Perioperative or only adjuvant gemcitabine plus nab-paclitaxel for resectable pancreatic cancer (NEONAX)-a randomized phase II trial of the AIO pancreatic cancer group.

BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).

COVID-19 in cancer patients: clinical characteristics and outcome-an analysis of the LEOSS registry.

INTRODUCTION: Since the early SARS-CoV-2 pandemic, cancer patients have been assumed to be at higher risk for severe COVID-19. Here, we present an analysis of cancer patients from the LEOSS (Lean European Open Survey on SARS-CoV-2 Infected Patients) registry to determine whether cancer patients are at higher risk. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 435 cancer patients and 2636 non-cancer patients with confirmed SARS-CoV-2 infection, enrolled between March 16 and August 31, 2020. Data on socio-demographics, comorbidities, cancer-related features and infection course were collected. Age-, sex- and comorbidity-adjusted analysis was performed. Primary endpoint was COVID-19-related mortality. RESULTS: In total, 435 cancer patients were included in our analysis. Commonest age category was 76-85 years (36.5%), and 40.5% were female. Solid tumors were seen in 59% and lymphoma and leukemia in 17.5% and 11% of patients. Of these, 54% had an active malignancy, and 22% had recently received anti-cancer treatments. At detection of SARS-CoV-2, the majority (62.5%) presented with mild symptoms. Progression to severe COVID-19 was seen in 55% and ICU admission in 27.5%. COVID-19-related mortality rate was 22.5%. Male sex, advanced age, and active malignancy were associated with higher death rates. Comparing cancer and non-cancer patients, age distribution and comorbidity differed significantly, as did mortality (14% vs 22.5%, p value < 0.001). After adjustments for other risk factors, mortality was comparable. CONCLUSION: Comparing cancer and non-cancer patients, outcome of COVID-19 was comparable after adjusting for age, sex, and comorbidity. However, our results emphasize that cancer patients as a group are at higher risk due to advanced age and pre-existing conditions.

Objective Estimates Improve Risk Stratification for Primary Graft Dysfunction after Lung Transplantation.

Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.

Elevated plasma long pentraxin-3 levels and primary graft dysfunction after lung transplantation for idiopathic pulmonary fibrosis.

Primary graft dysfunction (PGD) after lung transplantation may result from ischemia reperfusion injury (IRI). The innate immune response to IRI may be mediated by Toll-like receptor and IL-1-induced long pentraxin-3 (PTX3) release. We hypothesized that elevated PTX3 levels were associated with PGD. We performed a nested case control study of lung transplant recipients with idiopathic pulmonary fibrosis (IPF) or chronic obstructive pulmonary disease (COPD) from the Lung Transplant Outcomes Group cohort. PTX3 levels were measured pretransplant, and 6 and 24 h postreperfusion. Cases were subjects with grade 3 PGD within 72 h of transplantation and controls were those without grade 3 PGD. Generalized estimating equations and multivariable logistic regression were used for analysis. We selected 40 PGD cases and 79 non-PGD controls. Plasma PTX3 level was associated with PGD in IPF but not COPD recipients (p for interaction < 0.03). Among patients with IPF, PTX3 levels at 6 and 24 h were associated with PGD (OR = 1.6, p = 0.02 at 6 h; OR = 1.4, p = 0.008 at 24 h). Elevated PTX3 levels were associated with the development of PGD after lung transplantation in IPF patients. Future studies evaluating the role of innate immune activation in IPF and PGD are warranted.

Plasma cytokines and chemokines in primary graft dysfunction post-lung transplantation.

Primary graft dysfunction (PGD) after lung transplantation causes significant morbidity and mortality. We aimed to determine the role of cytokines and chemokines in PGD. This is a multicenter case-control study of PGD in humans. A Luminex analysis was performed to determine plasma levels of 25 chemokines and cytokines before and at 6, 24, 48 and 72 h following allograft reperfusion in 25 cases (grade 3 PGD) and 25 controls (grade 0 PGD). Biomarker profiles were evaluated using a multivariable logistic regression and generalized estimating equations. PGD cases had higher levels of monocyte chemotactic protein-1 (MCP-1)/chemokine CC motif ligand 2 (CCL2) and interferon (IFN)-inducible protein (IP-10)/chemokine CXC motif ligand 10 (CXCL10) (both p < 0.05), suggesting recruitment of monocytes and effector T cells in PGD. In addition, PGD cases had lower levels of interleukin (IL-13) (p = 0.05) and higher levels of IL-2R (p = 0.05). Proinflammatory cytokines, including tumor necrosis factor (TNF)-alpha, and IFN-gamma decreased to very low levels after transplant in both PGD cases and controls, exhibiting no differences between the two groups. These findings were independent of clinical variables including diagnosis in multivariable analyses, but may be affected by cardiopulmonary bypass. Profound injury in clinical PGD is distinguished by the upregulation of selected chemokine pathways, which may useful for the prediction or early detection of PGD if confirmed in future studies.

[Functional morphology of the large intestinal mucosa of horses (Equus przewalskii f. caballus) with special regard to the epithelium]. / Uber die funktionelle Morphologie der Dickdarm-Mukosa vom Pferd (Equus przewalskii f. caballus) unter besonderer Berücksichtigung ihres Epithels.

The mucous membrane of the caecum and colon ascendens of adult horses was first studied using light and transmission electron microscopy. In the surface epithelium there was an inconspicuous constellation of organelles, otherwise there was a lot of mitochondria as a source of energy for absorptive performances. Moreover, enlarged intercellular spaces exist as an indication of an increased uptake of water and electrolytes. In the basal region of Lieberkühn's crypts there were single enteroendocrine cells and numerous granules in the apical epithelial cytoplasm. The functional meaning of these granules is contrarily discussed in the literature. There was no epithelial activity of alkaline phosphatase. Against that a small positive reaction of adenosine triphosphatase was observed at the lateral plasmalemata of the epithelial cells. The sense of these findings with regard to the transport of substances in the equine large intestine is discussed.

Induction of P-450 in workers exposed to dioxin.

OBJECTIVES: To examine the effects of occupational exposure to substances contaminated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) on cytochrome P-4501A2 activity in a cross sectional medical survey. METHODS: The exposed workers had been employed at two chemical plants > 15 years earlier in the manufacture of 2,4, 5-trichlorophenol and its derivatives. The control group consisted of people with no occupational exposure to phenoxy herbicides and who lived within the communities of the exposed workers. A total of 58 workers and 125 unexposed controls participated in the analysis. Cytochrome P-450 activity was assessed with test that measures caffeine metabolites in the urine. A ratio of metabolites of caffeine (CMR) constituted a measure of P-4501A2 activity. RESULTS: Compared with the control group in multivariate logistic regression, raised non-significant associations were found for three of four categories of TCDD in exposed workers (TCDD < 20 pg/g, odds ratio (OR) 1.7, 95% confidence interval (95% CI) 0.6 to 5.0, TCDD 20-66, OR 0.3, 95% CI 0.0 to 1.7; TCDD 67-147, OR 2.3, 95% CI 0.6 to 8.8; TCDD > or = 148, OR 3.1, 95% CI 0.8 to 12.5). We found a strongly significant association of CMR and urinary cotinine, a measure of smoking, and urinary free ethanol. We found weak non-significant associations between P-4501A2 activity and increased serum TCDD among workers. CONCLUSIONS: The absence of an association between serum TCDD and cytochrome P-4501A2 may be due to the size of the study, insensitivity of the CMR to assess cytochrome P-4501A2 activity, or inadequate levels of exposure, although these were among the highest in human groups tested.

[Endocrine cells in the epithelium of the fetal large intestine of cattle (Bos primigenius taurus) from the cytomorphological aspect]. / Uber endokrine Zellen im fetalen Dickdarmepithel des Rindes (Bos primigenius taurus) unter zytomorphologischem Aspekt).

In the epithelium of the fetal bovine large intestine there are endocrine cells, predominantly at the base of the crypts. According to morphological characteristics, EC-cells and L-cells can be readily distinguished.

[Adenosine triphosphatases in the bovine endometrium and in the trophoblast during implantation. Microscopic and electron microscopic investigations (author's transl)]. / Adenosintriphosphatasen im bovinen Endometrium und im Trophoblasten während der Implantation Licht- und elektronenmikroskopische Untersuchungen.

Investigations of the bovine epithelium uteri and trophoblast between the 22nd and 24th day after insemination have been made according to the method of FARQUHAR and PALADE (1966) concerning the activity and microstructural localization of the Mg++-, Ca++- as well as the (Mg++-Na+-K+)-ATPases which may be made active (E. C. 3.6.1.3). The evidence of the ATPases in the so-called free cells during the pre-implantative stage is associated with a production of immunoglobulin A and thus the importance of these cells within the scope of an immunological position of reaction of the endometrium is being discussed. On the epithelium uteri there is a correlation at first between the activity of this hydrolase, which can only be proved at the later pre-contact stage, and the microstructural symptoms of increasing secretion. During the subsequent stage of apposition and after consolidated implantation ATPase-dependent transportations through membranes are likely to serve in the formation of hemotrophs as well as in the hemotroph metabolism. Finally, an attempt is made to give an explanation of the precipitate depositions on the cells of the uterine glands.

Alkaline phosphatase in the bovine endometrium and trophoblast during the early phase of implantation.

Alkaline phosphatase in the endometrial and chorionic epithelium from the 22nd to 24th day post insemination was investigated according to the method of Hugon and Borgers (1966a, b). In the precontact phase the reaction products of this enzyme were found light microscopically in the caruncular and intercaruncular area in the apical part of the uterine surface epithelium. Although a definite, continuing reaction line between the maternal and fetal epithelium was present in the apposition phase, there was no activity of this phospho-monoesterase ascertainable following consolidated adhesion. Independent of implantation, lead salt precipitate was observed in the apical cytoplasma in the upper third of the uterine epithelial glands. Electron microscopic investigations in the precontact phase demonstrated the localisation of the reaction products of this hydrolase as electron dense grains on the outer plasma lamella of the uterine microvilli. During apposition this reaction appeared on the microvilli of the dark uterine epithelium and the cell membrane of the trophoblast cells. In addition to the existence of alkaline phosphatase on the microvilli of the uterine glandular cells, reaction products were discernable in the kinocilia between the inner lamellar of their plasma membranes and the tubules ring, as well as between the latter and the central tubule pair. There is a possibility that this hydrolase plays a role in the transport of metabolites for the purpose of histiogenic uterine milk production.

Cytochemical establishment of acid phosphatase in the bovine endometrium and trophoblast during implantation.

Acid phosphatase in the endometrial surface epithelium is seen in connection with autophagy and autolysis. In the precontact and initial apposition stage, enzyme-positive Golgi vesicles, lysosomes and secretion granules all indicate autophage performance of the dark uterine epithelial cells in the sense of a histiogene embryotrophe development. At the time of progressing apposition this is joined by cell degradation with the aim of histiolytical uterine milk production. Following the completed implantation in the adhesion phase no activity with autophagy and autolysis-correlated acid phosphatase can be established. In trophoblast giant cells the localisation of acid phosphatase speaks for secretional processes. The incidence of this enzyme in the adhesion stage in "ordinary" trophoblast cells leads to the supposition of autophage processes which must be investigated in more detail. The endometrial gland epithelium shows the same acid phosphatase-dependent autophage indications in the upper third of the glands as shown in the surface epithelium prior to apposition. However, the acid phosphatase activity and the secretion deduced therefrom, thus the histiogene embryotrophe development, is conserved during the whole early gravidity of the cow, independent of the implantation process.