Time to first disease progression, but not beta2-microglobulin, predicts outcome in myeloma patients who receive thalidomide as salvage therapy

BACKGROUND: Baseline parameters that may be predictive of outcome after thalidomide treatment have been investigated to identify which myeloma patient subgroups will most benefit from this drug. METHODS: Thalidomide has been used as a salvage regimen at the study institution since 1999. A total of 102 myeloma patients who were diagnosed between January 1999 and February 2005 were evaluable for intention-to-treat analysis; 78 patients received thalidomide (at a dose of 100 mg/day continuously) and dexamethasone (at a dose of 40 mg/day on Days 1-4 each month) (TD) as salvage treatment whereas 24 patients died or were lost to follow-up before the initiation of TD. Several parameters such as serum beta2-microglobulin, serum C-reactive protein, immunoglobulin A isotype, hemoglobin, stage of disease, bone marrow plasmacytosis, age, serum creatinine, gender, stem cell transplantation at the time of diagnosis, and time to first disease progression were analyzed in association with overall survival (OS). RESULTS: The OS from the time of diagnosis was 43.8 months. Using univariate analysis, factors found to be associated with a shorter OS were a creatinine level > or =2 mg/dL (P = .05), stage III (P = .04), and time to first disease progression < or =12 months (P < .0001). The only factor that remained significantly associated with a shorter OS in multivariate models was time to first disease progression < or =12 months (P = .0006). Elevated serum beta2-microglobulin was not found to be predictive of poor OS. CONCLUSIONS: Time to first disease progression >12 months was found to be the best indicator of OS. Elevated serum beta2-microglobulin, generally considered to be a poor prognostic factor, was not found to be predictive of outcome.     

Inhibition of 13-cis retinoic acid-induced gene expression of homeobox B7 by thalidomide

Thalidomide and 13-cis retinoic acid (RA) show anticancer effects as sole agents or in combination with other drugs. However, induction of homeobox (HOX) gene expression by 13-cis RA may contribute to tumor progression thereby potentially limiting its efficacy. The purpose was to test if thalidomide can inhibit 13-cis RA-induced HOXB7 expression and whether thalidomide may enhance the antiproliferative effect of 13-cis RA in U343MG glioblastoma cells. Quantitative real-time PCR showed significant inhibition of 13-cis RA-induced HOXB7 expression by thalidomide with IC(50) approximately 0.1-0.2 microg/ml when given simultaneously with 13-cis RA but not when administered 18 h later (p < 0.0001). 13-cis RA alone inhibited proliferation and colony formation in a concentration-dependent manner whereas growth inhibition by thalidomide alone at 5-100 microg/ml was constant at 80-90% of controls. At 10% serum concentration, growth inhibition by a combination of the 2 drugs was additive but at 1% serum, growth inhibition was synergistic. It is concluded that thalidomide inhibits the RA-induced HOXB7 expression in glioblastoma cells and that 13-cis RA/thalidomide combinations can in principle enhance cytotoxicity. The improved cell kill induced by thalidomide is attributed to downregulation of growth stimulatory factors induced by 13-cis RA. Implications for the modus operandi of thalidomide in embryogenesis are noted.     

Antiangiogenic approach in soft-tissue sarcomas

Soft-tissue sarcomas (STS) are a group of more than 50 malignancies characterized by their rarity. The most effective treatments available only achieve a response rate (RR) of around 20%. Therefore, new therapeutic strategies are needed. Neoangiogenesis is one of the most fundamental mechanisms in cancer and many studies suggest that it also plays a crucial role in STS. Positive results from two Phase III trials in STS with drugs that target angiogenesis have recently been reported, showing an increase in progression-free survival. These data, although promising, are still insufficient and further investigations are needed. STS are unusual among solid tumors, in which single agent angiogenesis inhibitors produce a significant benefit. Unfortunately, we are currently not able to reliably define according to the histological subtype who are the patients that may benefit from this strategy. Moreover, it is clear that single agent treatment is insufficient, hence the current focus is on combination studies.     

Novel approaches to the treatment of chronic graft-versus-host disease

Chronic graft-versus-host disease (cGvHD) continues to be the major problem in long-term survivors of allogeneic haematopoietic stem cell transplants and is the principal cause of morbidity and non-relapse mortality. Over the past twenty years, diagnosis, prophylaxis and treatment of cGvHD have slowly evolved. An effective therapy for cGvHD is designed to prevent complications through targeting the disease mechanisms. None of the present therapies for cGvHD are successful in the majority of patients. Conventional drugs in different combinations can control the disease in approximately 50% of patients. Attempts to improve survival have led to evaluation of several alternative approaches in the treatment of refractory cGvHD with varying degrees of success. Clinical trials are needed to establish the role of these new approaches in the treatment of cGvHD as first line or salvage therapy without causing significant side effects. This review summarises the currently available knowledge on conventional and new treatment approaches for cGvHD.     

Novel therapies for renal cell carcinoma

Metastatic renal cell cancer remains a disease which is difficult to treat medically. Prognosis often depends more on intrinsic disease features than on treatment choices. In this review, we examine novel therapies and scientific directions surrounding the RCC treatment problem. Reports relating chromosomal aberrations and of comparative gene expression analyses relating to RCC, are reviewed briefly. The central role of the von Hippel Lindau protein in clear cell RCC pathogenesis is evident. The limited contribution of conventional cytotoxic chemotherapy is mentioned. Some clinically applied agents whose clinical results are highlighted include 5-FU, retinoids, thalidomide, razoxane and IL-12. Features of the pathophysiology of von Hippel Lindau protein are described, with attention to potential novel therapies targeting HIF-1α, VEGF, TGF-β1 and TGF-α pathways. Immunotherapy is being explored in many angles. Most basic are cytokine therapies incorporating new IL-2 and IFN-α schedules. Newer cytokine-based drugs include pegylated forms and IL-12. Allogeneic mini-transplantation has generated much interest. Tumour-associated antigens are being used to direct therapy using both identified and non-identified epitopes. A variety of tumour-cell vaccine and dendritic-cell vaccine clinical approaches are discussed. Finally, nephrectomy for known metastatic disease has been demonstrated to be helpful in retrospective and now prospective trials. Resection of metastases is also discussed. We are optimistic that the further clinical development among these novel therapies will improve the outlook for metastatic RCC.     

Monotherapy with thalidomide for treatment of spinal cord hemangioblastomas in a patient with von Hippel–Lindau disease

Von Hippel–Lindau (VHL) disease is a cancer‐prone syndrome characterized by abnormalities in vascular proliferation and the development of both the visceral and CNS tumors. Complications from hemangioblastoma are among the principal causes of death from this syndrome. Antiangiogenic therapy has been used with different modalities in patients suffering from such complications. Here, we describe an adolescent with VHL complicated by progressive, multifocal spinal hemangioblastomas. Treatment with single‐agent thalidomide over the course of 3 years was associated with an unexpected stabilization of the disease. The antiangiogenic effect of thalidomide may be associated with the control of progressive hemangioblastoma. Pediatr Blood Cancer 2009;53:464–467. © 2009 Wiley‐Liss, Inc.     

沙利度胺及氨甲蝶呤抗CIA大鼠滑膜血管新生及其作用机制的研究

目的研究沙利度胺、氨甲蝶呤对大鼠Ⅱ型胶原诱导型关节炎血管新生的影响及相关的机制。方法建立类风湿性关节炎大鼠模型.自造模次日治疗组分别给予沙利度胺、甲氨蝶呤和沙利度胺联合甲氨蝶呤治疗,在第6周取膝关节应用免疫组化检测其滑膜的微血管密度(MVD),取血清进行Western Blot检测大鼠体内血管内皮细胞生长因子(VEGF)、基质金属蛋白酶-1、2、3、9的表达并计算相对含量。结果①免疫组织化学染色显示沙利度胺、氨甲蝶呤和沙利度胺联合氨甲蝶呤治疗模型大鼠可使关节滑膜中新生血管数量明显减少.微血管密度(MVD)明显降低(P<0.05).以沙利度胺联合氨甲蝶呤组作用最强。②沙利度胺、氨甲蝶呤和沙利度胺联合氨甲蝶呤可抑制VEGF、MMP-1、2、3、9表达(P均<0.05)。结论沙利度胺和氨甲蝶呤可能通过抑制VEGF,MMP-1、2、3、9的表达而发挥抗滑膜血管新生的作用,且两者有协同作用。     

The natural history of occult or angiodysplastic gastrointestinal bleeding in von Willebrand disease

Recurrent gastrointestinal bleeding is one of the most challenging complications encountered in the management of patients with von Willebrand disease (VWD). The commonest cause is angiodysplasia, but often no cause is identified due to the difficulty in making the diagnosis. The optimal treatment to prevent recurrences remains unknown. We performed a retrospective study of VWD patients with occult or angiodysplastic bleeding within the setting of the von Willebrand Disease Prophylaxis Network (VWD PN) to describe diagnostic and treatment strategies. Centres participating in the VWD PN recruited subjects under their care with a history of congenital VWD and gastrointestinal (GI) bleeding due to angiodysplasia, or cases in which the cause was not identified despite investigation. Patients with acquired von Willebrand syndrome or those for whom the GI bleeding was due to another cause were excluded. Forty‐eight patients from 18 centres in 10 countries were recruited. Seven individuals had a family history of GI bleeding and all VWD types except 2N were represented. Angiodysplasia was confirmed in 38%, with video capsule endoscopy and GI tract endoscopies being the most common methods of making the diagnosis. Recurrent GI bleeding in VWD is associated with significant morbidity and required hospital admission on up to 30 occasions. Patients were treated with multiple pharmacological agents with prophylactic von Willebrand factor concentrate being the most efficient in preventing recurrence of the GI bleeding. The diagnosis and treatment of recurrent GI bleeding in congenital VWD remains challenging and is associated with significant morbidity. Prophylactic treatment with von Willebrand factor concentrate was the most effective method of preventing recurrent bleeding but its efficacy remains to be confirmed in a prospective study.