Pronator quadratus flap for burn reconstruction.

Full-thickness skin loss in the distal volar forearm presents a challenge to the burn surgeon. Two cases are presented in which a pronator quadratus muscle flap with split-thickness skin was used to cover the underlying tendons and nerves. The unique vascular perfusion makes this a useful and predictable transfer.

First-line Herceptin monotherapy in metastatic breast cancer.

The pivotal phase II and III Herceptin trials proved the efficacy and safety of second- or third-line single-agent Herceptin and first-line Herceptin in combination with chemotherapy, respectively. In the current trial, 114 patients were randomized to one of two dose groups of first-line Herceptin monotherapy: standard dose of 4 mg/ kg initial dose followed by 2 mg/kg intravenous (i.v.) weekly; or high dose of 8 mg/kg initial dose followed by 4 mg/kg i.v. weekly. The regimen was generally well tolerated. A similar incidence of adverse events was demonstrated in the two dose groups with the possible exception of acute infusion-related events such as fever and chills as well as rash and dyspnea, which appear to be more prevalent in the higher dose group. The overall response rate was 26% and response rates were similar between the two dose groups (24% for the standard Herceptin dose group and 28% for the high Herceptin dose group). Subgroup analysis determined a higher response rate in IHC 3+ patients (35%) and FISH-positive patients (41%). When women with stable disease for > or =6 months were included with responders, the clinical benefit rate in IHC 3+ patients was 47%. Median survival was 24.4 months, which is comparable with the survival rate seen in the pivotal phase III combination trial (25 months). Therefore, single-agent Herceptin is an important new option for the first-line treatment of HER2-positive metastatic breast cancer patients.

Phase II study of direct intralesional gene transfer of allovectin-7, an HLA-B7/beta2-microglobulin DNA-liposome complex, in patients with metastatic melanoma.

Cutaneous melanoma is one of the most rapidly increasing cancers in the United States. Because of the lack of effective treatment options and toxicities of most chemotherapeutic and radiation regimes, immunotherapies such as vaccination therapy represent an attractive approach for patients with advanced melanoma. The purpose of this study was to evaluate the response rate, time to progression, and survival of patients with metastatic melanoma treated by direct intratumoral injection with Allovectin-7 (a plasmid DNA encoding the genes HLA-B7 and beta2-microglobulin complexed with a cationic lipid mixture, DMRIE/DOPE. Fifty-two patients with metastatic melanoma were enrolled in this Phase II study. Therapy consisted of six intratumoral injections of 10 microg of Allovectin-7 over a 9-week period. Treatment was well tolerated. Treatment-related adverse events were mild to moderate, the most frequent of which were ecchymosis, pruritus (and/or discomfort at the injection site), and pneumothoraces. Regression of the injected lesion was observed in 18% of patients, including one complete response, three partial responses, and five minor responses. An overall response rate of 4% (two partial responses) was documented, and nine patients (18%) maintained stable disease for at least 11 weeks. Six patients remained alive 25.1 to 39.4 months from their first injection, including two patients with local (injected tumor) responses and one patient with an overall disease partial response. This study demonstrates that intratumoral administration of Allovectin-7 in metastatic melanoma is safe and can produce both responses in injected lesions and in overall disease. Clinical trials optimizing patient selection and combining Allovectin-7 with other modalities of therapy are currently ongoing in an effort to improve response rates.

First-line, single-agent Herceptin(R) (trastuzumab) in metastatic breast cancer. a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(R) (trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer.

PURPOSE: To determine whether Myocet (liposome-encapsulated doxorubicin; The Liposome Company, Elan Corporation, Princeton, NJ) in combination with cyclophosphamide significantly reduces doxorubicin cardiotoxicity while providing comparable antitumor efficacy in first-line treatment of metastatic breast cancer (MBC). PATIENTS AND METHODS: Two hundred ninety-seven patients with MBC and no prior chemotherapy for metastatic disease were randomized to receive either 60 mg/m(2) of Myocet (M) or conventional doxorubicin (A), in combination with 600 mg/m(2) of cyclophosphamide (C), every 3 weeks until disease progression or unacceptable toxicity. Cardiotoxicity was defined by reductions in left-ventricular ejection fraction, assessed by serial multigated radionuclide angiography scans, or congestive heart failure (CHF). Antitumor efficacy was assessed by objective tumor response rates (World Health Organization criteria), time to progression, and survival. RESULTS: Six percent of MC patients versus 21% (including five cases of CHF) of AC patients developed cardiotoxicity (P =.0002). Median cumulative doxorubicin dose at onset was more than 2,220 mg/m(2) for MC versus 480 mg/m(2) for AC (P =.0001, hazard ratio, 5.04). MC patients also experienced less grade 4 neutropenia. Antitumor efficacy of MC versus AC was comparable: objective response rates, 43% versus 43%; median time to progression, 5.1% versus 5.5 months; median time to treatment failure, 4.6 versus 4.4 months; and median survival, 19 versus 16 months. CONCLUSION: Myocet improves the therapeutic index of doxorubicin by significantly reducing cardiotoxicity and grade 4 neutropenia and provides comparable antitumor efficacy, when used in combination with cyclophosphamide as first-line therapy for MBC.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

First-line, single-agent Herceptin(trastuzumab) in metastatic breast cancer: a preliminary report.

Following confirmation of the appropriate dosage, safety and potential efficacy of Herceptin(trastuzumab) in small-scale phase I and II trials involving patients with refractory disease, a large trial was conducted in 222 patients with breast cancer who had relapsed after one or two chemotherapy regimens for their metastatic disease. The results showed a positive and durable overall response rate (15% according to a response evaluation committee (REC) assessment) using trastuzumab monotherapy (initial dose 4 mg/kg intravenously (i.v.) followed by 2 mg/kg i.v. weekly). In another recently completed phase II trial, 113 patients were randomised to two dose levels (initial dose of 4 mg/kg i.v. dose followed by 2 mg/kg i.v. weekly, or initial dose of 8 mg/kg followed by 4 mg/kg i.v. weekly) of single-agent trastuzumab as first-line therapy for metastatic disease. The preliminary overall response rate was 23% based on investigator assessment, and tolerability was excellent as in previous trials; efficacy was similar in both dose groups, but the side-effects tended to be more frequent in the higher dose group. The preferred dosage is therefore the same as that currently recommended, i.e. an initial dose of 4 mg/kg i.v. followed by 2 mg/kg weekly i.v. until disease progression.

Novel immunologic and biologic therapies for breast cancer.

The treatment of breast cancer has benefited substantially from the introduction of trastuzumab in 1998. Yet trastuzumab only represents the first of a series of newer biologic therapies that will change the manner in which patients with breast cancer are treated. Initially, biologic therapies will be used in combination with existing chemotherapeutic agents. However, as biologic therapies improve, chemotherapeutic agents are likely to be replaced with biologic agents that are more effective, less toxic, and more patient- and tumor-specific. Promising classes of agents include monoclonal antibodies and cancer vaccines.

Targeted antiangiogenic therapy for cancer using Vitaxin: a humanized monoclonal antibody to the integrin alphavbeta3.

Angiogenesis plays a central role in the growth and metastasis of cancers. Strategies aimed at interfering with tumor blood supply offer promise for new cancer therapies. Vitaxin (an anti-alphavbeta3 antibody) interferes with blood vessel formation by inducing apoptosis in newly generated endothelial cells. This Phase I study evaluates the safety and pharmacokinetics of Vitaxin in humans with cancer. Eligible patients demonstrated progressive tumors with stage IV disease and an Eastern Cooperative Oncology Group performance status < or =2. Treatment consisted of six weekly infusions of Vitaxin. Escalating doses from 0.1 and 4.0 mg/kg/week were evaluated based on the expectation that plasma levels would bracket the effective in vitro concentration. Escalation beyond 4 mg/kg/week was limited by drug availability. Adverse events were assessed weekly. Pharmacokinetics were performed weekly through week 9. Clinical response was assessed at week 9. Of 17 patients treated, 14 were evaluable for response. Treatment was well tolerated with little or no toxicity. The most common side effect was infusion-related fever, which could be controlled with prophylactic antipyretics. Doses > or =1 mg/kg/week produced plasma concentrations sufficient to saturate the alphavbeta3 receptor in vitro (25 microg/ml). Vitaxin demonstrated a half-life in excess of 5 days at higher doses with no accumulation over 6 weeks of therapy. One patient demonstrated a partial response, and seven patients demonstrated stable disease. Three patients received Vitaxin beyond the first cycle of therapy. Each of these patients demonstrated disease stabilization that in one case lasted 22 months. At the doses and schedule studied, Vitaxin appears safe and potentially active, suggesting that vascular integrin alphavbeta3 represents a clinically relevant antiangiogenic target for prolonged cancer therapy.

A pilot study of the anti-CD20 monoclonal antibody rituximab in patients with refractory immune thrombocytopenia.

We conducted a prospective pilot phase I/II clinical trial to evaluate the toxicity and response rate of the chimeric anti-CD20 monoclonal antibody, rituximab (Rituxan; Genentech, Inc, South San Francisco, CA, and IDEC Pharmaceutical Corporation, San Diego, CA), in the treatment of patients with immune thrombocytopenic purpura. Patients with a clinical diagnosis of idiopathic thrombocytopenic purpura who had failed corticosteroid therapy and whose platelet count was less than 75,000/microL were eligible for the study. Rituximab was administered in a dose-escalation fashion using doses ranging from 50 to 375 mg/m2 weekly for 4 weeks. Thirteen patients have been enrolled on the trial to date and 12 have completed the full course of treatment. No unusual toxicity was noted in this patient population. None of the three patients at the lowest dose level achieved a clinical response. Three of nine patients (30%) who have received rituximab at doses close or equal to the full dose have shown an objective clinical response (two complete responses, one partial response). The study is currently ongoing, and conclusions regarding the overall response rate, clinical parameters that influence response, surrogate markers of response, and the underlying mechanism of response remain to be addressed. The current study should provide answers to a number of important questions regarding the role of rituximab in the treatment of this and other autoimmune disorders.

Phase I/II trial of IDEC-Y2B8 radioimmunotherapy for treatment of relapsed or refractory CD20(+) B-cell non-Hodgkin's lymphoma.

PURPOSE: Yttrium-90 ibritumomab tiuxetan (IDEC-Y2B8) is a murine immunoglobulin G1 kappa monoclonal antibody that covalently binds MX-DTPA (tiuxetan), which chelates the radioisotope yttrium-90. The antibody targets CD20, a B-lymphocyte antigen. A multicenter phase I/II trial was conducted to compare two doses of unlabeled rituximab given before radiolabeled antibody, to determine the maximum-tolerated single dose of IDEC-Y2B8 that could be administered without stem-cell support, and to evaluate safety and efficacy. PATIENTS AND METHODS: Eligible patients had relapsed or refractory (two prior regimens or anthracycline if low-grade disease) CD20(+) B-cell low-grade, intermediate-grade, or mantle-cell non-Hodgkin's lymphoma (NHL). There was no limit on bulky disease, and 59% had at least one mass > or = 5 cm. RESULTS: The maximum-tolerated dose was 0.4 mCi/kg IDEC-Y2B8 (0.3 mCi/kg for patients with baseline platelet counts 100 to 149,000/microL). The overall response rate for the intent-to-treat population (n = 51) was 67% (26% complete response [CR]; 41% partial response [PR]); for low-grade disease (n = 34), 82% (26% CR; 56% PR); for intermediate-grade disease (n = 14), 43%; and for mantle-cell disease (n = 3), 0%. Responses occurred in patients with bulky disease (> or = 7 cm; 41%) and splenomegaly (50%). Kaplan-Meier estimate of time to disease progression in responders and duration of response is 12.9+ months and 11.7+ months, respectively. Adverse events were primarily hematologic and correlated with baseline extent of marrow involvement with NHL and baseline platelet count. One patient (2%) developed an anti-antibody response (human antichimeric antibody/human antimouse antibody). CONCLUSION: These phase I/II data demonstrate that IDEC-Y2B8 radioimmunotherapy is a safe and effective alternative for outpatient therapy of patients with relapsed or refractory NHL. A phase III study is ongoing.

Radioimmunotherapy of relapsed non-Hodgkin's lymphoma with zevalin, a 90Y-labeled anti-CD20 monoclonal antibody.

Approximately 55,400 new cases of non-Hodgkin's lymphoma (NHL) are diagnosed each year, with the overall prevalence of the disease now estimated to be 243,000. Until recently, treatment alternatives for advanced disease included chemotherapy with or without external beam radiation. Based on the results of several clinical trials, the chimeric monoclonal antibody Rituximab has now been approved by the United States Food and Drug Administration as a treatment for patients with relapsed or refractory, low-grade or follicular, B-cell NHL. Several other monoclonal antibodies in conjugated and unconjugated forms have been evaluated in the treatment of NHL. Ibritumomab, the murine counterpart to Rituximab, radiolabeled with 90Y (Zevalin), is presently being evaluated in clinical trials. The success of radioimmunotherapy is dependent upon the appropriate choice of antibody, isotope, and chelator-linker. The Ibritumomab antibody targets the CD20 antigen. The antibody is covalently bound to the chelator-linker tiuxetan (MX-DTPA), which tightly chelates the isotope 90Y. To date, two Phase I/II Zevalin clinical trials have been completed in patients with low-grade, intermediate-grade, and mantle cell NHL. The overall response rate was 64% in the first trial and 67% in the later trial. Phase II and III trials are ongoing.

Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis.

PURPOSE: To evaluate the efficacy and safety of a slow-release formulation of cytarabine (DepoCyt; Chiron Corp, Emeryville, CA, and Skye Pharma, Inc, San Diego, CA) that maintains cytotoxic concentrations of cytarabine (ara-C) in the CSF of most patients for more than 14 days. PATIENTS AND METHODS: Twenty-eight patients with lymphoma and a positive CSF cytology were randomized to receive DepoCyt 50 mg once every 2 weeks or free ara-C 50 mg twice a week for 1 month. Patients whose CSF cytology converted to negative and who did not have neurologic progression received an additional 3 months of consolidation therapy and then 4 months of maintenance therapy. All patients received dexamethasone 4 mg orally bid on days 1 through 5 of each 2-week cycle. RESULTS: The response rate was 71% for DepoCyt and 15% for ara-C on an intent-to-treat basis (P =.006). All of the patients on the DepoCyt arm but only 53% of those on the ara-C arm were able to complete the planned 1-month induction therapy regimen. Time to neurologic progression and survival trend in favor of DepoCyt (median, 78.5 v 42 days and 99.5 v 63 days, respectively; P >.05). DepoCyt treatment was associated with an improved mean change in Karnofsky performance score at the end of induction (P =.041). The major adverse events on both arms were headache and arachnoiditis, which were often caused by the underlying disease. CONCLUSION: DepoCyt injected once every 2 weeks produced a high response rate and a better quality of life as measured by Karnofsky score relative to that produced by free ara-C injected twice a week.

An etoposide-resistant lung cancer subline overexpresses the multidrug resistance-associated protein.

We have characterised an etoposide-resistant subline of the small-cell lung cancer cell line, UMCC-1, derived at our centre. Subline UMCC-1/VP was developed by culturing the parent line in increasing concentrations of etoposide over 16 months. UMCC-1/VP is 20-fold resistant to etoposide by MTT assays, relative to the parent line, and is cross-resistant to doxorubicin, vincristine and actinomycin D, but not to taxol, cisplatin, melphalan, thiotepa or idarubicin. Topoisomerase II immunoblotting demonstrates a 50% reduction of the protein in the resistant subline. The UMCC-1/VP subline demonstrates a marked decrease in the accumulation of [3H]etoposide relative to the parent line, as well as a modest reduction in the accumulation of daunorubicin. Reverse transcription-polymerase chain reaction assays demonstrate no detectable mdr1 expression but marked expression of the multidrug resistance-associated protein (MRP) gene in the resistant subline. Northern blotting with an MRP cDNA probe confirms marked overexpression of the MRP gene only in the UMCC-1/VP subline. Western blotting with antisera against MRP peptide confirms a 195 kDa protein band in the UMCC-1/VP subline. Southern blotting experiments demonstrate a 10-fold amplification of the MRP gene in the resistant subline. Depletion of glutathione with buthionine sulphoximine sensitised UMCC-1/VP cells to daunorubicin and etoposide. Our studies indicate that MRP gene expression may be induced by etoposide and may lead to reduced accumulation of the drug.

Rapid and sensitive high-performance liquid chromatographic assay for novobiocin in human serum.

In this paper we present a new HPLC method for the determination of novobiocin in human serum. The assay uses mitomycin C as an internal standard, protein precipitation with acetonitrile, an ODS reversed-phase column with an isocratic mobile phase of acetonitrile-0.01 M phosphoric acid (80:20, v/v), and UV detection at 340 nm. The assay has a lower limit of quantitation of 1 microgram/ml and is linear over the range of 1-1000 micrograms/ml. The assay is ideally suited for use in clinical trials as it requires minimal amounts of serum, is highly sensitive and reproducible, is performed with minimal sample preparation, and involves a short run time. It should prove important in evaluating the potential of novobiocin as a means to modulate resistance to antineoplastic chemotherapy and in therapeutic drug monitoring of the growing number of patients receiving novobiocin to control methicillin-resistant Staphylococcus aureus infections.

Alterations in Ca2+ transport ATPase and P-glycoprotein expression can mediate resistance to thapsigargin.

Resistance to the intracellular Ca2+ pump inhibitor thapsigargin (TG) is associated with overexpression of both Ca2+ transport ATPase and the multidrug resistance (mdr) transporter P-glycoprotein (pgp). This is supported by increased resistance to TG following transfection of a functional pgp1 cDNA, and reversal of TG resistance with known inhibitors of pgp function. However, pgp is unlikely to represent the only mechanism of resistance to TG. Cell lines selected for high levels of resistance to TG (250-fold) show only a 3.7-fold increase in pgp expression and a 2-fold increase in cross-resistance to other drugs of the mdr class. Overexpression of endogenous Ca2+ transport ATPase may represent a second mechanism of resistance to TG. Increased Ca2+ ATPase expression (3-fold) is seen in cells made resistant to TG, and TG resistance increases with the transfection of a specific Ca2+ ATPase cDNA into DC-3F cells. If these transfectants are then made resistant to TG, both the endogenous Ca2+ ATPase and the exogenously transfected Ca2+ ATPase become overexpressed. These studies suggest that while TG may be a substrate for pgp, acquired resistance to TG can involve alterations in both pgp and Ca2+ ATPase expression. Additional, as yet unidentified, mechanisms of resistance may be involved in resistance to TG.

Potential applications of high-dose megestrol acetate in breast cancer.

Empiric clinical trials have revealed new mechanisms by which hormonal therapies may exert their antitumor effects. Initial studies using escalated doses of agents like toremifene and megestrol acetate have yielded interesting results, showing responses in hormone-receptor-negative patients and in patients progressing after standard doses, respectively. A trial by Cancer and Leukemia Group B randomizing patients with advanced breast cancer to standard-dose (160 mg) megestrol acetate or to 5 or 10 times the standard dose (800 and 1,600 mg) has completed accrual. It is hoped that these results will provide a definitive answer to the dose-response issue for breast cancer. However, regardless of this trial's ultimate outcome, higher doses of megestrol acetate have demonstrated important new effects on appetite stimulation and weight gain; ongoing laboratory research promises potential roles for megestrol acetate in the reversal of chemotherapeutic drug-induced tumor resistance.