Real-world outcomes following third or subsequent lines of therapy: A Danish population-based study on 189 patients with relapsed/refractory large B-cell lymphomas.

Outcome data of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) beyond the second line are scarce outside of clinical trials. Novel therapies in the R/R setting have been approved based on single-arm trials, but results need to be contextualized by real-world outcomes. Medical records from 3753 Danish adults diagnosed with DLBCL were reviewed. Patients previously treated with rituximab and anthracycline-based chemotherapy who received the third or later line (3 L+) of treatment after 1 January 2015, were included. Only 189 patients with a median age of 71 years were eligible. The median time since the last line of therapy was 6 months. Patients were treated with either best supportive care (22%), platinum-based salvage therapy (13%), low-intensity chemotherapy (22%), in clinical trial (14%) or various combination treatments (32%). The 2-year OS-/PFS estimates were 25% and 12% for all patients and 49% and 17% for those treated with platinum-based salvage therapy. Age ≥70, CNS involvement, elevated LDH and ECOG ≥2 predicted poor outcomes, and patients with 0-1 of these risk factors had a 2-year OS estimate of 65%. Only a very small fraction of DLBCL patients received third-line treatment and were eligible for inclusion. Outcomes were generally poor, but better in intensively treated, fit young patients with limited disease.

Genetic variants in the adenosine triphosphate-binding cassette transporter A1 and risk of age-related macular degeneration.

Genetic variants in ABCA1 are associated with higher concentrations of high-density lipoprotein (HDL) cholesterol. Higher HDL cholesterol concentrations are observationally and genetically associated with higher risk of age-related macular degeneration (AMD). However, whether amino acid-changing genetic variants in ABCA1 associated with high HDL cholesterol concentrations confer a higher risk of AMD in the general population is currently unknown. We tested this hypothesis. The study included 80,972 individuals (1,370 AMD cases) from the Copenhagen General Population Study (CGPS) and 9,584 individuals (142 AMD cases) from the Copenhagen City Heart Study (CCHS) with 10 to 18 years of follow-up. We created an HDL cholesterol weighted allele score based on amino acid-changing ABCA1 variants with a minor allele frequency above 0.001 and divided it into tertiles. The study included 55% women. Mean age was 58 years. The ABCA1 allele score for the third versus the first tertile was associated with HRs (95% confidence intervals (CIs)) of 1.30 (1.14-1.49) for all-cause AMD, 1.26 (1.06-1.50) for nonneovascular AMD, and 1.31 (1.12-1.53) for neovascular AMD in a multivariable adjusted model. On a continuous scale, higher concentrations of genetically determined HDL cholesterol were associated with higher risk of all-cause AMD, nonneovascular AMD, and neovascular AMD in an age- and sex adjusted model and in a multivariable adjusted model. In conclusion, amino acid-changing genetic variants in ABCA1 associated with higher HDL cholesterol concentrations were also associated with higher risk of AMD, suggesting a role for ABCA1 in AMD pathogenesis.

Less postoperative pain and shorter length of stay after robot-assisted retrorectus hernia repair (rRetrorectus) compared with laparoscopic intraperitoneal onlay mesh repair (IPOM) for small or medium-sized ventral hernias.

BACKGROUND: The optimal repair of ventral hernia remains unknown. We aimed to evaluate the results after robotic-assisted laparoscopic transabdominal repair with retrorectus mesh placement (rRetrorectus) compared with laparoscopic intraperitoneal onlay mesh repair (IPOM) for patients with small- or medium-sized ventral hernia. METHODS: This was a retrospective cohort study of consecutive patients undergoing elective rRetrorectus or IPOM repair for small or medium-sized primary ventral or incisional hernias. The primary outcome was the postoperative need for transverse abdominis plane (TAP) block or epidural analgesia, secondary outcomes were length of stay and postoperative complications. All patients were followed for 30 days postoperatively. RESULTS: A total of 59 patients were included undergoing rRetrorectus (n = 27) and IPOM (n = 32). Patients in the two groups were comparable in terms of age, sex, comorbidities, smoking status, body mass index (BMI), and type of hernia. The median fascial defect area was slightly larger in the rRetrorectus group (9 cm2 vs. 6.2 cm2, P = 0.031). The duration of surgery was longer for rRetrorectus (median 117.2 min. vs. 84.4, P = 0.003), whereas the postoperative need for TAP block or epidural analgesia was less after rRetrorectus compared with IPOM (3.7% versus 43.7%, P = 0.002). There were no severe complications or reoperations after either procedure. The length of stay was shorter after rRetrorectus (median 0 vs. 1 day, P < 0.001). CONCLUSIONS: rRetrorectus was associated with reduced postoperative analgesic requirement and shorter length of stay compared with laparoscopic IPOM. Registration Clinicaltrial.gov: NCT05320055.

Umbilical Hernia Repair in Patients with Cirrhosis and in Patients with Severe Comorbidities-A Nationwide Cohort Study.

INTRODUCTION: Umbilical hernia is a frequent condition in patients with cirrhosis. The aim of the study was to evaluate the risks associated with umbilical hernia repair in patients with cirrhosis in the elective and emergency setting. Secondly, to compare patients with cirrhosis with a population of patients with equally severe comorbidities but without cirrhosis. METHODS: Patients with cirrhosis who underwent umbilical hernia repair from January 1, 2007, to December 31, 2018, were included from the Danish Hernia Database. A control group of patients with a similar Charlson score (≥ 3) without cirrhosis was generated using propensity score matching. The primary outcome was postoperative re-intervention within 30 days following hernia repair. Secondary outcomes were mortality within 90 days and readmission within 30 days following hernia repair. RESULTS: A total of 252 patients with cirrhosis and 504 controls were included. Emergency repair in patients with cirrhosis was associated with a significantly increased rate of re-intervention (54/108 (50%) vs. 24/144 (16.7%), P < 0.001), 30-day readmission rate (50/108 (46.3%) compared with elective repair vs. 36/144 (25%) (P < 0.0001)), and 90-day mortality (18/108 (16.7%) vs. 5/144 (3.5%), P < 0.001). Patients with cirrhosis were more likely to undergo a postoperative re-intervention compared with comorbid patients without cirrhosis (OR = 2.10; 95% CI [1.45-3.03]). CONCLUSION: Patients with cirrhosis and other severe comorbidity undergo emergency umbilical hernia repair frequently. Emergency repair is associated with increased risk of poor outcome. Patients with cirrhosis undergo a postoperative reintervention more frequently than patients with other severe comorbidity undergoing umbilical hernia repair.

Sinonasal B-cell lymphomas: A nationwide cohort study, with an emphasis on the prognosis and the recurrence pattern of primary diffuse large B-cell lymphoma.

Lymphomas of the nasal cavity and paranasal sinuses (NPS) are rare. Knowledge on sinonasal B-cell lymphoma (SNBCL) primarily comes from case series or single-center studies on small cohorts. We sought to determine the subtype distribution, clinical characteristics, disease behavior, and prognosis on a nationwide scale, with an emphasis on prognostic factors for the most common sinonasal lymphoma, primary sinonasal diffuse large B-cell lymphoma (PSDLBCL). We collated all data from medical records and national databases on patients registered with SNBCL from 1980 through 2018 in the national pathology registry and collected all tissue samples for validation of diagnosis. We included 205 patients and found 10 different subtypes of lymphoma. Diffuse large B-cell lymphoma (DLBCL) was the predominant subtype (80%). The incidence of SNBCL was 0.14/100,000 person-years. The five-year progression-free survival (PFS) and overall survival rates for PSDLBCL were 50% and 56%, respectively. For PSDLBCL, Rituximab showed a statistically significant effect (Hazard Ratio 0.22, p < 0.001), whereas consolidative radiotherapy combined with immunochemotherapy was of limited value (PFS, p = 0.93). When treatment failure occurred, DLBCL showed a distinct pattern of recurrence/dissemination to the NPS, skin, breast, central nervous system (CNS), and/or testis. Collectively, DLBCL comprised a clear majority of SNBCLs, although nine other subtypes were represented. Data showed that immunochemotherapy increased survival for PSDLBCL and that the addition of radiotherapy did not benefit patients. Furthermore, treatment failure for sinonasal DLBCL showed a possible common pathogenesis with primary extranodal lymphomas of specific locations (e.g., CNS, skin, breast, and testis).

Shared Risk Factors between Dementia and Atherosclerotic Cardiovascular Disease.

Alzheimer's disease is the most common form of dementia, and the prodromal phases of Alzheimer's disease can last for decades. Vascular dementia is the second most common form of dementia and is distinguished from Alzheimer's disease by evidence of previous stroke or hemorrhage and current cerebrovascular disease. A compiled group of vascular-related dementias (vascular dementia and unspecified dementia) is often referred to as non-Alzheimer dementia. Recent evidence indicates that preventing dementia by lifestyle interventions early in life with a focus on reducing cardiovascular risk factors is a promising strategy for reducing future risk. Approximately 40% of dementia cases is estimated to be preventable by targeting modifiable, primarily cardiovascular risk factors. The aim of this review is to describe the association between risk factors for atherosclerotic cardiovascular disease and the risk of Alzheimer's disease and non-Alzheimer dementia by providing an overview of the current evidence and to shed light on possible shared pathogenic pathways between dementia and cardiovascular disease. The included risk factors are body mass index (BMI); plasma triglyceride-, high-density lipoprotein (HDL) cholesterol-, low-density lipoprotein (LDL) cholesterol-, and total cholesterol concentrations; hypertension; diabetes; non-alcoholic fatty liver disease (NAFLD); physical inactivity; smoking; diet; the gut microbiome; and genetics. Furthermore, we aim to disentangle the difference between associations of risk factors in midlife as compared with in late life.

Polygenic risk scores: how much do they add?

PURPOSE OF REVIEW: Current methods to assess genetic risk of familial hypercholesterolemia and coronary artery disease (CAD) focus on testing monogenic mutations in well known genes. Here we review recent developments in polygenic risk scores (PRSs) for LDL cholesterol and for CAD, and how they may add to current risk prediction algorithms. RECENT FINDINGS: PRSs can identify 10-20 times as many individuals at high polygenic risk compared with monogenic mutations, and PRSs can modulate the effect of a monogenic variant on risk. Current risk factor prediction tools for prevention of CAD incompletely capture polygenic susceptibility, and PRSs may identify subgroups of patients who are likely to benefit more from lipid-lowering therapy. Finally, PRSs can be quantified already at birth, long before other risk factors used to predict CAD, and before clinical manifestations of disease. SUMMARY: PRSs for CAD may soon be incorporated into clinical practice. Therefore, there is an urgent need to establish both analytical and clinical reporting standards for PRSs, and for validating scores in different ethnicities. Thresholds for intervention need to be established for PRSs and integrated into established risk scores. Training programs are needed for clinical staff to learn to communicate polygenic risk in a comprehensive way to the patient.

Triglycerides as a Shared Risk Factor between Dementia and Atherosclerotic Cardiovascular Disease: A Study of 125 727 Individuals.

BACKGROUND: Risk factors for atherosclerotic cardiovascular disease such as smoking, hypertension, physical inactivity, and diabetes have also been associated with risk of dementia. Whether hypertriglyceridemia represents a shared risk factor as well remains unknown. We tested the hypothesis that hypertriglyceridemia is associated with increased risk of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke. METHODS: Using the Copenhagen General Population Study and the Copenhagen City Heart Study, we examined the association between increased plasma triglycerides and risk of non-Alzheimer dementia, Alzheimer disease, and ischemic stroke with Cox regression. RESULTS: On a continuous scale, higher concentrations of plasma triglycerides were associated with increased risk of non-Alzheimer dementia and ischemic stroke, but not with Alzheimer disease. In age, sex, and cohort adjusted models, the highest percentile of triglycerides (median 629 mg/dL; 7.1 mmol/L) versus the 1-50th percentiles (median 89 mg/dL; 1.0 mmol/L) was associated with hazard ratios of 1.75 (95% confidence interval: 1.17-2.63) for non-Alzheimer dementia, 1.18 (0.73-1.91) for Alzheimer disease, and of 1.89 (1.50-2.38) for ischemic stroke. Corresponding hazard ratios were 1.62 (1.08-2.44), 1.25 (0.77-2.02), and 1.57 (1.24-1.98) in models adjusted multifactorially, and 1.79 (1.16-2.87), 1.18 (0.73-1.92), and 1.46 (1.10-1.95) in models adjusted multifactorially and additionally for apolipoprotein E (APOE) genotype, respectively. Results were similar after excluding individuals who had an event within 2 years after study entry. CONCLUSIONS: Moderate hypertriglyceridemia was associated with increased risk of both non-Alzheimer dementia and ischemic stroke, highlighting plasma triglycerides as a shared risk factor between dementia and atherosclerotic cardiovascular disease.

Veterinary Students Have a Higher Risk of Contracting Cryptosporidiosis when Calves with High Fecal Cryptosporidium Loads Are Used for Fetotomy Exercises.

An outbreak of cryptosporidiosis among veterinary students performing fetotomy exercises on euthanized calves took place in September 2018 in Denmark. A prospective cohort investigation was performed to identify risk factors and provide guidance for preventing outbreaks of cryptosporidiosis in this setting. Ninety-seven students attended the fetotomy exercises and completed a questionnaire about symptoms and potential risk behavior. Real-time PCR was used to detect Cryptosporidium spp. in stool samples from students and to quantify the fecal parasite load in the calves used for the exercises. gp60 subtyping was carried out for the Cryptosporidium-positive samples. Our case definition was based on participation in a fetotomy exercise, reported symptoms, and laboratory results. Eleven laboratory-confirmed or probable cases (11%) were identified in two outbreaks during the prospective study period, with attack rates of 4/10 (40%) and 7/9 (78%), respectively. The risk factors for cryptosporidiosis we identified were performing the exercise on a diarrheic calf, reporting visible fecal contamination on the personal protective equipment (PPE), and reporting problems with PPE during the exercise. Cryptosporidium parvum IIaA15G2R1 was detected in both cases and calves. A significantly higher proportion of the calves aged 7 days old and above were positive compared with younger calves. Furthermore, a high fecal Cryptosporidium load in a calf was associated with a higher probability of an outbreak among the students. Based on our results, using noninfected calves for the exercises, appropriate use of PPE, and thorough hand hygiene are recommended to reduce the risk of contracting cryptosporidiosis in connection with fetotomy exercises.IMPORTANCECryptosporidium spp. can cause severe diarrhea in infected individuals. Cryptosporidium parvum is zoonotic, and cattle are the main reservoir. In several countries, outbreaks of cryptosporidiosis have occurred in veterinary students after handling calves. We carried out a 1-year-long prospective study to investigate the occurrence of these recurrent cryptosporidiosis outbreaks in Denmark. Our investigation used a One Health approach and combined comprehensive epidemiological approaches and laboratory methods applied to both students and calves in the setting of the fetotomy exercises. Two outbreaks took place during the study period; additionally, we retrospectively identified two more suspected outbreaks prior to the study period. The results illustrated a high risk of contracting cryptosporidiosis among veterinary students in the setting of the fetotomy exercises, especially when using calves with high fecal Cryptosporidium loads. Our data can be used to inform future efforts to prevent transmission of Cryptosporidium parvum to students during fetotomy exercises.

Novel genes in LDL metabolism--a comprehensive overview.

PURPOSE OF REVIEW: To summarize recent findings from genome-wide association studies (GWAS), whole-exome sequencing of patients with familial hypercholesterolemia and 'exome chip' studies pointing to novel genes in LDL metabolism. RECENT FINDINGS: The genetic loci for ATP-binding cassette transporters G5 and G8, Niemann-Pick C1-Like protein 1, sortilin-1, ABO blood-group glycosyltransferases, myosin regulatory light chain-interacting protein and cholesterol 7α-hydroxylase have all consistently been associated with LDL cholesterol levels and/or coronary artery disease in GWAS. Whole-exome sequencing and 'exome chip' studies have additionally suggested several novel genes in LDL metabolism including insulin-induced gene 2, signal transducing adaptor family member 1, lysosomal acid lipase A, patatin-like phospholipase domain-containing protein 5 and transmembrane 6 superfamily member 2. Most of these findings still require independent replications and/or functional studies to confirm the exact role in LDL metabolism and the clinical implications for human health. SUMMARY: GWAS, exome sequencing studies, and recently 'exome chip' studies have suggested several novel genes with effects on LDL cholesterol. Novel genes in LDL metabolism will improve our understanding of mechanisms in LDL metabolism, and may lead to the identification of new drug targets to reduce LDL cholesterol levels.

Visible age-related signs and risk of ischemic heart disease in the general population: a prospective cohort study.

BACKGROUND: Cardiovascular disease is 1 of the most common age-related diseases, and also 1 of the most common causes of death in the general population. We tested the hypothesis that visible age-related signs associate with risk of ischemic heart disease (IHD), myocardial infarction (MI), and death in the general population, independent of chronological age. METHODS AND RESULTS: 10,885 individuals aged 20 to 93 years free of IHD were followed from 1976 through 1978 until June 2011 with 100% complete follow-up. During these 35 years of follow-up, 3401 participants developed IHD and 1708 developed MI. Presence of frontoparietal baldness, crown top baldness, earlobe crease, and xanthelasmata was associated with increased risk of IHD or MI after multifactorial adjustment for chronological age and well-known cardiovascular risk factors. The risk of IHD and MI increased stepwise with increasing number of age-related signs with multifactorially adjusted hazard ratios up to 1.40 (95% confidence interval, 1.20-1.62) for IHD and 1.57 (1.28-1.93) for MI, in individuals with 3 to 4 versus no age-related signs at baseline (P for trend <0.001). In all age groups in both women and men, absolute 10-year risk of IHD and MI increased with increasing number of visible age-related signs. CONCLUSIONS: Male pattern baldness, earlobe crease, and xanthelasmata-alone or in combination-associate with increased risk of ischemic heart disease and myocardial infarction independent of chronological age and other well-known cardiovascular risk factors. This is the first prospective study to show that looking old for your age is a marker of poor cardiovascular health.

No difference in incidence of port-site hernia and chronic pain after single-incision laparoscopic cholecystectomy versus conventional laparoscopic cholecystectomy: a nationwide prospective, matched cohort study.

BACKGROUND: Conventional laparoscopic cholecystectomy (CLC) is regarded as the gold standard for cholecystectomy. However, single-incision laparoscopic cholecystectomy (SLC) has been suggested to replace CLC. This study aimed at comparing long-term incidences of port-site hernia and chronic pain after SLC versus CLC. METHODS: We conducted a matched cohort study based on prospective data (Jan 1, 2009-June 1, 2011) from the Danish Cholecystectomy Database with perioperative information and clinical follow-up. Consecutive patients undergoing elective SLC during the study period were included and matched 1:2 with patients subjected to CLC using pre-defined criteria. Follow-up data were obtained from the Danish National Patient Registry, mailed patient questionnaires, and clinical examination. A port-site hernia was defined as a repair for a port-site hernia or clinical hernia located at one or more port sites. RESULTS: In total, 699 patients were eligible and 147 patients were excluded from the analysis due to pre-defined criteria. The rate of returned questionnaires was 83%. Thus, 552 (SLC, n = 185; CLC, n = 367) patients were analyzed. The median observation time was 48 months (range 1-65) after SLC and 48 months (1-64) after CLC (P = 0.940). The total cumulated port-site hernia rate was 4 % and 6 % for SLC and CLC, respectively (P = 0.560). Incidences of moderate/severe chronic pain were 4 % and 5 % after SLC and CLC, respectively (P = 0.661). CONCLUSIONS: We found no difference in long-term incidence of port-site hernia or chronic pain after SLC versus CLC.

Health-related quality of life scores changes significantly within the first three months after hernia mesh repair.

BACKGROUND: Patient-related outcome measures (PROM) such as quality of life (QoL) after hernia repair are important to monitor, since QoL is an important indication of a hernia repair. Carolinas Comfort Scale (CCS) is a hernia-specific questionnaire regarding health-related QoL after a mesh hernia repair. The primary objective of this study was to monitor changes in health-related QoL over time after different mesh hernia repair procedures using the CCS. METHODS: We performed a prospective study with an exploratory, intraobserver design enrolling consecutive patients who were to undergo elective mesh hernia repair. Four different hernia repair techniques were included and analyzed specifically for each surgical group. Patients scored themselves using CCS preoperatively and at several fixed times postoperatively. Since no gold standard exists for either hernia-specific QoL questionnaires or change of scores on PROMs as a function of time after hernia repair, we compared the CCS scores with the visual analog scale (VAS) scores reflecting the subdomains of the CCS. RESULTS: A total of 166 patients completed the study. CCS scores for QoL, pain, sensation of mesh, and activity limitations changed significantly with time during the 90-day study period. Furthermore, CCS and VAS showed significant agreement and correlation (ρ = 0.52-0.82, P < 0.001). CONCLUSIONS: The present study is the first to demonstrate significant changes over time in health-related QoL using the CCS after four different types of hernia repair with mesh.