Langerhans cell histiocytosis: a review of past, current and future therapies

The goal of therapy in Langerhans cell histiocytosis (LCH) is to decrease the activity and proliferation of histiocytes, lymphocytes and macrophages that cause the disease. Patients with disease that is localized to skin, bone and lymph node (defined as "nonrisk" organs) generally have a good prognosis and require minimal treatment. However, patients with lesions in "risk" organs (liver, spleen, lung, bone marrow) have a worse overall prognosis regarding mortality and morbidity. Likewise, patients with LCH in the central nervous system (CNS), vertebrae, facial bones or bones of the anterior or middle cranial fossa are at higher risk for morbidity and recurrent disease. LCH in the orbit, mastoid or temporal skull regions are classified as "CNS risk" because of an increased frequency of developing diabetes insipidus and other endocrine abnormalities or parenchymal brain lesions. Outcomes of patients with LCH in only one bone in "nonrisk" locations are generally benign, and the disease responds well to several treatment modalities including observation, surgical excision, steroid injection or radiation therapy. The last is generally reserved for a single vertebral lesion or when a risk of pathologic fracture exists in the greater trochanter. The greatest challenge in treatment of LCH is patients with multisystem disease. Patients with persistent or worsening disease in risk organs by the end of the first 6-12 weeks of therapy have significantly decreased overall survival regardless of treatment. Additionally, optimal treatment for patients with late-onset CNS symptoms and adults with LCH remain to be defined. In this article we will review the evolution of multicenter and international treatment studies as well as the current Histiocyte Society research treatment protocol, LCH-III. We also review experiences with a variety of agents that have been used to treat LCH outside of clinical trials. Since LCH is a rare disease in children and adults, these patients should be enrolled on clinical trials whenever possible to advance our knowledge of the optimal therapeutic interventions and long-term outcomes.     

儿童朗格汉斯细胞组织细胞增生症的诊治新进展

朗格汉斯细胞组织细胞增生症(Langerhans cell histiocytosis,LCH)是一组以CD1a+、CD207+树突状细胞异常增生为特点的组织细胞增生性疾病,临床表现复杂多样,可侵犯单器官、多器官及多系统,以骨骼、皮肤及垂体损伤常见,分为单系统LCH、高危多系统LCH、低危多系统LCH及特定部位LCH四类;目前主要有炎症性增生学说与肿瘤性增生假说,现多认为与丝裂原活化蛋白激酶(MAPK)通路异常活化密切相关。病理仍是诊断的金标准,而液体活检将可能成为新的无创性确诊手段,根据侵犯的部位、范围及程度制定个体化的治疗方案。近年来,靶向治疗已成为研究的热点,并有望取代传统的治疗方案,但在儿童中的使用仍处于临床研究阶段。现就儿童LCH临床特点及诊治新进展进行综述,以期提高临床诊疗水平。     

An update on the treatment of pediatric-onset Langerhans cell histiocytosis through pharmacotherapy

Introduction: Langerhans cell histiocytosis (LCH) is a rare myeloid neoplasia driven by activation mutations alongside the MAPK pathway. Its broad spectrum of clinical manifestations and diverse course and clinical outcome, make interpretation of trial data difficult. Use of different stratification systems further complicates comparison among trials.

Areas covered: This review summarizes the published data derived from prospective clinical trials from Phase II onwards. PubMed was searched using combinations of the keywords ‘Langerhans cell histiocytosis’, ‘histiocytosis X’, ‘pediatric’, ‘children’, ‘treatment’, and ‘therapy’. Only full-length papers published in English and German were included in the review.

Expert opinion: Mortality in multisystem LCH is restricted to patients with involvement of risk organs (hematopoiesis, liver and spleen) at diagnosis, and is particularly high (up to 60–70%) if systemic therapy fails to control the disease. For the rest of the cohort, mortality is almost negligible, and the main challenges are disease relapses and related permanent consequences (encountered in up to 50% of the survivors). While systemic therapy has clearly improved survival of patients with most severe disease form, its role in providing sustained disease control and preventing permanent consequences in patients with ‘low risk’ disease is less clear.     

急性肺栓塞的溶栓治疗进展

急性肺栓塞是临床上具有较高发病率和死亡率的常见病,除抗凝外,溶栓治疗是一种有效的治疗方法;基于急性肺栓塞早期死亡风险进行危险分层,将急性肺栓塞患者分为高危、中危、低危三种状况并区别对待,对溶栓治疗有重要指导意义。     

Sequential intravenous/oral antibiotic vs. continuous intravenous antibiotic in the treatment of pyogenic liver abscess

AIM: Pyogenic liver abscesses result in substantial morbidity and mortality. Antimicrobial regimens using sequential intravenous/oral therapy may reduce the length of hospital stay. In this retrospective analysis, the efficacy of continuous intravenous antibiotic therapy (group I) vs. sequential intravenous/oral antibiotic therapy (group II) was studied in patients with pyogenic liver abscess. METHODS: One hundred and twelve consecutive patients (55 in group I and 57 in group II) with pyogenic liver abscess were analysed. Clinical response, length of hospital stay and relapse rates were examined. RESULTS: Group II had a significantly shorter duration of intravenous antibiotic treatment (3.2 weeks vs. 5.9 weeks, P < 0.01) and a shorter length of hospital stay (28 days vs. 42 days, P < 0.01) when compared to group I. Oral antibiotics were prescribed for a median duration of 2.9 weeks in group II after discharge. No relapse occurred within 6 weeks after the completion of treatment in both groups. The cost of therapy was significantly lower in group II than in group I by 33%. CONCLUSIONS: A sequential intravenous/oral antibiotic regime is a safe and effective treatment for pyogenic liver abscess. This reduces the cost of therapy and the length of hospital stay.     

Treatment of gestational trophoblastic tumors

A brief discussion of the definition, etiology, epidemiology, classification, and prognosis of the gestational trophoblastic tumor (GTT) is presented. Current therapeutic options are summarized. GTTs arise from fetal tissues and can be divided into three histologic categories, hydatidiform mole, chorioadenoma destruens, and choriocarcinoma. Clinically, it is classified as nonmetastatic, metastatic-low risk, or metastatic-high risk. Diagnosis is based on clinical signs and symptoms, ultrasound and X-ray examinations, and the presence of elevated serum levels of the B-subunit of human chorionic gonadotropin (hCG). Primary therapy for hydatidiform mole is evacuation of the uterine contents. Prophylaxis for metastases with actinomycin D sometimes is performed, but generally is not recommended. For persistent disease that is classified as nonmetastatic or low-risk metastatic, a methotrexate-leucovorin rescue protocol is preferred, with actinomycin D used in patients who show resistance to the regimen. Standard therapy for high-risk metastatic disease involves triple agent therapy with methotrexate, actinomycin D, and chlorambucil, but toxicity is significant. Other alternatives include the modified Bagshawe protocol, a VBC (vinblastine, bleomycin, cisplatin) regimen, cisplatin in combination with vincristine and high-dose methotrexate, and VP16-213 (etoposide) in combination with other agents. Other treatment modalities include radiation and surgery. Use of the most appropriate therapies can maximize the survival of a patient with gestational trophoblastic disease.     

Review article: the role of antisecretory therapy in the management of non-variceal upper gastrointestinal bleeding

Non-variceal, upper gastrointestinal bleeding accounts for 300,000 hospitalizations annually in the US and the risk of rebleeding and mortality remain high. The aim of this study was to review the incidence and causes of non-variceal upper gastrointestinal haemorrhage, criteria for early discharge, risk stratification and intravenous vs. oral proton-pump inhibitor use. Peptic ulcer disease accounts for 45% of all admissions for upper gastrointestinal bleeding. Clinical and endoscopic predictors of adverse outcome have been identified. The Rockall scoring system identifies patients who can be considered for early discharge after endoscopy. Evidence supports the use of intravenous proton-pump inhibitor therapy for patients with bleeding ulcers associated with high-risk stigmata. Patients who are clinically stable and in whom upper endoscopy has shown an ulcer with a clean base or a flat pigmented spot have a low risk for rebleeding and may be discharged early on oral proton-pump inhibitor therapy. Proton-pump inhibitor treatment reduces ulcer rebleeding but does not affect overall mortality. In the US, most patients with ulcer bleeding have low-risk stigmata, and thus, can be treated with oral proton-pump inhibitors and discharged early.     

双水平气道正压通气对慢性阻塞性肺疾病急性加重期合并呼吸衰竭的治疗作用

目的 探讨经鼻面罩双水平气道正压通气(BiPAP)在慢性阻塞性肺疾病(COPD)急性加重期合并呼吸衰竭的治疗作用.方法 将46例COPD合并急性呼吸衰竭患者随机分为2组,每组23例,标准治疗组给予常规抗感染、支气管扩张剂、呼吸兴奋剂、祛痰药、激素、氧疗、纠正酸碱失衡的治疗.经鼻面罩BiPAP治疗组在标准治疗的基础上,采用美国伟康公司BiPAP Harmony S/T型呼吸机进行辅助通气.观察2组患者治疗前后生命体征及血气分析变化,比较插管率、病死率、住院时间、住院费用.结果 2组治疗24 h后,BiPAP治疗组在心率、呼吸频率、血气方面均显著优于标准组(P＜0.05),BiPAP组插管率、病死率、住院时间、住院费用较标准治疗组明显降低(P＜0.05).结论 经鼻面罩BiPAP通气适合治疗COPD合并急性呼吸衰竭患者,其在改善临床症状和动脉血气指标方面均优于标准治疗,可明显缩短住院时间,降低住院费用,降低插管率、病死率.     

Outpatient therapy for febrile neutropenia: clinical and economic implications

Although febrile episodes in neutropenic patients remain a potentially life-threatening complication of anticancer chemotherapy, considerable progress has been achieved in understanding this issue. Febrile neutropenic patients represent a heterogeneous population that displays a very variable risk for serious medical complications. It has also been ascertained that in low-risk patients, the standard of care can be safely and effectively shifted from traditional hospital-based, parenteral, empiric, broad-spectrum antibacterial therapy to outpatient treatment, even for the entire duration of the febrile episode. Furthermore, in the last years some risk assessment models have been developed to identify, at the onset of febrile episodes, low-risk neutropenic patients who are most likely to have a favourable outcome (and who can effectively and safely be treated on an outpatient basis). With respect to traditional hospital-based therapy, the outpatient treatment of low-risk patients is associated with several advantages, including a conspicuous cost saving. Some strategies for inpatient therapy, such as switching from intravenous to oral antibacterials and early discharge, can allow some cost containment; however, the most substantial decrease in costs can be obtained by using outpatient treatment over the entire febrile episode, especially by using oral antibacterials. In spite of the considerable number of clinical studies published over the past 20 years, only limited pharmacoeconomic data on this issue are available. Future comparative studies between outpatient and inpatient treatment of febrile neutropenia, in addition to clinical outcomes (e.g. survival, time to clinical response), should therefore include the following: (i) a detailed analysis of total costs, specifying the setting of outpatient treatment and the method of administration of antimicrobial agents (home nursing, self administration or treatment at infusion centres or at a low-care unit of the hospital); (ii) cost of inpatient treatment if outpatient therapy fails; and (iii) out-of-pocket expenses incurred by the patients.     

Development of an immune gene prognostic classifier for survival prediction and respond to immunocheckpoint inhibitor therapy/chemotherapy in endometrial cancer

Immunotherapy has provided a promising therapeutic strategy for endometrial cancer (EC). The present study aims to develop a prognostic classifier based on immune-related genes (IRGs) to stratify EC patients. A total of 15 prognosis-related IRGs were further filtrated by multivariate Cox regression: LTA, TMSB15A, S100A14, PLA2G2A, PDGFRA, CLDN4, CTF1, PRLH, PTN, SST, HTR3E, NRP1, RORA, THRA and CBLC. A prognostic signature was constructed to split EC patients into the high-risk and low-risk group with statistically different survival outcomes, indicating good potential for the prognostic signature in survival surveillance. Furthermore, five compounds with potential anti-tumor effects were selected, including ciclopirox, ikarugamycin, vincamine, mevalolactone, and thiamazole. The abundance of follicular helper T cells, regulatory T cells and M0 macrophages were significantly enhanced in the high-risk group while resting memory CD4+ T cells, gamma delta T cells, M2 macrophages and resting mast cells were markedly elevated in the low-risk group. Memory activated CD4+ T cells, CD8+ T cells and activated mast cells were three most correlative with riskscore. An immunophenoscore (IPS) analysis revealed that patients of the low-risk group had a higher IPS and more inclined to respond to immune checkpoint inhibitors. Mutation analysis showed that patients of the low-risk group represented more tumor mutation burden but low riskscore, thus getting better prognosis. Patients of the low-risk group were more sensitive for gemcitabine, bleomycin, vinblastine, vinorelbine and methotrexate by prediction. We constructed a potential prognostic model and might offer new insight on the identification of new immune-related biomarkers and target therapy in EC.     

运动平板试验Duke评分对胸痛患者危险分层及预后的价值

目的评价运动平板试验Duke评分(DTS)对胸痛患者危险分层及预后评估的应用价值。方法选择169例运动试验阳性和可疑阳性同时行冠状动脉造影的患者为研究对象,按Duke评分分为DTS低危组(Duke≥5分,n=35)、中高危组(DTS<+5,n=134),比较两组患者冠状动脉病变和临床特点,随访两年比较2组发生主要不良心血管事件(MACE)的概率,分析DTS预测MACE的价值。结果在中高危组中限制性心绞痛发作例数、ST段偏移≥1 mm例数、运动时ST段改变涉及导联数目、ST段偏移值均明显高于DTS低危组(P<0.05);而运动持续时间和运动最大心率明显低于DTS低危组(P<0.05)。DTS与冠脉病变的严重程度相关,冠脉造影结果显示低危组冠脉造影Gensini积分低于中高危组(P<0.0001);胸痛患者有随访资料的169例,失访9例,160例完成随访,失访率为5.33%。MACE主要发生在随访1个月,在DTS中高危组中发生MACE明显高于DTS低危组(P<0.05);logistic多因素回归分析显示,DTS是心血管事件发生的危险因素(OR=1.434,1.278¹.609;Waldχ2=37.7076,P<0.0001)。结论运动试验DTS与冠状动脉病变狭窄程度高度相关;DTS中高危组发生MACE明显高于低值组,应用该评分可以有效地对临床中胸痛患者进行危险分层及预后的评估,对于DTS中高危组的患者应迅速进行评估并考虑早期行再灌注治疗。     

克拉屈滨治疗伴有尿崩儿童朗格汉斯细胞组织细胞增多症疗效观察

目的：探讨克拉屈滨（Cladribine,2-CdA）对于常规治疗无效的伴有尿崩儿童朗格汉斯细胞组织细胞增多症（Langerhans cell histiocytosis,LCH）疗效。方法：7例伴有尿崩症状的LCH患儿予2~4个疗程2-CdA[5 mg·（m²·d）^-1×5 d]+阿糖胞苷[Ara-c,1 000 mg·（m²·d）^-1×5 d]治疗,观察临床症状体征及辅助检查变化情况,并监测不良反应。结果：6例患儿治疗后临床症状缓解达非活动性疾病状态,1例患儿最终因肝功能衰竭死亡。7例患儿无严重不良反应导致治疗中断。结论：2-CdA对于常规治疗无效的伴有尿崩儿童LCH疗效好,为难治复发的LCH提供治疗新思路。     

Medical management of langerhans cell histiocytosis from diagnosis to treatment

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a heterogeneous disease, involving the accumulation of langerhans cells in various organs. The physician's perception of the disease varies considerably depending on their experience, the presentation of the disease or the short-term treatment outcome. As this disease is very rare, only a limited number of large surveys exist in the literature and many aspects of the management of patients remain obscure or controversial. AREAS COVERED: An expert opinion on the diagnosis and medical management of LCH is presented in this paper. The diagnostic procedures, including differential diagnosis, initial clinical workup and criteria for initiating therapy are reviewed, as well as disease evaluation criteria and therapeutic approaches. Controversial issues in the medical management of LCH patients (aged less than 18 years) are also briefly discussed. EXPERT OPINION: Further fundamental and clinical research is still needed in this field. Progress may be expected from collaborations organized at national and international levels, among collaborative groups and expert networks. Collections of tissue and blood samples in biobanks must also be organized. New international protocols will be opened to patient accrual and represent an opportunity to further develop global research.     

Challenging issues in neonatal candidiasis

Abstract

In an era of quality improvement and ‘getting to zero (infections and/or related mortality),’ neonatal candidiasis is ripe for evidence-based initiatives. Knowledge of each institution’s invasive Candida infection (ICI) incidence and infection-related mortality is critical to evaluate disease burden and effective interventions. Evidenced-based interventions include: antifungal prophylaxis, starting with appropriate dosing, and prompt removal of central venous catheters (CVC). There is A-I evidence supporting antifungal prophylaxis with fluconazole, and it should be considered in every neonatal intensive care unit (NICU). The literature supports targeting infants <1000?g and/or ≤27 weeks, because this group has high infection-related mortality and neurodevelopmental impairment in 57% of survivors. Antifungal prophylaxis has been shown to nearly eliminate infection-related mortality. Interventions start with prenatal initiatives, with women being treated for vaginal candidiasis, especially with preterm labor or complications. Targeting modifiable risk factors, including restriction policies for use of third- and fourth-generation cephalosporins, carbapenems, H2-antagonists, proton pump inhibitors, and postnatal steroids; guidelines for CVC care and removal; and feeding practices, with promotion of early feedings and breast milk, may also reduce risk. A few studies have emerged on empiric antifungal therapy with sepsis evaluations for preterm infants <1500?g and other high-risk patients that have shown favorable effects of eliminating mortality, but these have not been compared to appropriate antifungal therapy and central line removal. Further study of empiric therapy, prospective treatment studies with higher targeted dosing of amphotericin B preparations, fluconazole, and new antifungals with prompt CVC removal may contribute to a 100% survival rate for those infants >1000?g and ≥28 weeks not receiving antifungal prophylaxis. Evaluation of ICI incidence and mortality by gestational age and birth week should be followed in each NICU, to evaluate infection control and prevention.     

The effectiveness of combining hormone therapy and radiotherapy in the treatment of prostate cancer

Hormone therapy is commonly used for many patients with prostate cancer. Radiotherapy occupies a prominent role in the treatment of locally-advanced, localised, and postsurgical prostate cancer. Hormone therapy and radiotherapy are often used in combination. In this article, the major features of the hormone/radiotherapy interactions are reviewed, with emphasis on the role of combination treatment for locoregional disease. The reported results suggest a biochemical survival advantage to the use of hormone therapy with radiotherapy, in virtually all settings of non-metastatic disease, with the weakest database being in the setting of low-risk, early-stage disease. Further data are needed in order to identify the optimum target population, combination of agents, and hormone duration, as a function of patient and disease factors.     

The effectiveness of combining hormone therapy and radiotherapy in the treatment of prostate cancer

Hormone therapy is commonly used for many patients with prostate cancer. Radiotherapy occupies a prominent role in the treatment of locally-advanced, localised, and postsurgical prostate cancer. Hormone therapy and radiotherapy are often used in combination. In this article, the major features of the hormone/radiotherapy interactions are reviewed, with emphasis on the role of combination treatment for locoregional disease. The reported results suggest a biochemical survival advantage to the use of hormone therapy with radiotherapy, in virtually all settings of non-metastatic disease, with the weakest database being in the setting of low-risk, early-stage disease. Further data are needed in order to identify the optimum target population, combination of agents, and hormone duration, as a function of patient and disease factors.     

A risk and benefit assessment of treatment for AIDS-related Kaposi's sarcoma.

Kaposi's sarcoma is the most common malignancy observed in patients with HIV-1 infection, and causes considerable morbidity and, when the lungs are involved, mortality. Therapy should be based on an evaluation of prognostic factors, in particular the extent and rate of tumour growth, patient symptoms, immune system condition and concurrent complications of AIDS. Nevertheless, considering the palliative role of Kaposi's sarcoma therapy, the potential benefits of therapy must be weighed against the high risk of adverse effects. Therefore, quality of life assessment is an integral component of therapeutic decisions. Localised Kaposi's sarcoma cutaneous tumours have been successfully treated with surgical excision, laser therapy, liquid nitrogen cryotherapy and radiotherapy. In patients with moderately extensive cutaneous or mucosal disease and CD4+ cell counts of > or =200/ml, immunotherapy and antiretroviral drugs are indicated. Preliminary results indicate that antiretroviral therapy might be effective and well tolerated in the treatment of less advanced Kaposi's sarcoma. In patients with aggressive and extensive mucocutaneous disease or with visceral manifestations of Kaposi's sarcoma, systemic cytotoxic therapy is indicated. However, the optimal treatment has yet to be found. The combination of doxorubicin, bleomycin and vincristine (ABV) has produced high overall response rates and is indicated as first-line treatment for patients with life-threatening or visceral disease. In patients who are leucopenic and require chemotherapy, single or dual agents associated with lower myelotoxicity [i.e. bleomycin, vincristine/vinblastine or a combination of bleomycin and vincristine/vinblastine (BV)] are most widely used. Other effective cytotoxic regimens are liposomal anthracyclines, paclitaxel and vinorelbine. To date, 3 randomised trials have compared these drugs to ABV and BV. In a large phase III study, the efficacy of liposomal daunorubicin was comparable with that of ABV. In 2 phase III studies, liposomal doxorubicin was compared with ABV and BV regimens and was found to be significantly more effective in producing objective responses. Therefore, liposomal doxorubicin, although more myelosuppressive than the BV regimen, is now considered by many physicians as the first-line therapy in patients with advanced stage Kaposi's sarcoma. Paclitaxel and vinorelbine have potential in Kaposi's sarcoma, but additional studies are needed to evaluate different schedules and to compare their activity with that of the reference regimens. Institution or continuation of both effective antiretroviral therapy and prophylaxis of opportunistic infections should be recommended to all patients receiving systemic cytotoxic therapies. However, attention must be paid to the cross-toxicity and possible pharmacokinetic interactions between antiretrovirals and antineoplastics.     

Eosinophilic granuloma of the skin: response to intralesional corticosteroid injection

Langerhans cell histiocytosis (LCH) is a histiocytic disorder in which the Langerhans cell is arrested in a premature, partially active state. The disease comprises a spectrum of disorders, the most benign of which is a single-system unifocal disease. Lesions in single-system LCH are typically limited to the bone. We report a case of a 66-year-old man with a single-system disease limited to the skin, who was successfully treated with intralesional triamcinolone. This minimally invasive treatment method warrants further studies of intralesional corticosteroid injection for skin lesions of LCH.     

Infliximab therapy in children and adolescents with inflammatory bowel disease

This review summarises the present knowledge of infliximab therapy in children with inflammatory bowel disease (IBD) based on the available published literature. Infliximab, the chimeric monoclonal IgG(1) antibody to tumour necrosis factor-alpha, is indicated for medically refractory luminal and fistulising paediatric Crohn's disease. Recently, ulcerative colitis case series in children and adolescents suggested that infliximab might also be effective for treatment of ulcerative colitis resistant to standard medical therapy. Induction therapy with infliximab 5 mg/kg at weeks 0, 2 and 6 is routinely used. Since the majority of patients will relapse if not re-treated, a long-term approach with systematic re-treatment with 5 mg/kg every 8-12 weeks is recommended. Maintenance therapy every 8 weeks was superior to 12 weeks' administration in maintaining response and remission in the largest-to-date paediatric randomised trial. Concomitant immunosuppressive therapy reduces the risk of infliximab antibody formation and infusion reactions, and prolongs the duration of treatment success. Severe reactions may not be an absolute contraindication to future infliximab therapy. Premedication does not prevent the development of infusion reactions; however, it is indicated for prevention of subsequent infusion reactions. Adverse events and safety findings in children are comparable to those observed in adults. Latent tuberculosis needs to be screened for. Malignancy rates in paediatric patients treated with infliximab do not seem to be increased. However, newly reported cases of hepatosplenic T-cell lymphoma in young patients with IBD treated with infliximab and mercaptopurine therapy raise concern, and long-term follow-up studies are necessary to determine the true malignancy risk.     

The correlation of vinblastine pharmacokinetics to toxicity in testicular cancer patients

The clinical pharmacokinetics of vinblastine administered by continuous 5-day infusion (3 mg/m2/day) was studied in 12 patients with primary testicular cancer. Serum vinblastine concentrations were determined by radioimmunoassay on serum collected over a 10-day period. Steady-state vinblastine concentrations were achieved within 60 to 108 hours (median, 72 hours). Vinblastine pharmacokinetics were analyzed and correlated to hematologic and nonhematologic toxicity. Hematologic toxicity was severe (granulocytopenia of less than 500/microL) in all patients; however, no correlation of vinblastine pharmacokinetics to duration of granulocytopenia or nadir was noted. Nonhematologic toxicity, however, showed a direct correlation to steady-state vinblastine concentrations. Two distinct groups of patients were identified by a toxicity score evaluating nonhematologic toxicity: as low (group A) or high (group B). The toxicity score was calculated for each patient based on accumulated toxicity during the course of treatment. The mean toxicity score for all patients was 7.11 and for groups (A and B) it was 4.0 and 9.6, respectively (P = .02). Steady-state vinblastine concentration for each patient was compared with toxicity where the mean steady-state vinblastine concentration was 7.3 ng/mL for all patients, and 5.8 ng/mL and 8.5 ng/mL for groups A and B, respectively (P = .01). These steady-state vinblastine concentrations correlated directly with the mean toxicity scores revealing that patients with high steady-state vinblastine concentrations demonstrated more nonhematologic toxicity. Application of these data to pharmacokinetically directed studies are warranted to investigate this relationship and designate dosages of vinblastine to avoid excessive toxicity.