Tumor recurrence and survival in patients treated for thymomas and thymic squamous cell carcinomas: a retrospective analysis.

PURPOSE: Thymic epithelial tumors (TET) are rare epithelial neoplasms of the thymus with considerable histologic heterogeneity. This retrospective study focused on the correlation of WHO-defined TET histotypes with survival and tumor recurrence in a large cohort of patients receiving different modes of treatment. PATIENTS AND METHODS: Two hundred twenty-eight patients were followed for up to 21 years (median, 60 months; range, 1 to 252 months) after primary surgery. Forty-two patients received adjuvant radiotherapy (mean dose, 53 Gy), and 33 patients received adjuvant chemotherapy. RESULTS: Seventy-six (88%) of 86 patients with WHO type A, AB, and B1 thymomas were treated by surgery alone, with three tumor relapses after 3 to 10 years (median, 3.4 years). Twelve of 67 patients with WHO type B2 and B3 thymomas in Masaoka stages I and II were treated by adjuvant radiotherapy without evidence of tumor recurrence after 1 to 12 years (median, 4 years). Among 75 patients with B2 and B3 thymomas with incomplete resection or a tumor stage III or higher, the recurrence rate was 34% (n = 23) after 0.5 to 17 years (median, 5 years) in patients receiving adjuvant radiochemotherapy, compared to 78% (seven of nine patients) in patients without adjuvant radiochemotherapy. Incomplete tumor resection was associated with a high recurrence rate (65%) and a poor prognosis (P <.01). CONCLUSION: The long-term outcome of TET patients is related to tumor stage, WHO histotype, completeness of surgical removal, and type of treatment. Prospective trials are warranted to formally address the efficacy of adjuvant therapy in the treatment of localized and advanced malignant TETs.     

Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.

PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (> or = 3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune response.     

Cystatin C: efficacy as screening test for reduced glomerular filtration rate

Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and creatinine clearance were measured in 226 patients with various nephropathies, covering the entire range of renal function, to evaluate the efficacy of cystatin C as a screening test to detect reduced creatinine clearance in comparison to creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular impairment were compared to assess whether cystatin C performed differently in either glomerular or tubular impairment. Cystatin C detected reduced creatinine clearance with higher sensitivity (97 vs. 83%), and higher negative predictive value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of cystatin C as derived from receiver-operating characteristic plot was significantly higher (p < 0.05). In the subgroups with glomerular or tubular impairment, cystatin C and creatinine did not significantly differ with regard to efficacy. Serum cystatin C is as efficacious as serum creatinine to detect reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a screening test may even be superior compared to creatinine. In addition, the efficacy of cystatin C is independent of either glomerular or tubular impairment.     

Papers Please - Predictive Factors of National and International Attitudes Toward Immunity and Vaccination Passports: Online Representative Surveys

BackgroundIn response to the COVID-19 pandemic, countries are introducing digital passports that allow citizens to return to normal activities if they were previously infected with (immunity passport) or vaccinated against (vaccination passport) SARS-CoV-2. To be effective, policy decision-makers must know whether these passports will be widely accepted by the public and under what conditions. This study focuses attention on immunity passports, as these may prove useful in countries both with and without an existing COVID-19 vaccination program; however, our general findings also extend to vaccination passports.ObjectiveWe aimed to assess attitudes toward the introduction of immunity passports in six countries, and determine what social, personal, and contextual factors predicted their support.MethodsWe collected 13,678 participants through online representative sampling across six countries—Australia, Japan, Taiwan, Germany, Spain, and the United Kingdom—during April to May of the 2020 COVID-19 pandemic, and assessed attitudes and support for the introduction of immunity passports.ResultsImmunity passport support was moderate to low, being the highest in Germany (775/1507 participants, 51.43%) and the United Kingdom (759/1484, 51.15%); followed by Taiwan (2841/5989, 47.44%), Australia (963/2086, 46.16%), and Spain (693/1491, 46.48%); and was the lowest in Japan (241/1081, 22.94%). Bayesian generalized linear mixed effects modeling was used to assess predictive factors for immunity passport support across countries. International results showed neoliberal worldviews (odds ratio [OR] 1.17, 95% CI 1.13-1.22), personal concern (OR 1.07, 95% CI 1.00-1.16), perceived virus severity (OR 1.07, 95% CI 1.01-1.14), the fairness of immunity passports (OR 2.51, 95% CI 2.36-2.66), liking immunity passports (OR 2.77, 95% CI 2.61-2.94), and a willingness to become infected to gain an immunity passport (OR 1.6, 95% CI 1.51-1.68) were all predictive factors of immunity passport support. By contrast, gender (woman; OR 0.9, 95% CI 0.82-0.98), immunity passport concern (OR 0.61, 95% CI 0.57-0.65), and risk of harm to society (OR 0.71, 95% CI 0.67-0.76) predicted a decrease in support for immunity passports. Minor differences in predictive factors were found between countries and results were modeled separately to provide national accounts of these data.ConclusionsOur research suggests that support for immunity passports is predicted by the personal benefits and societal risks they confer. These findings generalized across six countries and may also prove informative for the introduction of vaccination passports, helping policymakers to introduce effective COVID-19 passport policies in these six countries and around the world.     

A novel N-hydroxy-N′-aminoguanidine derivative inhibits ribonucleotide reductase activity: Effects in human HL-60 promyelocytic leukemia cells and synergism with arabinofuranosylcytosine (Ara-C)

Ribonucleotide reductase (RR; EC 1.17.4.1) is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA replication. RR is upregulated in tumor cells and therefore considered to be an excellent target for cancer chemotherapy.ABNM-13 (N-hydroxy-2-(anthracene-2-yl-methylene)-hydrazinecarboximidamide), a novel N-hydroxy-N′-aminoguanidine has been designed to inhibit RR activity using 3D molecular space modeling techniques. In this study, we evaluated its effect on human HL-60 promyelocytic leukemia cells. ABNM-13 proved to be a potent inhibitor of RR which was displayed by significant alterations of deoxyribonucleoside triphosphate (dNTP) pool balance and a highly significant decrease of incorporation of radiolabeled cytidine into DNA of HL-60 cells. Diminished RR activity caused replication stress which was consistent with activation of Chk1 and Chk2, resulting in downregulation/degradation of Cdc25A. In contrast, Cdc25B was upregulated, leading to dephosphorylation and activation of Cdk1. The combined disregulation of Cdc25A and Cdc25B was the most likely cause for ABNM-13 induced S-phase arrest. Finally, we combined ABNM-13 with the first-line antileukemic agent arabinofuranosylcytosine (Ara-C) and found that ABNM-13 synergistically potentiated the antineoplastic effects of Ara-C.Due to these promising results, ABNM-13 deserves further preclinical and in vivo testing.     

Comparison of Nicolaides’ risk evaluation for down’s syndrome with a novel software: an analysis of 1,463 cases

Objective The individual risk assessment of fetal Down’s syndrome based on measurement of nuchal translucency (NT) according to Nicolaides, optionally complemented by the determination of PAPP-A and free beta HCG has progressively supplanted other search strategies for fetal aneuploidies. It could be shown that this diagnostic strategy equally detects other numeric aneuploidies at a comparable rate. A positive test result is also predictive for the presence of a fetal malformation. In this field, several computer programs are available for clinical use. The objective of our study was to re-evaluate the first consecutive 1463 NT-risk calculations determined by Nicolaides’ method and to compare the risk calculation to the JOY software (NT-risk calculation module, JOY Patient Database) introduced in 2002. Material and methods At the Department of Obstetrics and Gynecology, Hannover Medical School, 1463 consecutive complete data sets comprising first trimester screening performed between May 2, 2000 and June 26, 2003 and corresponding fetal outcome were analysed using risk assessment based on the Nicolaides method (PIA Fetal Database NT-Module) and compared with the risk evaluation as determined by the JOY software (JOY Patient Database NT module). A risk exceeding 1:300 was considered to indicate the need for further invasive testing. In a first step, only cytogenetically detectable chromosomal aberrations were analysed. Then, a second evaluation including fetal malformations was performed. Results Among the 1463 cases, 1445 (98.77%) fetuses revealed to be cytogenetically healthy. Both softwares showed identical detection rates at the genetic and somatic level:13 cases of Down-Syndrome (0.89%), 2 cases of trisomy 18 (0.14%), one case of triploidy, one Turner-Syndrome, one Klinefelter-Syndrome (0.07% each) were detected. A positive test result was found in 15 cases ending in a spontaneous abortion, intrauterine death or peripartum death (1.03%) and in 22 cases of fetal malformation (1.50%). At the level of genetic detection the test positive rate dropped from 92 (PIA) to 71 (JOY) (-22.8%). At the level of combined adverse outcome the test positive rate was reduced from 100 (PIA) to 76 (JOY) (-22.0%), thus yielding in a marked improvement of the characteristic test performance parameters. Conclusion The novel, recently developed JOY software package allowed reliable evaluation of the risk for aneuploidy with increased specificity whereas sensitivity was unchanged. Our data suggest an improvement of the screening for aneuploidy when using this novel software: With an identical detection rate, the number of unnecessary invasive measures may be reduced.     

The significance of intracardiac Doppler sonography in terms of fetal growth retardation

Introduction

The proper function of the fetal heart is indispensable for the fetal development and the normal fetal growth. For prenatal medicine, Doppler sonography offers the possibility of a non-invasive method to examine the fetal cardiovascular function under normal and pathological circumstances. The role of the Doppler sonography is to identify those fetuses who have a high risk factor for developing a pre- or intrapartual asphyxia and therefore have to be delivered promptly. This study aimed at evaluating the clinical value of the intracardiac Doppler sonography (IDS) and at scrutinizing its usefulness during the supervision of the pregnancy of intrauterine growth restricted (IUGR) fetuses.

Materials and methods

In a prospective research at the Medical School of Hanover, fetal IDS was applied to 174 pregnant women between the 21 and 37 weeks of gestation (WG). The e-wave and the a-wave, the E/A ratio, and the TVI (time velocity integral) were measured at the atrioventricular (AV) valves. The PV (peak velocity) as well as the TVI were determined at both the aortic and the pulmonary valve. Normal range curves were compiled for all measured parameters.

Results

Alongside a control group with untroubled gravidity, which consisted of 153 patients, IUGR fetuses, who formed a collective of 21 patients, were Doppler sonographically examined.While the gestational age advanced, an increase of both the e-wave and the a-wave above the AV-valves could be ascertained, which lead to an E/A ratio <1. Above the semilunar valves there was indicated a slight steady increase of the TPV, the PV as well as the TVI. Normal range curves, which largely correspond to those described in the literature, were compiled for the collective of the pregnancies without pathological findings (n = 153). In comparison to the standard collective, there were no significant differences from the collective of the growth restricted fetuses (n = 21).

Conclusion

A temporal informational advantage of pathological intracardiac Doppler values for high risk pregnancies (IUGR) could not be retraced in the examined collective.Doppler sonography traces acute and chronic deficits, which are indicated by hemodynamic changes of the fetus’s blood supply. The clinical importance of IDS as regards dystrophic fetuses has to be ascertained in continuative studies: In the stage of compensatory placental insufficiency (IUGR, arterial Doppler without ARED-flow, venous Doppler without pathological findings) the IDS cannot provide an informational advantage. Contrastingly, the diagnostic potential of the IDS as a screening method of fetal cardiac insufficiency during decompensative placental insufficiency (IUGR, arterial Doppler with ARED-flow, venous Doppler normal or pathological) remains indistinct and should therefore be prospectively evaluated within this high risk group and contrastingly compared to the significance of the venous Doppler sonography (informational advantage?).