Genetic background influences susceptibility to chemotherapy-induced hematotoxicity.

Hematotoxicity is a life-threatening side effect of many chemotherapy regimens. Although clinical factors influence patient responses, genetic factors may also play an important role. We sought to identify genomic loci that influence chemotherapy-induced hematotoxicity by dosing Diversity Outbred mice with one of three chemotherapy drugs; doxorubicin, cyclophosphamide or docetaxel. We observed that each drug had a distinct effect on both the changes in blood cell subpopulations and the underlying genetic architecture of hematotoxicity. For doxorubicin, we mapped the change in cell counts before and after dosing and found that alleles of ATP-binding cassette B1B (Abcb1b) on chromosome 5 influence all cell populations. For cyclophosphamide and docetaxel, we found that each cell population was influenced by distinct loci, none of which overlapped between drugs. These results suggest that susceptibility to chemotherapy-induced hematotoxicity is influenced by different genes for different chemotherapy drugs.

[Prevalence and risk factors of drug induced liver disease: a survey based study in pharmacies]. / Häufigkeit und Risikofaktoren medikamentös-toxischer Leberschäden: eine umfragebasierte Studie in Apotheken.

AIM: The reported incidence of drug-induced liver injury (DILI) ranges from 1 in 10,000 to 1 in 100,000 patients for most drugs, but the true incidence is expected to be much higher. Several risk factors for DILI susceptibility have been suggested, however there is insufficient data to define an individual risk profile. Therefore it was our aim to study the prevalence of DILI and potential risk factors within adult pharmacy customers in Germany. METHODS: We conducted two 6 week-survey studies in 30 pharmacies in 2011 and 2012, respectively, using a newly developed questionnaire comprising questions on demography, (liver) diseases, liver enzyme activities, and drug history. In each study, anonymized questionnaires were presented to non-selected adult customers taking (non-)prescription drugs. RESULTS: Combining the datasets from the 2011 and 2012 surveys, in total 1098 questionnaires were evaluated (mean age 57.7 ±â€Š17.1 years; 62.6 % females, return rate 15.25 %). Overall, 141 individuals (12.8 %) reported elevated liver enzymes due to drugs, in 65 cases (5.9 %) the medication had to be stopped, and 20 customers (1.8 %) reported that they had been admitted to hospital due to DILI. Compared to individuals without adverse hepatic drug reactions (n = 957), the 141 persons with potential DILI presented more often the following risk factors in multivariate analysis: chronic liver disease (14.4 % vs. 2.4 %, odds ratio [OR] 4.2, 95 % confidence interval [CI] 2.0 - 9.0), chronic renal insufficiency (20.0 vs. 6.8 %, OR 2.2, 95 % CI 1.3 - 3.7), diabetes (34 vs. 15.3 %, OR 2.0, 95 % CI 1.3 - 3.2), family history of chronic liver disease (19.9 vs. 7.7 %, OR 2.1, 95 % CI 1.2 - 3.6), and continuous drug intake for more than 5 years (80.9 vs. 59.3 %, OR 2.1, 95 % CI 1.3 - 3.5). CONCLUSION: These studies show an unexpected high prevalence of DILI in pharmacy customers and identify multiple potential risk factors.

A genetic variant in the promoter of phosphate-activated glutaminase is associated with hepatic encephalopathy.

BACKGROUND: Hepatic encephalopathy (HE) is a serious complication of liver cirrhosis. Recently, a microsatellite in the promoter region of the phosphate-activated glutaminase (GLS ) gene was associated with the risk of HE. The aim of the present study was to investigate, using the critical flicker frequency (CFF) test, whether the described GLS variant increases the risk of developing HE in patients with cirrhosis. METHODS: We recruited 158 patients (66% men; mean age 59 years, range 23-86) with liver cirrhosis. Mean model for end-stage liver disease score was 13.8 (range 5-35); 48% of patients presented with Child-Pugh score B or C. The presence and severity of HE were determined by the CFF test, with frequencies ≤39 Hz denoting cases. GLS variants were genotyped by sequencing the microsatellite in the promoter region and were classified as short, long or short-long forms (depending on the length of the macrosatellite alleles). RESULTS: In total, 53% of patients had abnormal CFF results (i.e. ≤39 Hz; range for entire cohort 26-57). The GLS microsatellite distribution amongst patients was short form (20%), long form (32%) and short-long form (48%) and was consistent with Hardy-Weinberg equilibrium. CFF values differed significantly between groups (P = 0.043). Carriers of the GLS long microsatellite had a significantly higher risk of HE according to multivariate analyses (odds ratio 3.23, 95% confidence interval 1.46-7.13, P = 0.004). CONCLUSION: CFF results were significantly lower amongst carriers of the GLS long microsatellite. Our findings support the role of the GLS long microsatellite in the development of HE; this could be important for identifying susceptible patients and for the prevention of this condition.

The number needed to treat to prevent mortality and cirrhosis-related complications among patients with cirrhosis and HCV genotype 1 infection.

Cirrhotic patients with chronic hepatitis C virus (HCV) infection remain at risk for complications following sustained virological response (SVR). Therefore, we aimed to evaluate treatment efficacy with the number needed to treat (NNT) to prevent clinical endpoints. Mortality and cirrhosis-related morbidity were assessed in an international multicentre cohort of consecutively treated patients with HCV genotype 1 infection and cirrhosis. The NNT to prevent death or clinical disease progression (any cirrhosis-related event or death) in one patient was determined with the adjusted (event-free) survival among patients without SVR and adjusted hazard ratio of SVR. Overall, 248 patients were followed for a median of 8.3 (IQR 6.2-11.1) years. Fifty-nine (24%) patients attained SVR. Among patients without SVR, the adjusted 5-year survival and event-free survival were 94.4% and 80.0%, respectively. SVR was associated with reduced all-cause mortality (HR 0.15, 95% CI 0.05-0.48, P = 0.002) and clinical disease progression (HR 0.16, 95% CI 0.07-0.36, P < 0.001). The NNT to prevent one death in 5 years declined from 1052 (95% CI 937-1755) at 2% SVR (interferon monotherapy) to 61 (95% CI 54-101) at 35% SVR (peginterferon and ribavirin). At 50% SVR, which might be expected with triple therapy, the estimated NNT was 43 (95% CI 38-71). The NNT to prevent clinical disease progression in one patient in 5 years was 302 (95% CI 271-407), 18 (95% CI 16-24) and 13 (95% CI 11-17) at 2%, 35% and 50% SVR, respectively. In conclusion, the NNT to prevent clinical endpoints among cirrhotic patients with HCV genotype 1 has declined enormously with the improvement of antiviral therapy.

[Biliary diseases in the elderly]. / Gallenwegserkrankungen im Alter.

Gallstone disease is more common in the elderly. In this short review, we summarize guideline-based recommendations for the diagnosis and treatment of biliary diseases in elderly patients. Warning episodes of biliary colic represent a general indication for cholecystectomy to avoid stone-related complications. Elderly patients with mild and moderate acute cholecystitis should undergo urgent cholecystectomy. After endoscopic retrograde cholangiography and stone extraction as well as mild acute biliary pancreatitis, cholecystectomy should be performed during the same hospital admission. Since the elevated risk of gallstone carriers to develop biliary cancer increases with age, cholecystectomy also protects against cancer.

[Recurrent hypoglycemia with elevated insulin levels in a 75-year-old man]. / 75-jähriger Patient mit rezidivierenden Hypoglykämien bei Insulinexzess.

Hirata syndrome is a rare differential diagnosis for recurrent hypoglycemia. This immune-mediated disease is associated with the formation of autoantibodies targeting insulin. Although the syndrome resolves spontaneously in the majority of patients, our case illustrates that individual patients require continuous immunosuppressive therapy.

[Economics of operating room use at a university eye hospital]. / Wirtschaftlichkeit der Operationssaalnutzung an einer Universitäts-Augenklinik.

BACKGROUND: In ophthalmologic surgery, there are usually short operation times and thus many changes between the individual operations, which are not subject to remuneration. As in maximum care hospitals consecutive different operations with different durations are often performed, emergency operations have to be inserted and further training of colleagues is practiced, it is particularly important to generate the shortest possible transfer times in order to have both sufficient operation time and to be able to treat as many cases as possible. The aim of this work is to evaluate the efficiency of the surgical performance of a university eye hospital. MATERIAL AND METHOD: The surgeries performed in 2021 at the MHH Eye Clinic were evaluated with respect to the spectrum, number, surgery duration, transfer times and process times. In terms of personnel, each operating room was staffed with one assistant anesthesiologist, one nurse anesthetist, two operating room nurses, one surgeon, and 20% senior anesthesiologist supervision. Based on a theoretical concept, which provides an increased staffing ratio while maintaining the same infrastructure, it was calculated how many more surgeries could be performed if the transfer time was halved and whether the additional financial expense could be compensated. RESULTS: With a total of n = 2712 surgeries performed during regular duty hours (244 working days) in 2 operating rooms (average daily n = 11.1; weekly n = 53.6 and monthly n = 237.1), the average surgery duration was 37 min and the transition time 43 min. This means that the operating rooms were used for surgery for 51% of the total operating time. Main procedures were vitrectomy with n = 1350 and cataract surgery with n = 1308. The new personnel concept provided one additional operating room nurse per operating room and one additional anesthesiologist for both operating rooms. The additional costs for this personnel expenditure were calculated at approx. 300,000 € per year. The halving of the transfer time from 43 min to about 21 min through possible overlapping induction and parallel work, which was not possible until now, results in an additional operation time of about 100 min per operating room, so that at least 4 additional operations can be planned and performed. In this way, with stringent implementation and the same spatial structures with stable fixed costs, n = 976 more operations could be performed, which, minus the personnel costs, the additional material costs for surgery and anesthesia of 557,042 € and the inpatient hotel costs of 600,663 €, with an average length of stay of 2.8 days, would result in an additional revenue of about 2.4 times the additional personnel costs at the current flat rate of 3739.40 € and an average case mix index of the MHH Eye Hospital of 0.649 (total revenue: 2,155,449 €; profit margin II: 701,389 €) for the considered surgical patient collective in 2021. CONCLUSION: An increase of the personnel expenditure in the operating room for surgical subjects such as ophthalmology with shorter interventions and many changes is economically worthwhile also for a large hospital in order to enable and optimize overlapping transfers of anesthesia and surgical care. This should therefore also be considered separately, contrary to standardized staffing of the overall hospital, in order to use existing resources with their fixed costs as optimally as possible.

MUTYH hotspot mutations in unselected colonoscopy patients.

AIM: Biallelic MutY human homologue (MUTYH) germline mutations predispose to recessively inherited adenomatous polyposis, designated MUTYH-associated polyposis (MAP), and colorectal cancer (CRC). The hotspot mutations p.Y179C and p.G396D account for the majority of pathogenic variants of MUTYH in Caucasians. Our aim was to evaluate the prevalence of MUTYH mutations in a prospective cohort of unselected patients with different colorectal diseases. METHOD: The hotspot mutations p.Y179C and p.G396D were genotyped in 352 consecutive patients undergoing colonoscopy at our tertiary referral centre. Exons 2-14 were sequenced in hotspot mutation carriers to exclude additional variants. RESULTS: Overall, we identified five heterozygous p.Y179C mutations and three heterozygous p.G396D mutations in seven hotspot mutation carriers (risk allele frequencies 0.7% and 0.4%, respectively). Two of these hotspot mutation carriers harboured a heterozygous p.Q338H variant, which is of uncertain clinical significance, on the other allele. Three individuals were biallelic MUTYH variant carriers (p.Y179C/p.G382D: typical MAP; p.Y179C/p.Q338H: atypical MAP with late onset and lower polyp burden; p.G382D/p.Q338H: inflammatory bowel disease), and four subjects were monoallelic mutation carriers. CONCLUSION: MUTYH-associated disease, and hence genetic counselling and MUTYH genetic testing, should be considered in the clinical routine of an endoscopy unit, but the wide range of phenotypes represents a challenge for patient identification. The clinical significance of p.Q338H should be evaluated in future case-control studies because compound heterozygotes for pathogenic mutations and p.Q338H may be at increased risk for mild polyposis or CRC. In addition, MUTYH should be assessed as a potential susceptibility gene for the development of colitis-associated CRC in future.

[Personalised hepatology - current concepts, developments and expectations in the post-genome era]. / Personalisierte Hepatologie - Gegenwärtige Konzepte, Entwicklungen und Erwartungen im Postgenomzeitalter.

Promoted by the decoding of the human genome as part of the human genome project, individualised therapy approaches have become a realistic perspective for therapies that are more effective, less prone to side effects and economically reasonable. This also applies to chronic liver disease. With the aim not only to expand the current knowledge base through basic research on the underlying disease processes and treatment options but also to identify and characterise biomarkers, the creation of genetic fingerprints for individualised diagnosis, prognosis and treatment of patients takes its place in the centre of translational hepatology. For certain liver diseases personalised therapy approaches are already existent. Examples are the determination of viral genotypes, viral kinetics and genotyping of the IL28B polymorphism to optimise the treatment of chronic hepatitis C. The challenges of the next few years relate to the broadening of the knowledge base, the establishment of reliable and standardised technologies, and the development of intelligent bioinformatics strategies for data analysis and data integration. The following review not only summarises the current state of progress and possibilities of personalised medicine in hepatological diseases, but also explains the technical background of the limitations that currently hinder a consistent clinical implementation.

Severe hepatocellular dysfunction in obstetric cholestasis related to combined genetic variation in hepatobiliary transporters.

Obstetric cholestasis (OC) is a cholestatic disorder with a prominent genetic background including variation in diverse hepatobiliary lipid transporters, such as ABCB4 (phospholipids) and ABCB11 (bile salts). Given a marked hepatocellular dysfunction in an OC patient indicated by > 40-fold rise in alanine aminotransferase activity and minor gamma-glutamyl transpeptidase increases, we performed genotyping of candidate gene variants associated with adult cholestatic phenotypes. Genetic analysis revealed the heterozygous ABCB4 mutation p.R590Q, the ABCB11 variant p.V444A and the lithogenic ABCG8 variant p.D19H. Aggregation of multiple hepatobiliary transporter variants is rare in OC, and may cooperate to negatively modulate hepatobiliary transport capacities.

Pre-endoscopy SARS-CoV-2 testing strategy during COVID-19 pandemic: the care must go on.

BACKGROUND: In response to the COVID-19 pandemic, endoscopic societies initially recommended reduction of endoscopic procedures. In particular non-urgent endoscopies should be postponed. However, this might lead to unnecessary delay in diagnosing gastrointestinal conditions. METHODS: Retrospectively we analysed the gastrointestinal endoscopies performed at the Central Endoscopy Unit of Saarland University Medical Center during seven weeks from 23 March to 10 May 2020 and present our real-world single-centre experience with an individualized rtPCR-based pre-endoscopy SARS-CoV-2 testing strategy. We also present our experience with this strategy in 2021. RESULTS: Altogether 359 gastrointestinal endoscopies were performed in the initial period. The testing strategy enabled us to conservatively handle endoscopy programme reduction (44% reduction as compared 2019) during the first wave of the COVID-19 pandemic. The results of COVID-19 rtPCR from nasopharyngeal swabs were available in 89% of patients prior to endoscopies. Apart from six patients with known COVID-19, all other tested patients were negative. The frequencies of endoscopic therapies and clinically significant findings did not differ between patients with or without SARS-CoV-2 tests. In 2021 we were able to unrestrictedly perform all requested endoscopic procedures (> 5000 procedures) by applying the rtPCR-based pre-endoscopy SARS-CoV-2 testing strategy, regardless of next waves of COVID-19. Only two out-patients (1893 out-patient procedures) were tested positive in the year 2021. CONCLUSION: A structured pre-endoscopy SARS-CoV-2 testing strategy is feasible in the clinical routine of an endoscopy unit. rtPCR-based pre-endoscopy SARS-CoV-2 testing safely allowed unrestricted continuation of endoscopic procedures even in the presence of high incidence rates of COVID-19. Given the low frequency of positive tests, the absolute effect of pre-endoscopy testing on viral transmission may be low when FFP-2 masks are regularly used.

[Performance and cost calculation for a university ophthalmological outpatient clinic]. / Leistungs- und Kostenkalkulation für eine universitäre, augenheilkundliche Hochschulambulanz.

BACKGROUND: Outpatient procedures at a university hospital are generally considered to be unprofitable. In the present publication we evaluate the turnover and costs of the university eye outpatient department of the Hannover Medical School (MHH) in terms of a cost unit accounting as well as providing a summary of the workload. MATERIAL AND METHOD: Given the data of the hospital information system (IS-H/i.s.h.med from SAP) and a proprietary software (TimeElement), all patient contacts in the year 2019 were evaluated. The latter software is applied in a standardized manner to record the patient flow of our outpatient service in real time electronically. The total costs consist of personnel, material and room costs including infrastructure of the MHH and are compared to the flat-rate revenues according to the university outpatient contract (HSA) as well as further revenues from internal referral services, self-pay patients, outpatient surgery and cooperation contracts for intravitreal injections (IVOM). RESULTS: With an average full-time equivalent (FTE) headcount of 10.63 assistant physicians, 3.6 specialist physicians, and 21 nonphysicians (plus 4 Federal Volunteer Service, BUFDI) in our policlinic, we have determined €â€¯2,927,022 in personnel costs, including overheads, for the entire year. Including infrastructure (€â€¯524,942), material and equipment costs with overheads and internal cost allocation of €â€¯258.657, the total costs in 2019 resulted in €â€¯3,710,621. In contrast, the total income in 2019 was €â€¯3,524,737 generated through the abovementioned patient segments, resulting in a deficit of €â€¯-185,884 (5%). Our data provide evidence that regular outpatient revenues are insufficient and are mainly balanced by outpatient surgery, IVOMs and self-pay patients. In total, there were 19,453 patient contacts during regular office hours (with 17,305 billable cases). At n = 9943, the majority of the contacts were HSA visits; however, only 82% of the cases could effectively be charged due to multiple visits per quarter. The median total patient attendance was 3.21 h (mean 3.38 h). On average, 78 patient contacts were counted per working day. The analysis with TimeElement unveiled a median of n = 2 physician contacts per patient (mean n = 1.91). The median duration per interaction with a physician was 17.98 min (mean 23.23 min). For diagnostics, we counted a median of n = 2 interactions per patient (mean n = 2.31), with an entire interaction lasting a median of 18.30 min (mean 22.60 min). In total n = 37,363 individual diagnostic procedures were recorded in 2019, with SD-OCT being the primary procedure at n = 10,888. CONCLUSION: The cost/turnover calculation showed a marginal financial loss through our ophthalmological outpatient department. Thus, the costs of a university eye outpatient department in Lower Saxony do not seem to be sufficiently covered by direct outpatient revenues. Maintaining quarterly flat rates for all cases of the outpatient department would require a fee of about €â€¯214 in our setting to remain cost neutral. Currently, the lower flat rates in the HSA area are compensated by other areas. Obviously, the high content-related workload in our setting requires a high personnel expenditure with a considerable personnel cost contribution of nearly 80%.

Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis.

BACKGROUND & AIMS: Toll-like receptor (TLR) 2 and nucleotide-binding oligomerisation domain (NOD) 2 recognize distinct pathogen-associated molecular patterns (PAMS) on the cell surface and in the cytoplasm, respectively. Since they may contribute to susceptibility to spontaneous bacterial peritonitis (SBP), we studied the effects of TLR2 gene variants on susceptibility for SBP in relation to the previously reported NOD2 alleles. METHODS: Overall, 150 patients with liver cirrhosis and ascites were genotyped for TLR2 gene variants -16934 (rs4696480), Arg753Gln (rs5743708), Pro631His (rs5743704) and the TLR2 GT microsatellite polymorphism in intron 2. Patients were monitored for SBP over two years. TLR2 SNPs were identified by hybridization probe assays on a LightCycler system. Numbers of GT repeats were determined with an ABI310 sequencer and Genescan Analysis 2.1 software. RESULTS: Fifty two patients (35%) had SBP. Unlike the TLR2 Arg753Gln and Pro631His mutations, SBP was significantly more frequent in patients with the TLR2 -16934 TT genotype (38.5% vs. 15.3%; p = 0.002) and in carriers with two long tandem GT repeat alleles (>20) (53.8% vs. 25.5%; p = 0.001). A multivariate analysis confirmed TLR2 GT microsatellite polymorphism (OR = 3.8, p = 0.002) and NOD2 variants (OR = 3.3, p = 0.011) as independent predictors of SBP, and the simultaneous presence of both risk factors indicated a particularly high risk for SBP (OR = 11.3, p = 0.00002). CONCLUSIONS: Analogous to NOD2 risk variants, TLR2 polymorphisms indicate increased susceptibility toward SBP in cirrhotic patients with ascites, and the combination of the TLR2 GT microsatellite polymorphism with at least one NOD2 risk variant enables improved identification of patients with a high risk for SBP.

Progression of liver fibrosis in HIV/HCV genotype 1 co-infected patients is related to the T allele of the rs12979860 polymorphism of the IL28B gene.

OBJECTIVE: HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rs12979860 C/T polymorphism in the IL28B gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection. METHODS: In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rs12979860 genotypes were analysed in 84 HCV/HIV co-infected patients. IL28B genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rs12979860 C/T genotypes over two years. RESULTS: 82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of IL28B genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various IL28B-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047). CONCLUSION: Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.