Diagnosis and management of acute lower gastrointestinal bleeding: European Society of Gastrointestinal Endoscopy (ESGE) Guideline.

1: ESGE recommends that the initial assessment of patients presenting with acute lower gastrointestinal bleeding should include: a history of co-morbidities and medications that promote bleeding; hemodynamic parameters; physical examination (including digital rectal examination); and laboratory markers. A risk score can be used to aid, but should not replace, clinician judgment.Strong recommendation, low quality evidence. 2 : ESGE recommends that, in patients presenting with a self-limited bleed and no adverse clinical features, an Oakland score of ≤ 8 points can be used to guide the clinician decision to discharge the patient for outpatient investigation.Strong recommendation, moderate quality evidence. 3 : ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and no history of cardiovascular disease, a restrictive red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 7 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of 7-9 g/dL is desirable.Strong recommendation, low quality evidence. 4 : ESGE recommends, in hemodynamically stable patients with acute lower gastrointestinal bleeding and a history of acute or chronic cardiovascular disease, a more liberal red blood cell transfusion strategy, with a hemoglobin threshold of ≤ 8 g/dL prompting red blood cell transfusion. A post-transfusion target hemoglobin concentration of ≥ 10 g/dL is desirable.Strong recommendation, low quality evidence. 5: ESGE recommends that, in patients with major acute lower gastrointestinal bleeding, colonoscopy should be performed sometime during their hospital stay because there is no high quality evidence that early colonoscopy influences patient outcomes.Strong recommendation, low quality of evidence. 6 : ESGE recommends that patients with hemodynamic instability and suspected ongoing bleeding undergo computed tomography angiography before endoscopic or radiologic treatment to locate the site of bleeding.Strong recommendation, low quality evidence. 7 : ESGE recommends withholding vitamin K antagonists in patients with major lower gastrointestinal bleeding and correcting their coagulopathy according to the severity of bleeding and their thrombotic risk. In patients with hemodynamic instability, we recommend administering intravenous vitamin K and four-factor prothrombin complex concentrate (PCC), or fresh frozen plasma if PCC is not available.Strong recommendation, low quality evidence. 8 : ESGE recommends temporarily withholding direct oral anticoagulants at presentation in patients with major lower gastrointestinal bleeding.Strong recommendation, low quality evidence. 9: ESGE does not recommend withholding aspirin in patients taking low dose aspirin for secondary cardiovascular prevention. If withheld, low dose aspirin should be resumed, preferably within 5 days or even earlier if hemostasis is achieved or there is no further evidence of bleeding.Strong recommendation, moderate quality evidence. 10: ESGE does not recommend routinely discontinuing dual antiplatelet therapy (low dose aspirin and a P2Y12 receptor antagonist) before cardiology consultation. Continuation of the aspirin is recommended, whereas the P2Y12 receptor antagonist can be continued or temporarily interrupted according to the severity of bleeding and the ischemic risk. If interrupted, the P2Y12 receptor antagonist should be restarted within 5 days, if still indicated.Strong recommendation, low quality evidence.

Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage (NVUGIH): European Society of Gastrointestinal Endoscopy (ESGE) Guideline - Update 2021.

1: ESGE recommends in patients with acute upper gastrointestinal hemorrhage (UGIH) the use of the Glasgow-Blatchford Score (GBS) for pre-endoscopy risk stratification. Patients with GBS ≤ 1 are at very low risk of rebleeding, mortality within 30 days, or needing hospital-based intervention and can be safely managed as outpatients with outpatient endoscopy.Strong recommendation, moderate quality evidence. 2: ESGE recommends that in patients with acute UGIH who are taking low-dose aspirin as monotherapy for secondary cardiovascular prophylaxis, aspirin should not be interrupted. If for any reason it is interrupted, aspirin should be re-started as soon as possible, preferably within 3-5 days.Strong recommendation, moderate quality evidence. 3: ESGE recommends that following hemodynamic resuscitation, early (≤ 24 hours) upper gastrointestinal (GI) endoscopy should be performed. Strong recommendation, high quality evidence. 4: ESGE does not recommend urgent (≤ 12 hours) upper GI endoscopy since as compared to early endoscopy, patient outcomes are not improved. Strong recommendation, high quality evidence. 5: ESGE recommends for patients with actively bleeding ulcers (FIa, FIb), combination therapy using epinephrine injection plus a second hemostasis modality (contact thermal or mechanical therapy). Strong recommendation, high quality evidence. 6: ESGE recommends for patients with an ulcer with a nonbleeding visible vessel (FIIa), contact or noncontact thermal therapy, mechanical therapy, or injection of a sclerosing agent, each as monotherapy or in combination with epinephrine injection. Strong recommendation, high quality evidence. 7 : ESGE suggests that in patients with persistent bleeding refractory to standard hemostasis modalities, the use of a topical hemostatic spray/powder or cap-mounted clip should be considered. Weak recommendation, low quality evidence. 8: ESGE recommends that for patients with clinical evidence of recurrent peptic ulcer hemorrhage, use of a cap-mounted clip should be considered. In the case of failure of this second attempt at endoscopic hemostasis, transcatheter angiographic embolization (TAE) should be considered. Surgery is indicated when TAE is not locally available or after failed TAE. Strong recommendation, moderate quality evidence. 9: ESGE recommends high dose proton pump inhibitor (PPI) therapy for patients who receive endoscopic hemostasis and for patients with FIIb ulcer stigmata (adherent clot) not treated endoscopically. (A): PPI therapy should be administered as an intravenous bolus followed by continuous infusion (e. g., 80 mg then 8 mg/hour) for 72 hours post endoscopy. (B): High dose PPI therapies given as intravenous bolus dosing (twice-daily) or in oral formulation (twice-daily) can be considered as alternative regimens.Strong recommendation, high quality evidence. 10: ESGE recommends that in patients who require ongoing anticoagulation therapy following acute NVUGIH (e. g., peptic ulcer hemorrhage), anticoagulation should be resumed as soon as the bleeding has been controlled, preferably within or soon after 7 days of the bleeding event, based on thromboembolic risk. The rapid onset of action of direct oral anticoagulants (DOACS), as compared to vitamin K antagonists (VKAs), must be considered in this context.Strong recommendation, low quality evidence.

Is fasting still necessary prior to contrast-enhanced computed tomography? A randomized clinical study.

OBJECTIVES: There is very limited evidence to support the common practice of preparative fasting prior to contrast-enhanced computerized tomography (CT). This study examined the effect of withholding fasting orders, prior to contrast-enhanced CT, on the incidence of aspiration pneumonitis and adverse gastrointestinal symptoms. METHODS: This randomized controlled trial enrolled hospitalized patients referred for non-emergency, contrast-enhanced CT scan to either at least 4 h of fasting or to an unrestricted consumption of liquids and solids up to the time of CT. The primary outcome was incidence of aspiration pneumonitis and the secondary outcomes were rates of adverse gastrointestinal symptoms (nausea and/or vomiting). RESULTS: After excluding participants with incomplete follow-up, a total of 1080 participants were assigned to the fasting group and 1011 were assigned to the non-fasting group. Aspiration pneumonitis was not identified in either group. The mean time of fasting in the fasting group was 8.4 ± 1.6 h. Rates of nausea and vomiting were not statistically different between the fasting group compared with the non-fasting group, 6.6% vs. 7.6% (p = 0.37) and 2.6% vs. 3.0% (p = 0.58), respectively. A subgroup analysis of patients who were required to drink oral contrast agent (n = 1257) showed that rates of nausea and vomiting were not statistically different between the fasting and non-fasting groups, 6.8% vs. 8.0% (p = 0.42) and 2.6% vs. 3.6% (p = 0.3), respectively. CONCLUSIONS: Withholding fasting orders prior to contrast-enhanced CT was not associated with a greater risk of aspiration pneumonitis or a significant increase in rates of adverse gastrointestinal symptoms. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03533348 KEY POINTS: • Is fasting necessary prior to contrast-enhanced computed tomography (CT)? • In this randomized clinical study including 2091 participants referred to non-emergency contrast-enhanced CT scan, withholding preparative fasting was not associated with a greater risk of aspiration pneumonitis or clinically significant increase in rates of adverse gastrointestinal symptoms. • Eating and drinking prior to contrast-enhanced CT can be allowed and are not associated with an increased risk of aspiration pneumonitis.

COVID-19 classification of X-ray images using deep neural networks.

OBJECTIVES: In the midst of the coronavirus disease 2019 (COVID-19) outbreak, chest X-ray (CXR) imaging is playing an important role in diagnosis and monitoring of patients with COVID-19. We propose a deep learning model for detection of COVID-19 from CXRs, as well as a tool for retrieving similar patients according to the model's results on their CXRs. For training and evaluating our model, we collected CXRs from inpatients hospitalized in four different hospitals. METHODS: In this retrospective study, 1384 frontal CXRs, of COVID-19 confirmed patients imaged between March and August 2020, and 1024 matching CXRs of non-COVID patients imaged before the pandemic, were collected and used to build a deep learning classifier for detecting patients positive for COVID-19. The classifier consists of an ensemble of pre-trained deep neural networks (DNNS), specifically, ReNet34, ReNet50¸ ReNet152, and vgg16, and is enhanced by data augmentation and lung segmentation. We further implemented a nearest-neighbors algorithm that uses DNN-based image embeddings to retrieve the images most similar to a given image. RESULTS: Our model achieved accuracy of 90.3%, (95% CI: 86.3-93.7%) specificity of 90% (95% CI: 84.3-94%), and sensitivity of 90.5% (95% CI: 85-94%) on a test dataset comprising 15% (350/2326) of the original images. The AUC of the ROC curve is 0.96 (95% CI: 0.93-0.97). CONCLUSION: We provide deep learning models, trained and evaluated on CXRs that can assist medical efforts and reduce medical staff workload in handling COVID-19. KEY POINTS: • A machine learning model was able to detect chest X-ray (CXR) images of patients tested positive for COVID-19 with accuracy and detection rate above 90%. • A tool was created for finding existing CXR images with imaging characteristics most similar to a given CXR, according to the model's image embeddings.

Sacral Soft Tissue Deformations When Using a Prophylactic Multilayer Dressing and Positioning System: MRI Studies.

PURPOSE: The sacrum is the most common location of pressure injuries (PIs) in bedridden patients. The purpose of this study was to measure the effect of specific pressure preventive devices on sacral skeletal muscle, subcutaneous fat, and skin tissue deformations. SUBJECTS AND SETTING: The sample comprised 3 healthy adults residing in a community setting in Tel Aviv, Israel. DESIGN: Descriptive, comparative design. METHODS: Tissue thickness changes of 3 healthy adults were measured using magnetic resonance imaging (MRI) in weight-bearing sacral skin, subcutaneous fat, and muscle. Changes in tissue thickness were compared under the following conditions: (1) lying supine on a rigid surface (unpadded MRI table), (2) lying on a standard foam mattress, (3) lying on a mattress after application of a prophylactic multilayer dressing, and (4) lying on a standard foam mattress with a prophylactic multilayer dressing and a positioning system. One-way analysis of variance and post hoc Tukey-Kramer multiple pairwise comparisons were used to compare outcomes. RESULTS: The mattress, the prophylactic multilayer dressing, and the turning and positioning device when applied together resulted in significantly lower deformation levels of each of the soft tissue layers (ie, skin, subcutaneous fat, and muscle separately) as well as of the total soft tissue bulk, with respect to the rigid MRI table (P < .05). CONCLUSION: Study findings suggest that a combination of preventive interventions may reduce the risk of developing a sacral PI.

Electrically conductive catheter inhibits bacterial colonization.

PURPOSE: To design, prototype, and assess a custom vascular access catheter for its ability to inhibit bacterial colonization in vitro and to optimize electric parameters for efficacy and safe translation. MATERIALS AND METHODS: A vascular access catheter with conductive elements was designed and custom fabricated with two electrodes at the tip, separated by a nonconductive segment. The catheter was colonized with Staphylococcus aureus and incubated at predetermined current levels (4-8 µA) and durations (4-24 h). Catheters were compared using bacterial counts and scanning electron microscopy (SEM). RESULTS: Bacteria colony-forming units were reduced significantly (P < .05) by > 90% (91.7%-100%) in all uninterrupted treatment arms that included electric current (4 µA or 8 µA) of at least 8 hours' duration. Qualitative analysis using SEM revealed that the treated catheter exposed to electric current had markedly less bacteria compared with the untreated catheter. CONCLUSIONS: This catheter with conductive elements inhibits bacterial colonization in vitro when very small electric current (4-8 µA) is applied across the tip for 8-24 hours. In vivo validation is requisite to future translation to the clinical setting.

Phase I study of heat-deployed liposomal doxorubicin during radiofrequency ablation for hepatic malignancies.

PURPOSE: A phase I dose escalation study was performed with systemically delivered lyso-thermosensitive liposomal doxorubicin (LTLD). The primary objectives were to determine the safe maximum tolerated dose (MTD), pharmacokinetic properties, and dose-limiting toxicity (DLT) of LTLD during this combination therapy. MATERIALS AND METHODS: Subjects eligible for percutaneous or surgical radiofrequency (RF) ablation with primary (n = 9) or metastatic (n = 15) tumors of the liver, with four or fewer lesions as large as 7 cm in diameter, were included. RF ablation was initiated 15 minutes after starting a 30-minute intravenous LTLD infusion. Dose levels between 20 mg/m(2) and 60 mg/m(2) were evaluated. Magnetic resonance imaging, positron emission tomography, and computed tomography were performed at predetermined intervals before and after treatment until evidence of recurrence was seen, administration of additional antitumor treatment was performed, or a total of 3 years had elapsed. RESULTS: DLT criteria were met at 60 mg/m(2), and the MTD was defined as 50 mg/m(2). RF ablation was performed during the peak of the plasma concentration-time curve in an effort to yield maximal drug deposition. LTLD produced reversible, dose-dependent neutropenia and leukopenia. CONCLUSIONS: LTLD can be safely administered systemically at the MTD (50 mg/m(2)) in combination with RF ablation, with limited and manageable toxicity. Further evaluation of this agent combined with RF ablation is warranted to determine its role in the management of liver tumors.

Association of proton pump inhibitor use with the development of febrile neutropenia in lymphoma patients.

Background: Proton pump inhibitors (PPIs), although relatively safe drugs for reduction of gastric acid production, continue to raise concerns (i.e. potential infectious complications, electrolyte disturbances). PPIs are frequently administered to hemato-oncological patients receiving chemotherapy. The study main objective is to investigate whether PPI use by hemato-oncological patients receiving chemotherapy raises the risk of febrile neutropenia.Methods: This is a retrospective database study of patients under hemato-oncological follow up between January 2007 and December 2015, treated with different chemotherapy regimens. Comparative analysis assessed frequencies and types of febrile neutropenia among patients with or without PPI treatment. Multivariate analyses were performed adjusting for age, sub-type of malignancy and specific PPI administered.Results: 247 patients were included, 18-91 years of age (mean 61.6 ± 16), 120 (48.58%) female; amongst 66 (26%) how were hospitalized for febrile neutropenia, 50 (75.8%) received PPIs.Multivariate analysis found three risk factors associated with the development of febrile neutropenia in hematological patients: age, diffuse large B-cell lymphoma and treatment with PPIs.Conclusion: A statistically significant association was demonstrated between PPI treatment and the development of febrile neutropenia among hemato-oncological patients. The clinical implications necessitate further caution in administering PPIs to patients with hematological malignancy receiving chemotherapy.

New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease.

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer's disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual's manifestation of AD as influenced by a coercive inflammatory gut.

CT definition of the surgical apex in the orbit.

The orbital apex is an undefined but well understood concept of Orbital Surgeons. We sought to determine the surgical apex area specifically where the volume ratio decreases significantly impacting on the optic nerve. A retrospective analysis using PACS program processing, measured the right retrobulbar space volume changes in 100 randomly selected cases without orbital pathology where CT was performed for non-ophthalmic indications. Volume of the retrobulbar space was measured between two recognizable landmarks. The first landmark being the point of exit of the optic nerve from the eye and the second landmark the optic nerve's point of exit from the orbit. The measured length between these two points was divided into five equal segments, V1-V5. The volumes of all 5 segments were compared and the most significant area of volume depletion was established. The mean numeric value of measured orbital volumes was compared. A ratio difference of V1/V2 was less than 2, V2/V3 was 2.32 (± 0.27), V3/4 was 3.24 (± 0.39), and V4/V5 was 5.67 (± 1.66). The most remarkable difference in ratio was between V4 and V5 (mean 5.67 ± 1.66 with p < .0001). The V3 segment (the posterior 3/5 of the retrobulbar space volume) is the location where decrease in orbital volume impacts, and measured ratios are statistically significant. We defined the surgical apex as the posterior 3/5 of the retro-bulbar orbital space. It is consequently the area of higher risk for optic nerve compression. This definition could be routinely utilized by ophthalmologists and neuroradiologists when evaluating masses affecting the orbit.

Ultrasound elastography reveals the relation between body posture and soft-tissue stiffness which is relevant to the etiology of sitting-acquired pressure ulcers.

OBJECTIVE: Sitting-acquired pressure ulcers (PUs) are common in wheelchair users. These PUs are often serious and may involve deep tissue injury (DTI). Investigating the mechanical properties of the tissues susceptible to DTI may help in guiding the prevention and early detection of PUs. In this study, shear wave elastography (SWE) was used to measure the normative mechanical properties of the soft tissues of the buttocks, i.e. skeletal muscle and subcutaneous fat, under the ischial tuberosities, in a convenient sample of healthy adults without weight bearing and with weight bearing of different times. APPROACH: We compared the stiffness properties of these soft tissues between the lying prone and sitting postures, to determine whether there are detectable property changes that may be associated with the type of posture. We hypothesized that muscle contractions and 3D tissue configurations associated with the posture may influence the measured tissue stiffnesses. MAIN RESULTS: Our results have shown that indeed, SWE values differed significantly across postures, but not over time in a specific posture or for the right versus left sides of the body. SIGNIFICANCE: We have therefore demonstrated that soft-tissue stiffness increases when sitting with weight bearing and may contribute to increasing the potential PU risk in sitting compared to lying prone, given the stiffer behavior of tissues observed in sitting postures.

The use of Ursolit for gallstone prophylaxis following bariatric surgery: a randomized-controlled trial.

BACKGROUND: Although bariatric surgery (BS) predisposes patients to development of gallstone formation, a preventive strategy is still in debate. AIM: To compare the incidence of gallstone formation between patients treated with ursodeoxycholic acid (UDCA) vs. placebo for a duration of 6 months following BS. METHODS: This multicenter randomized, double-blind controlled trial entails treatment with UDCA vs. an identical-looking placebo. The primary outcome was gallstone formation, as measured by abdominal ultrasound. RESULTS: The data of 209 subjects were enrolled in the study, and 92 subjects completed the study and were analyzed (n = 46 for each study group). The high dropout rate was mainly due to difficulties in adding more medications and swallowing the pill. Among the subjects who completed the study, 77.2% were women, and their mean age and pre-surgery BMI were 42.2 ± 10.2 years and 44.4 ± 6.1 kg/m2, respectively. Gallstone formation was recorded in 45.7% (n = 21) vs. 23.9% (n = 11) of subjects among placebo vs. UDCA groups, respectively, p = 0.029. Subgroup-analysis, according to surgery type, found that the results were significant only for SG subjects (p = 0.041), although the same trend was observed for OAGB/RYGB. Excess Weight Loss percent (%EWL) at 6 months post-surgery was 66.0 ± 17.1% vs. 71.8 ± 19.5% for the placebo and UDCA groups, respectively; p = 0.136. A trend towards a reduction in prescribed comorbidity medications was noted within-groups during the follow-up period, as compared to baseline, with no between-group differences (p ≥ 0.246). Moreover, no between-group differences were found for blood test results (p ≥ 0.063 for all). CONCLUSION: Administration of UDCA significantly decreased gallstone formation at 6 months at following BS. CLINICALTRIALS. GOV NUMBER: NCT02319629.

The Role of Transcatheter Arterial Embolization in the Management of Nonvariceal Upper Gastrointestinal Bleeding.

Nearly 50 years ago, catheter angiography was introduced as a means of both diagnosing and treating nonvariceal upper gastrointestinal bleeding. Technological advances and innovations have resulted in the introduction of microcatheters that, using a coaxial technique, are capable of selecting third-order arterial branches and of delivering a wide array of embolic agents. This article reviews the imaging diagnosis of nonvariceal upper gastrointestinal bleeding, the techniques of diagnostic and therapeutic angiography, the angiographic appearance of the various etiologies of nonvariceal upper gastrointestinal bleeding, the rationale behind case-specific selection of embolic agents as well as the anticipated outcome of transcatheter arterial embolization.

A urologic stethoscope? Urologist performed sonography using a pocket-size ultrasound device in the point-of-care setting.

PURPOSE: Ultrasound is commonly used in urology. Technical advances with reduced size and cost led to diffusion of small ultrasound devices to many clinical settings. Even so, most ultrasound studies are performed by non-urologists. We aimed to evaluate the utility of a pocket-size ultrasound device (Vscan™ GE Healthcare) and the quality of urologist performed study. METHODS: Three consecutive studies were performed: (1) a urologist using the pocket ultrasound, (2) a sonographist using the pocket ultrasound, and (3) a sonographist using a standard ultrasound device. Thirty-six patients were evaluated with a basic urologic ultrasound study. An excepted deviation between studies was preset for numeric parameters and t test performed. Ordinal parameters were analyzed using Cohen's kappa coefficient. RESULTS: Kidney length, renal pelvis length, renal cyst diameter, post-void residual and prostate volume (transabdominal) differences were found to be insignificant when comparing a urologist pocket ultrasound study to a sonographist standard ultrasound study (P = 0.15; P = 0.21; P = 0.81; P = 0.32; P = 0.07, respectively). Hydronpehrosis evaluation (none, mild, moderate and severe) and the presence of ureteral jet signs conferred a high inter-observer agreement when comparing the above studies using the Cohen's kappa coefficient (K = 0.63; K = 0.62, respectively). CONCLUSIONS: Urologist performed pocket ultrasound study is valid in evaluating the upper and lower urinary tract and is practical in many clinical scenarios. The urologic stethoscope is now becoming a reality within reach.

Phase I study of hepatic arterial melphalan infusion and hepatic venous hemofiltration using percutaneously placed catheters in patients with unresectable hepatic malignancies.

PURPOSE: We conducted a phase I study of a 30-minute hepatic artery infusion of melphalan via a percutaneously placed catheter and hepatic venous hemofiltration using a double balloon catheter positioned in the retrohepatic inferior vena cava to shunt hepatic venous effluent through an activated charcoal filter and then to the systemic circulation. The purpose of the study was to demonstrate feasibility in an initial cohort and subsequently determine the maximum tolerated dose and dose-limiting toxicity of melphalan. PATIENTS AND METHODS: The initial cohort (n = 12) was treated with 2.0 mg/kg of melphalan before dose escalation to 3.5 mg/kg (n = 16). Total hepatic drug delivery, systemic levels, and percent filter efficiency were determined. Patients were assessed for hepatic and systemic toxicity and response. RESULTS: A total of 74 treatments were administered to 28 patients. Twelve patients with primary and metastatic hepatic tumors received 30 treatments (mean, 2.5 per patient) at an initial melphalan dose of 2.0 mg/kg. At 3.5 mg/kg, a dose-limiting toxicity (neutropenia and/or thrombocytopenia) was observed in two of six patients. Transient grade 3/4 hepatic and systemic toxicity was seen after 19% and 66% of treatments, respectively. An overall radiographic response rate of 30% was observed in treated patients. In the 10 patients with ocular melanoma, a 50% overall response rate was observed, including two complete responses. CONCLUSION: Delivery of melphalan via this system is feasible, with limited, manageable toxicity and evidence of substantial antitumor activity; 3 mg/kg is the maximum safe tolerated dose of melphalan administered via this technique.

Pulmonary angiography for the diagnosis of thromboembolic events in the non-human primate.

BACKGROUND: Evaluating possible thromboembolic events in the non-human primate has traditionally required euthanasia, significantly limiting the ability to conduct longitudinal studies. We hypothesized that pulmonary angiography could offer a safe, reproducible, and non-lethal means to assess for pulmonary embolus in the non-human primate. METHODS: Eleven rhesus primates were studied using standard pulmonary angiography techniques. Five animals studied had previously received humanized anti-CD154 antibodies (associated with thromboembolism risk) in the context of skin transplantation 2 years before the angiography study. Four primates were studied after receiving mouse anti-human CD154 antibody following allogeneic islet or skin transplantation. RESULTS: Angiography was successful in all primates. We observed no complications, and all animals promptly recovered from the procedure. Angiographic findings consistent with thromboembolism were demonstrated in the three primates actively receiving anti-CD154 antibody and in one primate that last received anti-CD154 nearly 2 years before the study. The study was normal in both the streptozotocin-induced diabetic control animals. Histopathology of the lungs confirmed thrombus in two of the four primates, but no thromboembolus was identified in the other two. The first had limited pathologic evaluation without fine slices, and in the second (treated 2 years before with a humanized anti-CD154), ascariasis was found in the area identified as abnormal by the angiogram. CONCLUSIONS: Minimally invasive pulmonary angiography is a safe, reproducible, and inexpensive method to assess possible thromboembolic events in the non-human primate. This method may allow for the longitudinal assessment of non-human primates given novel agents that may promote thromboembolism.

Rabbit antithymocyte globulin induction and sirolimus monotherapy supports prolonged islet allograft function in a nonhuman primate islet transplantation model.

BACKGROUND: We reported that rabbit anti-thymocyte globulin (RATG) induction followed by maintenance immunosuppression with sirolimus supports human kidney allograft survival and asked if this combination would promote islet allograft survival in our primate model. METHODS: Using intra-arterial streptozotocin infusion, we rendered four cynomolgus primates diabetic with undetectable C-peptide levels. Animals were maintained on insulin therapy for at least 1 month, and then islets from mixed lymphocyte reaction mismatched primates were infused into the portal vein. Immediately before the islet allotransplant and for 6 additional days, primates were infused with RATG (20 mg/kg) and given a sirolimus dose to achieve a 24-hr trough level of 8 to 14 ng/mL. RESULTS: The regimen resulted in profound peripheral and lymph node lymphocyte depletion for up to 1 month. Repopulation was gradual thereafter. One primate remained insulin-independent for 169 days and rejected after a sirolimus-dose reduction. Two primates died on day 23 while insulin independent because of wound dehiscence, and a third died on day 30 with high sirolimus levels. Liver sections revealed well-vascularized islets with no signs of inflammation. CONCLUSION: Using a nonhuman primate islet transplant model, RATG plus sirolimus supports islet survival as long as proper sirolimus levels are maintained, but the therapy is limited by sirolimus toxicity. Our findings suggest that RATG is not toxic for islets and thus may be considered in future clinical trails while recognizing that sirolimus monotherapy, with its difficult-to-achieve therapeutic dosing, may not be sufficient to maintain long-term islet allograft function in an autoimmune environment.