Tabakassoziierte Krebserkrankungen in Deutschland – Entwicklung der Inzidenz und Mortalität seit 1995

Background and Objectives

Tobacco consumption is the most important cancer risk factor. In Germany, about 15% of all new cancer cases can be attributed to smoking. The aim of this paper is to analyze the incidence and mortality trends in tobacco-associated cancer cases in Germany for the last two decades.

Materials and Methods

Age standardized incidence and mortality rates were calculated for tumors of the upper aerodigestive tract and lower urinary tract for the period from 1995 to 2014/2015. In addition, average annual percentage changes were calculated with joinpoint regression analysis. Regarding lung cancer, trends in incidence and mortality rates were also stratified by different age groups and trends in mortality rates were analyzed by birth cohorts.

Results

The incidence and mortality rates among men are declining for all tobacco-associated cancers except esophageal cancer. Lung cancer mortality rates showed the greatest decrease with ?1.9% on average per year. The incidence rates among women increased for all tobacco-associated cancers except lower urinary tract cancers. The increase in lung cancer incidence was greatest with 3.3% on average per year. Among men there was a continuous decline over all birth cohorts regarding the chance of dying of lung cancer at a certain age. Among women, the chance of dying of lung cancer increased for all birth cohorts until 1960.

Conclusions

The present analyses regarding tobacco-associated cancers in Germany reflect the changes in smoking prevalence with a deferment of multiple decades.

     

The role of Müller cell glucocorticoid signaling in diabetic retinopathy

Graefe's Archive for Clinical and Experimental Ophthalmology - Diabetic retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the...     

Molecular diagnosis of kidney transplant failure based on urine

In light of the organ shortage, there is a great responsibility to assess postmortal organs for which procurement has been consented and to increase the life span of transplanted organs. The former responsibility has moved many centers to accept extended criteria organs. The latter responsibility requires an exact diagnosis and, if possible, omission of the harmful influence on the transplant. We report the course of a kidney transplant that showed a steady decline of function over a decade, displaying numerous cysts of different sizes. Clinical workup excluded the most frequent causes of chronic transplant failure. The filed allocation documents mentioned the donor’s disease of oral‐facial‐digital syndrome, a rare ciliopathy, which can also affect the kidney. Molecular diagnosis was performed by culturing donor tubular cells from the recipient´s urine more than 10 years after transplantation. Next‐generation panel sequencing with DNA from tubular urinary cells revealed a novel truncating mutation in OFD1, which sufficiently explains the features of the kidney transplants, also found in the second kidney allograft. Despite this severe donor disease, lifesaving transplantation with good long‐term outcome was enabled for 5 recipients.     

TMPRSS2-ERG Fusions Are Strongly Linked to Young Patient Age in Low-grade Prostate Cancer

Based on next-generation sequencing of early-onset prostate cancer (PCa), we earlier demonstrated that PCa in young patients is prone to rearrangements involving androgen-regulated genes—such as transmembrane protease, serine 2 (TMPRSS2)–v-ets avian erythroblastosis virus E26 oncogene homolog (ERG) fusion—and provided data suggesting that this situation might be caused by increased androgen signaling in younger men. In the same study, an accumulation of chromosomal deletions was found in cancers of elderly patients. To determine how age-dependent molecular features relate to cancer phenotype, an existing data set of 11 152 PCas was expanded by additional fluorescence in situ hybridization analyses of phosphatase and tensin homolog (PTEN), 6q15 and 5q21. The results demonstrate that the decrease in TMPRSS2–ERG fusions with increasing patient age is limited to low-grade cancers (Gleason ≤3 + 4) and that the significant increase in the deletion frequency with age was strictly limited to ERG-negative cancers for 6q15 and 5q21 but to ERG-positive cancers for PTEN. These data suggest that the accumulation of non–androgen-linked genomic alterations with advanced patient age may require an appropriate microenvironment, such as a positive or negative ERG status. The strong link of ERG activation to young patient age and low-grade cancers may help to explain a slight predominance of low-grade cancers in young patients.     

Population pharmacokinetics of artesunate and dihydroartemisinin during long-term oral administration of artesunate to patients with metastatic breast cancer

Purpose

The purpose of this study were firstly to characterize the population pharmacokinetics of artesunate (ARS) and its active metabolite dihydroartemisinin (DHA) in patients with metastatic breast cancer during long-term (>3 weeks) daily oral ARS administration and secondly to study the relationship between salivary and plasma concentrations of DHA.

Methods

Drug concentration-time data from 23 patients, receiving oral ARS (100, 150, or 200 mg OD), was analyzed using nonlinear mixed effects modeling. A combined drug-metabolite population pharmacokinetic model was developed to describe the plasma pharmacokinetics of ARS and DHA in plasma. Saliva drug concentrations were incorporated as being directly proportional to plasma concentrations.

Results

A first-order absorption model for ARS linked to a combined two-compartment disposition model for ARS and one-compartment disposition model for DHA provided the best fit to the data. No covariates were identified that could explain between-subject variability. A time-dependent increase in apparent elimination clearance of DHA was observed. Salivary DHA concentrations were proportionally correlated with total DHA plasma concentrations, with an estimated slope factor of 0.116.

Conclusions

Population pharmacokinetics of ARS and DHA in patients with breast cancer was well described by a combined drug-metabolite model without any covariates and with an increase in apparent elimination clearance of DHA over time. The estimated DHA saliva/plasma ratio was in good agreement with the reported DHA unbound fraction in human plasma. Saliva ARS concentrations correlated poorly with plasma concentrations. This suggests the use of saliva sampling for therapeutic drug monitoring of DHA. However, further studies are warranted to investigate the robustness of this approach.     

Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination

Myelin/oligodendrocyte glycoprotein (MOG) is a target antigen for myelin-destructive Abs in autoimmune central nervous system demyelinating disorders. Little is known about the molecular and structural basis of these pathogenic Ab responses. Here, we have characterized anti-MOG Ab specificities in the marmoset model of experimental allergic encephalomyelitis, by means of a combinatorial IgG-Fab library. We found that a diverse population of Ig genes encodes for auto-Abs that exclusively recognize conformation-dependent antigenic targets on MOG. These antigenic domains correspond to exposed epitopes in vivo, as the Fab fragments recognize native MOG in situ in marmoset brain tissue. The Ab fragments described here represent Ab specificities that are common constituents of the humoral immune repertoire against MOG in outbred populations, as demonstrated by their ability to displace native anti-MOG Abs present in sera from MOG-immune marmosets and patients with multiple sclerosis. Furthermore, neuropathological analysis and characterization of Ab epitope specificities in animals immunized with MOG or MOG-derived peptides revealed that only conformation-dependent Abs are associated with demyelinating activity, suggesting that epitope recognition is an important factor for Ab pathogenicity. Our findings provide novel and unexpected knowledge on the diversity of anti-MOG Ab responses in nonhuman primates and humans, and will permit the dissection of pathogenic auto-Ab properties in multiple sclerosis.     

Nationwide analysis on surgical procedures for patients with endometrial cancer in Germany: Results of the AGO pattern of care studies from the years 2013, 2009, and 2006

Purpose

In 2013, 2009, and 2006, the Arbeitsgemeinschaft Gynäkologische Onkologie evaluated the therapeutic approaches and the adherence to their guidelines for endometrial carcinoma (EC) in Germany. Here, we present the results concerning the surgical procedures.

Methods

A questionnaire was developed and sent to 682 German gynecological departments in 2013 (775 in 2009 and 500 in 2006). The results were compared with the recommendations of the guideline and with each other.

Results

Responses were available in 40.0 % in 2013, 33.3 % in 2009, and 35.8 % in 2006, respectively. Pelvic lymphadenectomy (LAN) was performed in accordance with the guidelines with some exceptions in 2013, 2009, and 2006, whereas paraaortic LAN was performed in accordance with the guideline only in 2009. Histological high-risk subtypes of EC received pelvic and paraaortic LAN in 2013, 2009, and 2006 in accordance with the guidelines with small exceptions. LAN for Patients, who were postoperatively upstaged or upgraded, was not conducted in accordance with the guidelines in 2013, 2009, and 2006. In 2013, 84.6 % of the participants offered the laparoscopic approach (LSA) for hysterectomy and bilateral salpingo-oophorectomy, 63.3 % for pelvic LAN, and 49.1 % for paraaortic LAN, respectively. More participants offered the LSA in 2013 compared to 2009 and 2006 (p values <0.014).

Conclusions

The paraaortic LAN was the second operation on patients, who are postoperatively upstaged, and the LSA was not conducted in accordance with the guideline. Improvements concerning surgical treatment are possible and might lead to higher survival rates and a reduction of morbidity in patients with EC in Germany.     

PROTEIN DISULFIDE ISOMERASE LIKE 5-1 is a susceptibility factor to plant viruses

Protein disulfide isomerases (PDIs) catalyze the correct folding of proteins and prevent the aggregation of unfolded or partially folded precursors. Whereas suppression of members of the PDI gene family can delay replication of several human and animal viruses (e.g., HIV), their role in interactions with plant viruses is largely unknown. Here, using a positional cloning strategy we identified variants of PROTEIN DISULFIDE ISOMERASE LIKE 5–1 (HvPDIL5-1) as the cause of naturally occurring resistance to multiple strains of Bymoviruses. The role of wild-type HvPDIL5-1 in conferring susceptibility was confirmed by targeting induced local lesions in genomes for induced mutant alleles, transgene-induced complementation, and allelism tests using different natural resistance alleles. The geographical distribution of natural genetic variants of HvPDIL5-1 revealed the origin of resistance conferring alleles in domesticated barley in Eastern Asia. Higher sequence diversity was correlated with areas with increased pathogen diversity suggesting adaptive selection for bymovirus resistance. HvPDIL5-1 homologs are highly conserved across species of the plant and animal kingdoms implying that orthologs of HvPDIL5-1 or other closely related members of the PDI gene family may be potential susceptibility factors to viruses in other eukaryotic species.Infectious diseases caused by plant viruses threaten agricultural productivity and reduce globally attainable agricultural production by about 3% (1). In specific pathosystems, plant viruses can result in the loss of the entire crop. For example, the devastation of cassava production by cassava mosaic geminiviruses (CMGs) in Uganda during the 1990s led to widespread food shortages and famine-related deaths (2). Unfortunately protecting plants against viruses (especially soil-borne viruses) by using agrochemicals to control virus vectors is seldom efficient from economic or ecological perspectives. Therefore, crop protection based on naturally occurring virus resistance is key to minimizing losses and achieving sustainable crop yields.Positive-strand RNA viruses represent the largest group of plant viruses (3). They cause a very high proportion of the important infectious virus diseases in agriculture (4, 5). Such plant viruses carry a reduced genome that encodes a limited set of functional proteins (4–10 viral proteins)—insufficient to complete the entire virus replication and proliferation cycle (6). Instead, over evolutionary time, viruses recruited host factors to perform the infectious life cycle (7). This dependence on host factors establishes a possibility that plants can evolve escape, tolerance, or resistance mechanisms to ameliorate the consequences of viral infection. The absence of essential host factors could interfere with the infection process or restrict proliferation (8) leading to either mono- or polygenic recessive resistance (5). Prominent examples of such susceptibility factors that are conserved in multiple plant–virus systems are the EUKARYOTIC TRANSLATION INITIATION FACTORS (EIF)4E, iso4E, 4G, and iso4G (9). Translation initiation factors may interact directly with viral RNA where they catalyze the initiation of translation of viral polyproteins (10, 11). In addition, to establish replication and assembly complexes during infection, viruses typically create membrane-bound environments, referred to as “virus factories” (12). There, cellular chaperones such as HSP70 and DNAJ-like proteins likely contribute to the correct folding and translocation of substrates (12, 13). However, only a few such host factors are known (7, 9, 14).Barley yellow mosaic virus disease caused by barley yellow mosaic virus (BaYMV) and barley mild mosaic virus (BaMMV) (both belong to Bymoviruses) seriously threatens winter barley production in Europe and East Asia (4). Infection leads to yellow discoloration and stunted growth and may result in yield loss of up to 50% (15). Soil-borne transmission via the plasmodiophorid Polymyxa graminis prohibits plant protection by chemical measures, and breeding for resistant cultivars is therefore the only practicable way to prevent yield loss. The naturally occurring recessive resistance locus rym11 confers complete broad-spectrum resistance to all known European isolates of BaMMV and BaYMV (16–19). In the present study, we used a positional cloning strategy to identify the gene underlying rym11-based resistance. We show that it is a susceptibility factor belonging to a gene family of PROTEIN DISULFIDE ISOMERASES (PDIs), and is highly conserved across eukaryotic species. We observe a strong correlation between natural allelic variation and geographic distribution, suggesting that both the origin and subsequent adaptive selection for rym11-based resistance in winter barley occurred in East Asia.