Immunomodulatory imide drugs inhibit human detrusor smooth muscle contraction and growth of human detrusor smooth muscle cells, and exhibit vaso-regulatory functions.

BACKGROUND: The immunomodulatory imide drugs (IMiDs) thalidomide, lenalidomide and pomalidomide may exhibit therapeutic efficacy in the prostate. In lower urinary tract symptoms (LUTS), voiding and storage disorders may arise from benign prostate hyperplasia, or overactive bladder. While current therapeutic options target smooth muscle contraction or cell proliferation, side effects are mostly cardiovascular. Therefore, we investigated effects of IMiDs on human detrusor and porcine artery smooth muscle contraction, and growth-related functions in detrusor smooth muscle cells (HBdSMC). METHODS: Cell viability was assessed by CCK8, and apoptosis and cell death by flow cytometry in cultured HBdSMC. Contractions of human detrusor tissues and porcine interlobar and coronary arteries were induced by contractile agonists, or electric field stimulation (EFS) in the presence or absence of an IMID using an organ bath. Proliferation was assessed by EdU assay and colony formation, cytoskeletal organization by phalloidin staining, RESULTS: Depending on tissue type, IMiDs inhibited cholinergic contractions with varying degree, up to 50 %, while non-cholinergic contractions were inhibited up to 80 % and 60 % for U46619 and endothelin-1, respectively, and EFS-induced contractions up to 75 %. IMiDs reduced viable HBdSM cells in a time-dependent manner. Correspondingly, proliferation was reduced, without showing pro-apoptotic effects. In parallel, IMiDs induced cytoskeletal disorganization. CONCLUSIONS: IMiDs exhibit regulatory functions in various smooth muscle-rich tissues, and of cell proliferation in the lower urinary tract. This points to a novel drug class effect for IMiDs, in which the molecular mechanisms of action of IMiDs merit further consideration for the application in LUTS.

QoL during KTd or KRd induction followed by K maintenance or observation in transplant noneligible patients with newly diagnosed multiple myeloma: Longitudinal and cross-sectional analysis of the randomized AGMT 02 study.

Understanding the impact of induction and maintenance therapy on patients' quality of life (QoL) is important for treatment selection. This study aims to compare patient-reported QoL between patients treated with KTd or KRd induction therapy and K maintenance therapy or observation. QoL was assessed using the EORTC QOL-C 30 and QOL-MY20 questionnaires in the AGMT-02 study, in which 123 patients with newly diagnosed transplant ineligible multiple myeloma were randomized to nine cycles of either KTd or KRd induction therapy, followed by 12 cycles of K maintenance therapy, or observation. Longitudinal assessments showed statistically significant improvements in global health-related QoL, various disease symptoms and pain for both treatment regimens. KTd improved insomnia and fatigue, and KRd improved physical functioning. Cross-sectional comparisons indicated a "slight" superiority of KTd over KRd in several scales, with the exception of higher neuropathy scores with KTd. During maintenance, longitudinal comparisons showed no statistically significant changes. Cross-sectional comparisons revealed a "slight" improvement in cognitive functioning during carfilzomib therapy, but a worsening in most other QoL scales. Induction therapy led to improvements in most QoL items, while maintenance therapy with K maintenance was associated with "slight" or "moderate" impairments in several QoL scales compared with the observation group.

Environmental Signals.

Environmental factors have long been known to play a role in the pathogenesis of congenital heart disease (CHD), but this has not been a major focus of research in the modern era. Studies of human exposures and animal models demonstrate that demographics (age, race, socioeconomic status), diseases (e.g., diabetes, hypertension, obesity, stress, infection, high altitude), recreational and therapeutic drug use, and chemical exposures are associated with an increased risk for CHD. Unfortunately, although studies suggest that exposures to these factors may cause CHD, in most cases, the data are not strong, are inconclusive, or are contradictory. Although most studies concentrate on the effects of maternal exposure, paternal exposure to some agents can also modify this risk. From a mechanistic standpoint, recent delineation of signaling and genetic controls of cardiac development has revealed molecular pathways that may explain the effects of environmental signals on cardiac morphogenesis and may provide further tools to study the effects of environmental stimuli on cardiac development. For example, environmental factors likely regulate cellular signaling pathways, transcriptional and epigenetic regulation, proliferation, and physiologic processes that can control the development of the heart and other organs. However, understanding of the epidemiology and risk of these exposures and the mechanistic basis for any effects on cardiac development remains incomplete. Further studies defining the relationship between environmental exposures and human CHD and the mechanisms involved should reveal strategies to prevent, diagnose, and treat CHD induced by environmental signals.

Teratogenicity is more likely a function of primary and secondary pharmacology than caused by chemically reactive metabolites: a critical evaluation of 40 years of scientific research.

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives.Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms.Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted.

The emerging role of targeted protein degradation to treat and study cancer.

The evolution of cancer treatment has provided increasingly targeted strategies both in the upfront and relapsed disease settings. Small-molecule inhibitors and immunotherapy have risen to prominence with chimeric antigen receptor T-cells, checkpoint inhibitors, kinase inhibitors, and monoclonal antibody therapies being deployed across a range of solid organ and haematological malignancies. However, novel approaches are required to target transcription factors and oncogenic fusion proteins that are central to cancer biology and have generally eluded successful drug development. Thalidomide analogues causing protein degradation have been a cornerstone of treatment in multiple myeloma, but a lack of in-depth mechanistic understanding initially limited progress in the field. When the protein cereblon (CRBN) was found to mediate thalidomide analogues' action and CRBN's neo-targets were identified, existing and novel drug development accelerated, with applications outside multiple myeloma, including non-Hodgkin's lymphoma, myelodysplastic syndrome, and acute leukaemias. Critically, transcription factors were the first canonical targets described. In addition to broadening the application of protein-degrading drugs, resistance mechanisms are being overcome and targeted protein degradation is widening the scope of druggable proteins against which existing approaches have been ineffective. Examples of targeted protein degraders include molecular glues and proteolysis targeting chimeras (PROTACs): heterobifunctional molecules that bind to proteins of interest and cause proximity-induced ubiquitination and proteasomal degradation via a linked E3 ligase. Twenty years since their inception, PROTACs have begun progressing through clinical trials, with early success in targeting the oestrogen receptor and androgen receptor in breast and prostate cancer respectively. This review explores important developments in targeted protein degradation to both treat and study cancer. It also considers the potential advantages and challenges in the translational aspects of developing new treatments. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Old drug, new use: The thalidomide-based fluorescent probe for cysteine detection and imaging in living cells.

Thalidomide, as a high-profile cereblon (CRBN) ligand, has attracted much attention because of its ability to target protein degradation. In this study, we are committed to developing a new fluorescent probe THD-1 based on thalidomide, aiming at improving the performance of cysteine fluorescent probe in optical properties and biocompatibility. The experimental results showed that THD-1, as a cysteine fluorescent probe, owned the characteristics of obvious colorimetric change, fast response time, good selectivity and high sensitivity. The mechanism of THD-1 sensing cysteine was further verified to ensure its reliability and effectiveness. It was also worth mentioning that THD-1 was successfully applied to the biological imaging of cysteine in living A549 cells, which highlighted its value in practical application. Overall, thalidomide, as a clinically approved drug, not only enriches the fluorescent skeleton library, but also paves a new way for the further development of fluorescent probes.

Multiple Mucosal Ulcers Induced by Ixekizumab: A Case Report.

OBJECTIVES: Ixekizumab, an interleukin (IL)-17A inhibitor, exerts its therapeutic effects in psoriasis by inhibiting the interleukin (IL)-17 signaling pathway. Common adverse reactions to ixekizumab include injection site reactions and upper respiratory tract infections (URIs), while occurrences of inflammatory bowel disease (IBD) and multiple mucosal ulcers are infrequent. We present a case of a 51-year-old man who developed multiple mucosal ulcers after ixekizumab treatment. METHODS: A 51-year-old man presented to our hospital with a 1-month history of pharyngalgia. The flexible laryngoscope displayed mild hyperemia in the pharyngeal mucosa and tonsils, redness and swelling of the epiglottis, as well as multiple ulcers in the oral cavity, uvula, and epiglottis. These ulcers did not improve with conventional treatment. RESULTS: Upon evaluation, the ulcers were an immune-related adverse event induced by ixekizumab. Consequently, a decision was made to discontinue the drug and initiate a therapeutic regimen including corticosteroids and thalidomide. Eventually, the patient's symptoms abated. CONCLUSIONS: Biologics are now becoming increasingly popular in psoriasis. It is vital for clinicians to be aware of this potential adverse event and to identify and intervene early to alleviate patients' suffering.

Efficacy and safety of thalidomide in gastrointestinal angiodysplasias: systematic review and meta-analysis with trial sequential analysis of randomized controlled trials.

Background: Gastrointestinal (GI) angiodysplasias is a potential cause of life-threatening bleeding. Thalidomide may have a certain effect on the treatment. Objectives: We aim to evaluate the efficacy and safety of thalidomide and used trial sequential analysis (TSA) to assess the need for further randomized controlled trials (RCTs). Design: Meta-analysis of RCTs. Data sources and methods: We systematically searched Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE), Embase, WanFang, and China National Knowledge Infrastructure databases for RCTs evaluating thalidomide in GI angiodysplasias without language restrictions. We used a random-effects model to obtain pool data and followed Grading of Recommendations Assessment, Development and Evaluation framework. TSA was employed to control the risk of random errors and to evaluate the validity of our conclusions. Results: Three RCTs were included involving 279 patients with the proportion of small intestinal angiodysplasias of 87.1%. Thalidomide led to improved mean change of hemoglobin level [mean difference (MD): 3.06, 95% confidence interval: 2.66-3.46] without severe adverse effects occurring. Other secondary endpoints, including effective response rate, cessation of bleeding after treatment, hospitalization rate because of bleeding, change in duration of hospital stays for bleeding, transfused red cell requirements, and overall adverse effects, also showed significantly better outcomes in the thalidomide group compared to the control group. TSA for all outcomes exceeded required information sizes, and cumulative Z curve all traverse trial sequential monitoring boundary. Conclusion: Almost all of the evidence was of moderate quality, suggesting that thalidomide holds promise for treating GI angiodysplasias, with favorable safety profiles. TSA suggests that conducting large-scale real-world research is recommended over relying solely on RCTs conducted within the same population and trial design. Trial registration: This meta-analysis protocol was registered on PROSPERO (CRD42023480621).

Monoclonal gammopathy of clinical significance in a young patient treated with melphalan-thalidomide-prednisone.

Key Clinical Message: We report an observation of a young patient presenting with severe type 1 cryoglobulinemic vasculitis revealing a monoclonal gammopathy of clinical significant. Treatment with Melphalan-Thalidomide Prednisone improved the symptoms. Early diagnosis would prevent serious tissue damage. Abstract: Monoclonal gammopathy encompass diverse clinical forms. Only the cancerous form, multiple myeloma (MM), is treated based on specific diagnostic criteria. A new clinical entity, monoclonal gammopathy of clinical significance (MGCS), warrants special attention due to its need for specific treatment. It involves patients with signs of potentially severe organ involvement that do not meet MM criteria. We present the case of a 34-year-old Malagasy woman with severe type I cryoglobulinemic vasculitis associated with noncancerous monoclonal gammopathy, showing a favorable outcome after treatment with Thalidomide. Symptoms included toe necrosis, a severe ulcer on the left calf evolving for 3 months, and stocking-like dysesthesias. Investigations revealed monoclonal gammopathy at 30.1 g/L, proteinuria at 1 g/24 h, medullary plasma cell at 6%, and circulating cryoglobulin of Ig kappa type. CRAB criteria (anemia, hypercalcemia, renal insufficiency, and osteolysis) were absent. Treatment with Thalidomide, combined with corticosteroids and local care for 4 months, resulted in ulcer healing, disappearance of dysesthesias, and persistent normalization of gammaglobulin. Our case underscores the importance of specific treatment for MGCS.

The dark side of drug repurposing. From clinical trial challenges to antimicrobial resistance: analysis based on three major fields.

Drug repurposing is a strategic endeavor that entails the identification of novel therapeutic applications for pharmaceuticals that are already available in the market. Despite the advantageous nature of implementing this particular strategy owing to its cost-effectiveness and efficiency in reducing the time required for the drug discovery process, it is essential to bear in mind that there are various factors that must be meticulously considered and taken into account. Up to this point, there has been a noticeable absence of comprehensive analyses that shed light on the limitations of repurposing drugs. The primary aim of this review is to conduct a thorough illustration of the various challenges that arise when contemplating drug repurposing from a clinical perspective in three major fields-cardiovascular, cancer, and diabetes-and to further underscore the potential risks associated with the emergence of antimicrobial resistance (AMR) when employing repurposed antibiotics for the treatment of noninfectious and infectious diseases. The process of developing repurposed medications necessitates the application of creativity and innovation in designing the development program, as the body of evidence may differ for each specific case. In order to effectively repurpose drugs, it is crucial to consider the clinical implications and potential drawbacks that may arise during this process. By comprehensively analyzing these challenges, we can attain a deeper comprehension of the intricacies involved in drug repurposing, which will ultimately lead to the development of more efficacious and safe therapeutic approaches.

Long-Term Follow-Up of Patients Undergoing Thalidomide Therapy for Transfusion-Dependent ß-Thalassaemia: A Single-Center Experience.

Objective: We evaluated the long-term safety and efficacy of thalidomide in the treatment of transfusion-dependent ß-thalassemia (TDT). Methods: Fifty patients with TDT were treated with thalidomide and followed-up for 5 years. Thalidomide at a 50 mg dose was administered once a day after dinner. The dose was increased to 150 mg/d after 3 d if well tolerated. After 1 year of treatment, the hemoglobin (Hb) level was stabilized at its maximum, and thalidomide was gradually reduced and maintained at the minimum dose. The hematological response, transfusion dependence, and haemolytic indicators were assessed. Results: At 9 month of follow-up, 38 (76%) patients achieved an excellent response, 1 (2%) a good response, 4(8%) a minor response, and 7(14%) did not show a response. The overall response rate was 86%. At 9 months, the Hb level increased from 79.0 ± 13.2 g/L at baseline to 99.0 ± 13.7g/L (P<0.001). Patients who achieved excellent response continued to show an increase in Hb levels during follow-up. At 48 months, the mean Hb level was 98.99 ± 10.3g/L; 21 patients (84.0%) became transfusion independent. Thalidomide was reduced and maintained to 25 mg/d in three of these patients. Moreover, five patients completed 60 months of follow-up, and with a mean Hb level of 99.8 ± 6.7g/L. During follow-up, grade 1-2 adverse drug reactions were noted; however, no grade 3 or higher adverse event was reported. However, no decrease in hemolytic indicators was observed. Conclusion: Thalidomide was well tolerated in the long term, while it significantly improved Hb levels and reduced the transfusion burden.

Whole blood transcriptomics reveals the enrichment of neutrophil activation pathways during erythema nodosum leprosum reaction.

Introduction: Patients with the multibacillary form of leprosy can develop reactional episodes of acute inflammation, known as erythema nodosum leprosum (ENL), which are characterized by the appearance of painful cutaneous nodules and systemic symptoms. Neutrophils have been recognized to play a role in the pathogenesis of ENL, and recent global transcriptomic analysis revealed neutrophil-related processes as a signature of ENL skin lesions. Methods: In this study, we expanded this analysis to the blood compartment, comparing whole blood transcriptomics of patients with non-reactional lepromatous leprosy at diagnosis (LL, n=7) and patients with ENL before administration of anti-reactional treatment (ENL, n=15). Furthermore, a follow-up study was performed with patients experiencing an ENL episode at the time of diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Validation in an independent cohort (ENL=8; LL=7) was performed by RT-qPCR. Results: An enrichment of neutrophil activation and degranulation-related genes was observed in the ENL group, with the gene for the neutrophil activation marker CD177 being the most enriched gene of ENL episode when compared to its expression in the LL group. A more pro-inflammatory transcriptome was also observed, with increased expression of genes related to innate immunity. Validation in an independent cohort indicated that S100A8 expression could discriminate ENL from LL. Supernatants of blood cells stimulated in vitro with Mycobacterium leprae sonicate showed higher levels of CD177 compared to the level of untreated cells, indicating that the leprosy bacillus can activate neutrophils expressing CD177. Of note, suggestive higher CD177 protein levels were found in the sera of patients with severe/moderate ENL episodes when compared with patients with mild episodes and LL patients, highlighting CD177 as a potential systemic marker of ENL severity that deserves future confirmation. Furthermore, a follow-up study was performed with patients at the time of ENL diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Enrichment of neutrophil pathways was sustained in the transcriptomic profile of patients undergoing treatment; however, important immune targets that might be relevant to the effect of thalidomide at a systemic level, particularly NLRP6 and IL5RA, were revealed. Discussion: In conclusion, our study reinforces the key role played by neutrophils in ENL pathogenesis and shed lights on potential diagnostic candidates and novel therapeutic targets that could benefit patients with leprosy.

Immunomodulatory drugs: a promising clinical ally for cancer immunotherapy.

While immunomodulatory imide drugs (IMiDs) have been authorised for treatment of haematological cancers for over two decades, the appreciation of their ability to stimulate antitumour T cell and natural killer (NK) cell responses is relatively recent. Clinical trial data increasingly show that targeted immunotherapies, such as antibodies, T cells, and vaccines, improve outcomes when delivered in combination with the IMiD derivatives lenalidomide or pomalidomide. Here, we review these clinical data to highlight the relevance of IMiDs in combinatorial immunotherapy for both haematological and solid tumours. Further research into the molecular mechanisms of IMiDs and an increased understanding of their immunomodulatory effects may refine the specific applications of IMiDs and improve the design of future clinical trials, moving IMiDs to the forefront of combinatorial cancer immunotherapy.

Was thalidomide a placebo hypnotic?

Six decades ago the world learned that thalidomide, a seemingly non-toxic sedative and hypnotic, caused severe birth defects including the flipper-like deformity of the arms known as phocomelia. When thalidomide was tested against placebo by the trialist Louis Lasagna in 1960 (while the drug was banned from the U.S. marketplace), he found the 100-mg dosage equivalent to placebo, as well as greatly inferior to the 200-mg dosage, in producing sleep. Even as these findings were made known, a 100-mg dose of thalidomide was in general use as a sleep aid for pregnant women. It appears that unbeknownst to themselves, an untold number of pregnant women around the world who were prescribed thalidomide incurred the risks of a teratogen in return for the benefits of a sugar pill.

Strengthening Molecular Glues: Design Strategies for Improving Thalidomide Analogs as Cereblon Effectors and Anticancer Agents.

In the two decades since a novel thalidomide analog was last approved, many promising drug candidates have emerged with remarkable potency as targeted protein degraders. Likewise, the advent of PROTACs for suppressing 'undruggable' protein targets reinforces the need for new analogs with improved cereblon affinity, target selectivity and drug-like properties. However, thalidomide and its approved derivatives remain plagued by several shortcomings, such as structural instability and poor solubility. Herein, we present a review of strategies for mitigating these shortcomings and highlight contemporary drug discovery approaches that have generated novel thalidomide analogs with enhanced efficacy as cereblon effectors and/or anticancer agents.

Lenalidomide or Thalidomide for Transplant-Ineligible Patients With Newly Diagnosed Multiple Myeloma? An Overview of Systematic Reviews.

OBJECTIVES: To present an overview of evidence of efficacy, safety, and health-related quality of life of lenalidomide or thalidomide for transplant-ineligible multiple myeloma. METHODS: A literature search was performed in 5 databases until July 2022. We included systematic reviews with network meta-analyses of randomized controlled trials on the use of lenalidomide compared with thalidomide for transplant-ineligible multiple myeloma. The A Measurement Tool to Assess Systematic Reviews 2 was used to appraise the quality of included reviews. The results were focused on the lenalidomide + dexamethasone until disease progression (RDc) versus thalidomide + dexamethasone until disease progression (TDc) and induction with melphalan + prednisone + lenalidomide, followed by maintenance with lenalidomide (MPR-R) versus induction with melphalan + prednisone + thalidomide, followed by maintenance with thalidomide (MPT-T) regimens. RESULTS: Nine studies were included. Only 1 study did not show any weakness in critical domains of A Measurement Tool to Assess Systematic Reviews 2. For overall survival, RDc proved to be superior to TDc; however, no study showed significant difference between MPR-R and MPT-T. For progression-free survival, 2 of 3 studies showed that RDc is better than TDc; however, no difference between MPR-R and MPT-T was found. Regarding safety, these lenalidomide-based regimens had a lower risk for neurologic adverse events, with an increased risk of hematologic adverse events. No health-related quality of life meta-analyses were found. CONCLUSIONS: These findings suggest that, in terms of efficacy and safety, lenalidomide-based regimen is a good option for treatment of transplant-ineligible multiple myeloma in the public health system of Brazil, especially for those patients who develop severe neuropathy with thalidomide.

[Curcumin Combined with Thalidomide Inhibits Proliferation of KG-1 Cells and Its Related Mechanisms].

OBJECTIVE: To investigate the effects of curcumin combined with thalidomide on the proliferation and apoptosis of acute myeloid leukemia KG-1 cells, and its correlation with B-cell lymphoma-xL (Bcl-xL), signal transducer and activator of transcription 3 (STAT3). METHODS: MTT assay was used to detect the proliferation of KG-1 cells and screen the optimal combined concentration of curcumin and thalidomide. The effects of curcumin, thalidomide and their combination on the proliferation and apoptosis of KG-1 cells were analyzed by MTT method and flow cytometry, respectively. The mRNA expression levels of STAT3 and Bcl-xL in single-drug group, two-drug combination group and control group (untreated cells) were detected by real-time quantitative PCR. RESULTS: Both curcumin and thalidomide inhibited the proliferation of KG-1 cells in a concentration-dependent manner in the range of 20-100 µmol/L (r =0.657, r =0.681). The IC50 value of curcumin and thalidomide at 48 h was (42.07±0.50) µmol/L and (57.01±2.39) µmol/L, respectively. The cell proliferation inhibition rate of curcumin (40 µmol/L) + thalidomide (60 µmol/L) was (86.67±1.53)%, which was significantly higher than (51.67±1.15)% of curcumin (40 µmol/L) and (55.33±1.53)% of thalidomide (60 µmol/L) (both P < 0.05). Treated with curcumin and thalidomide alone or in combination, the apoptosis rate of KT-1 cells was (18.67±2.08)%, (21.33±2.52)%, and (46.67±1.53)%, respectively, which was significantly higher than (0.72±0.03)% of control group (all P < 0.05). The cell apoptosis rate of two-drug combination group was significantly higher than that of single-drug group (both P < 0.05). Compared with the control group, the mRNA expressions of STAT3 and Bcl-xL in single-drug group, two-drug combination group were significantly decreased (both P < 0.05). Compared with single-drug group, the mRNA expressions of STAT3 and Bcl-xL in two-drug combination group were also significantly decreased (both P < 0.05). CONCLUSION: Curcumin combined with thalidomide can synergistically down-regulate the expression of STAT3 and Bcl-xL, inhibit the proliferation of KG-1 cells, and induce apoptosis.

Safety and efficacy of thalidomide in treatment of gastrointestinal bleeding secondary to angioectasias: a systematic review and meta-analysis.

BACKGROUND: Thalidomide has been used for angioectasia-associated refractory gastrointestinal bleeding (GIB), with studies showing variable efficacy and side effects profile. We conducted a meta-analysis to reconcile the data. METHODS: Online databases were searched for studies evaluating thalidomide in patients with refractory/recurrent GIB due to angioectasias. The outcomes of interest were cessation of bleeding, rebleeding, need for blood transfusion, hospitalization and adverse events. Pooled proportions for incidence, and odds ratios (OR) for comparison with control were calculated along with 95% confidence interval (CI). RESULTS: A total of seven studies with 346 patients (n = 269 thalidomide, n = 77 control) were included. Thalidomide dose was usually started at 50-100mg/day. The mean age was 65 years, 45% patients were men, and mean follow-up was 1.8 years. The pooled clinical outcomes with thalidomide were: cessation of bleeding 42.2% (95% CI 36.02 to 48.41), rebleeding 30%, need for blood transfusion 20.1%, hospitalization 40% and adverse events 55.9%. When compared with the control group in 2 studies, patients on thalidomide had significantly higher odds of cessation of bleeding (OR 21.40, 95% CI 5.78 to 79.29, p < 0.00001) and adverse events, with lower need for blood transfusion and hospitalization. DISCUSSION: In patients with angioectasias-related refractory/recurrent GIB, the use of thalidomide results in significantly decreased bleeding risk and may play a role in the management of such patients.