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Systemic capillary leak syndrome (SCLS) is a rare and life-threatening disorder characterised by leaking of intravascular fluid to extravascular tissues. An association with immunotherapy and COVID-19 vaccination has been reported as potential triggers. A case of a patient in her 70s developing SCLS after the BNT162b2 (Pfizer-BioNTech) COVID-19 vaccination with a history of metastatic melanoma treated with nivolumab (PD-1 monoclonal antibody) and ipilimumab (anti-CTLA4 monoclonal antibody) is reported. The aetiology and management of SCLS are also reviewed in this case context., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

We report an interesting case of pericardial effusion associated with idiopathic systemic capillary leak syndrome (ISCLS) following administration of SARS-CoV-2 vaccine. This patient initially presented with dyspnoea and chest pain, with non-pitting oedema and clear lung fields. The diagnosis of ISCLS was made based on the clinical syndrome and laboratory evidence of polycythaemia and hypoalbuminaemia. An enlarging pericardial effusion was diagnosed on transthoracic echocardiogram. Daily point-of-care ultrasound (POCUS)-guided volume management and serial transthoracic echocardiograms contributed to avoidance of refractory shock, cardiac tamponade and critical care admission., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Systemic capillary leak syndrome is a rare and life-threatening disorder, characterized by recurrent episodes of unexplained hypotension, hemoconcentration, and hypoalbuminemia. This condition is caused by leakage of plasma and proteins into the extravascular space and can be classified as either idiopathic or secondary. Secondary systemic capillary leak syndrome can result from cancer, infections, medications, or surgery. Systemic capillary leak syndrome frequently develops as a side effect of denileukin diftitox treatment of refractory cutaneous T-cell lymphoma. However, the pathophysiology of this disease is not well understood. Herein, we report a case of denileukin diftitox-induced systemic capillary leak syndrome., (© 2022. The Author(s) under exclusive licence to The Japan Society of Nephrology.)

Introduction: The occurrence of systemic capillary leak syndrome under immune checkpoint inhibitors has seldom been reported in the literature., Observation: We report two cases of systemic capillary leak syndrome that occurred with nivolumab (anti-PD-1 antibody) for one, and with an anti-PD-1/CTLA-4 bi-specific antibody for the other. Patients presented with anasarca, hypoalbuminemia, acute kidney injury and, in one case, circulatory collapse. Immune checkpoint inhibitor causality was retained in the lack of evidence for other causes of secondary capillary leak syndrome or for an idiopathic form. The symptoms resolved after a few days of supportive measures (associated with glucocorticoids in one case)., Discussion: A high index of suspicion is required for the diagnosis of immune checkpoint inhibitors-induced systemic capillary leak syndrome because its presentation may differ from that of the idiopathic form. Activated CD8 + T-cells play a prominent role in the occurrence of immune checkpoint inhibitors-induced capillary leakage via their cytolytic action on the vascular endothelium. Treatment relies on supportive measures and discontinuation of the immune checkpoint inhibitor while the place of immunomodulatory drugs remains to be defined., (Copyright © 2022 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.)

Capillary leak syndrome is a disease with a high mortality rate. Its signs and symptoms are nonspecific. Generalized edema, hypotension, hypoproteinemia, and hemoconcentration are the characteristics of capillary leak syndrome. Here we report three cases of capillary leak syndrome developed after being treated with gemcitabine and paclitaxel. Immediate treatment with corticosteroids may be life-saving., (© Journal of the Association of Physicians of India 2011.)

Snakebite envenomation caused by the Western and Eastern Russell's Vipers (Daboia russelii and Daboia siamensis) may potentially induce capillary leak syndrome (CLS), while the use of antivenom in treating this has not been well examined. This study investigated the CLS-inducing toxicity of Russell's Viper venoms from various sources and examined the neutralization activity of regionally available antivenoms, using a newly devised mouse model. D. russelii venoms demonstrated a more consistent vascular leakage activity (76,000-86,000 CLS unit of vascular leak index, a function of the diameter and intensity of Evans Blue dye extravasation into dermis) than D. siamensis venoms (33,000-88,000 CLS unit). Both species venoms increased hematocrits markedly (53-67%), indicating hemoconcentration. Regional antivenoms (DsMAV-Thailand, DsMAV-Taiwan, VPAV-India) preincubated with the venoms effectively neutralized the CLS effect to different extents. When the antivenoms were administered intravenously post-envenomation (challenge-rescue model), the neutralization was less effective, implying that CLS has a rapid onset that preceded the neutralizing activity of antivenom, and/or the antivenom has limited biodistribution to the venom's inoculation site. In conclusion, Russell's Viper venoms of both species from various locales induced CLS in mice. Antivenoms generally had limited efficacy in neutralizing the CLS effect. Innovative treatment for venom-induced CLS is needed., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Competing Interests: Intérêts concurrents: Aucun déclaré.

A young man with smoldering multiple myeloma died of hypotensive shock 2.5 days after severe acute respiratory syndrome coronavirus 2 vaccination. Clinical findings suggested systemic capillary leak syndrome (SCLS); the patient had experienced a previous suspected flare episode. History of SCLS may indicate higher risk for SCLS after receiving this vaccine.

Competing Interests: Competing interests: None declared.

Systemic capillary leak syndrome (SCLS) is a life-threatening disease. It is characterized by severe capillary hyperpermeability to proteins resulting in hemoconcentration, hypoalbuminemia and hypovolemic shock. Its treatment remains supportive, and the prognosis is generally poor. We report on a 51-year old male with melanoma treated with nivolumab for 1 year. 1 month following the completion of the treatment, the patient presented with signs of hypovolemic shock, anasarca, hemoconcentration and hypoalbuminemia. After excluding other diseases, a diagnosis of nivolumab-induced systemic capillary leak syndrome was made. A high dose of intravenous steroid therapy was promptly initiated without any significant clinical improvement. Intravenous immunoglobulin therapy was then administered with normalization of blood pressure, hemoconcentration and complete resolution of anasarca. Intravenous immunoglobulin should be considered a first-line treatment option for this rare phenomenon.

Capillary-leak syndrome is strongly associated with cytokine activity states. It is an ill-recognized adverse effect of checkpoint inhibitors treatment, which are typically associated with cellular immune response. We describe two patients with capillary leak syndrome following immune checkpoint inhibitors treatment. We present linking mechanisms between checkpoint inhibitors, cellular immunity, cytokine action and endothelial damage. We suggest that capillary-leak syndrome is a unique adverse effect of immunotherapy, resulting from complex interactions between cellular and cytokine activation and that its expression is probably depending on inherent host immune variabilities.

Programmed death 1 (PD-1) inhibitors are increasingly used for the treatment of malignancies. Despite the clinical benefits, unpredictable and potentially fatal side-effects may occur. We report a psoriatic patient who developed systemic capillary leak syndrome (SCLS) after starting a PD-1 checkpoint inhibitor. In order to determine which factors could trigger the development of SCLS in a patient with stable psoriasis after starting anti-PD-1 therapy, serum cytokines were serially measured before and after the development of SCLS in this patient. We also retrospectively reviewed 28 previously reported patients presenting clinical exacerbations of pre-existing psoriasis or the de novo induction of psoriasis after anti-PD-1 therapy. In 16 of the 28 patients (57.1%), the interval between last anti-PD-1 therapy and exacerbations of pre-existing psoriasis or the de novo induction of psoriasis was less than 28 days. The timing of the onset of SCLS in this patient was coincident with the increase in lymphocyte counts and at 22 days after last anti-PD-1 therapy. In 75%, however, anti-PD-1 therapy was able to be restarted and was tolerated well. Increased levels of interleukin (IL)-2, IL-6, interferon-γ and tumor necrosis factor-α, in addition to a persistent increase in vascular endothelial growth factor (VEGF), were detected at onset of SCLS. An increase in pro-inflammatory cytokines and VEGF, when combined with a rapid and sequential recovery of neutrophils and lymphocytes after anti-PD-1 therapy, would predict the development of SCLS. Clinicians need to be aware that patients with psoriasis are at risk of a potentially fatal disease, SCLS, when anti-PD-1 therapy is started., (© 2020 Japanese Dermatological Association.)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematological malignancy, characterized by poor prognosis if treated with conventional therapy. Allogenic hematologic stem cell transplant can improve survival and can be curative, but it is available in a small percentage of patients given that the median age at diagnosis is 70 years. In this scenario it is assumed that only the development of precision medicine-driven therapy will change BPDCN patient prognosis. CD123 (the α-subunit of interleukin (IL)-3 receptor) is over-expressed on BPDCN cells surface and seems to be the ideal marker to develop antibody-based therapies. Tagraxofusp (Elzonris ® ), a recombinant immunotoxin consisting of human interleukin-3 fused to a truncated diphtheria toxin, has been approved by FDA in December 2018 for the treatment of BPDCN in adult and pediatric patients. tagraxofusp has shown promising clinical activity, with a high overall response rate and quite manageable safety profile even in elderly patients. It seems to improve overall survival too, but comparative trials are necessary to confirm this. Adverse events are commonly reported and the most important are transaminitis, thrombocytopenia and capillary leak syndrome (CLS). Therefore, to prevent the onset of severe CLS is recommended to reserve tagraxofusp for patients with preserved hepatic and cardiac functions, and to strictly observe serum albumin level. Further studies are required to resolve many several unanswered questions about tagraxofusp. In this review, we will resume and discuss pharmacological characteristic of tagraxofusp, results of clinical trials leading to its approval by FDA in 2018 and future perspectives about its use in BPDCN and other hematological malignancies.

Background: Retinoids are widely used in dermatology. Adverse effects are frequent and require clinical and laboratory monitoring. Herein we report the case of a patient with secondary capillary leak syndrome (SCLS) associated with acitretin. We then present a review of the literature on systemic retinoids and SFCS., Patients and Methods: A 57-year-old patient consulted following the onset of severe type I pityriasis rubra pilaris. Treatment was initiated comprising topical corticosteroids combined with acitretin at a dose of 0.5mg/kg/day. On the eighth day, voluminous edema appeared, accompanied by weight gain of 8kg in 48h and hypotension. The laboratory assessment showed hypoalbuminemia and hemoconcentration. Acitretin-induced SCLS was diagnosed based on the triple signs of hemoconcentration, hypoalbuminemia and hypotension, as well as rapid improvement following discontinuation of acitretin., Discussion: We collected 7 published clinical cases between 1981 and 2018, including our own case report. Retinoids were indicated only in severe cutaneous diseases. The mean time to onset of SLCS is 9.8 days, with a return to normal 17 days after discontinuation of retinoids. Capillary leak syndrome is a rare and under-diagnosed clinical-laboratory syndrome that must be recognized in order to avoid potentially fatal inappropriate management. It is a rare adverse effect of retinoids used in dermatology and the pathophysiology remains unclear., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Recombinant immunotoxins (RITs) are chimeric proteins composed of an Fv and a protein toxin being developed for cancer treatment. The Fv brings the toxin to the cancer cell, but most of the RITs do not reach the tumor and are removed by other organs. To identify cells responsible for RIT removal, and the pathway by which RITs reach these cells, we studied SS1P, a 63-kDa RIT that targets mesothelin-expressing tumors and has a short serum half-life. The major organs that remove RIT were identified by live mouse imaging of RIT labeled with FNIR-Z-759. Cells responsible for SS1P removal were identified by immunohistochemistry and intravital two-photon microscopy of kidneys of rats. The primary organ of SS1P removal is kidney followed by liver. In the kidney, SS1P passes through the glomerulus, is taken up by proximal tubular cells, and transferred to lysosomes. In the liver, macrophages are involved in removal. The short half-life of SS1P is due to its very rapid filtration by the kidney followed by degradation in proximal tubular cells of the kidney. In mice treated with SS1P, proximal tubular cells are damaged and albumin in the urine is increased. SS1P uptake by kidney is reduced by coadministration of l-lysine. Our data suggests that l-lysine administration to humans might prevent SS1P-mediated kidney damage, reduce albumin loss in urine, and alleviate capillary leak syndrome., Competing Interests: Competing interest statement: I.P. is the inventor on many immunotoxin patents that have all been assigned to NIH. I.P. and A.T.F. are coauthors on a 2016 article. They did not collaborate directly on the work. X.-F.L., J.W., Q.Z., I.P., and E.S. are affiliated with the National Cancer Institute.

Background: Neuroblastoma is the most common extracranial solid tumour of childhood with extremely heterogeneous bio-logical and clinical behaviour. Despite advances in its treatment, the long-term prognosis of patients with a high-risk and relapsed neuroblastoma remains poor. The implementation of immunotherapy into the treatment protocols has the potential to improve it. Dinutuximab, a chimeric monoclonal antibody, leads to the apoptosis of tumour cells through binding to the GD2 receptor. The article aim is to present the first experience of our centre with dinutuximab treatment., Patients and Methods: In 2018-2019, we administered 31 cycles of dinutuximab to seven patients. Five patients with high-risk neuroblastoma received dinutuximab in the first line, in two patients with relapse, dinutuximab was administered in the second line of treatment. To evaluate the toxicity of the treatment, the nursing records of patients during immunotherapy were retrospectively analysed., Results: Two patients treated with dinutuximab in the first line are in complete remission, three patients achieved a partial response. Both patients with relapsed neuroblastoma were dia-gnosed with a second relapse after immunotherapy and died of disease progression. The treatment tolerance was acceptable in most patients - in six patients adverse events were managed with adequate supportive care. These were mainly symptoms of capillary leak syndrome, pain and hypersensitivity reactions. In one patient, the treatment was discontinued due to severe neurotoxicity., Conclusion: Dinutuximab has a proven benefit in the eradication of the minimal residual disease in the treatment of neuroblastoma. Immunotherapy is currently the standard for first-line treatment of high-risk neuroblastoma. Its role in the treatment of relapsed neuroblastoma is a subject of several ongoing studies as well as the optimization of therapeutic regimens. Dinutuximab administration is associated with a considerable risk of severe adverse reactions, so the treatment belongs to the hands of an experienced paediatric oncology centre.

Capillary leak syndrome (CLS) is a rare but fatal disease, which has been reported following the infusions of interleukin-2, tumor necrosis factor, granulocyte-colony stimulating factor, certain monoclonal antibodies, and gemcitabine, suggesting that drugs can also cause CLS. In this study, seven Wilm's tumor cases with CLS had been presented, which was suggested to be caused following administration of vincristine (VCR). From January 1st, 2014 to December 31st, 2016, medical records from Wilm's tumor patients were reviewed to identify those diagnosed with CLS. Moreover, the following data were extracted for each patient, including age, gender, histological subtyping, tumor stage, risk group, biomarkers, chemotherapy regimen and dosage, surgery details, clinical manifestation of CLS, treatment regimen of CLS, and patient outcomes. From January 1st, 2014 to December 31st, 2016, a total of seven patients with Wilms tumor were identified with a diagnosis of VCR-associated CLS. Typically, for these seven cases in our study, the predominant features of CLS included interstitial pneumonia and pulmonary edema. Moreover, steroid therapy was demonstrated as the most effective therapy in our study. The clinical features of VCR-induced CLS are distinct, and pediatric oncologists should be aware of CLS that manifests as interstitial pneumonia and pulmonary edema during the VCR treatment for patients with Wilm's tumor.

Background: Blastic plasmacytoid dendritic-cell neoplasm (BPDCN) is an aggressive hematologic cancer that is caused by transformed plasmacytoid dendritic cells that overexpress interleukin-3 receptor subunit alpha (IL3RA or CD123). Tagraxofusp (SL-401) is a CD123-directed cytotoxin consisting of human interleukin-3 fused to truncated diphtheria toxin., Methods: In this open-label, multicohort study, we assigned 47 patients with untreated or relapsed BPDCN to receive an intravenous infusion of tagraxofusp at a dose of 7 μg or 12 μg per kilogram of body weight on days 1 to 5 of each 21-day cycle. Treatment continued until disease progression or unacceptable toxic effects. The primary outcome was the combined rate of complete response and clinical complete response among patients who had not received previous treatment for BPDCN. A secondary outcome was the duration of response., Results: Of the 47 patients, 32 were receiving tagraxofusp as first-line treatment and 15 had received previous treatment. The median age of the patients was 70 years (range, 22 to 84). Among the 29 previously untreated patients who received tagraxofusp at a dose of 12 μg per kilogram, the primary outcome occurred in 21 (72%), and the overall response rate was 90%; of these patients, 45% went on to undergo stem-cell transplantation. Survival rates at 18 and 24 months were 59% and 52%, respectively. Among the 15 previously treated patients, the response rate was 67%, and the median overall survival was 8.5 months. The most common adverse events were increased levels of alanine aminotransferase (64%) and aspartate aminotransferase (60%), hypoalbuminemia (55%), peripheral edema (51%), and thrombocytopenia (49%). Capillary leak syndrome was reported in 19% of the patients and was associated with one death in each of the dose subgroups., Conclusions: In adult patients with untreated or relapsed BPDCN, the use of tagraxofusp led to clinical responses. Serious adverse events included capillary leak syndrome; hepatic dysfunction and thrombocytopenia were common. (Funded by Stemline Therapeutics and the Leukemia and Lymphoma Society Therapy Acceleration Program; ClinicalTrials.gov number, NCT02113982.)., (Copyright © 2019 Massachusetts Medical Society.)

Antibody-toxin fused agents or immunotoxins, are a newly engineered class of cytotoxic agents consisting of a bacterial or plant toxin moiety hooked up either to a monoclonal antibody or a specific growth factor. Nevertheless, acquiring a full potency in clinic is mostly restricted due to the Capillary leak syndrome (CLS), a serious immune provoked, life-threatening side effect, subsequent to the endothelial damage, resulting in fluid escape from the bloodstream into tissues including lungs, muscle and brain, developing organ failure and eventually death. Proposed underlying mechanisms include direct damage to endothelial cells, acute inflammation, Lymphokine-activated killer (LAK) cells engagement, alteration in cell-cell/cell-matrix connectivities and cytoskeletal dysfunction. Very poor biodistribution and heterogeneous extravasation pattern in tumor site result in accumulation of ITs close to the extravasation site, gradual toxin release and initiation of nearby endothelial cells lysis, secretion of pro-inflammatory cytokines, development of acute inflammation and engagement of Lymphokine-activated killer (LAK) cells. Intrinsic immunogenicity of applied toxin moiety is another important determinant of CLS incidence. Toxins with more intrinsic immunogenicity possess more probability for CLS development. Recently, development of new generations of antibodies and mutated toxins with conserved cytotoxicity has partly tapered risk of CLS development. Here, we describe probable mechanisms involved in CLS and introduce some of the recently applied strategies for lessening incidence of CLS as much as possible., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

A 56-year-old woman presented with anasarca, hypoalbuminaemia and hypotension following cycle 3 day 1 of adjuvant gemcitabine for stage II pancreatic cancer. Due to the temporal nature of presentation, suspicion for gemcitabine-induced capillary leak syndrome was included in the differential diagnosis. Vascular endothelial growth factor levels were elevated at 707 pg/mL (reference range: 9-86 pg/mL). Corticosteroids were initiated, resulting in complete resolution of symptoms and hypotension. The patient suffered relapse of symptoms on discontinuation of steroids, further supporting chronic capillary leak syndrome., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Colorectal cancer is the third most common cancer diagnosed in the USA each year. Oxaliplatin, a platinum-based chemotherapy agent, is part of the standard adjuvant chemotherapy regimen FOLFOX (oxaliplatin with 5-fluorouracil [5-FU] and leucovorin [LV]) for the treatment of stage III and some high-risk stage II colorectal cancers. Although oxaliplatin is generally well tolerated, certain side effects such as nausea, vomiting, and peripheral neuropathy are common. We report a case of oxaliplatin-induced capillary-leak syndrome in a 63-year-old man undergoing his 12th and final cycle of FOLFOX for stage III colorectal cancer. To our knowledge, this is the first case of systemic capillary leak syndrome (SCLS) reported in association with oxaliplatin. Currently, there is no prevention for SCLS. Documenting future cases of SCLS attributed to oxaliplatin is vital, as SCLS is associated with significant morbidity and mortality and no standard treatments beyond supportive care measures exist. Early recognition and diagnosis are therefore essential to improving patient outcomes., (© The Author(s) 2015.)

Although TNF-α possesses promising anticancer activity, clinical application is limited partly due to cardiovascular toxicities. TNF-α effects on vessels are likely related to vascular toxicity, but much remains poorly understood. Similarly, IL-2 is an attractive treatment option for cancers but its clinical use is limited by the side effect of vascular leak syndrome (VLS). We report here that TNF-α alone can trigger VLS. Administration of recombinant TNF-α induced VLS in normal mice and TNF-α transgenic mice exhibited VLS. Perivascular infiltrates in the lungs and specific cytokines in serum were observed in VLS-induced mice. This study shed a new light on the critical role of the TNF-α in IL-2-induced or non IL-2-induced VLS and provides important points to TNF-α therapy., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Background: To investigate in-vitro antagonistic effect of low-dose liquiritigenin on gemcitabine-induced capillary leak syndrome (CLS) in pancreatic adenocarcinoma via inhibiting reactive oxygen species (ROS)- mediated signalling pathways., Materials and Methods: Human pancreatic adenocarcinoma Panc-1 cells and human umbilical vein endothelial cells (HUVECs) were pre-treated using low-dose liquiritigenin for 24 h, then added into gemcitabine and incubated for 48 h. Cell viability, apoptosis rate and ROS levels of Panc-1 cells and HUVECs were respectively detected through methylthiazolyldiphenyl-tetrazoliumbromide (MTT) and flow cytometry. For HUVECs, transendothelial electrical resistance (TEER) and transcellular and paracellular leak were measured using transwell assays, then poly (ADP-ribose) polymerase 1 (PARP-1) and metal matrix proteinase-9 (MMP9) activity were assayed via kits, mRNA expressions of p53 and Rac-1 were determined through quantitative polymerase chain reaction (qPCR); The expressions of intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and PARP-1 were measured via western blotting., Results: Low-dose liquiritigenin exerted no effect on gemcitabine-induced changes of cell viability, apoptosis rate and ROS levels in Panc-1 cells, but for HUVECs, liquiritigenin (3 μM) could remarkably elevate gemcitabine- induced decrease of cell viability, transepithelial electrical resistance (TEER), pro-MMP9 level and expression of ICAM-1 and VCAM-1 (p<0.01). Meanwhile, it could also significantly decrease gemcitabine-induced increase of transcellular and paracellular leak, ROS level, PARP-1 activity, Act-MMP9 level, mRNA expressions of p53 and Rac-1, expression of PARP-1 and apoptosis rate (p<0.01)., Conclusions: Low-dose liquiritigenin exerts an antagonistic effect on gemcitabine-induced leak across HUVECs via inhibiting ROS-mediated signalling pathways, but without affecting gemcitabine-induced Panc-1 cell apoptosis. Therefore, low-dose liquiritigenin might be beneficial to prevent the occurrence of gemcitabine-induced CLS in pancreatic adenocarcinoma.

Systemic capillary leak syndrome (SCLS) is a rare health condition. It is characterized by recurrent episodes of generalized edema and severe hypotension along with hypoproteinemia. The condition is under recognized because of its nonspecific signs and symptoms, and high mortality rate. SCLS triggered by trastuzumab, a target drug for Her2-positive breast cancer patients, has not been previously reported. A 59-year-old Chinese woman, diagnosed with breast cancer with accompanying liver and bone metastasis, was treated with 3 cycles of docetaxel with capecitabine and a regimen of 12 cycles of capecitabine with trastuzumab. The patient developed systemic capillary leak syndrome during the 16th cycle of chemotherapy. Post-diagnosis treatment regimen is also presented in the current case report. SCLS has been previously observed in breast cancer patients. However, SCLS incidence post-chemotherapeutic treatment with trastuzumab has not been reported elsewhere. Hence, our report highlights the need for rigorous investigation of the side effects of trastuzumab usage and the increasing need of insightful diagnosis to manage any incidence of SCLS. The case provides valuable experience for treating the uncommon adverse effects of trastuzumab in Her2-positive breast cancer patients.

Background: Differentiation syndrome is a life-threatening complication of therapy that is carried out with agents used for acute promyelocytic leukemia. Its physiopathology comprehends the production of inflammatory mediators by differentiating granulocytes, endothelial and alveolar cells due to stimulation by all-trans retinoic acid and leading to sustained systemic inflammation., Methods: Treatment with high cut-off continuous veno-venous hemodialysis (HCO-CVVHD) was performed to reduce the circulating mediators of systemic inflammation., Results: After 52 h of treatment, an important reduction was observed in inflammatory mediators (IL-1β: from 10 to 2 pg/ml; IL-8: from 57 to 40 pg/ml; TNF-α: from 200 to 105 pg/ml; IL-6: from 263 to 91 pg/ml), as well as in anti-inflammatory mediators (IL-10: from 349 to 216 pg/ml)., Conclusions: HCO-CVVHD should be explored as a part of treatment in systemic inflammation states other than sepsis (e.g., differentiation syndrome). Furthermore, its immunomodulatory effects could be particularly useful in immunocompromised patient treated with corticosteroids., (© 2014 S. Karger AG, Basel.)

Introduction: Excessive vascular permeability is a characteristic feature of ALI. We have previously demonstrated that UFH prevents LPS-induced disruption of endothelial barrier function in vitro. It was the objective of this study to determine whether UFH may attenuate endotoxin-induced lung vascular leak in mice and to further explore the possible underlying mechanisms., Methods: C57BL/6J mice were randomly divided into the control, LPS and LPS plus UFH groups. Sepsis was induced by intraperitoneal injection of LPS at a dose of 30 mg/kg. Mice in the LPS plus UFH group were intravenously received 8 units UFH (heparin sodium) diluted in 20 μl sterile saline at 0.5 h before the injection of LPS., Results: 1) UFH pretreatment attenuated LPS-induced histopathological changes in Lung at 6 h; 2) Pretreatment of mice with UFH ameliorated LPS-induced lung edema and lung vascular leak at 6 h; 3) UFH pretreatment dramatically inhibited RhoA and ROCK activation in the lung tissues of LPS-treated mice (3 and 6 h). 4) UFH pretreatment significantly down-regulated ROCK1 gene expression, but did not affect the increased expression of ROCK2 mRNA in the lung tissues of LPS-treated mice at 3 or 6 h., Conclusion: These data suggest that UFH may attenuate endotoxin-induced lung vascular leak by regulating RhoA/Rho kinase pathway., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Interleukin 21 (IL21) is a T-cell-derived 4-helix-bundle cytokine that has sequence homology to the IL2 family. Recombinant human interleukin 2 (rIL2) is approved for the treatment of metastatic melanoma and renal cell carcinoma. However, toxicity of rIL2, including induction of vascular leak syndrome (VLS), has limited use of this cytokine to a small proportion of eligible patients. Both rIL2 and murine IL21 (mIL21) have potent antitumor efficacy in murine models. The purpose of the current study was to compare the ability of mIL21 and rIL2 to induce vascular leakage in a mouse model. Pulmonary and hepatic uptake of Evans blue dye, serum cytokine levels, spleen cell immunophenotype, and histologic changes in lung and liver were evaluated to detect VLS. High-dose (200 μg) rIL2 treatment induced vascular leakage in mice, evidenced by inflammatory cell infiltration and fluid extravasation into the lung and liver and increased levels of TNFα, IFNγ, IL5, MCP1, and IL6 in serum. In contrast, an equivalent dose of mIL21 resulted in minimal vascular leakage with no evidence of cytopenia or cytokine production. These results support the use of IL21 as a cancer immunotherapeutic agent, potentially providing an antitumor response without induction of VLS.

SS1P is a recombinant immunotoxin (RIT) engineered for the targeted elimination of malignant cells that express the tumor-associated antigen mesothelin. It is composed of an antimesothelin antibody variable fragment (Fv) linked to a cytotoxic fragment of Pseudomonas exotoxin A (PE) that includes domains II and III of native PE. The clinical use of SS1P is limited by its propensity to induce neutralizing antibodies and to cause a dose-limiting capillary leak syndrome (CLS) in patients. In this article, we describe a reengineered SS1P with improved properties that overcome these deficits. The redesign of SS1P consists of (i) removing the bulk of PE domain II (residues 251-273 and 284-394 of native PE), leaving only an 11-residue furin cleavage site, (ii) adding a Gly-Gly-Ser peptide linker after the furin cleavage site, and (iii) replacing eight highly solvent-exposed residues in the catalytic domain of PE. The new molecule, SS1-LR/GGS/8M, has cytotoxic activity comparable with SS1P on several mesothelin-expressing cell lines and remarkably improved activity on primary cells from patients with mesothelioma. In a mouse xenograft tumor model, high doses of SS1-LR/GGS/8M elicit antitumor activity superior to the activity of SS1P at its maximum-tolerated dose. In addition, SS1-LR/GGS/8M has greatly decreased ability to cause CLS in a rat model and reduced antigenicity or reactivity with antibodies to the sera of patients previously treated with SS1P.

Despite increasing use of "targeted therapy," interleukin-2 (IL-2) is unique, because this cytokine can induce long-term remissions in 5% to 7% of patients with metastatic melanoma and renal cancer. Clinical use of IL-2 is limited by severe toxicities, such as hypotension and vascular leak syndrome (VLS). Nitric oxide seems to be involved in the pathogenesis of these toxicities. On the basis of previous studies, we hypothesized that the endothelial nitric oxide synthase (eNOS) is the major source of nitric oxide. Mice with a knockout of the eNOS isoenzyme were treated with IL-2 (800,000 IU twice daily for 5 d). Blood pressure and vascular leak were measured. Inhibitors of superoxide, nitric oxide, and soluble guanylate cyclase were used to probe the mechanism. These experiments showed that IL-2 treatment increased eNOS messenger ribonucleic acid expression and nitric oxide metabolite excretion in eNOS knockout mice. Unlike normal and inducible nitric oxide synthase knockout mice, eNOS knockout mice proved resistant to IL-2-induced hypotension and vascular leak. Although hypotension seems to be mediated by superoxide or peroxynitrite, vascular leak seemed to be mediated by nitric oxide. Inhibition of guanylate cyclase and cyclic guanylate monophosphate formation during IL-2 treatment using methylene blue (MB)-inhibited vascular leak. MB treatment did not interfere with IL-2-induced antitumor mechanisms. Our experiments established that eNOS is a key mediator of IL-2-induced VLS and hypotension. A clinical trial of MB infusion during IL-2 therapy is currently being planned.

Background: Capillary leak syndrome (CLS) is a rare condition characterized by recurrent episodes of generalized edema and severe hypotension associated with hypoproteinemia. Interleukin-11 (IL-11) is a promising therapeutic agent for thrombocytopenia. A direct correlation between IL-11 and CLS has never been reported previously, particularly in patients with hepatic carcinoma., Case Presentation: We describe two cases of CLS after IL-11 administration in two males with thrombocytopenia. Case 1 was a 46-year-old man with recurrence of hepatic carcinoma who was treated with IL-11 (3 mg per day). After four days of therapy, hypotension and hypoproteinemia were detected. The chest X-ray and B ultrasound of the abdomen showed pleural effusion and ascites. IL-11 was then discontinued, fluid resuscitation was performed, and fresh frozen plasma and packed red blood cells were transfused into this patient. The patient had recovered after 19 days of treatment. Case 2 was a 66-year-old man who had undergone radiofrequency ablation (RFA) for hepatic carcinoma. He was treated with IL-11 (3 mg per day) for thrombocytopenia. After two days of therapy, this patient complained of dyspnea with bilateral edema of the hands. Laboratory values showed hypoproteinemia. IL-11 was stopped and human albumin was transfused at a rate of 10 g per day. On the 4th day, fluid resuscitation was performed. The patient had recovered after treatment for two weeks., Conclusions: The detection of IL-11-induced CLS supports the hypothesis that CLS could be a severe side effect of IL-11 treatment in some patients. These two case reports also demonstrate that patients with hepatic carcinoma who experience this rare form of CLS after treatment with IL-11 seem to respond to a therapeutic regimen that involves hydroxyethyl starch, albumin, and diuretic therapy. Liver cancer patients might be more susceptible to CLS because of poor liver function and hypersplenia. In addition, bleeding after RFA might be a further inducer of CLS.

1. Early postnatal events might play a critical role in the development of cardiorespiratory diseases of prematurity. Although the exact mechanism is unknown, capillary leakage resulting in increased interstitial fluid volume has been postulated to play a critical role. We investigated the effects of capillary leakage, induced by a volume load, on cardiopulmonary and systemic haemodynamics immediately after preterm delivery. 2. Fetal sheep were instrumented at 129 days gestation, delivered and ventilated. After 15 min, lambs in the volume load group received intravenous saline (50 mL/kg) infused over 10 min; control lambs received no infusion. At 30 min, lambs underwent a pulmonary challenge by increasing positive end-expiratory pressure (PEEP) by 2 cmH(2)O every 10 min to 10 cmH(2)O, with similar decrements back to baseline PEEP. Pulmonary blood flow (PBF) and arterial pressures were recorded in real-time and cardiovascular variables were measured by Doppler echocardiography. 3. Total protein concentration in the bronchoalveolar-lavage fluid was higher in volume load lambs compared with controls, and histological interstitial fluid retention was evident in volume load lambs, both indicative of capillary leak. PBF increased immediately after the volume load, but PBF, pulmonary and systemic arterial pressures, and oxygenation all deteriorated during the PEEP challenge compared with controls, coinciding with an increase in downstream pulmonary resistance. Three of six volume load lambs had pulmonary haemorrhage, which was not observed in control lambs. 4. Capillary leakage had moderate effects, but subsequent high levels of PEEP had significant negative effects on cardiopulmonary and respiratory function in preterm lambs. Capillary leakage might contribute to postnatal cardiopulmonary failure in preterm infants., (© 2011 The Authors. Clinical and Experimental Pharmacology and Physiology © 2011 Blackwell Publishing Asia Pty Ltd.)

Objective: To describe the first case of bortezomib-induced capillary leak syndrome (CLS), a rare but potentially life-threatening condition characterized by the shift of intravascular fluid and protein to the interstitial space., Case Summary: A 65-year-old female with relapsed multiple myeloma developed fluid retention, ascites, and general anasarca following bortezomib administration (1.3 mg/m(2) on days 1, 4, 8, and 11). Aggressive albumin infusion and loop diuretics did not lead to improvement and the patient received 2 sessions of hemodialysis for pulmonary edema. Although the bortezomib dose was reduced (0.7 mg/m(2) on days 1, 4, and 11) for the second cycle, CLS recurred after treatment. Dexamethasone was given along with bortezomib in the third cycle and subsequent CLS was prevented. The patient's multiple myeloma responded partially to the treatment, but the patient later died from cardiac amyloidosis., Discussion: Bortezomib is associated with several well-known adverse effects, such as peripheral neuropathy, thrombocytopenia, and gastrointestinal complications. CLS has not previously been reported to be associated with bortezomib. In this case, CLS developed twice after the patient received bortezomib treatment. The severity of CLS was dose-dependent and this adverse effect was preventable by concomitant use of steroids; this clearly demonstrated the close relationship between CLS and bortezomib in this patient. Using the Naranjo probability scale, the occurrence of CLS related to bortezomib treatment was probable., Conclusions: Our report demonstrates CLS as an unusual adverse effect of bortezomib. As bortezomib use may become more common, clinicians should be aware of this novel but potentially life-threatening adverse effect. Based on our experience, timely management with steroids is important in dealing with this complication.

Clofarabine has significant efficiency in children with relapsed or refractory leukemia. In previous pediatric trials, various adverse effects have been described. In this case, we report a child with refractory acute lymphoblastic leukemia who developed fatal capillary leak syndrome during clofarabine therapy.