Association of Early Postoperative Regional Oxygen Saturation Measures and Development of Necrotizing Enterocolitis in Neonates Following Cardiac Surgery.

Necrotizing enterocolitis (NEC) is a relatively common complication in neonates with single ventricle physiology following heart surgery. Near-infrared spectroscopy (NIRS) is used to measure regional oxygen saturations in neonates in the postoperative period. We sought to investigate the association of somatic regional oxygen saturation (srSO2) and cerebral regional oxygen saturation (crSO2) in the early postoperative period and the subsequent development of NEC. We performed a retrospective cohort study of neonates who underwent cardiac surgery with cardiopulmonary bypass from October 2017 to September 2021 at the University of Virginia Children's Hospital. Values of srSO2 and crSO2 were captured over the first 48 h following surgery. 166 neonates were included and the median age at time of surgery was 8 days. NEC was diagnosed in 18 neonates following heart surgery with a median interval from surgery to diagnosis of 7 days. Neonates with single ventricle physiology had lower average crSO2 (62% vs 78%, p < 0.001), average srSO2 (72% vs 86%, p < 0.001), average crSO2 to srSO2 ratio (0.874 vs 0.913, p < 0.001), and an increased average srSO2-crSO2 difference (10% vs 8%, p = 0.03). Adjusting for single ventricle physiology, lower average crSO2 was associated with the development of definite NEC (modified Bell's criteria stage IIa and higher) (OR = 0.86, 95% CI 0.78-0.96, p = 0.007). Lower crSO2 values in the early postoperative period in neonates following cardiac surgery was associated with an increased risk in the subsequent development of NEC.

Targeting the complexity of ERBB2 biology in gastroesophageal carcinoma.

ERBB2 is the most prominent therapeutic target in gastroesophageal adenocarcinoma (GEA). For two decades, trastuzumab was the only treatment available for GEA overexpressing ERBB2. Several drugs showing evidence of efficacy over or in complement to trastuzumab in breast cancer failed to show clinical benefit in GEA. This resistance to anti-ERBB2 therapy is peculiarly recurrent in GEA and is mostly due to tumor heterogeneity with the existence of low expressing ERBB2 tumor clones and loss of ERBB2 over time. The development of new ERBB2 testing strategies and the use of antibody-drug conjugates having a bystander effect are providing new tools to fight heterogeneity in ERBB2-positive GEA. Co-amplifications of tyrosine kinase receptors, alterations in mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways and in proteins controlling cell cycle are well known to contribute resistance to anti-ERBB2 therapy, and they can be targeted by dual therapy. Recently described, NF1 mutations are responsible for Ras phosphorylation and activation and can also be targeted by MEK/ERK inhibition along with anti-ERBB2 therapy. Multiple lines of evidence suggest that immune mechanisms involving antibody-dependent cell-mediated cytotoxicity are preponderant over intracellular signaling in anti-ERBB2 therapy action. A better comprehension of these mechanisms could leverage immune action of anti-ERBB2 therapy and elucidate efficacy of combinations associating immunotherapy and anti-ERBB2 therapy, as suggested by the recent intermediate positive results of the KEYNOTE-811 trial.

Relevance of biopsy-derived pancreatic organoids in the development of efficient transcriptomic signatures to predict adjuvant chemosensitivity in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients are frequently treated by chemotherapy. Even if personalized therapy based on molecular analysis can be performed for some tumors, PDAC regimens selection is still mainly based on patients' performance status and expected efficacy. Therefore, the establishment of molecular predictors of chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. We have recently developed an RNA-based signature that predicts the efficacy of adjuvant gemcitabine using 38 PDAC primary cell cultures. While demonstrated its efficiency, a significant association with the classical/basal-like PDAC spectrum was observed. We hypothesized that this flaw was due to the basal-like biased phenotype of cellular models used in our strategy. To overcome this limitation, we generated a prospective cohort of 27 consecutive biopsied derived pancreatic organoids (BDPO) and include them in the signature identification strategy. As BDPO's do not have the same biased phenotype as primary cell cultures we expect they can compensate one with each other and cover a broader range of molecular phenotypes. We then obtained an improved signature predicting gemcitabine sensibility that was validated in a cohort of 300 resected PDAC patients that have or have not received adjuvant gemcitabine. We demonstrated a significant association between the improved signature and the overall and disease-free survival in patients predicted as sensitive and treated with adjuvant gemcitabine. We propose then that including BDPO along primary cell cultures represent a powerful strategy that helps to overcome primary cell cultures limitations producing unbiased RNA-based signatures predictive of adjuvant treatments in PDAC.

[Analysis of the skin cancer incidence in Hamburg]. / Untersuchung der Hautkrebshäufigkeit in Hamburg.

BACKGROUND: The aim of health geographical research is to identify regional variations in health and care and their causes. Regional differences are also evident in skin cancer incidence, but knowledge about small-scale, inner-city variations is not yet available. OBJECTIVES: How can the inner-city variations in skin cancer incidence in Hamburg, Germany, be described and how can initial indications of their causes be identified? METHODS: The study area is the city of Hamburg and the data source is the Hamburg City Health Study with N = 10,000 persons aged 45-74 years. Descriptive methods are used to characterise the regional variation in skin cancer prevalence adjusted for age and sex. A correlation analysis provides information on possible associations with sociodemographic conditions in the city districts and district clusters. RESULTS: Skin cancer prevalence varies within the urban area with high prevalences (maximum 13.8%) in the north-east and south-west of Hamburg. Weak to medium correlations with selected sociodemographic variables are found. For example, the higher the living space per inhabitant (r = 0.35), the higher the skin cancer prevalence in the district. CONCLUSIONS: The Hamburg City Health Study shows regional and inner-city disparities and possible associations between skin cancer prevalence and local sociodemographic conditions. However, further and methodologically more extensive studies are necessary in order to make detailed statements.

[Methods for analysing spatial data : Using the example of skin cancer prevalence in Germany]. / Methoden zur Analyse räumlicher Daten : Beispiel der regionalen Hautkrebsprävalenz in Deutschland.

BACKGROUND: Studies show a spatial variation in skin cancer frequencies, but the causes have not been fully understood. When analysing spatial patterns and correlations, different approaches need to be considered, as the data have special features due to their spatial structure. AIM OF THE STUDY: Why the spatial consideration of skin cancer frequencies is important at all, and which methods of analysis are useful is considered in more detail in this article. The article provides an introduction and overview of statistical methods that are important for the spatial analysis of skin cancer frequencies. MATERIALS AND METHODS: At first it is shown which descriptive methods, such as statistical smoothing, can be applied. Next, spatial cluster and regression analyses will be discussed. Testing for spatial autocorrelation will be considered. RESULTS: In particular, the spatial dependence of the data on neighbouring regions, which if ignored can lead to biased estimates, is of particular importance in the analysis of spatial data and requires special spatial analysis methods. DISCUSSION: This article provides an introduction and overview of statistical methods relevant to the spatial analysis of skin cancers.

A transcriptomic signature to predict adjuvant gemcitabine sensitivity in pancreatic adenocarcinoma.

BACKGROUND: Chemotherapy is the only systemic treatment approved for pancreatic ductal adenocarcinoma (PDAC), with a selection of regimens based on patients' performance status and expected efficacy. The establishment of a potent stratification associated with chemotherapeutic efficacy could potentially improve prognosis by tailoring treatments. PATIENTS AND METHODS: Concomitant chemosensitivity and genome-wide RNA profiles were carried out on preclinical models (primary cell cultures and patient-derived xenografts) derived from patients with PDAC included in the PaCaOmics program (NCT01692873). The RNA-based stratification was tested in a monocentric cohort and validated in a multicentric cohort, both retrospectively collected from resected PDAC samples (67 and 368 patients, respectively). Forty-three (65%) and 203 (55%) patients received adjuvant gemcitabine in the monocentric and the multicentric cohorts, respectively. The relationships between predicted gemcitabine sensitivity and patients' overall survival (OS) and disease-free survival were investigated. RESULTS: The GemPred RNA signature was derived from preclinical models, defining gemcitabine sensitive PDAC as GemPred+. Among the patients who received gemcitabine in the test and validation cohorts, the GemPred+ patients had a higher OS than GemPred- (P = 0.046 and P = 0.00216). In both cohorts, the GemPred stratification was not associated with OS among patients who did not receive gemcitabine. Among gemcitabine-treated patients, GemPred+ patients had significantly higher OS than the GemPred-: 91.3 months [95% confidence interval (CI): 61.2-not reached] versus 33 months (95% CI: 24-35.2); hazard ratio 0.403 (95% CI: 0.221-0.735, P = 0.00216). The interaction test for gemcitabine and GemPred+ stratification was significant (P = 0.0245). Multivariate analysis in the gemcitabine-treated population retained an independent predictive value. CONCLUSION: The RNA-based GemPred stratification predicts the benefit of adjuvant gemcitabine in PDAC patients.

Regional variations in the use of statutory skin cancer screenings in Germany: population-based spatial multisource analysis.

BACKGROUND: Due to the increasing incidence of skin cancer, programmes for the prevention of skin cancer have been developed and implemented in Germany. However, utilization of skin cancer screenings shows marked regional differences. Reasons and predictors of such variations are unclear. OBJECTIVES: The objective of the study is to identify predictors for regional use of skin cancer screening variations in Germany. METHODS: Analysis of the population set of ambulatory claims data (2009-2015) of the statutory health insurances (SHI) in Germany (70.2 million people in 2015). Skin cancer screening utilization rate was determined on county level. Descriptive, cluster and multivariate analyses were performed to identify spatial patterns in skin cancer screening utilization. RESULTS: Overall, 6.5-7.9 million people participated in skin cancer screenings. Utilization rates of people ≥35 years of age were 9.74% (2009) and 10.96% (2015). Marked regional variations were identified between the counties. Dermatologists in Saxony and Westphalia-Lippe as well as general practitioners in Lower Saxony and North Rhine showed particularly high utilization rates. Multiple regression analyses demonstrated e.g. positive associations between the skin cancer screening utilization rates and employees with higher vocational qualifications and shorter travel time by car to the nearest major urban centre. CONCLUSION: Utilization rates of skin cancer screening vary largely in Germany with specific spatial patterns. Multivariate analyses demonstrate associations with socio-economic and geographical determinants. The results indicate the importance of health policy measures. These should be used in a more targeted manner in the regions in order to increase utilization of skin cancer screening.

[Real world data sources for health services research on skin cancer]. / Real-world-Datenquellen für die Versorgungsforschung zum Hautkrebs.

Health services research in dermatology with the objective to improve prevention, efficient diagnostics and treatment of skin cancer requires real world data from all sectors. This article provides an overview of currently available relevant real world data sources and the utilization potential. It lists exemplary results of existing studies: secondary data analyses based on billing data from statutory health insurance funds were used among other things to estimate the participation rate in the statutory skin cancer screening. This was approximately 31% in the 2­year period and was higher in the western German federal states than in the eastern ones. Furthermore, participation was higher for women than for men. Regional data in combination with sociostructural and sociodemographic indicators are available for planning of dermatological care and the analysis points to an association with the prevalence of skin cancer. Primary data are available and necessary for recording patient reported endpoints and evaluating the treatment of skin cancer patients by dermatologists. Extensive histopathological databases record not only clinical markers of skin cancer but also sociodemographic characteristics of the patients and indicate a correlation between the time of diagnosis or therapy and the insurance status and place of residence. In addition to the utilization potential, specific limitations of the data sources are listed.

Gas and seismicity within the Istanbul seismic gap.

Understanding micro-seismicity is a critical question for earthquake hazard assessment. Since the devastating earthquakes of Izmit and Duzce in 1999, the seismicity along the submerged section of North Anatolian Fault within the Sea of Marmara (comprising the "Istanbul seismic gap") has been extensively studied in order to infer its mechanical behaviour (creeping vs locked). So far, the seismicity has been interpreted only in terms of being tectonic-driven, although the Main Marmara Fault (MMF) is known to strike across multiple hydrocarbon gas sources. Here, we show that a large number of the aftershocks that followed the M 5.1 earthquake of July, 25th 2011 in the western Sea of Marmara, occurred within a zone of gas overpressuring in the 1.5-5 km depth range, from where pressurized gas is expected to migrate along the MMF, up to the surface sediment layers. Hence, gas-related processes should also be considered for a complete interpretation of the micro-seismicity (~M < 3) within the Istanbul offshore domain.

Epidemiology of skin cancer in the German population: impact of socioeconomic and geographic factors.

BACKGROUND: Skin cancer being the most common cancer in Germany has shown increasing incidence in the past decade. Since mostly caused by excessive UV exposure, skin cancer is largely related to behaviour. So far, the impact of regional and sociodemographic factors on the development of skin cancer in Germany is unclear. OBJECTIVES: This study aimed to investigate the association of potential predictive factors with the prevalence of skin cancers in Germany. METHODS: Nationwide ambulatory care claims data from persons insured in statutory health insurances (SHI) with malignant melanoma (MM, ICD-10 C43) and non-melanocytic skin cancer (NMSC, ICD-10 C44) in the years 2009-2015 were analysed. In addition, sociodemographic population data and satellite-based UV and solar radiation data were associated. Descriptive and multivariate (spatial) statistical analyses (e.g. Bayes' smoothing) were conducted on county level. RESULTS: Data from 70.1 million insured persons were analysed. Age-standardized prevalences per 100 000 SHI insured persons for MM and NMSC were 284.7 and 1126.9 in 2009 and 378.5 and 1708.2 in 2015. Marked regional variations were observed with prevalences between 32.9% and 51.6%. Multivariate analysis shows among others statistically significant positive correlations between higher income and education, and MM/NMSC prevalence. CONCLUSION: Prevalence of MM and NMSC in Germany shows spatio-temporal dynamics. Our results demonstrate that regional UV radiation, sunshine hours and sociodemographic factors have significant impact on skin cancer prevalence in Germany. Individual behaviour obviously is a major determinant which should be subject to preventive interventions.

Concurrent hydrocelectomy during inguinal herniorrhaphy is a risk factor for complications and reoperation: data from rural Haiti.

PURPOSE: Series of conventional inguinal herniorrhaphy from low and middle income countries (LMICs) suggest elevated rates of morbidity, mortality, and recurrence, although the reasons remain incompletely understood. We sought to identify risk factors for adverse outcomes from inguinal herniorrhaphy performed in a resource-limited LMIC setting. METHODS: We performed mesh-free modified Bassini inguinal herniorrhaphies on 141 consecutive patients with 156 inguinal hernias over 10 months in rural Haiti. We prospectively followed these patients for complications. RESULTS: No intraoperative or perioperative deaths occurred. Follow-up was poor, with 20 patients (14%) returning after discharge. 14 complications were identified in 11 patients, yielding an identified complication rate per herniorrhaphy of 9%. Five complications required reoperation, for an overall reoperative complication rate per herniorrhaphy of 3%. Reoperative complications included one postoperative hemorrhage, one persistent painful cord mass, and three infected hematomas or seromas. On univariate analysis, trends towards complication and need for reoperation were noted with concurrent repair of an ipsilateral hydrocele (OR 4.5, p = 0.300, for complication; OR 9.0, p = 0.115, for reoperative complication). CONCLUSIONS: In rural Haiti, we found that adding ipsilateral hydrocele repair to inguinal herniorrhaphy may elevate the risk of both complications and need for reoperation. This previously unreported association is of high relevance to surgical practice across tropical LMICs, where concurrent inguinal hernia and hydrocele is common.

[Risk characteristics and survival rates of malignant melanoma in Germany and the Netherlands]. / Risikomerkmale und Überlebensrate des malignen Melanoms in Deutschland und den Niederlanden.

BACKGROUND: Mortality and lethality of malignant melanoma (MM) show marked variations throughout Europe, thereunder a higher risk within the Netherlands (NL) when compared to Germany (D). GOAL AND METHODS: Comparison of systems and exploration of possible causal factors that could explain the difference between D and NL. Comparative healthcare research analysis using published international literature, as well as publicly accessible databases, and a subsequent hypothesis-generating analysis. RESULTS: The higher rate of excised MM less than 1 mm in diameter in D (65 % vs. 45 %) confirms the clinical reports of the cancer registries. The biological factors for the emergence of MM, such as skin type, do not seem to significantly differ from each other. Among the further potential predictors there are no relevant differences within, for example, geographical conditions and the qualifications of the treating physicians. Primary prevention has a longer continual tradition in D. Here, secondary prevention is characterized by population-based extensive screening, which does not occur within the NL. In addition, distinct differences are found regarding access to dermatologists. CONCLUSION: System access to a medical specialist and the prevention of skin cancer are currently the most distinctive potential determinants of more favorable MM survival rate in Germany.

[Regional differences in the health care of basal cell carcinoma]. / Regionale Unterschiede in der Versorgung des Basalzellkarzinoms.

BACKGROUND: Basal cell carcinoma (BCC) is the most common type of skin cancer in Germany. So far, it is unclear whether regional variations exist in the health care of the BCC. OBJECTIVES: Analysis of regional variations in health care (e. g., skin cancer screening) and their causes using the example of BCC. MATERIALS AND METHODS: Qualitative and quantitative analysis of the regional health care situation of BCC based on three studies was undertaken. These studies include the analysis of n = 7015 histopathological indications whose average tumor thickness is regarded as a characteristic of the quality of care, and a secondary data analysis of GK insured (n = 6.1 million DAK-insured persons), and a nationwide survey (FORSA) of n = 1004 participants focusing on the use of skin cancer screening. RESULTS: Analysis of the histopathological examination showed regional variations in average tumor depth of penetration. These are associated with the rural/urban characteristics of the region and individual sociodemographic indicators (e. g., employment sector or education). The results for age- and gender-specific use (DAK data) showed higher participation rates regarding skin cancer screening in western than in eastern federal states (Bundesländer). Moreover, it was revealed that the trend for using skin cancer screening was higher in urban than in rural areas. The results of population-related surveys confirm this trend. CONCLUSION: Although it is not possible to compare the studies directly, all three showed an association between city/state and the use of skin cancer screenings. In addition, sociodemographic characteristics that are related to the quality of health care were identified.

Mortality risk in symptomatic patients with nonobstructive coronary artery disease: a prospective 2-center study of 2,583 patients undergoing 64-detector row coronary computed tomographic angiography.

OBJECTIVES: We examined mortality risk in relation to extent and composition of nonobstructive plaques by 64-detector row coronary computed tomographic angiography (CCTA). BACKGROUND: The prognostic significance of nonobstructive coronary artery plaques by CCTA is poorly understood. METHODS: We prospectively evaluated consecutive adults from 2 centers undergoing 64-detector row CCTA without prior documented coronary artery disease (CAD) and without obstructive (≥50%) CAD by CCTA. Luminal diameter stenosis severity was classified for each segment as none (0%) or mild (1% to 49%), and plaque composition was classified as noncalcified, calcified, or mixed. RESULTS: During 3.1 ± 0.5 years, 54 intermediate-term (≥90 days) deaths occurred among 2,583 patients (2.09%), with 4 early (<90 days) deaths. Adjusted for CAD risk factors, the presence of any nonobstructive plaque was associated with higher mortality (hazard ratio [HR]: 1.98, 95% confidence Interval [CI]: 1.06 to 3.69, p = 0.03), with the highest risk among those exhibiting nonobstructive CAD in 3 epicardial vessels (HR: 4.75, 95% CI: 2.10 to 10.75, p = 0.0002) or ≥5 segments (HR: 5.12, 95% CI: 2.16 to 12.10, p = 0.0002). Higher mortality for nonobstructive CAD was observed even among patients with low 10-year Framingham risk (3.4%, p < 0.0001) as well as those with no traditional, medically treatable CAD risk factors, including diabetes mellitus, hypertension, and dyslipidemia (6.7%, p < 0.0001). No independent relationship between plaque composition and incident mortality was observed. Importantly, patients without evident plaque experienced a low rate of incident death during follow-up (0.34%/year). CONCLUSIONS: The presence and extent of nonobstructive plaques augment prediction of incident mortality beyond conventional clinical risk assessment.

[Epidemiology of psoriasis in Germany--analysis of secondary health insurance data]. / Epidemiologie der Psoriasis in Deutschland--Auswertung von Sekundärdaten einer gesetzlichen Krankenversicherung.

BACKGROUND: In Germany, population-based data on the epidemiology of psoriasis are still rare. This study aims to assess the prevalence of psoriasis in the total population as well as for subgroups relevant to health care. As further epidemiological parameters the severity and regional distribution of psoriasis were analysed. METHODS: A secondary analysis of data collected routinely for the members of a nationwide statutory health insurance company was conducted. Prevalences were calculated for a closed cohort of continuously insured persons in 2005. Defined criteria for the existence of psoriasis were at least one diagnoses of psoriasis (ICD-10) relating to ambulatory or hospital treatment or disability. RESULTS: 33,981 of the 1,344,071 continuously insured persons in 2005 were diagnosed with psoriasis, thus the one-year-prevalence in this cohort was 2.53%. Up to the age of 80 years the prevalence rate was increasing with increasing age and highest for the age groups from 50 to 79 years (range: 3.99-4.18%). Insured persons up to 20 years had a prevalence of 0.73%. Regional differences showed up after stratification for broad categories (1 digit) of ZIP codes: Lowest prevalence rates were seen in the south (2.17%) and highest (2.78%) in the north and western regions of Germany. CONCLUSIONS: If the prevalence rate of 2.5% assessed in this study is applied to the total resident population, 2 million people are treated because of psoriasis in Germany. Routine data from health insurance companies are a relevant and suitable data source to assess the prevalence of chronic diseases (under medical treatment) in the population.

[Bilateral chronic subdural hematoma: spontaneous intracranial hypotension?]. / Hématome sous-dural chronique bilatéral: une hypotension intracrânienne spontanée?

We report a case of bilateral chronic subdural hematoma (SDH) in a 48-year-old man, who presented with postural headaches, tinnitus and progressive confusion without intoxication, head trauma or abnormal hemostasis. Magnetic resonance imaging revealed cerebellar tonsillar herniation in the foramen magnum and a deformation of the brainstem. Outcome was normal after surgery. We discuss about the rare causes of SDH in young adults.

Case report: malignant teratoma in the thyroid gland.

Malignant teratomas of the thyroid gland are rare. These are highly malignant tumours with a high frequency of local recurrence and metastases following surgery. We report a case of malignant teratoma of the thyroid gland in a 35-year-old female, who developed local recurrence immediately following total thyroidectomy. Despite achieving local control following chemotherapy and local radiotherapy, the patient developed distant relapse illustrating the aggressive nature of the disease.

Studies on the in vitro and in vivo genotoxicity of [2,2-dimethyl-6- (4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5-yl]-acetic acid.

[2,2-Dimethyl-6-(4-chlorophenyl)-7-phenyl-2,3-dihydro-1H-pyrrolizine-5- yl]-acetic acid (CAS 156897-06-2, ML 3000) was examined for genotoxic activity in bacteria and mammalian cells in vitro as well as in vivo. The substance did not increase gene mutation frequencies either in a bacterial system or in a cultured V79 cell line of the Chinese hamster. Both in vitro tests were conducted in the presence and absence of S9-mix. In the unscheduled DNA synthesis assay in vitro with primary rat hepatocytes, negative results were also obtained. A cytogenetic analysis of the bone marrow of male and female Wistar rats was performed. After oral application ML 3000 did not increase the number of cells with structural chromosomal aberrations. The results suggest that ML 3000 has no genotoxic potential in vitro and in vivo.