funding was obtained from the project “Advancing cancer research: from basic knowledge to application” NORTE-01-0145-FEDER-000029: “Projetos Estruturados de I & D & I”, funded by Norte 2020—Programa Operacional Regional do Norte. Additional funding was obtained from the project PTDC/MED-ONC/31438/2017 (The other faces of Telomerase: Looking beyond tumor immortalization), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), COMPETE 2020—Operational Programme for Competitiveness and Internationalization (POCI) and by Portuguese funds through FCT under project POCI-01-0145-FEDER-016390: CANCEL STEM”

Three Dimensional MHD Simulation of Circumbinary Accretion Disks: Disk Structures and Angular Momentum Transport

We present the first three-dimensional magnetohydrodynamic (MHD) simulations of a circumbinary disk surrounding an equal mass binary. The binary maintains a fixed circular orbit of separation $a$. As in previous hydrodynamical simulations, strong torques by the binary can maintain a gap of radius $\simeq 2a$. Streams curve inward from $r \simeq 2a$ toward the binary; some of their mass passes through the inner boundary, while the remainder swings back out to the disk. However, we also find that near its inner edge the disk develops both a strong $m=1$ asymmetry and growing orbital eccentricity. Because the MHD stresses introduce more matter into the gap, the total torque per unit disk mass is $\simeq 14$ times larger than found previously. The inner boundary accretion rate per unit disk mass is $\simeq 40$ times greater than found from previous hydrodynamical calculations. The implied binary shrinkage rate is determined by a balance between the rate at which the binary gains angular momentum by accretion and loses it by gravitational torque. The large accretion rate brings these two rates nearly into balance, but in net, we find that $\dot a/a < 0$, and its magnitude is about 2.7 times larger than predicted by the earlier hydrodynamic simulations. If the binary comprises two massive black holes, the accretion rate may be great enough for one or both to be AGN, with consequences for the physical state of the gas both in the disk body and in its inner gap.Comment: 69 pages,19 figures, ApJ accepted version (add one more appendix discussing the binary's eccentricity growth

Sub-Milankovitch cycles in periplatform carbonates from the early Pliocene Great Bahama Bank

High-resolution bulk sediment (magnetic susceptibility and aragonite content) and δ18O records from two different planktonic foraminifera species were analyzed in an early Pliocene core interval from the Straits of Florida (Ocean Drilling Program site 1006). The δ18O record of the shallow-dwelling foraminifera G. sacculifer and the aragonite content are dominated by sub-Milankovitch variability. In contrast, magnetic susceptibility and the δ18O record of the deeper-dwelling foraminifera G. menardii show precession cycles. The relationship between the aragonite and the paleoproxy data suggests that the export of sediment from the adjacent Great Bahama Bank was triggered directly by atmospheric processes rather than by sea level change. We propose a climate mechanism that bears similarities with the semiannual cycle component of eastern equatorial Pacific sea surface temperatures under present-day conditions

Whiting–related sediment export along the Middle Miocene carbonate ramp of Great Bahama Bank.

International audienc

Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial

Background Metastatic castration-resistant prostate cancers are enriched for DNA repair gene defects (DRDs) that can be susceptible to synthetic lethality through inhibition of PARP proteins. We evaluated the anti-tumour activity and safety of the PARP inhibitor niraparib in patients with metastatic castration-resistant prostate cancers and DRDs who progressed on previous treatment with an androgen signalling inhibitor and a taxane. Methods In this multicentre, open-label, single-arm, phase 2 study, patients aged at least 18 years with histologically confirmed metastatic castration-resistant prostate cancer (mixed histology accepted, with the exception of the small cell pure phenotype) and DRDs (assessed in blood, tumour tissue, or saliva), with progression on a previous next-generation androgen signalling inhibitor and a taxane per Response Evaluation Criteria in Solid Tumors 1.1 or Prostate Cancer Working Group 3 criteria and an Eastern Cooperative Oncology Group performance status of 0–2, were eligible. Enrolled patients received niraparib 300 mg orally once daily until treatment discontinuation, death, or study termination. For the final study analysis, all patients who received at least one dose of study drug were included in the safety analysis population; patients with germline pathogenic or somatic biallelic pathogenic alterations in BRCA1 or BRCA2 (BRCA cohort) or biallelic alterations in other prespecified DRDs (non-BRCA cohort) were included in the efficacy analysis population. The primary endpoint was objective response rate in patients with BRCA alterations and measurable disease (measurable BRCA cohort). This study is registered with ClinicalTrials.gov, NCT02854436. Findings Between Sept 28, 2016, and June 26, 2020, 289 patients were enrolled, of whom 182 (63%) had received three or more systemic therapies for prostate cancer. 223 (77%) of 289 patients were included in the overall efficacy analysis population, which included BRCA (n=142) and non-BRCA (n=81) cohorts. At final analysis, with a median follow-up of 10·0 months (IQR 6·6–13·3), the objective response rate in the measurable BRCA cohort (n=76) was 34·2% (95% CI 23·7–46·0). In the safety analysis population, the most common treatment-emergent adverse events of any grade were nausea (169 [58%] of 289), anaemia (156 [54%]), and vomiting (111 [38%]); the most common grade 3 or worse events were haematological (anaemia in 95 [33%] of 289; thrombocytopenia in 47 [16%]; and neutropenia in 28 [10%]). Of 134 (46%) of 289 patients with at least one serious treatment-emergent adverse event, the most common were also haematological (thrombocytopenia in 17 [6%] and anaemia in 13 [4%]). Two adverse events with fatal outcome (one patient with urosepsis in the BRCA cohort and one patient with sepsis in the non-BRCA cohort) were deemed possibly related to niraparib treatment. Interpretation Niraparib is tolerable and shows anti-tumour activity in heavily pretreated patients with metastatic castration-resistant prostate cancer and DRDs, particularly in those with BRCA alterations