The prevention and management of stroke in sickle cell anaemia

Perhaps the most important clinical complication of sickle cell anaemia is stroke, an event that occurs in ～ 5 – 10% of children who inherit this disorder. To prevent recurrent or progressive CNS damage, the institution of regular red blood cell (RBC) transfusions is the standard of care. In addition, children at high risk of developing stroke, as screened by transcranial Doppler, also benefit from regular RBC transfusions for stroke prevention. In this review, standard and novel techniques of RBC transfusion, and also alternative therapies to treat children with or at risk for stroke are considered. In addition, haematopoietic cell transplantation, the only curative option for sickle cell anaemia, is considered, and speculation about its present and future application in this clinical setting is discussed.     

High-dose Hydroxyurea and G-CSF to Collect Philadelphia-Negative Cells in Chronic Myeloid Leukemia: Preliminary Results

Five patients with Ph+ chronic myeloid leukemia and no detectable diploid cells in the marrow received 6 g hydroxyurea twice daily for 7 days followed by G-CSF to harvest Ph- cells 1-84 months after diagnosis. Three were in first chronic phase, and two in accelerated phase. One stopped hydroxyurea after 4 doses due to intractable vomiting and was not apheresed, while two stopped hydroxyurea after 9 and 11 doses because of mucositis and skin rash. Two tolerated all doses; one with no significant side effects, and one with mucositis and painful plantar rash. The nadir leukocyte, neutrophil, and platelet counts were 0.4-0.8, 0-0.1, and 2-19 × 10⁹/L respectively. Apheresis was commenced when the leukocytes were 1.2-3.8 × 10⁹/L 9-10 days after starting G-CSF, and 6 aphereses were performed. Four collections were 100% Ph+, and two 22% and 90% Ph-. The total nucleated cell, CD34+/CD34- subset, CD34+/CD33+ subset, and CFU-GM yields per kg per collection were 0.48-2.38 (median 1.18) × 10⁸, 0-0.48 (median 0.012) × 10⁶, 0.028-10.19 (median 0.92) × 10⁶, and 0.29-41.81 (median 21.78) × 10⁴ respectively. We conclude that hydroxyurea in the dose we used is poorly tolerated, and is associated with significant adverse effects including severe myelosuppression. It is possible to harvest diploid cells during recovery, but achievement of Ph-negativity appears to be erratic and cell yields are poor.     

不同致“阳虚”药对雄大鼠骨代谢影响的实验研究

目的：探讨不同致“阳虚”药物对雄大鼠骨代谢的影响。方法：实验用３月龄ＳＤ大鼠３２只，随机分为对照组（Ａ１）组１、对照组（Ａ２）组２、激素（Ｂ）组和羟基脲（Ｃ组），Ａ１和Ａ２组灌喂生理盐水１ｍｌ／ｋｇ，Ｂ组灌喂泼尼松４．５ｍｇ／ｋｇ，Ｃ组灌喂羟基脲０．２５ｇ／ｋｇ，每周３次，３个月后用图象分析仪对四组大鼠胫骨中段的骨片进行动态及静态测算和分析。结果：Ｂ组和Ｃ组分别与Ａ１组和Ｂ１组比较，都出现骨吸收大于骨形成，导致骨量丢失，从而出现皮质骨变薄，骨髓腔增大。结论：致“阳虚”药物泼尼松和羟基脲均可引起大鼠骨质疏松，但二者所造成骨量丢失的机理不尽相同。     

羟基脲对雄大鼠密质骨代谢影响的定量研究

采用３月龄♂ＳＤ大鼠１６只，随机分为对照组和羟基脲组，后者每周喂羟基脲三次，３ｍｏｎ后对两组大鼠胫骨中段的骨片用图象分析仪进行测算和分析。羟基脲组和对照组比较；皮质骨面积百分数减少７％（Ｐ＜０．００１）、骨髓腔面积百分数增加２８％（Ｐ＜０．００１）、内骨膜面皮质骨的荧光标记周长百分数增加８０％（Ｐ＜０．０５）、骨矿化沉积率增加３９７％（Ｐ＜０．０５）、骨形成率增加５２９％（Ｐ＜０．０５）、骨吸收周长百分数增加１５６％（Ｐ＜０．０５）。所获参数反映出用羟基脲能建立大鼠骨质疏松模型，并认为在＂阳虚＂状态下会造成骨量丢失。     

Cell kill kinetics with hydroxyurea

The effects of various concentrations of hydroxyurea (HU) on a human lymphoid cell line in exponential growth phase have been studied using a combination of methods, including determination of the total and viable cell counts; the cells' relative DNA content, measured in a flow microfluorimeter after staining with a fluorescent Feulgen technique; the mitotic index; and the percentage of cells incorporating thymidine-³ H (TdR-³ H) during brief and continuous exposure to the isotope both in the presence and absence of colcemid. A significant redistribution of the cells in the various phases of the cell cycle occurred during the first 24 hr of continuous treatment with 10^-3 M and 10^-2 MHU as follows: (1) division of cells in G₂; (2) depletion of mid and late S phase cells due to early cell death; (3) movement of most G₁ cells at a normal rate into early S phase where they accumulate; and (4) arrest of the remaining cells in G₁, which represented the surviving population after treatment for 96 hr or longer. After removal of the drug, the cell fraction blocked in early S phase progressed semisynchronously through S, but many of the cells were unable to complete division. Their capacity to recover depended on the drug concentration and duration of exposure, but in general the cellular injury caused by HU was more reversible than that caused by “equivalent” concentrations of arabinosylcytosine.     

Hydroxyurea Chemotherapy for Unresectable or Residual Meningioma

Meningiomas represent 18–20% of all intracranial tumors and have a 10-year recurrence rate of 20–50%, despite aggressive surgery and irradiation. In addition, many tumors are not amenable to surgery due to their deep location or proximity to delicate structures. Chemotherapy is being explored as another potential treatment option for unresectable or refractory meningiomas. Hydroxyurea is an agent that inhibits ribonucleotide reductase and can induce apoptosis in meningioma cell cultures and animal models. We have placed 17 patients with unresectable or residual meningioma on hydroxyurea chemotherapy (20mg/kg/d orally). The mean age of our cohort was 57.2 years; 13 patients were female. Eleven patients had actively growing tumors or neurological progression at the onset of chemotherapy. Sixteen patients were evaluable for response. Fourteen of the 16 patients (88%) responded with stable disease ranging from 20 to 144+ weeks (median 80 weeks; 10 patients still accruing time). Three of the responders progressed after 20, 36, and 56 weeks, respectively. Two patients had progressive disease after 10 weeks. Toxicity was hematologic in most patients; leukopenia was most common. Nine patients (53%) required dosage reductions (250–500mg/d) secondary to hematologic toxicity. Hydroxyurea appears to have modest activity against meningiomas and should be considered in patients with unresectable tumors or large residual tumors following surgical resection.     

Prolonged Oral Hydroxyurea and Concurrent 3d-Conformal Radiation in Patients with Progressive or Recurrent Meningioma: Results of a Pilot Study

Summary Purpose: Treatment of recurrent and progressive meningiomas remains a challenge in clinical neurooncology. This study was designed to evaluate the efficacy of the simultaneous application of 3d-conformal radiotherapy and chemotherapy with hydroxyurea (HU). Patients and methods: Twenty-one patients with recurrent or progressive meningiomas (13 benign, 4 atypical and malignant, 4 with unproven histology) received treatment by fractionated 3d-conformal radiation (55.8–59.4 Gy) and concurrent HU, administered for a median time of three months with a daily dosage of 20 mg/kg. Response was evaluated using clinical and neuro-imaging data. Results: Disease stabilization was achieved in 14/21 patients (pts). Three pts had significant improvement of tumor associated neurological symptoms with imaging criteria of minor response. Progression free survival rates 1 year and 2 years after the initiation of radio-chemotherapy were 84% and 77%, respectively. At the time of analysis a total of 6/21 pts presented with progressive disease with a median time to progression of 59 weeks. Documented radio- and chemotherapy associated toxicity was minimal; only one patient discontinued HU treatment due to gastrointestinal symptoms such as anorexia and weight loss. Conclusion: Results obtained in this study indicate that treatment with HU and simultaneous radiotherapy is safe and effective with disease stabilization in the majority of patients. Randomized trials comparing radiosurgery versus radiochemotherapy versus fractionated radiotherapy are warranted.     

Hydroxyurea treatment for unresectable meningioma

BACKGROUND: Management of unresectable progressive meningioma remains controversial and constitutes a major challenge since therapeutic options including chemotherapy and hormone modulation are limited. Recent data have suggested that hydroxyurea treatment may have an antitumoral effect. The purpose of this prospective phase II study was to evaluate the efficacy of hydroxyurea treatment for unresectable progressive meningioma. METHODS: From 1997 to 1999, consecutive patients presenting unresectable meningioma with clinically and/or neuroradiologically documented progression were considered for entry into this protocol. Previous radiotherapy was not a mandatory inclusion criteria. Treatment consisted of continuous oral administration of hydroxyurea at a dose of 20 mg/kg per day. Follow-up assessment included physical examination, computed tomography (CT), and magnetic resonance imaging (MRI) performed every three months, as well as regular blood testing. The primary endpoint was documentation of objective response by MRI or CT. RESULTS: The intent-to-treat population was 43 patients with at least 18 months follow-up. Median age was 60.4 years. Twenty-eight patients had undergone surgery following initial diagnosis. The meningioma was located in the skull base in 67% of patients. Histology was benign in 18 and atypical in 10. The eligible population included 36 patients with documented progressive disease at the time of inclusion; with progression documented clinically in 29 (67.5%) and/or radiologically in 20 (46%). In 7 patients, clinical or radiological progression could not be confirmed. The intent-to-treat analysis at median 26 months follow-up revealed objective response to hydroxyurea in only 3 patients (7%) including one on the basis of improvement in visual symptoms and two on MRI analysis. Progressive disease was observed clinically or radiologically in 26 patients (60.5%). Of the eligible population (n=36), 2 achieved an objective response and 13 (36%) exhibited stabilization under hydroxyurea therapy, while 21 (58%) progressed under treatment. Overall tolerance was good but anemia (grade I-II) and asthenia (grade I-II) were observed in 28% and 23.5% respectively. Treatment was discontinued in 3 patients because of chronic skin toxicity in one and anemia and asthenia in two. CONCLUSION: Hydroxyurea treatment is of marginal efficacy for meningioma and must not be considered as an alternative if radiotherapy or surgery is feasible. New efficient medical treatments are still required for progressive meningiomas.