Objective The aim of this multi-institutional non randomized phase II trial was to determine the efficacy and safety of single agent aflibercept (VEGF Trap), a recombinant fusion protein that blocks multiple vascular endothelial growth factor isoforms, in women with gynecologic soft tissue sarcoma. Methods Patients were enrolled in two cohorts each with Simon two stage designs: uterine leiomyosarcoma and carcinosarcoma of endometrial, ovarian or fallopian tube origin. Eligibility criteria included ≤ 2 prior lines of chemotherapy for metastatic disease and ECOG performance status ≤ 2. Aflibercept 4 mg/kg was administered intravenously on day 1 of a 14 day cycle. Primary endpoints were objective response and disease stabilization (Progression Free Survival (PFS) at 6 months). Results 41 patients with uterine leiomyosarcoma and 22 patients with carcinosarcoma (19 uterine, 3 ovarian) were enrolled on study. In the leiomyosarcoma cohort, eleven (27%) patients had stable disease (SD), 4 with SD lasting at least 24 weeks. The 6 month PFS was 17%, with median time to progression (TTP) of 1.8 (95% CI:1.6–2.1) months. In the carcinosarcoma cohort, two (9%) patients had SD, one lasting > 24 weeks, median TTP was 1.6 months (95%CI: 1.1–1.7) No partial responses were observed in patients from either cohort. Grade 3 or more aflibercept related toxicity was uncommon and included hypertension, fatigue, headache and abdominal pain. Conclusions Single agent aflibercept has modest activity in patients with uterine leiomyosarcoma and minimal activity in women with carcinosarcoma.
SARS‐CoV‐2 infection is clinically heterogeneous, ranging from asymptomatic to deadly. A few patients with COVID‐19 appear to recover from acute viral infection but nevertheless progress in their disease and eventually die, despite persistent negativity at molecular tests for SARS‐CoV‐2 RNA. Here, we performed post‐mortem analyses in 27 consecutive patients who had apparently recovered from COVID‐19 but had progressively worsened in their clinical conditions despite repeated viral negativity in nasopharyngeal swabs or bronchioalveolar lavage for 11–300 consecutive days (average: 105.5 days). Three of these patients remained PCR‐negative for over 9 months. Post‐mortem analysis revealed evidence of diffuse or focal interstitial pneumonia in 23/27 (81%) patients, accompanied by extensive fibrotic substitution in 13 cases (47%). Despite apparent virological remission, lung pathology was similar to that observed in acute COVID‐19 individuals, including micro‐ and macro‐vascular thrombosis (67% of cases), vasculitis (24%), squamous metaplasia of the respiratory epithelium (30%), frequent cytological abnormalities and syncytia (67%), and the presence of dysmorphic features in the bronchial cartilage (44%). Consistent with molecular test negativity, SARS‐CoV‐2 antigens were not detected in the respiratory epithelium. In contrast, antibodies against both spike and nucleocapsid revealed the frequent (70%) infection of bronchial cartilage chondrocytes and para‐bronchial gland epithelial cells. In a few patients (19%), we also detected positivity in vascular pericytes and endothelial cells. Quantitative RT‐PCR amplification in tissue lysates confirmed the presence of viral RNA. Together, these findings indicate that SARS‐CoV‐2 infection can persist significantly longer than suggested by standard PCR‐negative tests, with specific infection of specific cell types in the lung. Whether these persistently infected cells also play a pathogenic role in long COVID remains to be addressed. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
This cross-sectional study aimed to estimate mammogram coverage in the State of Goiás, Brazil, describing the supply, demand, and variations in different age groups, evaluating 98 mammography services as observational units. We estimated the mammogram rates by age group and type of health service, as well as the number of tests required to cover 70% and 100% of the target population. We assessed the association between mammograms, geographical distribution of mammography machines, type of service, and age group. Full coverage estimates, considering 100% of women in the 40-69 and 50-69-year age brackets, were 61% and 66%, of which the Brazilian Unified National Health System provided 13% and 14%, respectively. To achieve 70% coverage, 43,424 additional mammograms would be needed. All the associations showed statistically significant differences (p < 0.001). We conclude that mammogram coverage is unevenly distributed in the State of Goiás and that fewer tests are performed than required.
Even with access to sufficient nutrients and atmosphere, Plasmodium falciparum can barely be cultured at maximum growth capacity in vitro conditions. Because of this behavior, it has been suggested that P. falciparum has self-regulatory mechanisms in response to density stress. Only recently has this process begun to be acknowledged and characteristics of a programmed cell death been assigned to the parasite at high parasitaemia in vitro cultures. In searching for death signals within the parasite community, we have found that extracellular vesicles (EVs) of P. falciparum from high parasitaemia cultures are able to induce programmed cell death processes in the population. A comparative proteomic analysis of EVs from low (EVL) and high (EVH) parasitaemia cultures was conducted, pointing to lactate dehydrogenase from P. falciparum (PfLDH) as the only parasite protein overexpressed in the later. Although the major function of P. falciparum lactate dehydrogenase (PfLDH) is the conversion of pyruvate to lactate, a key process in the production of energy in most living organisms, we investigated its possible role in the mechanism of parasite density control by intercellular signaling, given that PfLDH had already been listed as a component of extracellular vesicles of P. falciparum. In this study we present evidence of the EV-associated PfLDH regulation of parasite population by inducing apoptosis in highly parasitized cultures.
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