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Daratumumab for patients with myeloma with early or late relapse after initial therapy: subgroup analysis of CASTOR and POLLUX.
Spencer, A, Moreau, P, Mateos, MV, Goldschmidt, H, Suzuki, K, Levin, MD, Sonneveld, P, Orlowski, RZ, Yoon, SS, Usmani, SZ, et al
Blood advances. 2024;(2):388-398
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Abstract
High-risk multiple myeloma (MM) is often defined based on cytogenetic abnormalities, but patients who relapse early after initial therapy are considered a functional high-risk group. In the phase 3 CASTOR and POLLUX studies, daratumumab plus bortezomib/dexamethasone (D-Vd) or lenalidomide/dexamethasone (D-Rd) improved progression-free survival (PFS) and overall survival (OS), regardless of cytogenetic risk, and achieved higher rates of complete response or better (≥CR) and minimal residual disease (MRD) negativity vs that with Vd/Rd alone in relapsed/refractory MM. Post hoc analyses of CASTOR and POLLUX evaluated patient subgroups with 1 prior line of therapy based on timing of progression/relapse (early or late) after initiation of first line of therapy. PFS consistently favored the daratumumab-containing regimens across subgroups using both a 24- and 18-month early-relapse cutoff. In the CASTOR/POLLUX pooled data set, daratumumab reduced the risk of disease progression or death by 65% (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.26-0.48; P < .0001) in the early-relapse (<24 months) subgroup and by 65% (HR, 0.35; 95% CI, 0.26-0.47; P < .0001) in the late-relapse (≥24 months) subgroup. OS also favored the daratumumab-containing regimens in both the early-relapse (HR, 0.62; 95% CI, 0.45-0.86; P = .0036) and late-relapse (HR, 0.67; 95% CI, 0.48-0.93; P = .0183) subgroups in the pooled population using a 24-month cutoff. Rates of ≥CR and MRD negativity (10-5) were higher with daratumumab vs control, regardless of progression/relapse timing. Although daratumumab is unable to fully overcome the adverse prognosis of early relapse, our results support the use of daratumumab for patients with 1 prior line of therapy, including for those who progress/relapse early after initial therapy and are considered to have functional high-risk MM. These trials were registered at www.clinicaltrials.gov as #NCT02136134 (CASTOR) and #NCT02076009 (POLLUX).
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Phase II Trial Evaluating Esophageal Anastomotic Reinforcement with a Biologic, Degradable, Extracellular Matrix after Total Gastrectomy and Esophagectomy.
Vos, EL, Nakauchi, M, Capanu, M, Park, BJ, Coit, DG, Molena, D, Yoon, SS, Jones, DR, Strong, VE
Journal of the American College of Surgeons. 2022;(5):910-917
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Abstract
BACKGROUND A biologic, degradable extracellular matrix (ECM) has been shown to support esophageal tissue remodeling, which could reduce the risk of anastomotic leak following total gastrectomy and esophagectomy. We evaluated the safety and efficacy of reinforcing the anastomosis with ECM in reducing anastomotic leak as compared to a matched cohort. STUDY DESIGN In this single-center, nonrandomized phase II trial, gastric or esophageal adenocarcinoma patients undergoing total gastrectomy or esophagectomy were recruited from November 2013 through December 2018. ECM was surgically wrapped circumferentially around the anastomosis. Anastomotic leak was assessed clinically and by contrast study and defined as clinically significant if requiring invasive treatment (grade 3 or higher). Anastomotic stenosis, other adverse events, symptoms, and dysphagia score were collected by standardized forms at regular follow-up visits at approximately postoperative days (POD) 21 and 90. Patients receiving ECM were compared to a cohort matched for surgery type and age. RESULTS ECM placement was not feasible in 9 of 75 patients (12%), resulting in 66 patients receiving ECM. Total gastrectomy was performed in 50 patients (76%) and esophagectomy in 16 (24%). Clinically significant anastomotic leak was diagnosed in 6 of 66 patients (9.1%) (3/50 [6.0%] after gastrectomy, 3/16 [18.8%] after esophagectomy); this rate did not differ from that in the matched cohort (p = 0.57). Stenosis requiring invasive treatment occurred in 8 patients (12.5%), and 10 patients (15.6%) reported not being able to eat a normal diet at POD 90. No adverse events related to ECM were reported. CONCLUSIONS Esophageal anastomotic reinforcement after total gastrectomy or esophagectomy with a biologic, degradable ECM was mostly feasible and safe, but was not associated with a statistically significant decrease in anastomotic leak.
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MOMENTUM: momelotinib vs danazol in patients with myelofibrosis previously treated with JAKi who are symptomatic and anemic.
Verstovsek, S, Chen, CC, Egyed, M, Ellis, M, Fox, L, Goh, YT, Gupta, V, Harrison, C, Kiladjian, JJ, Lazaroiu, MC, et al
Future oncology (London, England). 2021;(12):1449-1458
Abstract
Hallmark features of myelofibrosis (MF) are cytopenias, constitutional symptoms and splenomegaly. Anemia and transfusion dependency are among the most important negative prognostic factors and are exacerbated by many JAK inhibitors (JAKi). Momelotinib (MMB) has been investigated in over 820 patients with MF and possesses a pharmacological and clinical profile differentiated from other JAKi by inhibition of JAK1, JAK2 and ACVR1. MMB is designed to address the complex drivers of iron-restricted anemia and chronic inflammation in MF and should improve constitutional symptoms and splenomegaly while maintaining or improving hemoglobin in JAKi-naive and previously JAKi-treated patients. The MOMENTUM Phase III study is designed to confirm and extend observations of safety and clinical activity of MMB.
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Busulfan, etoposide, cytarabine, and melphalan as a high-dose regimen for autologous stem cell transplantation in peripheral T-cell lymphomas.
Jo, JC, Kim, JS, Lee, JH, Lee, JH, Im, SN, Lee, SM, Yoon, SS, Kim, IH, Bae, SH, Lee, YJ, et al
Annals of hematology. 2021;(1):189-196
Abstract
Given the unsatisfactory survival in patients who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) for peripheral T-cell lymphomas (PTCLs), we conducted a prospective trial of busulfan (Bu), etoposide (E), cytarabine (A), and melphalan (M) (BuEAM), including IV Bu instead of carmustine (BCNU) as in standard BEAM, as a high-dose regimen in such patients. This study evaluated the efficacy and toxicity of BuEAM as a high-dose regimen for ASCT in patients with T-cell lymphomas. The high-dose chemotherapy at seven centers in Korea included Bu (3.2 mg/kg IV qd from day 6 to day 5), E (200 mg/m2 IV bid on day 4 and day 3), A (1 g/m2 IV qd on day 4 and day 3), and M (140 mg/m2 IV qd on day 2). Eighty-one patients were enrolled in this study. The main subtypes were peripheral T-cell lymphoma, not other specified (n = 32, 39.5%), NK/T-cell lymphoma (n = 22, 27.5%), and angioimmunoblastic T-cell lymphoma (n = 12, 14.8%). Upfront and salvage ASCTs were performed in 65 (80.2%) and 16 (19.8%) patients, respectively. The disease status of the patients before ASCT was 54 patients (66.7%) with complete response and 27 patients (33.3%) with partial response. The common grade-III toxicities were anorexia (8.6%), diarrhea (7.4%), and stomatitis (4.9%). No veno-occlusive disorder was noted. Fifty-six (69.1%) and seven (8.6%) patients achieved complete and partial response, respectively, after ASCT, although 17 patients (21.0%) showed progressive disease. At a median follow-up duration of 49.3 months, the estimated 3-year progression-free survival and overall survival were 55.2% and 68.2% in all patients. The BuEAM high-dose regimen for ASCT was well tolerated and seemed to be effective in patients with T-cell lymphomas.
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Indications for Total Gastrectomy in CDH1 Mutation Carriers and Outcomes of Risk-Reducing Minimally Invasive and Open Gastrectomies.
Vos, EL, Salo-Mullen, EE, Tang, LH, Schattner, M, Yoon, SS, Gerdes, H, Markowitz, AJ, Mandelker, D, Janjigian, Y, Offitt, K, et al
JAMA surgery. 2020;(11):1050-1057
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Abstract
IMPORTANCE CDH1 variants are increasingly identified on commercially available multigene panel tests, calling for data to inform counseling of individuals without a family history of gastric cancer. OBJECTIVES To assess association between CDH1 variant pathogenicity or family history of gastric or lobular breast cancer and identification of signet ring cell cancer and to describe outcomes of risk-reducing minimally invasive and open total gastrectomy. DESIGN, SETTING, AND PARTICIPANTS This cohort study was performed from January 1, 2006, to January 1, 2020, in 181 patients with CDH1 germline variants from a single institution. INTERVENTIONS Genetic counseling, esophagogastroduodenoscopy, and possible total gastrectomy. MAIN OUTCOMES AND MEASURES CDH1 variant classification, family cancer history, findings of signet ring cell carcinoma at esophagogastroduodenoscopy and surgery, postoperative events and weight changes, and follow-up. RESULTS Of 181 individuals with CDH1 germline variants (mean [SD] age at time of testing, 44 [15] years; 126 [70%] female), 165 harbored a pathogenic or likely pathogenic variant. Of these patients, 101 underwent open (n = 58) or minimally invasive (n = 43) total gastrectomy. Anastomotic leaks that required drainage were infrequent (n = 3), and median long-term weight loss was 20% (interquartile range [IQR], 10%-23%). In those undergoing minimally invasive operations, more lymph nodes were retrieved (median, 28 [IQR, 20-34] vs 15 [IQR, 9-19]; P < .001) and the hospital stay was 1 day shorter (median, 6 [IQR, 5-7] vs 7 [IQR, 6-7] days; P = .04). Signet ring cell cancer was identified in the surgical specimens of 85 of 95 patients (89%) with a family history of gastric cancer and 4 of 6 patients (67%) who lacked a family history. Among the latter 6 patients, 4 had a personal or family history of lobular breast cancer, including 2 with signet ring cell cancer. Of the 16 patients with pathogenic or likely pathogenic CDH1 variants who presented with locally advanced or metastatic gastric cancer, 3 (19%) had no family history of gastric cancer or personal or family history of lobular breast cancer. CONCLUSIONS AND RELEVANCE Total gastrectomy may be warranted for patients with pathogenic or likely pathogenic CDH1 variants and a family history of gastric or lobular breast cancer and may be appropriate for those without a family history. A minimally invasive approach is feasible and may be preferred for selected patients.
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Disruption of the Gut Ecosystem by Antibiotics.
Yoon, MY, Yoon, SS
Yonsei medical journal. 2018;59(1):4-12
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The gut microbiome is a complex ecosystem of different micro-organisms, such as bacteria, viruses and fungi, living in the human intestines. It’s involved in numerous functions, such as extracting energy and nutrition from food, protecting against disease-causing microorganisms, and supporting the immune system of the host, and therefore affecting human health and disease. This paper is a review of studies on the effects of antibiotics on the gut microbiota. It outlines how different types of antibiotics can alter the intestinal environment and the composition of the microbes, resulting in various physiological changes that can trigger disease. Relevant mechanisms, such as inflammatory response and the use of intestinal nutrients by infectious bacteria are discussed. Finally, it discusses faecal microbiota transplantation (FMT) and probiotics as treatment approaches, aimed at restoring a disturbed intestinal environment.
Abstract
The intestinal microbiota is a complex ecosystem consisting of various microorganisms that expands human genetic repertoire and therefore affects human health and disease. The metabolic processes and signal transduction pathways of the host and intestinal microorganisms are intimately linked, and abnormal progression of each process leads to changes in the intestinal environment. Alterations in microbial communities lead to changes in functional structures based on the metabolites produced in the gut, and these environmental changes result in various bacterial infections and chronic enteric inflammatory diseases. Here, we illustrate how antibiotics are associated with an increased risk of antibiotic-associated diseases by driving intestinal environment changes that favor the proliferation and virulence of pathogens. Understanding the pathogenesis caused by antibiotics would be a crucial key to the treatment of antibiotic-associated diseases by mitigating changes in the intestinal environment and restoring it to its original state.
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Efficacy and Safety of the Traditional Herbal Medicine, Gamiguibi-tang, in Patients With Cancer-Related Sleep Disturbance: A Prospective, Randomized, Wait-List-Controlled, Pilot Study.
Lee, JY, Oh, HK, Ryu, HS, Yoon, SS, Eo, W, Yoon, SW
Integrative cancer therapies. 2018;(2):524-530
Abstract
BACKGROUND Sleep disturbance is the second most bothersome symptom in patients with cancer, and it can significantly impair their quality of life. The aim of this study was to investigate the efficacy and safety of the traditional herbal medicine Gamiguibi-tang (GGBT) in patients with cancer-related sleep disturbance. METHODS We conducted a prospective, randomized, wait-list-controlled, open-label pilot clinical trial on cancer-related sleep disturbance. Patients with cancer experiencing poor sleep quality with a Pittsburgh Sleep Quality Index of at least 6 were randomly assigned to the GGBT and wait-list groups to receive GGBT and conventional care, respectively, for 2 weeks. The primary endpoint was the Insomnia Severity Index (ISI) score. Fatigue, depression, and cognitive impairment were assessed as the secondary endpoints by using the Brief Fatigue Inventory (BFI), Beck Depression Inventory (BDI), and Montreal Cognitive Assessment (MoCA). RESULTS Thirty participants who met the eligibility criteria were enrolled. Sleep disturbance assessed using the ISI improved significantly more in the GGBT group than in the wait-list group (-5.5 ± 4.4 vs 0.1 ± 1.1, P < .001). Fatigue level determined using the BFI also improved significantly more in the GGBT group than in the wait-list group (-0.8 ± 0.8 vs 0.0 ± 0.3, P = .002). The BDI and MoCA scores showed no significant changes. Adverse events were reported in two patients in the GGBT group and consisted of mild dyspepsia and mild edema. CONCLUSION GGBT may be a potential treatment option for cancer-related sleep disturbance. Further research is needed to investigate the efficacy and safety of GGBT.
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Deferasirox improves hematologic and hepatic function with effective reduction of serum ferritin and liver iron concentration in transfusional iron overload patients with myelodysplastic syndrome or aplastic anemia.
Cheong, JW, Kim, HJ, Lee, KH, Yoon, SS, Lee, JH, Park, HS, Kim, HY, Shim, H, Seong, CM, Kim, CS, et al
Transfusion. 2014;(6):1542-51
Abstract
BACKGROUND Transfusional iron overload and its consequences are challenges in chronically transfused patients with myelodysplastic syndromes (MDSs) or aplastic anemia (AA). STUDY DESIGN AND METHODS This was a prospective, multicenter, open-label study to investigate the efficacy of deferasirox (DFX) by serial measurement of serum ferritin (S-ferritin) level, liver iron concentration (LIC) level using relaxation rates magnetic resonance imaging, and other laboratory variables in patients with MDS or AA. RESULTS A total of 96 patients showing S-ferritin level of at least 1000 ng/mL received daily DFX for up to 1 year. At the end of the study, S-ferritin level was significantly decreased in MDS (p=0.02366) and AA (p=0.0009). LIC level was also significantly reduced by more than 6.7 mg Fe/g dry weight from baseline. Hemoglobin level and platelet counts were significantly increased from baseline (p=0.002 and p=0.025, respectively) for patients showing significant anemia or thrombocytopenia. Elevated alanine aminotransferase was also significantly decreased from baseline. CONCLUSIONS This study shows that DFX is effective in reducing S-ferritin and LIC level in transfusional iron overload patients with MDS or AA and is well tolerated. In addition, positive effects in hematologic and hepatic function can be expected with DFX. Iron chelation treatment should be considered in transfused patients with MDS and AA when transfusion-related iron overload is documented.
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Hematologic responses in patients with aplastic anemia treated with deferasirox: a post hoc analysis from the EPIC study.
Lee, JW, Yoon, SS, Shen, ZX, Ganser, A, Hsu, HC, El-Ali, A, Habr, D, Martin, N, Porter, JB
Haematologica. 2013;(7):1045-8
Abstract
Reports are emerging of hematologic responses associated with iron chelation therapy; however, studies are limited in aplastic anemia patients. Deferasirox reduced iron overload in aplastic anemia patients enrolled in the EPIC (Evaluation of Patients' Iron Chelation with Exjade(®)) study (n=116). A post hoc analysis of hematologic responses was conducted on 72 patients with evaluable hematologic parameters (according to UK guideline criteria), 24 of whom received deferasirox without concomitant immunosuppressive treatment. Partial hematologic responses were observed in 11 of 24 (45.8%) patients; all became transfusion-independent. One patient had an additional platelet response and one patient had an additional platelet and hemoglobin response. Mean serum ferritin levels at end of study were significantly reduced in partial hematologic responders (n=11; -3948 ± 4998 ng/mL; baseline 6693 ± 7014 ng/mL; percentage change from baseline -45.7%; P=0.0029). In non-responders, the reduction in serum ferritin was less pronounced (n=13; -2021 ± 3242 ng/mL; baseline 4365 ± 3063 ng/mL; % change from baseline -27.6%; P=0.0171). Alongside reduction in iron overload, deferasirox may, therefore, improve hematologic parameters in a subset of aplastic anemia patients. Further investigation is required to elucidate the mechanisms involved.
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Recombinant human epidermal growth factor on oral mucositis induced by intensive chemotherapy with stem cell transplantation.
Kim, KI, Kim, JW, Lee, HJ, Kim, BS, Bang, SM, Kim, I, Oh, JM, Yoon, SS, Lee, JS, Park, S, et al
American journal of hematology. 2013;(2):107-12
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Abstract
Oral mucositis (OM) is one of the most common and debilitating complications in patients undergoing intensive chemotherapy followed by hematopoietic stem cell transplantation (HSCT). The aim of this study was to evaluate the efficacy and safety of recombinant human epidermal growth factor (rhEGF) oral spray for OM induced by intensive chemotherapy followed by HSCT. Patients were randomly assigned to either the rhEGF group or placebo group. The severity of OM and self-reported quality of life (QOL) were assessed daily. A total of 58 patients were analyzed. Baseline characteristics were similar between the two groups. The incidence of NCI grade ≥ 2 OM was higher in the rhEGF group (78.6% vs. 50%, P = 0.0496). However, the duration of OM in patients with NCI grade ≥ 2 tended to be shorter in the rhEGF group (8.5 days vs. 14.5 days, P = 0.262). The QOL analysis in patients with World Health Organization (WHO) grade ≥ 3 OM showed that rhEGF significantly reduced limitations in swallowing (P = 0.039) and drinking (P = 0.042). The duration of hospitalization (P = 0.047), administration of total parenteral nutrition (P = 0.012), and the usage of opioid analgesics (P = 0.018) were significantly shorter in the rhEGF group with WHO grade ≥ 3 OM. Adverse events were mild and similar between the two groups. In conclusion, this analysis showed that rhEGF did not reduce the incidence of NCI grade ≥ 2 OM. However, the patients with WHO grade ≥ 3 OM in the rhEGF group showed better results compared to the placebo group for several secondary endpoints.