- Better pathologic complete response and relapse-free survival after carboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial. [JOURNAL ARTICLE]
- Oncotarget 2016 Jul 14.
No standard chemotherapy is used as neoadjuvant therapy in triple negative breast cancer (TNBC). This study has compared carboplatin plus paclitaxel with commonly used epirubicin plus paclitaxel as neoadjuvant chemotherapy (NAC) in TNBC.91 patients with a median age of 47 years (PC 47 patients, EP 44 patients) were enrolled. 65% of the patients were premenopausal. While the objective response rate was similar in the PC and EP arm (89.4% vs. 79.5%, P = 0.195), the pCR rate in the PC arm was significantly higher (38.6% vs. 14.0%, P = 0.014). The median follow-up time was 55.0 months. 5-year RFS were 77.6% and 56.2%, significantly higher in the PC arm, P = 0.043. No significant difference in OS was observed between the two arms (P = 0.350). Adverse events were similar, except for more thrombocytopenia in the PC arm (P = 0.001).Patients with stage II/III TNBC were randomized to receive either paclitaxel (175 mg/m2, day1) plus carboplatin (Area Under the Curve = 5, day2) (PC) or epirubicin (75mg/m2, day1) plus paclitaxel (175 mg/m2, day2) (EP) as NAC every three weeks for 4-6 cycles. The primary endpoint was rate of pathologic complete response (pCR).The secondary endpoints included relapse-free survival (RFS), overall survival (OS) and safety.This study suggested that the addition of carboplatin to paclitaxel was superior to the regimen of epirubicin plus paclitaxel as NAC for TNBC in terms of improving pCR rate and RFS. Further phase 3 study has already started.
- Mycophenolate mofetil for the treatment of children with immune thrombocytopenia and Evans syndrome. A retrospective data review from the Italian association of paediatric haematology/oncology. [JOURNAL ARTICLE]
- Br J Haematol 2016 Jul 22.
Mycophenolate mofetil (MMF) has been shown to be effective in children with immune thrombocytopenia (ITP) and Evans syndrome (ES), but data from larger series and details on the timing of the response are lacking. We evaluated 56 children treated with MMF for ITP (n = 40) or ES (n = 16), which was primary or secondary to autoimmune lymphoproliferative syndrome -related syndrome (ARS). Thirty-five of the 54 evaluable patients (65%) achieved a partial (18%) or complete (46%) response after a median (range) of 20 (7-137) and 37 (7-192) d, respectively. ITP and ES patients responded in 58% and 81% of cases (P = not significant, ns), with complete response in 32% and 81% (P = 0·01), respectively. 60% and 73% of children with primary disease and ARS responded (P = ns) with complete response in 34% and 68% of cases (P = 0·01), respectively. Six of 35 (17%) children relapsed after a median of 283 d (range 189-1036). Limited toxicity was observed in four patients. The median durations of treatment and follow-up were seven and 12·7 months, respectively. This is the largest reported cohort of patients treated with MMF for ITP/ES. The results show that MMF is effective and safe and provides a relatively quick response, suggesting that it has a potential role as an alternative to more aggressive and expensive second/further-line treatments.
- Thrombopoietin induces hematopoiesis from mouse ES cells via HIF-1α-dependent activation of a BMP4 autoregulatory loop. [Journal Article]
- Ann N Y Acad Sci 2016 Jul; 1375(1):38-51.
Understanding the molecular mechanisms underlying hematopoietic differentiation of embryonic stem (ES) cells may help to ascertain the conditions for the in vitro generation of hematopoietic cells. Previously, we found that patients with congenital amegakaryocytic thrombocytopenia (CAMT), who develop pancytopenia early after birth, harbor mutations within the thrombopoietin (TPO) receptor, c-MPL. This knowledge, together with observations in vitro and in vivo, suggests that TPO/c-MPL signaling promotes early hematopoiesis. However, the mechanisms underlying TPO signaling are not fully elucidated. Here, we describe a direct connection between TPO and bone morphogenetic protein 4 (BMP4) signaling pathways in determining the hematopoietic fate of ES cells. Morphogen BMP4 is known to induce early hematopoietic differentiation of ES cells. Treatment of ES cells with TPO induced the autocrine production of BMP4 with concomitant upregulation of the BMP receptor BMPR1A, phosphorylation of SMAD1, 5, 8, and activation of specific BMP4 target genes; this was mediated by TPO-dependent binding of transcription factor HIF-1α to the BMP4 gene promoter. Treatment of ES cells with the BMP antagonist noggin substantially reduced TPO-dependent hematopoietic differentiation of ES cells. Thus, our findings contribute to the establishment of techniques for generating hematopoietic cells from ES cells.
- Thromboembolic events secondary to tirofiban-induced thrombocytopenia being treated with thrombopoietin: A case report. [JOURNAL ARTICLE]
- Exp Ther Med 2016 Aug; 12(2):1177-1180.
A 68-year-old man presented with acute coronary syndrome (ACS). The glycoprotein/IIb/IIIa receptor antagonist tirofiban was administered to the patient to treat a right coronary artery slow flow detected during percutaneous coronary intervention. The patient developed very severe thrombocytopenia 8 h after tirofiban infusion with no signs of bleeding. Antiplatelet medication was discontinued immediately, methylprednisolone was administered and platelets were transfused. Thrombopoietin (TPO) was also applied to the patient as recommended by a hematology consultant. As a result, the patient had in-stent thrombosis and cerebral infarction, then another sirolimus-eluting stent was implanted in the proximal right coronary artery and intensive anti-platelet as well as intermittent dehydration to reduce intracranial pressure, and protection of the nervous system function treatment was also provided. The patient was left with a decreased muscle strength in the right limb muscle and fine movement disorder, which may have lead to a poor prognosis. To the best of our knowledge, this is the first case report of tirofiban-induced severe thrombocytopenia with secondary in-stent thrombosis and cerebral infarction from China. The experience of the diagnosis and treatment of this case may shed some light on the clinical use of TPO in tirofiban-induced thrombocytopenia.
- Severe Thrombocytopenia in Adults with Severe Acute Respiratory Distress Syndrome: Impact of Extracorporeal Membrane Oxygenation Use. [JOURNAL ARTICLE]
- ASAIO J 2016 Jul 20.
Extracorporeal membrane oxygenation (ECMO) use is perceived to cause thrombocytopenia (T), but the role of non-ECMO factors in the development of T remains unclear. We sought to evaluate the incidence and factors associated with severe T [platelet count ≤ 50,000/μL] in adults with severe acute respiratory distress syndrome (ARDS) managed with or without ECMO. The ECMO (n=32) vs. the non-ECMO (n=53) groups had a similar baseline platelet count (214,000 vs. 179,000/μL), APACHE II score (p=0.13), unfractionated heparin exposure (p=0.62), and severe T incidence (25 vs 19%, p=0.5). Although the APACHE II score (p=0.01), presence of liver failure (p=0.08), and platelet transfusion (p=0.0009) were different between the severe T [18/85 (21%)] and non-severe T groups [67/85 (79%], the incidence of septic shock (p=0.64), heparin infusion use (p=0.41), exposure to non-heparin T-causing medications (p=0.77) and ECMO use (p=0.5) were not. An adjusted multivariate linear regression model revealed that only the APACHE II score was independently associated with the development of severe T (p=0.01) but use of ECMO was not (p=0.32) ECMO use may not affect the incidence of severe T among adults with severe ARDS. Larger studies that are prospective in nature are required to confirm this finding.
- Bi-cytopenia possibly induced by anti-PD-1 antibody for primary malignant melanoma of the esophagus: A case report. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Jul; 95(29):e4283.
Anti-programmed cell death 1 antibody nivolumab is a promising agent for various cancers. Immune-related adverse events are recognized; however, bi-cytopenia with nivolumab has not been reported.A 73-year-old man was diagnosed with advanced primary malignant melanoma of the esophagus with liver, lung, and lymph node metastases. Previous therapies including dacarbazine and radiation of 39 Gy to the esophageal region were performed, but the liver metastases deteriorated. The patient was then administered nivolumab (2 mg/kg, every 3 weeks). After 3 cycles, the esophageal tumor and lymph nodes showed marked reductions in size, the lung metastases disappeared, and the liver metastases shrank partially. The treatment continued with 7 cycles for 4 months. However, severe anemia and thrombocytopenia appeared in the 6th cycle, and intermittent blood transfusions were required. The patient received high-dose intravenous methylprednisolone therapy for bi-cytopenia, but it was ineffective. Seven months after the initiation of nivolumab, the patient died of tumor. Although the mechanisms of bi-cytopenia were unclear, it could have been induced by nivolumab.The present case shows a rare but serious life-threatening bi-cytopenia possibly associated with nivolumab and suggests the importance of awareness of hematological adverse events during nivolumab therapy.
- Impact of sex disparities on the clinical manifestations in patients with systemic lupus erythematosus: A systematic review and meta-analysis. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Jul; 95(29):e4272.
Systemic lupus erythematosus (SLE) is a chronic autoimmune multiorgan disorder of unknown etiology. It affects both men and women, but with different disease manifestations of differing disease severity and in varying proportion, with a female predominance of approximately 90%. There have been numerous studies addressing this issue, especially its implications in relation to optimal sex-tailored treatment and improvement of survival rate; however, further research is warranted. A meta-analysis of studies was performed to compare the impact of sex on the clinical outcomes of SLE in different populations.A literature search of the MEDLINE/PubMed and EMBASE databases (until January 2016) was conducted to identify relevant articles. Clinical manifestations reported in these patients were considered as endpoints for this meta-analysis. Two independent reviewers determined eligibility criteria. A fixed-effect model has been used where a small heterogeneity was observed, or else, a random-effect model has been used among the studies. Odd ratio (OR) with 95% confidence interval (CI) was used to express the pooled effect on dichotomous variables, and the pooled analyses were performed with RevMan 5.3.Sixteen studies consisting of a total of 11,934 SLE patients (10,331 females and 1603 males) have been included in this meta-analysis. The average female-to-male ratio of all the included studies is around 9.3:1. Several statistically significant differences were found: alopecia, photosensitivity, and oral ulcers were significantly higher in female patients (OR 0.36, 95% CI 0.29-0.46, P < 0.00001; OR 0.72, 95% CI 0.63-0.83, P < 0.00001; and OR 0.70, 95% CI 0.60-0.82, P < 0.00001, respectively). Malar rash was significantly higher in female patients (OR 0.68, 95% CI 0.53-0.88, P = 0.003), and arthritis was significantly lower in male patients (OR 0.72, 95% CI 1.25-1.84, P < 0.00001). However, serositis and pleurisies were significantly higher in female patients (OR 1.52, 95% CI 1.25-1.84 P < 0.0001; and OR 1.26, 95% CI 1.07-1.48, P = 0.006, respectively). Renal involvement was higher in male patients (OR 1.51, 95% CI 1.31-1.75, P < 0.00001).The results of this meta-analysis suggest that alopecia, photosensitivity, oral ulcers, arthritis, malar rash, lupus anticoagulant level, and low level of C3 were significantly higher in female lupus patients, whereas renal involvement, serositis and pleurisies, thrombocytopenia, and anti-double stranded deoxyribonucleic acid level were predominant in male patients.
- Atopic dermatitis and association of risk for primary immune thrombocytopenia and autoimmune diseases among children: A nationwide population-based cohort study. [JOURNAL ARTICLE]
- Medicine (Baltimore) 2016 Jul; 95(29):e4226.
Primary immune thrombocytopenia (ITP) is currently defined as an acquired autoimmune disorder with persistent thrombocytopenia. However, the temporal interaction between T helper type 2 cell (Th2)-mediated allergic diseases and T helper type 1 cell (Th1)-mediated ITP remains unknown. Atopic dermatitis (AD) is considered one of the first steps in the atopic march. Herein, we conducted a population-based cohort analysis to investigate the risk of ITP in children with AD in comparison with non-AD controls. We subsequently compared the occurrence of other autoimmune diseases in ITP children in both AD and non-AD cohorts. From 2000 to 2007, 120,704 children with newly diagnosed AD and 241,408 randomly selected non-AD controls were included in the study. By the end of 2008, incidences of ITP in both cohorts and the AD cohort to non-AD cohort hazard ratios (HRs) and confidence intervals (CIs) were measured. Comparison of the occurrence of other autoimmune diseases in ITP between children with and without AD was analyzed. The incidence of ITP during the study period was 1.72-fold greater (95% CI: 1.13-2.62) in the AD cohort than in the non-AD cohort (6.96 vs 4.00 per 100,000 person-years). The risk was greatest among male children, children >2 years, those in densely populated areas, and those with white-collar parents. The HR of ITP in AD children increased significantly with the number of AD-related clinical visits (P < 0.001). The risk of developing ITP in the AD cohort was highest within the first 3 years after the diagnosis of AD (HR: 1.78; CI: 1.14-2.78). The AD cohort with ITP had a higher occurrence rate of other autoimmune diseases than the non-AD cohort with ITP. AD children had a greater risk of developing ITP and other autoimmune diseases. Further research is needed to clarify the role of allergy in the pathogenesis of ITP and autoimmune diseases.
- Pregnancy Outcomes in Chinese Patients with Systemic Lupus Erythematosus (SLE): A Retrospective Study of 109 Pregnancies. [JOURNAL ARTICLE]
- PLoS One 2016; 11(7):e0159364.
Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that primarily affects women during their reproductive years. The interaction between SLE and pregnancy remains debated. The objective of this study was to analyze the fetal and maternal outcomes of Chinese women with SLE. A total of 109 pregnancies in 83 SLE patients from June 2004 to June 2014 at a tertiary university hospital were reviewed retrospectively. Patients' characteristics, clinical and laboratory data during pregnancy were obtained from electronic medical records. After exclusion of elective abortions, the live birth rate was 61.5%. Significantly, APS (antiphospholipid syndrome), disease activity, hypertension, hypocomplementemia, thrombocytopenia, and anemia during pregnancy were more commonly observed in fetal loss pregnancies than in live birth pregnancies. Compared to the 64 women with a history of SLE, 19 women with new-onset lupus during pregnancy had worse pregnancy outcome. Furthermore, the 64 patients with a history of SLE were divided into lupus nephritis group and SLE group (non-renal involvement). We found that the lupus nephritis group had worse maternal outcome than the SLE group. We conclude that new-onset lupus during pregnancy predicts both adverse maternal and fetal outcomes, while a history of lupus nephritis predicts adverse maternal outcomes. It is essential to provide SLE women with progestational counseling and regular multispecialty care during pregnancy.
- Platelet Count Trends and Prevalence of Heparin-Induced Thrombocytopenia in a Cohort of Extracorporeal Membrane Oxygenator Patients. [JOURNAL ARTICLE]
- Crit Care Med 2016 Jul 15.
To assess the prevalence of heparin-induced thrombocytopenia and to study platelet count trends potentially suggestive of heparin-induced thrombocytopenia in a population of extracorporeal membrane oxygenator patients.Retrospective cohort study.A total of 926-bed teaching hospital.Extracorporeal membrane oxygenator patients who survived longer than 48 hours from extracorporeal membrane oxygenator initiation between January 1, 2009, and December 31, 2013.None.Demographic and clinical data were collected prospectively on all extracorporeal membrane oxygenator patients. Heparin-induced thrombocytopenia testing results and platelet count variables were obtained from the electronic medical record. We used our institutional algorithm to interpret the results of heparin-induced thrombocytopenia testing. Ninety-six extracorporeal membrane oxygenator patients met the inclusion criteria. Eight patients met the algorithm criteria for heparin-induced thrombocytopenia diagnosis and seven of those had documented thromboembolic event while on extracorporeal membrane oxygenator (prevalence of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia related thrombosis, 8.3 and 7.3, respectively). Heparin-induced thrombocytopenia positive patients were younger; all underwent venoarterial extracorporeal membrane oxygenator; spent more hours on extracorporeal membrane oxygenator; had significantly higher heparin-induced thrombocytopenia enzyme-linked immunosorbent assays optical density; had a higher prevalence of thromboembolic events and reached platelet count nadir later. There was no difference in mortality between heparin-induced thrombocytopenia positive and negative patients. Comparison of platelet count trends revealed that there was no statistically significant difference between the predefined study groups.Prevalence of heparin-induced thrombocytopenia and heparin-induced thrombocytopenia-related thrombosis among extracorporeal membrane oxygenator patients at our institution is relatively high. Using platelet count trends to guide decision to test for heparin-induced thrombocytopenia is not an optimal strategy in extracorporeal membrane oxygenator patients. Without a validated pretest probability clinical score, serosurveillance in a defined high-risk group of extracorporeal membrane oxygenator patients may be needed.