A retrospective clinical and microbial analysis of 32 patients with bilomas.

BACKGROUND: Bilomas are defined collections of bile fluids mainly caused by iatrogenic injuries of the bile duct system. Owing to the infrequency of this disease, studies addressing bilomas are rare. METHODS: By using an endoscopic database, this retrospective study identified 32 patients with bilomas treated between 2004 to 2015, in order to analyse aetiology, clinical presentation, spectrum of pathogens, and resolution rate of bilomas. RESULTS: 65.6% of the study population (21/32) developed bilomas after surgery and 21.9% (7/32) after endoscopic retrograde cholangiography (ERC). Icterus, fever, and abdominal pain were the leading symptoms. 93.9% (46/49) of microbiological bile cultures revealed a positive microbiology. The predominant microorganisms were the group of Enterobacteriaceae (43.0%, 52/121), followed by Enterococcus spp. (32.2%, 39/121), and Candida spp. (9.1%, 11/121). Multiresistant bacteria like Enterobacteriaceae were isolated from one quarter of all patients. Single or multimodal treatment resulted in an overall complication rate of 4.8% (9/188). Clinical follow-up analysis showed a complete resolution rate of 78.3% for interventional therapy and 80% in the non-interventional group. CONCLUSIONS: Pathogen spectrum of bilomas mainly comprises the group of Enterobacteriacae and Enterococcus spp., with a high proportion of multiresistant bacteria. Different interventional approaches are available for biloma drainage, which seem to be safe and effective for most patients. TRIAL REGISTRATION: German Clinical Trials Register DRKS00015208 , retrospectively registered.

Randomised controlled trial comparing preoperative carbohydrate loading with standard fasting in paediatric anaesthesia.

BACKGROUND: Preoperative fasting is a major cause of perioperative discomfort in paediatric anaesthesia and leads to postoperative insulin resistance, thus potentially enhancing the inflammatory response to surgery. Addressing these problems by preoperative carbohydrate intake has not been a well-defined approach in children. METHODS: We randomised 120 children scheduled for gastroscopy under general anaesthesia to either a control group of standard preoperative fasting or a study group receiving a carbohydrate beverage (PreOp™; Nutricia, Erlangen, Germany). Their stomach contents were aspirated endoscopically, and the volume and pH measured. Perioperative discomfort was evaluated using, among other parameters, an observational pain scale in ≤4-yr-olds and a VAS in >4-yr-olds. The investigators doing the endoscopies and outcome evaluations were blinded to the study group allocation. RESULTS: Compared with fasting, carbohydrate loading was associated with significantly less gastric content (P=0.01), fewer patients experiencing postoperative nausea (P=0.028), with no significant difference in postoperative vomiting. High preoperative VAS scores (>5) were recorded for only one child in the carbohydrate group vs five children in the fasting group. Bowel cleansing for simultaneous colonoscopies (n=61) made no difference to any of the intergroup findings. CONCLUSIONS: Preoperative carbohydrates can reduce nausea and gastric content, the latter being a surrogate parameter for the risk and severity of gastric aspiration into the lungs during anaesthesia. Our study adds knowledge for preoperative fasting guidelines in paediatric anaesthesia. CLINICAL TRIAL REGISTRATION: DRKS00005020.

Radial artery applanation tonometry for continuous non-invasive arterial pressure monitoring in intensive care unit patients: comparison with invasively assessed radial arterial pressure.

BACKGROUND: Radial artery applanation tonometry technology can be used for continuous non-invasive measurement of arterial pressure (AP). The purpose of this study was to evaluate this AP monitoring technology in intensive care unit (ICU) patients in comparison with invasive AP monitoring using a radial arterial catheter. METHODS: In 24 ICU patients (German university hospital), AP values were simultaneously recorded on a beat-to-beat basis using radial artery applanation tonometry (T-Line system; Tensys Medical, San Diego, CA, USA) and a radial arterial catheter (contralateral arm). The primary endpoint of the study was to investigate the accuracy and precision of the non-invasively assessed AP measurements with the Bland-Altman method based on averaged 10 beat AP epochs (n=2993 10 beat epochs). RESULTS: For mean AP (MAP), systolic AP (SAP), and diastolic AP (DAP), we observed a bias (±standard deviation of the bias; 95% limits of agreement; percentage error) of +2 mm Hg (±6; -11 to +15 mm Hg; 15%), -3 mm Hg (±15; -33 to +27 mm Hg; 23%), and +5 mm Hg (±7; -9 to +19 mm Hg; 22%), respectively. CONCLUSIONS: In ICU patients, MAP and DAP measurements obtained using radial artery applanation tonometry show clinically acceptable agreement with invasive AP determination with a radial arterial catheter. While the radial artery applanation tonometry technology also allows SAP measurements with high accuracy, its precision for SAP measurements needs to be further improved.

Non-invasive continuous arterial pressure measurement based on radial artery tonometry in the intensive care unit: a method comparison study using the T-Line TL-200pro device.

BACKGROUND: The T-Line TL-200pro (TL-200pro) device (Tensys Medical, Inc., San Diego, CA, USA), based on radial artery tonometry, provides an arterial pressure (AP) waveform and beat-to-beat values of systolic arterial pressure (SAP), mean arterial pressure (MAP), and diastolic arterial pressure (DAP). The aim of the study was to evaluate this non-invasive technique for continuous AP monitoring in medical intensive care unit (ICU) patients. METHODS: Arterial pressure measurements obtained using the TL-200pro technology were compared using Bland-Altman analysis with values measured directly from a femoral arterial catheter in 34 ICU patients. RESULTS: Arterial pressure values were analysed and compared in 4502 averaged 10-beat epochs. A bias of +0.72 mm Hg (95% limits of agreement -9.37 to +10.82 mm Hg) was observed for MAP. For SAP and DAP, there was a mean difference of -1.39 mm Hg (95% limits of agreement -18.74 to +15.96 mm Hg) and +4.36 mm Hg (95% limits of agreement -8.66 to +17.38 mm Hg), respectively. The percentage error for MAP, SAP, and DAP was 12%, 14%, and 21%, respectively. CONCLUSIONS: Arterial pressure measurement based on radial artery tonometry using the TL-200pro technology is feasible in medical ICU patients. The TL-200pro system is capable of providing MAP values with high accuracy (low mean difference) and precision (narrow limits of agreement) compared with MAP measured invasively using a femoral arterial catheter. The TL-200pro technology is promising for the measurement of SAP and DAP but further development is necessary to improve accuracy and precision.

Bispectral index monitoring of midazolam and propofol sedation during endoscopic retrograde cholangiopancreatography: a randomized clinical trial (the EndoBIS study).

INTRODUCTION: Bispectral index (BIS) monitoring provides a non-invasive measure of the level of sedation. The purpose of this randomized, single-blind clinical trial was to evaluate whether BIS monitoring of sedation would lead to improved oxygenation and a reduced rate of cardiopulmonary complications during endoscopy. PATIENTS AND METHODS: Patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) under procedural sedation with a combination of low dose midazolam and propofol were randomly assigned to either standard monitoring of sedation only (BIS-blinded arm) or an open arm in which additional BIS monitoring was available (BIS-open arm). In the BIS-open arm, propofol administration was to be withheld if BIS values were <55. The primary study end point was the mean oxygen saturation per patient. Secondary end points were the rates of cardiopulmonary complications, propofol dose, quality of sedation (patient cooperation as rated by the endoscopist and patient satisfaction), and recovery. RESULTS: A total of 144 patients were enrolled and included in the intention-to-treat analysis. Mean oxygen saturation per patient was 97.7% in the BIS-open arm and 97.6% in the BIS-blinded arm (P=0.71). Total rates of cardiopulmonary complications, single numbers of hypoxemic, bradycardic, and hypotensive events, mean propofol doses, and quality of sedation also showed no statistically significant differences between the groups. However, BIS monitoring did result in faster recovery of patients as reflected by shorter times to eye opening (P=0.001), first verbal response (P=0.02), and leaving the procedure room (P<0.001). CONCLUSIONS: The use of additional BIS monitoring did not lead to improved oxygenation or a reduced rate of cardiopulmonary complications. Recovery times after the procedure were shorter than with standard monitoring alone, but the clinical benefit for daily practice may be limited.

Hemodynamics after endoscopic submucosal injection of epinephrine in a porcine model.

BACKGROUND AND STUDY AIMS: Endoscopic submucosal injection of epinephrine may cause systemic effects on the cardiovascular system. The aim of this experimental study was to assess systemic hemodynamic changes after submucosal injection of epinephrine during upper gastrointestinal endoscopy in a porcine model. METHODS: Measurements were taken from 12 pigs under general anesthesia. During gastroscopy 5 mL of normal saline, and 2.5 mL and 5 mL of epinephrine (1:10,000) were injected into the submucosal layers of the gastric antrum, corpus, and distal esophagus. After each injection, the cardiac index and global end diastolic volume index (GEDVI, reflecting preload) were measured every 3 minutes by transpulmonary thermodilution for a minimum of 12 minutes. The following parameters were also recorded: heart rate, mean arterial pressure (MAP), and systemic vascular resistance index (SVRI, reflecting afterload). RESULTS: Significant hemodynamic changes were observed after submucosal injection of epinephrine into the esophagus, including heart rate (maximum + 4 %) and MAP (maximum - 4%) after injection of 2.5 mL epinephrine, and stronger changes in heart rate (maximum +13%), cardiac index (maximum +21%), MAP (maximum -4%), and SVRI (maximum -12%) after the injection of 5 mL epinephrine. After submucosal injection of epinephrine into the gastric antrum and corpus, hemodynamic effects were less evident. Here significant changes were observed in heart rate (maximum +3%), MAP (maximum -2%), cardiac index (maximum +7%), and SVRI (maximum -8%) only after the injection of 5 mL epinephrine into the antrum. CONCLUSION: Endoscopic submucosal injection of epinephrine is associated with changes in systemic hemodynamic parameters, especially when performed in the esophagus, and the procedure might therefore induce harmful side effects.

Stenotrophomonas maltophilia in the respiratory tract of medical intensive care unit patients.

The purpose of this study was to investigate characteristics of critically ill patients with Stenotrophomonas maltophilia (S. maltophilia) isolated from the respiratory tract, to identify risk factors for S. maltophilia-pneumonia and intensive care unit (ICU) mortality and to analyze antibiotic susceptibility of S. maltophilia. This was a retrospective analysis of 64 medical ICU patients with S. maltophilia in the respiratory tract. Thirty-six patients fulfilled the criteria for diagnosis of pneumonia. A significantly higher lung injury score (LIS) was observed in patients with pneumonia compared to patients with colonization (p=0.010). Independent risk factors for S. maltophilia-pneumonia were higher Sequential Organ Failure Assessment (SOFA) score (p=0.009) and immunosuppression (p=0.014). Patients with S. maltophilia-pneumonia had higher ICU mortality within a 28-day follow-up (p=0.040) and higher hospital mortality (p=0.018) than patients with colonization. The highest antibiotic susceptibility rates were observed to trimethoprim-sulfamethoxazole, tigecycline, and moxifloxacin. Higher SOFA score when S. maltophilia was isolated (p=0.001) and development of renal failure (p=0.021) were independent risk factors for ICU mortality. Higher SOFA score and immunosuppression are independent risk factors for S. maltophilia-pneumonia. Patients with S. maltophilia-pneumonia have a significantly higher ICU mortality within a 28-day follow-up, hospital mortality and LIS compared to patients with S. maltophilia-colonization.

Quality assessment and data analysis for microRNA expression arrays.

MicroRNAs are small (approximately 22 nt) RNAs that regulate gene expression and play important roles in both normal and disease physiology. The use of microarrays for global characterization of microRNA expression is becoming increasingly popular and has the potential to be a widely used and valuable research tool. However, microarray profiling of microRNA expression raises a number of data analytic challenges that must be addressed in order to obtain reliable results. We introduce here a universal reference microRNA reagent set as well as a series of nonhuman spiked-in synthetic microRNA controls, and demonstrate their use for quality control and between-array normalization of microRNA expression data. We also introduce diagnostic plots designed to assess and compare various normalization methods. We anticipate that the reagents and analytic approach presented here will be useful for improving the reliability of microRNA microarray experiments.

[Diagnosis and treatment of acute pancreatitis. Current recommendations]. / Diagnostik und Therapie der akuten Pankreatitis. Aktuelle Empfehlungen.

Acute pancreatitis is a potentially life-threatening illness, with a short time frame for diagnosis and treatment. A number of recent experimental and clinical multicentre trials as well as meta-analyses have provided more far-reaching recommendations compared to previous guidelines. To answer 12 key questions, we performed a review of recent literature and current guidelines. Diagnosis can be made on the basis of history, physical examination and serum lipase alone. Cholestatic parameters and upper abdominal ultrasound enable verification of biliary etiology. Poor prognostic indicators include elevated blood sugar, BUN and hematocrit. The latter suggests early, adequate volume replacement, which should be tailored to the clinical picture, echocardiography and/or modern hemodynamic parameters. In addition to opiate analgesia, meta-analyses support the use of endoscopic retrograde cholangiography in pancreatitis of biliary origin, antibiotics in necrotizing pancreatitis and early enteral feeding. Even where necrosis is present, conservative management (radiologically or endoscopically placed drains) is appropriate.

Biomarkers of Inflammation and Oxidative Stress among Adult Former Smoker, Current E-Cigarette Users-Results from Wave 1 PATH Study.

BACKGROUND: Former smokers who currently use e-cigarettes have lower concentrations of biomarkers of tobacco toxicant exposure than current smokers. It is unclear whether tobacco toxicant exposure reductions may lead to health risk reductions. METHODS: We compared inflammatory biomarkers (high-sensitivity C-reactive protein, IL6, fibrinogen, soluble intercellular adhesion molecule-1) and an oxidative stress marker (F2-isoprostane) among 3,712 adult participants in Wave 1 (2013-2014) of the Population Assessment of Tobacco and Health Study by tobacco user groups: dual users of cigarettes and e-cigarettes; former smokers who currently use e-cigarettes-only; current cigarette-only smokers; former smokers who do not currently use any tobacco; and never tobacco users. We calculated geometric means (GM) and estimated adjusted GM ratios (GMR). RESULTS: Dual users experienced greater concentration of F2-isoprostane than current cigarette-only smokers [GMR 1.09 (95% confidence interval, CI, 1.03-1.15)]. Biomarkers were similar between former smokers who currently use e-cigarettes and both former smokers who do not use any tobacco and never tobacco users, but among these groups most biomarkers were lower than those of current cigarette-only smokers. The concentration of F2-isoprostane decreased by time since smoking cessation among both exclusive e-cigarette users (P trend = 0.03) and former smokers who do not currently use any tobacco (P trend = 0.0001). CONCLUSIONS: Dual users have greater concentration of F2-isoprostane than smokers. Exclusive e-cigarette users have biomarker concentrations that are similar to those of former smokers who do not currently use tobacco, and lower than those of exclusive cigarette smokers. IMPACT: This study contributes to an understanding of the health effects of e-cigarettes.

Options in extracorporeal support of multiple organ failure.

Multiorgan failure is among the most frequent reasons of death in critically ill patients. Based on extensive and long-term use of renal replacement therapy, extracorporeal organ support became available for other organ failures. Initially, most of these techniques (e.g. extracorporeal membrane oxygenation, extracorporeal CO2 removal [ECCO2R] and extracorporeal liver support) were used as stand-alone single organ support systems. Considering multiple interactions between native organs ("crosstalk"), combined or integrated extracorporeal organ support (ECOS) devices are intriguing. The concept of multiple organ support therapy (MOST) providing simultaneous and combined support for different failing organs was described more than 15 years ago by Ronco and Bellomo. This concept also implicates overcoming the "compartmentalized" approach provided by different single organ specialized professionals by a multidisciplinary and multiprofessional strategy. The idea of MOST is supported by the failure of several recent studies on single organ support including liver and lung support. Improvement of outcome by ECOS necessarily depends on optimized patient selection, integrated organ support and limitation of its side effects. This implicates challenges for engineers, industry and healthcare professionals. From a technical viewpoint, modular combination of pre-existing technologies such as renal replacement, albumin-dialysis, ECCO2R and potentially cytokine elimination can be considered as a first step. While this allows for stepwise and individual combination of standard organ support facilities, it carries the disadvantage of large extracorporeal blood volume and surfaces as well as additive costs. The more intriguing next step is an integrated platform providing the capacity of multiple organ support within one device. (This article is freely available.).

Infected necrosis in severe pancreatitis--combined nonsurgical multi-drainage with directed transabdominal high-volume lavage in critically ill patients.

BACKGROUND: Infection of pancreatic necrosis is a life-threatening complication during the course of acute pancreatitis. In critically ill patients, surgical or extended endoscopic interventions are associated with high morbidity and mortality. Minimally invasive procedures on the other hand are often insufficient in patients suffering from large necrotic areas containing solid or purulent material. We present a strategy combining percutaneous and transgastric drainage with continuous high-volume lavage for treatment of extended necroses and liquid collections in a series of patients with severe acute pancreatitis. PATIENTS AND METHODS: Seven consecutive patients with severe acute pancreatitis and large confluent infected pancreatic necrosis were enrolled. In all cases, the first therapeutic procedure was placement of a CT-guided drainage catheter into the fluid collection surrounding peripancreatic necrosis. Thereafter, a second endosonographically guided drainage was inserted via the gastric or the duodenal wall. After communication between the separate drains had been proven, an external to internal directed high-volume lavage with a daily volume of 500 ml up to 2,000 ml was started. RESULTS: In all patients, pancreatic necrosis/liquid collections could be resolved completely by the presented regime. No patient died in the course of our study. After initiation of the directed high-volume lavage, there was a significant clinical improvement in all patients. Double drainage was performed for a median of 101 days, high-volume lavage for a median of 41 days. Several endoscopic interventions for stent replacement were required (median 8). Complications such as bleeding or perforation could be managed endoscopically, and no subsequent surgical therapy was necessary. All patients could be dismissed from the hospital after a median duration of 78 days. CONCLUSION: This approach of combined percutaneous/endoscopic drainage with high-volume lavage shows promising results in critically ill patients with extended infected pancreatic necrosis and high risk of surgical intervention. Neither surgical nor endoscopic necrosectomy was necessary in any of our patients.

Failure of current antibiotic first-line regimens and mortality in hospitalized patients with spontaneous bacterial peritonitis.

BACKGROUND: Increases in Gram-positive infections and infections with Enterobacteriaceae with antimicrobial resistance have been reported in patients with spontaneous bacterial peritonitis (SBP). This study was performed to investigate the rate of treatment failures of recommended empirical therapies and the impact on mortality. PATIENTS AND METHODS: A prospectively collected database comprising 101 patients with SBP (70 nosocomial, 31 community acquired) treated at a university hospital between 2002 and 2006 in Munich, Germany, was analyzed. RESULTS: 17 patients initially received a broader than recommended antibiotic regimen. Most of these were treated in the intensive care unit because of severe sepsis/septic shock. Hospital mortality in this group was 82%. A modification of therapy was necessary in 24 of the 84 patients receiving one of the published first-line therapies (cefotaxime, ampicillin/clavulanate, or ciprofloxacin). Mortality was significantly higher in these patients than in those with no change in treatment (66.7% vs 30%, p = 0.002). In 29 patients with positive cultures, mortality was also higher in those with an ineffective first-line treatment (90% vs 45%, p = 0.032). In the multivariable analysis, a modification of antibiotic treatment was an independent risk factor for mortality (odds ratio 5.876, 95% confidence interval 1.826-18.910, p = 0.003). In 41 culture-positive cases, the most commonly cultured pathogens were Escherichia coli (n = 17) and Enterococcus faecium (n = 10). Of the encountered bacterial microorganisms, 14 (33.3%) were resistant to cefotaxime, 17 (38.6%) were resistant to amoxicillin/clavulanate, and 19 (45.2%) were resistant to ciprofloxacin. 29 (64.4%) of the isolates were resistant to one of the recommended firstline antibiotic regimens, and 11 (24.4%) of the isolates were resistant to all three. CONCLUSION: Recommended empirical antibiotic regimens fail to achieve the desired effect in a substantial number of hospitalized patients with SBP. This has a negative impact on mortality.

Determination of enzyme activity inhibition by FTIR spectroscopy on the example of fructose bisphosphatase.

A mid-infrared enzymatic assay for label-free monitoring of the enzymatic reaction of fructose-1,6-bisphosphatase with fructose 1,6-bisphosphate has been proposed. The whole procedure was done in an automated way operating in the stopped flow mode by incorporating a temperature-controlled flow cell in a sequential injection manifold. Fourier transform infrared difference spectra were evaluated for kinetic parameters, like the Michaelis-Menten constant (K(M)) of the enzyme and Vmax of the reaction. The obtained K(M) of the reaction was 14 +/- 3 g L(-1) (41 microM). Furthermore, inhibition by adenosine 5'-monophosphate (AMP) was evaluated, and the K(M)(App) value was determined to be 12 +/- 2 g L(-1) (35 microM) for 7.5 and 15 microM AMP, respectively, with Vmax decreasing from 0.1 +/- 0.03 to 0.05 +/- 0.01 g L(-1) min(-1). Therefore, AMP exerted a non-competitive inhibition.

A rare reason for the end of a career in competitive tennis.

Stress fractures are reported in adolescents taking part in high standard sports and they are associated with specific sites for stress fractures. The first rib is also affected in rowers and ball throwing sports. This report describes the complications of such a case in a competitive tennis player at international level practicing 5 times a week with far-reaching consequences. Due to constant load dependent pain in the region of the right shoulder, standard diagnosis, X-ray, magnetic resonance imaging (MRI) and a computed tomography (CT) scan with 3-D reconstruction were done, showing a pseudoarthrosis of the first rib. Therefore, further treatment was conservative without pain relieve. At follow-up 5 years after onset of symptoms the patient did not play tennis, he did not complain pain, but control imaging still showed a pseudoarthrosis of the first rib. Our case shows that it is important, when treating shoulder pain in the overhead athlete, to think of the possibility of a stress fracture.

Advanced hemodynamic monitoring in intensive care medicine : A German web-based survey study.

BACKGROUND: Advanced hemodynamic monitoring is recommended in patients with complex circulatory shock. OBJECTIVES: To evaluate the current attitudes and beliefs among German intensivists, regarding advanced hemodynamic monitoring, the actual hemodynamic management in clinical practice, and the barriers to using it. MATERIALS AND METHODS: Web-based survey among members of the German Society of Medical Intensive Care and Emergency Medicine. RESULTS: Of 284 respondents, 249 (87%) agreed that further hemodynamic assessment is needed to determine the type of circulatory shock if no clear clinical diagnosis can be made. In all, 281 (99%) agreed that echocardiography is helpful for this purpose (transpulmonary thermodilution: 225 [79%]; pulmonary artery catheterization: 126 [45%]). More than 70% of respondents agreed that blood flow variables (cardiac output, stroke volume) should be measured in patients with hemodynamic instability. The parameters most respondents agreed should be assessed in a patient with hemodynamic instability were mean arterial pressure, cardiac output, and serum lactate. Echocardiography is available in 99% of ICUs (transpulmonary thermodilution: 91%; pulmonary artery catheter: 63%). The respondents stated that, in clinical practice, invasive arterial pressure measurements and serum lactate measurements are performed in more than 90% of patients with hemodynamic instability (cardiac output monitoring in about 50%; transpulmonary thermodilution in about 40%). The respondents did not feel strong barriers to the use of advanced hemodynamic monitoring in clinical practice. CONCLUSIONS: This survey study shows that German intensivists deem advanced hemodynamic assessment necessary for the differential diagnosis of circulatory shock and to guide therapy with fluids, vasopressors, and inotropes in ICU patients.

Drug-based perturbation screen uncovers synergistic drug combinations in Burkitt lymphoma.

Burkitt lymphoma (BL) is a highly aggressive B-cell lymphoma associated with MYC translocation. Here, we describe drug response profiling of 42 blood cancer cell lines including 17 BL to 32 drugs targeting key cancer pathways and provide a systematic study of drug combinations in BL cell lines. Based on drug response, we identified cell line specific sensitivities, i.e. to venetoclax driven by BCL2 overexpression and partitioned subsets of BL driven by response to kinase inhibitors. In the combination screen, including BET, BTK and PI3K inhibitors, we identified synergistic combinations of PI3K and BTK inhibition with drugs targeting Akt, mTOR, BET and doxorubicin. A detailed comparison of PI3K and BTKi combinations identified subtle differences, in line with convergent pathway activity. Most synergistic combinations were identified for the BET inhibitor OTX015, which showed synergistic effects for 41% of combinations including inhibitors of PI3K/AKT/mTOR signalling. The strongest synergy was observed for the combination of the CDK 2/7/9 inhibitor SNS032 and OTX015. Our data provide a landscape of drug combination effects in BL and suggest that targeting CDK and BET could provide a novel vulnerability of BL.

Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.

T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.