Uppsala University Hospital Research Articles

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with or without early post-operative intraperitoneal chemotherapy for appendix neoplasms with peritoneal metastases: A propensity score analysis

Introduction– Early post-operative intraperitoneal chemotherapy (EPIC) can be used after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with resectable peritoneal metastases (PM). Whether EPIC adds any benefit is debatable. Methods– We performed a retrospective case-control analysis of patients with PM of appendiceal origin treated by CRS + HIPEC ± EPIC at Uppsala University Hospital between 2004 and 2012. The 206 patients were divided into two groups depending on if they received EPIC or not. The two groups were propensity-matched with a 1:1 ratio. The patients in the EPIC group were mostly operated in the first three years of the unit’s experience. Results– After matching, 76 patients were left in each group. The groups were similar, except for the proportion of histological subtypes (p = 0.021) and chemotherapy agents used for HIPEC (0.017). Survival outcomes were stratified by histology. The patients who received EPIC had a longer hospital and ICU length of stay (15.71 vs 14.28 days, p = 0.049), (1.45 vs 1.05 days, p = 0.002), respectively. Post-operative complications were similar in both groups. Overall Survival (OS) and recurrence-free survival (RFS) did not differ for the patients with low-grade histology. The patients with high-grade tumors who received EPIC had a significantly worse OS (p = 0.0088) while having the same RFS as the patients who did not receive EPIC. ConclusionOur results suggest there is no benefit of EPIC in patients with advanced appendiceal tumors while increasing hospital and ICU length of stays. A suboptimal group matching might influence our results.

Trajectories of socio-economic position over four time points and mortality: The role of gender

Abstract Background Studies investigating the effect of social mobility on mortality in Sweden have used socioeconomic position (SEP) at only two time points and traditional methodological approaches. Our recent study has used SEP at four time points, but not employed latent class analyses when investigating the relationship between SEP trajectories and mortality in later life. Methods A cohort of 14,192 live births at Uppsala University Hospital between 1915-1929, of whom 97% were traced through parish records until routine registers became available in the 1960s. 5729 men and 5607 women were alive and living in Sweden in 1980. SEP was measured as social class of the head of household: at birth, in childhood (age 10, +/- five years), in adulthood (age 30-45, in the 1960 Census), and in later life (age 50-65, in the 1980 Census). Latent class analysis was employed to identify social class trajectories and Cox proportional hazard models used to estimate all-cause and cause-specific mortality (data from Causes of Death Register). Results Compared to men and women with stable high SEP trajectories, we found a higher risk of death from circulatory disease among men with stable low (HR 1.56, 95%CI 1.29-1.87), stable middle (HR 1.28, 95%CI 1.06-1.55) and upwardly mobile from low (HR 1.35, 95%CI 1.10-1.66) SEP trajectories, as well as in women with stable low or mobile from low to middle SEP trajectory (HR 1.27, 95%CI 1.02-1.59). SEP trajectories and total mortality showed similar, albeit, weaker associations in both genders. SEP trajectories were gender-specific and associations of SEP trajectories with circulatory disease mortality tended to be weaker in women. Conclusions Men's and women's socioeconomic position during childhood and over the life course affect their risk of late life all-cause mortality, and death from circulatory disease in particular. Improvements in social conditions at early stages of the life course are likely to contribute to reducing mortality at old age. Key messages Men’s and women’s socio-economic position during childhood and over the life course affect their risk of late life all-cause mortality and mortality from circulatory disease in particular. Trajectories of socioeconomic position across life course appear to be related to cause specific and total mortality in a gender specific pattern.

Arterial lactate in traumatic brain injury - Relation to intracranial pressure dynamics, cerebral energy metabolism and clinical outcome.

High arterial lactate is associated with disturbed systemic physiology. Lactate can also be used as alternative cerebral fuel and it is involved in regulating cerebral blood flow. This study explored the relation of endogenous arterial lactate to systemic physiology, pressure autoregulation, cerebral energy metabolism, and clinical outcome in traumatic brain injury (TBI). A retrospective study including 115 patients (consent given) with severe TBI treated in the neurointensive care unit, Uppsala university hospital, Sweden, 2008-2018. Data from cerebral microdialysis, arterial blood gases, hemodynamics and intracranial pressure were analyzed the first ten days post-injury. Arterial lactate peaked on day 1 post-injury (mean 1.7±0.7mM) and gradually decreased. Higher arterial lactate correlated with lower age (p-value<0.05), higher Marshall score (p-value<0.05) and higher arterial glucose (p-value<0.001) in a multiple regression analysis. Higher arterial lactate was associated with poor pressure autoregulation (p-value<0.01), but not to worse cerebral energy metabolism. Higher arterial lactate was also associated with unfavorable clinical outcome (p-value<0.05). High endogenous arterial lactate is a biomarker of poor systemic physiology and may disturb cerebral blood flow autoregulation.

Arterial Oxygenation in Traumatic Brain Injury-Relation to Cerebral Energy Metabolism, Autoregulation, and Clinical Outcome.

Background:Ischemic and hypoxic secondary brain insults are common and detrimental in traumatic brain injury (TBI). Treatment aims to maintain an adequate cerebral blood flow with sufficient arterial oxygen content. It has been suggested that arterial hyperoxia may be beneficial to the injured brain to compensate for cerebral ischemia, overcome diffusion barriers, and improve mitochondrial function. In this study, we investigated the relation between arterial oxygen levels and cerebral energy metabolism, pressure autoregulation, and clinical outcome.Methods:This retrospective study was based on 115 patients with severe TBI treated in the neurointensive care unit, Uppsala university hospital, Sweden, 2008 to 2018. Data from cerebral microdialysis (MD), arterial blood gases, hemodynamics, and intracranial pressure were analyzed the first 10 days post-injury. The first day post-injury was studied in particular.Results:Arterial oxygen levels were higher and with greater variability on the first day post-injury, whereas it was more stable the following 9 days. Normal-to-high mean pO2 was significantly associated with better pressure autoregulation/lower pressure reactivity index (P = .02) and lower cerebral MD-lactate (P = .04) on day 1. Patients with limited cerebral energy metabolic substrate supply (MD-pyruvate below 120 µM) and metabolic disturbances with MD-lactate-/pyruvate ratio (LPR) above 25 had significantly lower arterial oxygen levels than those with limited MD-pyruvate supply and normal MD-LPR (P = .001) this day. Arterial oxygenation was not associated with clinical outcome.Conclusions:Maintaining a pO2 above 12 kPa and higher may improve oxidative cerebral energy metabolism and pressure autoregulation, particularly in cases of limited energy substrate supply in the early phase of TBI. Evaluating the cerebral energy metabolic profile could yield a better patient selection for hyperoxic treatment in future trials.

Patient satisfaction with continuous epidural analgesia after major surgical procedures at a Swedish University hospital.

ObjectiveThe use of epidural analgesia after major surgery is a well-established analgesia method. Epidural analgesia for postoperative pain relief needs to be monitored regularly in order to evaluate patient satisfaction and avoid side effects. However, due to the new available regional techniques, the role of epidural analgesia is being questioned and data about patient satisfaction is lacking. The current study was designed to evaluate patient satisfaction with epidural analgesia, its efficacy and reasons for premature termination of epidural analgesia.Materials and methodsWe conducted a retrospective survey of all patients who undergone surgery at Uppsala University hospital between October 2012 and January 2014 requiring continuous epidural analgesia for postoperative pain relief. Patients’ satisfaction with epidural analgesia and its effectiveness were evaluated by using paper questionnaire.ResultsDuring the study period 579 epidurals were inserted in patients scheduled for vascular, hepatobiliary, esophageal and other major abdominal surgery. The average treatment time was 3.8±1.8 days. Epidural analgesia consisted either of bupivacaine 0.1%+sufentanil 1 μg/ml solution or ropivacaine 0.2% solution. If patient needed opiates during treatment with epidural analgesia, only ropivacaine 0,2% solution was used. 494 (87.9%) patients were satisfied with their analgesia with no difference in satisfaction between sexes being observed. In 62 cases (11.2%) patient controlled analgesia was used on top of epidural analgesia with ropivacaine 0.2% solution, and 50.8% of patients were satisfied in this group. 514 (91.4%) patients were reported as having a good effect, 24 (4.3%) patients reported or were tested to show some effect, and 24 (4.3%) had no effect. No major neurological complications (epidural hematoma or abscess) were observed.ConclusionsOur retrospective survey indicates that patients are satisfied with continuous epidural analgesia used in major surgery.

Prognostic implications of left ventricular myocardial work indices in cardiac amyloidosis.

Left ventricular (LV) myocardial work index (LVMWI) derived from pressure-strain analysis resembles a novel non-invasive method for LV function evaluation. LV global longitudinal strain (LVGLS) has proven beneficial for risk stratification in cardiac amyloidosis (CA) patients. This study aimed to evaluate the potential additive value of LVMWI for outcome prediction in CA patients. We enrolled 100 CA patients in the period 2014-19 from Aarhus University Hospital, Denmark and Uppsala University Hospital, Sweden. All patients underwent comprehensive echocardiographic evaluation and were prospectively followed until censuring date on 31 March 2019 or death. During follow-up, we registered major adverse cardiac events (MACE) comprising heart failure requiring hospitalization and all-cause mortality. The median follow-up was 490 (228-895) days. During follow-up, a total of 42% of patients experienced MACE and 29% died. Patients with LVMWI <1043 mmHg% had higher MACE risk than patients with LVMWI >1043 mmHg% [hazard ratio (HR) 2.3, 95% confidence interval (CI) 1.2-4.3; P = 0.01]. Furthermore, patients with LVMWI <1039 mmHg% also had higher all-cause mortality risk than patients with LVMWI >1039 mmHg% (HR 2.6, 95% CI 1.2-5.5; P < 0.05). Moreover, the apical-to-basal segmental work ratio was a significant MACE and all-cause mortality predictor. By combining LVMWI and apical-to-basal segmental work ratio, we obtained an independent model for all-cause mortality prediction (high vs. low risk: HR 6.4, 95% CI 2.4-17.1; P < 0.0001). In contrast, LVGLS did not predict all-cause mortality. LV myocardial work may be of prognostic value in CA patients by predicting both MACE and all-cause mortality.

Hyperreninemia and low total body water may contribute to acute kidney injury in COVID-19 patients in intensive care.

Corona virus disease 2019 (COVID-19) is primarily associated with respiratory failure but both renal and circulatory failure is a common occurrence in patients with more severe disease that require intensive care [1], or die of the disease [2]. The developing guidelines for treating COVID-19 patients in intensive care suggest a frugal fluid strategy to avoid acute respiratory distress syndrome [3]. However, this may leave fluid resuscitation insufficient for renal and circulatory function increasing the risk of acute kidney injury (AKI). This case series is part of a study approved by the National Ethical Review Agency (EPM; No. 2020-01623). Informed consent was obtained from the patient, or next of kin if the patient was unable give consent. The Declaration of Helsinki and its subsequent revisions were followed. Plasma renin as well as biochemistry was collected with routine clinical sampling in the morning and analysed by the clinical chemistry department at Uppsala University Hospital according to standard procedures. We present a case series where we found pronounced hyperreninemia in association with hypernatremia, hyperchloremia and low glomerular filtration rate primarily in patients late in their intensive care stay (Table 1).TABLE 1: Biochemistry of patients ordered by days after intensive care admissionThere are several possible explanations for these findings. One is that the ACE2 affinity of SARS-COV-2 [4] directly affects the renin–angiotensin system and drives renin secretion despite high circulating sodium chloride. However, the association with high sodium and chloride suggests extra cellular fluid contraction and for the kidneys excessively restrictive fluid therapy with hypovolemia and water deficit. An alternative is a virus-induced or cytokine-induced renin release acting as a pseudohypovolemia. In this setting, the combination of high renin and high chloride may interact through the tubuloglomerular feedback system to supress glomerular filtration rate, thereby contributing to the development of AKI in COVID-19 patients. The data may also suggest that this is an iatrogenic cause during intensive care as we do not see it in recently admitted patients. The restrictive use of fluid resuscitation in COVID-19 may be beneficial for the lungs but may also promote AKI. However, if coagulopathy and microthrombi contribute importantly to the progression as has been suggested, low circulating volume may impair pulmonary flow regulation and thereby oxygenation as well. Significantly, the use of renin–angiotensin blockers have been found to be associated with improved outcome [5], and the present data may suggest that ameliorating the overactivation of the renin–angiotensin system may be a mechanism. In conclusion, patients with COVID-19 tend to develop hyperreninemia combined with hypernatremia and hyperchloremia in intensive care, which is associated with AKI in a way that suggests hypovolemia or pseudohypovolemia. ACKNOWLEDGEMENTS Conflicts of interest There are no conflicts of interest.

Trends in reported antibiotic use among children under 5 years of age with fever, diarrhoea, or cough with fast or difficult breathing across low-income and middle-income countries in 2005–17: a systematic analysis of 132 national surveys from 73 countries

Global assessments of antibiotic consumption have relied on pharmaceutical sales data that do not measure individual-level use, and are often unreliable or unavailable for low-income and middle-income countries (LMICs). To help fill this evidence gap, we compiled data from national surveys in LMICs in 2005-17 reporting antibiotic use for sick children under the age of 5 years. Based on 132 Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 73 LMICs, we analysed trends in reported antibiotic use among children under 5 years of age with fever, diarrhoea, or cough with fast or difficult breathing by WHO region, World Bank income classification, and symptom complaint. A logit transformation was used to estimate the outcome using a linear Bayesian regression model. The model included country-level socioeconomic, disease incidence, and health system covariates to generate estimates for country-years with missing values. Across LMICs, reported antibiotic use among sick children under 5 years of age increased from 36·8% (uncertainty interval [UI] 28·8-44·7) in 2005 to 43·1% (33·2-50·5) in 2017. Low-income countries had the greatest relative increase; in these countries, reported antibiotic use for sick children under 5 years of age rose 34% during the study period, from 29·6% (21·2-41·1) in 2005 to 39·5% (32·9-47·6) in 2017, although it remained the lowest of any income group throughout the study period. We found a limited but steady increase in reported antibiotic use for sick children under 5 years of age across LMICs in 2005-17, although overlapping UIs complicate interpretation. The increase was largely driven by gains in low-income countries. Our study expands the evidence base from LMICs, where strengthening antibiotic consumption and resistance surveillance is a global health priority. Uppsala Antibiotic Centre, Uppsala University, Uppsala University Hospital, Makerere University, Gothenburg University.

Proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx) for endoscopic treatment of grade IV vesicoureteral reflux: Long-term observational study

Since 1993, children aged >1 year with persistent grade III-V vesicoureteral reflux (VUR) and febrile urinary tract infections (UTIs) attending Uppsala University Hospital have undergone endoscopic injection with proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx; Deflux®). Investigate long-term incidence of UTI, bladder dysfunction, ureteral reimplantation and overall clinical findings following endoscopic injection of NASHA/Dx. Children with grade IV VUR diagnosed by voiding cystourethrogram (VCUG) and dilating VUR persisting for >1 year were included in this study. 15-25 years after endoscopic treatment, patients' hospital charts were studied. Information on bladder function and UTIs was obtained via questionnaire, 8-18 years after endoscopic treatment. 185 patients (69 boys, 116 girls) were included in the study; 237 grade IV VUR ureters were treated. All study patients were diagnosed with VUR after a febrile UTI (i.e. pyelonephritis). According to the last voiding cystourethrogram, 69% of ureters showed a positive response (VUR grade 0-I), 7% had VUR grade II and 23% had VUR grade≥III. 46 patients (25%) required ureteral reimplantation during follow-up. Among patients treated during the second 5-year period compared with the first (1998-2003 versus 1993-1998), there was a significant decrease in the rate of ureteral reimplantation (31% vs 16%; p=0.0365). This difference may be attributable to developments over time in the injection technique. UTIs occurred in 30 patients (21% of the evaluable population): 28 females and 2 males. Febrile UTIs were reported in 14 patients (10%), all females. Forty-nine patients (34%) had bladder problems (e.g. underactivity, overactivity, incontinence). Five patients underwent ureteral reimplantation 'late', 6-10 years after the last endoscopic injection. In one male patient, calcification around the NASHA/Dx implantation site was observed during routine examination 2 years after endoscopic treatment; no intervention was required. No safety issues were observed in the remaining 97% of the study population. This study represents the longest published follow-up of Grade IV VUR patients undergoing endoscopic treatment. Three-quarters of patients did not need ureteral reimplantation. Optimal injection technique and higher injection volume were associated with a reduced ureteral reimplantation rate. Treatment with NASHA/Dx was durable and well tolerated: long-term risks of UTI, bladder dysfunction and recurrent VUR were low.

Inadequate laser coagulation is an important cause of treatment failure in Type 1 retinopathy of prematurity.

To examine the cause of treatment failures in Type 1 retinopathy of prematurity (ROP). The medical charts of all infants with disease persistence after laser treatment at Uppsala University Hospital, Sweden, during a 10-year period (2009-2019) were reviewed. RetCam photography and angiography were used to document the retinal appearance before and after retreatment. Ten infants (18 eyes), of whom nine were referred from other hospitals, had persistence of Type 1 ROP in zone I or zone II despite previous laser treatment. Their mean gestational age was 24weeks and their mean birth weight was 618g. Seven eyes were diagnosed as stage 3 plus, eight eyes as stage 4A and three eyes as stage 4B. In eight infants (14 eyes), inadequate laser coagulation was suspected to be the cause for persistence of type 1 disease. Two infants (four eyes) were appreciated to have persistence of plus disease because of presence of zone I disease. For persistence of Type 1 ROP, five infants (seven eyes) were treated with vitrectomy, two infants (three eyes) with laser photocoagulation and anti-vascular endothelial growth factor (VEGF), two infants (four eyes) with anti-VEGF alone and finally two infants (four eyes) with laser photocoagulation alone. The anatomical outcome was good in 14 eyes and poor in four eyes (three infants). Inadequate laser coagulation is an important cause of treatment failure of ROP Type 1. Another cause is laser coagulation in zone I. To minimize remaining visual disability, some kind of centralization of the ROP treatment is suggested.

Blood Pressure Variability and Optimal Cerebral Perfusion Pressure-New Therapeutic Targets in Traumatic Brain Injury.

Optimal cerebral perfusion pressure (CPPopt) is an autoregulatory-oriented target in the neurointensive care (NIC) of patients with traumatic brain injury (TBI), and deviation from CPPopt is associated with poor outcome. We recently found that blood pressure variability (BPV) is associated with deviation from CPPopt. To evaluate BPV and other variables related to deviation from CPPopt and to evaluate challenges and strategies for autoregulatory-oriented treatment in TBI. Data including arterial blood pressure and intracranial pressure (ICP) from 362 TBI patients treated at the NIC unit, Uppsala University Hospital, Sweden, between 2008 and 2016, were retrospectively analyzed day 2 to 5. Higher BPV was a strong predictor of both CPP deviation below and above CPPopt after multiple regression analyses. There was no other explanatory variable for CPP deviation above CPPopt, whereas also higher ICP and worse autoregulation (higher pressure reactivity index) were associated with CPP deviation below CPPopt. A higher BPV was, in turn, explained by older age, lower ICP, higher mean arterial blood pressure, and higher slow arterial blood pressure amplitude (0.018-0.067 Hz). BPV was strongly associated with deviation from CPPopt. High age is a risk factor for high BPV and hence CPP insults. Our treatment protocol is focused on avoiding CPP below 60 mm Hg. It is possible that a more restrictive upper level could generate more stable blood pressure and less deviation from CPPopt.

Auditory brainstem response (ABR) profiling in schizoaffective disorder.

The aim of the study was to assess whether the auditory brainstem response (ABR) profiling test for schizophrenia (SZ) would recognise schizoaffective disorder (SZA) patients as SZ or not. Male and female SZA patients (n = 16) from the psychosis unit at Uppsala University Hospital were investigated. Coded sets of randomised ABR recordings intermingled with patients with SZ, adult attention-deficit hyperactivity disorder (ADHD) and healthy controls were analysed by an independent party blinded to clinical diagnoses. The ABR profiling test for SZ was positive in 5/16 patients (31%) and negative in 11/16 patients (69%) with SZA. A surprising finding was that 4/16 (25%) SZA patients were positive for the ABR profiling test for ADHD. With the ABR profiling test, a minority of patients with SZA tested positive for SZ. In contrast, a majority (85%) of patients with SZ in a previous study tested positive. These preliminary results leave us ignorant whether SZA should be regarded as a SZ-like disorder or a psychotic mood disorder and add to the questions regarding the validity of this diagnostic entity. However, the ABR profiling method is still in its infancy and its exploration in a range of psychiatric disorders is warranted.

Abstract P2-08-03: Machine learning to identify and characterize metastatic breast cancer patients in Sweden: A population-based study. CLEE011ASE01

Abstract Background: Treatment decisions for metastatic breast cancer (mBC) patients are increasingly complex and this patient subset is poorly characterized. In Sweden, despite the availability of national health registers, it is currently difficult to identify mBC patients’ true prevalence and characteristics at the national level due to lack of variables or missing information on recurrence from early to late disease. Aim: Develop an algorithm trained to identify mBC patients in Swedish national health registers to estimate the number of mBC patients and to describe their characteristics and survival outcomes. Methods: This study was a retrospective database study performed on Swedish national data (National Patient Register, Prescribed Drug Register, Cancer Register and the Cause of Death Register) linked with metastatic status, outcome and biomarker data from a regional BC register (Uppsala University Hospital) via unique personal identification number. The regional BC register data, containing medical records of known mBC and non-mBC patients between 2009-2016, were divided into a training set (n=2,680) and a test set (n=670). Based on known mBC patients’ unique features, derived from linked national data, we developed a support-vector machine (SVM) trained to identify mBC patients (further detailed in the poster). The model’s performance to classify mBC patients was measured in the test set; accuracy: 97.3%, sensitivity: 90.0%, specificity: 98.2%, balanced accuracy: 94.1%. The SVM algorithm was utilized to predict prevalent mBC cases 2009-2016 nationally. Kaplan-Meier estimates were used to model overall survival (OS) as defined from date of first metastatic diagnosis (ICD10 C78 and/or C79). Cox proportional hazard models were used to test the association between hormone receptor status (HR+/HR-) and de novo/recurrent patients. Patients were assumed to be HR+ if they had ≥2 endocrine prescriptions and de novo in case of DFS ≤3 months. Results: Between 2009 and 2016 we found a total of 150,235 patients alive with a BC diagnosis. Within this population the SVM algorithm identified a subset of 13,826 (9.2%) mBC patients corresponding to an incidence of 1,318 per year (13.7 per 100,000) and a prevalence of 5,171 per year (53.8 per 100,000). Median age at mBC diagnosis was 67.5 years and median survival was estimated at 29.8 months. 18.3% of the total mBC population were de novo patients. Median age at diagnosis was 68.7 years for de novo mBC and 67.2 years for recurrent mBC, and survival was estimated at 30.1 months and 29.7 months, respectively, with a slightly better prognosis for de novo patients (HR: 0.92; p-value&amp;lt;0.01) after adjusting for age and HR status. HR+ expression showed statistically significant association with OS (HR: 0.50; p-value&amp;lt;0.001). Median survival was calculated for the mBC population by age group. Patients &amp;lt;50 years, 50-70 years and &amp;gt;70 years at mBC diagnosis had a median survival of 43.3, 37.2, 20.1 months, respectively. Conclusion: Previous studies have used machine learning for cancer detection or prognostication. Here we show that machine learning algorithms can be applied to identify patient subsets in national population health registers. With this study design we have been able to describe the epidemiology and survival of the full national Swedish mBC population; to our knowledge this is the first study to do so. Citation Format: Henrik Lindman, Mate Szilcz, Jonatan Freilich, Peter Carlqvist, Simona Vertuani, Barbro Holm. Machine learning to identify and characterize metastatic breast cancer patients in Sweden: A population-based study. CLEE011ASE01 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-08-03.

Early-life social and health determinants of adult socioeconomic position: associations and trends across generations

BackgroundSocial and biological circumstances at birth are established predictors of adult socioeconomic position (SEP). This study aims to assess the trends in these associations across two generations and examine the...

The 100 most-cited articles in urological surgery: A bibliometric analysis.

The purpose of this bibliometric analysis was to identify and assess the 100 most-cited articles (T100 articles) on urological surgery. The Web of Science (WoS) Core Collection database was used to investigate the T100 articles in the field of urological surgery. Different aspects of the T100 articles, including the countries, journals, authors, and topics, were analyzed. The number of citations of T100 articles published between 1989 and 2016 ranged from 334 to 2189. The T100 articles originated from 28 countries, with more than half originating from the USA (n=80). Professor Bill-Axelson A from Uppsala University Hospital published the largest number of T100 articles as the first author (4) and as a coauthor (1). The Memorial Sloan Kettering Cancer Center from the USA is the top institution with the most T100 articles in the field of urological surgery. The special journal Journal of Urology published 41 of the T100 articles, which had a total of 19780 citations. Our study analyzed the 100 most-cited articles in the field of urological surgery. The USA is the dominant country in terms of the number of T100 articles, scientists and institutions. Surgery related to urological cancer has garnered the most academic attention, especially prostate cancer and renal cancer.

Trends in Reported Antibiotic Use Among Sick Children Under Five Years Across Low- and Middle-Income Countries in 2005-2017: A Systematic Analysis of 132 National Surveys from 73 Countries

Background: Global antibiotic consumption assessments have relied on pharmaceutical sales data that do not measure individual-level use, and are often unreliable or unavailable for low- and middle-income countries (LMICs). To help fill this evidence gap, we compiled data from national surveys in LMICs in 2005-2017 reporting antibiotic use for sick children under five years. Methods: Based on 132 Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 73 LMICs, we analysed trends in proportion of reported antibiotic use among children under five years with fever, diarrhoea, or cough with fast or difficult breathing symptoms by region, income classification and symptom complaint. A logit transformation was employed to estimate the outcome using a linear Bayesian regression model. The model included country-level socioeconomic, disease incidence and health system covariates to generate estimates for country-years with missing values. Findings: Across LMICs, reported antibiotic use among sick children under five years increased from 36·8% (Uncertainty Interval (UI): 28·8%-44·7%) in 2005 to 43·1% (UI: 33·2%-50·5%) in 2017. Low-income countries experienced the greatest relative increase (34%) from 29·6% (UI: 21·2%-41·1%) in 2005 to 39·5% (UI: 32·9%-47·6%) in 2017 although levels remained lowest of any income group throughout the study period. Interpretation: We found a limited but steady increase in reported antibiotic use for sick children under five years across LMICs in 2005-2017 although overlapping uncertainty intervals complicate interpretation. This increase was driven by gains in low-income countries. Our study expands the evidence-base from LMICs where strengthening antibiotic consumption and resistance surveillance is a global health priority. Funding Statement: GA-B received doctoral student salary support from the Uppsala Antibiotic Centre and Uppsala University. AM and EWJ received salary support and post-doctoral funding from Uppsala University. SS received salary support from Uppsala University Hospital. FEK received salary support from Makerere University. LH-A received salary support from Gothenburg University. Declaration of Interests: All authors declare no competing interests. Ethics Approval Statement: This study was guided by the Preferred Reporting Items of Systematic Reviews and MetaAnalyses (PRISMA) guidelines.

Predictive Scores Underestimate Survival of Patients With Metastatic Spine Disease: A Retrospective Study of 315 Patients in Sweden.

Retrospective cohort study. To validate the precision of four predictive scoring systems for spinal metastatic disease and evaluate whether they underestimate or overestimate survival. Metastatic spine disease is a common complication to malignancies. Several scoring systems are available to predict survival and to help the clinician to select surgical or nonsurgical treatment. Three hundred fifteen adult patients (213 men, 102 women, mean age 67 yr) undergoing spinal surgery at Uppsala University Hospital, Sweden, due to metastatic spine disease 2006 to 2012 were included. Data were collected prospectively for the Swedish Spine Register and retrospectively from the medical records. Tokuhashi scores, Revised Tokuhashi Scores, Tomita scores, and Modified Bauer Scores were calculated and compared with actual survival data from the Swedish Population Register. The mean estimated survival time after surgery for all patients included was 12.4 months (confidence interval 10.6-14.2) and median 5.9 months (confidence interval 4.5-7.3). All four scores had significant correlation to survival (P < 0.0001) but tended to underestimate rather than overestimate survival. Modified Bauer Score was the best of the four scores to predict short survival, both regarding median and mean survival. Tokuhashi score was found to be the best of the scores to predict long survival, even though the predictions were inaccurate in 42% of the cases. Predictive scores underestimate survival for the patients which might affect important clinical decisions. 3.

Socio-economic position at four time points across the life course and all-cause mortality: updated results from the Uppsala Birth Cohort Multigenerational Study

Socio-economic position (SEP) is associated with all-cause mortality across all stages of the life course; however, it is valuable to distinguish at what time periods SEP has the most influence on mortality. Our aim was to investigate whether the effect of SEP on all-cause mortality accumulates over the life course or if some periods of the life course are more important. Our study population were from the Uppsala Birth Cohort Multigenerational Study, born 1915–29 at Uppsala University Hospital, Sweden. We followed 3,951 men and 3,601 women who had SEP at birth available, during childhood (at age ten), in adulthood (ages 30–45) and in later life (ages 50–65) from 15 September 1980 until emigration, death or until 31 December 2010. We compared a set of nested Cox proportional regression models, each corresponding to a specific life course model (critical, sensitive and accumulation models), to a fully saturated model, to ascertain which model best describes the relationship between SEP and mortality. Analyses were stratified by gender. For both men and women the effect of SEP across the life course on all-cause mortality is best described by the sensitive period model, whereby being advantaged in later life (ages 50–65 years) provides the largest protective effect. However, the linear accumulation model also provided a good fit of the data for women suggesting that improvements in SEP at any stage of the life course corresponds to a decrease in all-cause mortality.

P104 SELECTIVE LYMPHATIC EMBOLIZATION TO MANAGE SEVERE POSTOPERATIVE LYMPHATIC LEAK

Abstract Aim To describe methods and clinical outcomes in a cohort of patients at Uppsala University Hospital who underwent selective lymphatic embolization due to severe lymphatic leak. Background &amp; Methods Surgery for malignant disease with extensive lymph node dissection in the abdomen or thorax can be complicated by postoperative lymphatic leak. This is a relatively rare condition, associated with great morbidity and can be difficult to treat. Selective embolization of leaking lymphatic vessels is a recently introduced method for management of thoracic and abdominal lymphatic leaks. Patients that had undergone treatment with selective embolization for severe lymphatic leaks were studied retrospectively. Lymphatic leaks were diagnosed with dynamic contrast enhanced magnetic resonance imaging (MRI)-lymphangiography and/or nodal lymphangiography utilizing Lipiodol. Selective embolization of leaking lymphatic vessels was performed in local anesthesia through transabdominal access, selective catheterization of lymphatic vessels with microcatheters, followed by occlusion of the vessel with coils and glue. Alternatively the leaking lymphatic vessel was occluded by injection of Lipiodol or Fibrovein via an adjacent lymph node. Data was analyzed with descriptive statistics. Results The study comprised 14 patients with severe postoperative lymphatic leak (six following transthoracic esophageal resection and eight following abdominal resections). Prior to intervention the average daily lymph output was 2092 ml and average serum albumin was 19 g/l (range 7-27). Median time from primary surgery to selective embolization was 73 days indicating that conservative treatment had previously been tried and failed. Selective embolization was successful in 93% (n=13) and in nine patients the lymphatic leak ceased instantly. A few patients needed more than one embolization procedure. Median time in hospital care after embolization was two days. No procedure-related complications occurred and only one patient later needed open surgery due to persisting lymphatic leakage. Conclusion Selective lymphatic embolization appears to be a safe and effective method with potential to preclude open surgery in patients with persistent severe postoperative lymphatic leak. The procedure can be performed under local anesthesia but demands a highly skilled and dedicated interventional radiologist. The most detailed imaging to facilitate the procedure was achieved through dynamic contrast enhanced MRI-lymphangiography.

High-Throughput Functional Ex-Vivo Drug Testing and Multi-Omics Profiling in Patients with Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common leukemia in adults and the prognosis is dismal. The heterogeneity of driver mutations in AML from one patient to another is significant. Although new treatment targets and modalities have recently been introduced, a lack of therapies to cover the entire spectrum of molecularly distinct AML classes remains a challenge. Furthermore, often only a fraction of the patients carrying mutations actually respond to the drugs predicted to target such genomic subtypes in AML. Our question was if outcome can be improved by optimizing existing and emerging therapies? To address this, we applied direct functional drug testing ex vivo in patients with newly diagnosed AML, along with deep molecular profiling to identify new therapeutic and diagnostic opportunities for specific genetic subclasses. To date, 122 patient samples have been included in the study. We have collected AML patient mononuclear cells isolated from fresh bone marrow aspirates from the Karolinska University Hospital Huddinge and Uppsala University Hospital, or applied biobanked samples from the Swedish acute leukemia biobank. The cells from the patient are tested for 72h with up to 525 conventional and investigative oncology drugs in a 5-point concentration range to determine optimal treatment options. The test is based on bulk cell viability and the cells are cultured in bone marrow stroma-conditioned media. The data is compared to healthy bone marrow controls to filter out generally toxic drugs and combinations. Excess patient material is applied for multi-omics analysis, including genome sequencing, deep proteomic profiling, concentrations of soluble factors, bulk/single-cell RNA sequencing and mass cytometry. Our results indicate significant heterogeneity in functional drug responses across individual patients, even among those with the same founder mutations. We could identify potential targeted treatments for most patients based on the exvivo testing. For instance, patients that show resistance to the Bcl-2 inhibitor Venetoclax can be associated with a distinct drug sensitivity response pattern that includes drugs with different mechanisms of actions. Based on the clustering of drug response data in all clinical samples, we could identify groups of patients with similar global drug responses, and drugs with similar patterns of efficacy across all patients. Disclosures Lehmann: Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbive: Membership on an entity's Board of Directors or advisory committees; TEVA: Consultancy, Membership on an entity's Board of Directors or advisory committees. Kallioniemi:Medisapiens: Other: Co-founder and stockholder; Sartar Therapeutics: Other: Co-founder and stockholder; Astra-Zeneca: Other: Joint Grant; Pelago: Other: Joint Grant; Takara: Other: Joint Grant; Abbot: Other: Licensing income.