Alemtuzumab until minimal residual disease for chronic lymphocytic leukemia: Is it a new standard?
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Alemtuzumab↗
Biomedical subjects
Mark Goodman
Publications and source records attributed to Mark Goodman.
Molecular analysis of primary and recurrent giant cell tumors of bone.
The status of microsatellite markers located on chromosomes 1p36, 3p25, 5q23, 9p22, 10q23, 10q24, 17p13, and 19q12 was used to determine loss of heterozygosity (LOH) in primary giant cell tumors (GCT) of bone in 12 patients. The cases included primary, locally recurrent, and metastatic GCT; three tumors were classified as malignant GCT, based on their morphological features. Microdissection was performed on 24 paraffin-embedded tissue samples. An average of three separate topographic sites were microdissected from each tumor. Case selection in each instance was based on the availability of paired samples of tumor in primary GCTs and their corresponding recurrences, and the presence of normal tissue. The number of cases studied is too small for statistical studies, and thus the analysis is descriptive. All cases were informative for >80% of the markers used. Both primary GCTs and local recurrences and lung metastases displayed LOH of three or more markers, and intratumoral heterogeneity was frequent. Fractional allelic losses (FAL) were not different in recurrent and nonrecurrent GCT. FAL was greatest (>30%) in the metastatic group of GCT. Allelic losses of 1p, 9q, and 19q regions were frequent in all groups. LOH of 17p (in proximity to the p53 locus) and 9p occurred exclusively in the pulmonary metastases from GCT. LOH of 9q and 19q was present in primary as well as recurrent GCTs and in one malignant GCT. Involvement of 1p (including MYCL) and 9q regions has not been previously reported in GCT of bone. The pattern of LOH evident in the 17 markers used in the present study suggests that GCT with malignant features may follow an evolutionary pathway similar to the usual primary GCT of bone.
Adolescent↗
First, do no harm; second, make sure you are doing some good.
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Antineoplastic Combined Chemotherapy Protocols↗
Thalidomide effects in the post-transplantation setting in patients with multiple myeloma.
UNLABELLED: Thalidomide recently has been proven to have an impact on plasma cell dyscrasia through multiple mechanisms. Its effects on hematopoietic stem cells both in harvesting and in the immediate post-transplant setting are still unknown. We report on 12 cases (9 males and 3 females), median age 56 years old (range 41-65 years old) who underwent autologous peripheral stem cell transplantation for multiple myeloma and received thalidomide as maintenance therapy post-transplantation. Patients received various cytoreductive therapies prior to stem cell harvest. Eleven patients were in partial remission (PR) and one in complete remission (CR) on entry into the transplant phase of therapy. The median CD34+/kg harvested was 4.7 x 10(6) (range 1.9-55.4 x 10(6) CD34+/kg). All patients received intravenous melphalan 200 mg/m2 as their conditioning regimen. Six of twelve patients attained a CR post-transplant, and six a PR. Thalidomide was started after all patients engrafted post-transplant (absolute neutrophil count >0.5 x 10(9)/l and self-sustained platelet count >20 x 10(9)/l) and following satisfactory resolution of transplant toxicity including mucositis and diarrhea. Thalidomide was initiated at a median of 43 days post-transplant (range 23-138 days). The median leukocyte and platelet counts at the moment of thalidomide initiation were 5.8 x 10(9)/l (range 2.9-8.6 x 10(9)/l) and 196 x 10(9)/l (range 30-351 x 10(9)/l), respectively. Thalidomide was started at 100 mg daily, increasing 100 mg/day/month until reaching a dose of 400 mg/day. One patient failed to tolerate thalidomide due to CNS symptoms and stopped therapy at 12 days. Another patient stopped thalidomide therapy after 71 days, because of severe fatigue secondary to hypothyroidism. The most common adverse effects were constipation (5), rash (4), dry skin (3) and dizziness (3). No grade 3-4 adverse effects were documented. Neutropenia, previously reported as an adverse effect in this setting, was not seen to date in our cohort. All patients attained a CR or PR after transplant and thalidomide maintenance. We have had two relapses during a median follow-up of 68 weeks (range 42-172 weeks). CONCLUSION: Thalidomide appears to be a safe drug in the post-transplant setting, perhaps adding to the response achieved post-transplant without major toxicity. Longer follow up and future randomized trials will be needed to validate the role of thalidomide and its long-term effect when used as maintenance therapy in the post-transplant setting.
Aged↗
Prevalence of hepatitis C infection in patients with non-Hodgkin's lymphoma in South Florida and review of the literature.
The etiology of non-Hodgkin's lymphoma is unknown in the majority of the cases. Although Epstein-Barr virus, human T-cell leukemia-lymphoma virus and human herpes virus-8 have been established as casual agents in the pathogenesis of specific types of lymphoma, the role of hepatitis C virus (HCV) in lymphomagenesis remains controversial, with marked geographic variability. We conducted an epidemiologic study to evaluate the prevalence of hepatitis C virus infection in patients with lymphoma in South Florida. Ninety consecutive patients with lymphoma and 96 consecutive control patients with solid tumors were tested for HCV. HCV infection was detected in 2 patients with NHL (2.2%) and in 4 control patients (4.1%). Our study does not support the association between HCV and lymphoma in South Florida, US.
Case-Control Studies↗
Role of farnesyltransferase inhibitors in hematologic malignancies.
The treatment of hematologic malignancies has progressed in the last few years. Identification of new pathways and target molecules in leukemia has ushered in a promising new era of therapy. Ras mutations have recently been implicated in the pathogenesis of acute leukemia, and inhibition of Ras signaling through the use of farnesyltransferase inhibitors (FTIs) has shown promise in early trials in acute myeloid leukemia (AML). Responses have not correlated with the presence of Ras mutations, suggesting that novel pathways are involved. In several early trials, FTIs have shown activity as single agents in poor-risk AML, suggesting a potential role in combination with standard chemotherapy. FTIs are now being tested in other clinical settings, such as myelodysplasia, chronic myelogenous leukemia and multiple myeloma, with encouraging preliminary activity.
Enzyme Inhibitors↗
166Ho-DOTMP plus melphalan followed by peripheral blood stem cell transplantation in patients with multiple myeloma: results of two phase 1/2 trials.
Holmium-166 1, 4, 7, 10-tetraazcyclododecane-1, 4, 7, 10-tetramethylenephosphonate (166Ho-DOTMP) is a radiotherapeutic that localizes specifically to the skeleton and can deliver high-dose radiation to the bone and bone marrow. In patients with multiple myeloma undergoing autologous hematopoietic stem cell transplantation two phase 1/2 dose-escalation studies of high-dose 166Ho-DOTMP plus melphalan were conducted. Patients received a 30 mCi (1.110 Gbq) tracer dose of 166Ho-DOTMP to assess skeletal uptake and to calculate a patient-specific therapeutic dose to deliver a nominal radiation dose of 20, 30, or 40 Gy to the bone marrow. A total of 83 patients received a therapeutic dose of 166Ho-DOTMP followed by autologous hematopoietic stem cell transplantation 6 to 10 days later. Of the patients, 81 had rapid and sustained hematologic recovery, and 2 died from infection before day 60. No grades 3 to 4 nonhematologic toxicities were reported within the first 60 days. There were 27 patients who experienced grades 2 to 3 hemorrhagic cystitis, only 1 of whom had received continuous bladder irrigation. There were 7 patients who experienced complications considered to be caused by severe thrombotic microangiopathy (TMA). No cases of severe TMA were reported in patients receiving in 166Ho-DOMTP doses lower than 30 Gy. Approximately 30% of patients experienced grades 2 to 4 renal toxicity, usually at doses targeting more than 40 Gy to the bone marrow. Complete remission was achieved in 29 (35%) of evaluable patients. With a minimum follow-up of 23 months, the median survival had not been reached and the median event-free survival was 22 months. 166Ho-DOTMP is a promising therapy for patients with multiple myeloma and merits further evaluation.
Adult↗
Concurrent exposure to heat shock and H7 synergizes to trigger breast cancer cell apoptosis while sparing normal cells.
Most cancer therapies, including chemotherapy, kill tumor cells by inducing apoptosis. Consequently, the propensity of tumor cells to evade apoptotic signals contributes to therapeutic resistance. Here we show that breast cancer cells exhibiting a highly resistant phenotype undergo apoptosis when exposed to concurrent heat shock and H7, a potent serine/threonine kinase inhibitor. The anti-tumor effects of this combination are synergistic as neither treatment alone adversely affects breast cancer cell growth/survival. In contrast, non-malignant breast epithelial and hematopoietic progenitor cells are resistant to this combination therapy, thereby excluding non-specific cytotoxicity as the cause of tumor cell apoptosis. Heat or other cell stresses, including chemotherapy, preferentially enhance heat shock protein (hsp) synthesis, which serves to protect cells from potentially lethal consequences of heat shock stimuli. Ectopic overexpression of hsps in breast cancer cells protects against chemotherapy-induced apoptosis. Furthermore, increased hsps in primary breast cancers correlates with resistance to therapy and decreased survival. Stress-induced hsp synthesis is mediated by heat shock transcription factor 1 (HSF1). To simulate hsp overexpressing primary breast cancers, a number of breast cancer cell lines were transfected with HSF1d202-316, a constitutively activated form of HSF1 that leads to baseline overexpression of hsps in the absence of stress. Importantly, HSF1d202-316 transfected breast cancer cells undergo apoptosis following concurrent heat shock and H7. In light of its tumor selective activity against breast cancer cells that exhibit a highly resistant phenotype, concurrent H7 and heat shock warrants further investigation as a potential cancer therapy.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
Interaction of isoflurane with the dopamine transporter.
BACKGROUND: Isoflurane administration is known to increase extracellular dopamine (DA) concentration. Because the dopamine transporter (DAT) is a key regulator of DA, it is likely affected by isoflurane. This study investigates the hypothesis that isoflurane inhibits DA reuptake by causing DAT to be trafficked into the cell. METHODS: Rhesus monkeys were scanned with positron emission tomography (PET) using [18F]FECNT (a highly specific DAT ligand) while anesthetized with 1% isoflurane. The isoflurane was increased to 2%, and the animals were rescanned. Uptake was analyzed with the tissue reference method using the cerebellum as the reference tissue to determine the binding potential in the putamen. Immunohistochemistry and Western blot analyses were performed in rats to determine if isoflurane administration would change the total amount of DAT. Rats breathed air plus 2% isoflurane for 30 min, and then striatal DAT assays were rapidly performed. immunocytochemistry experiments were performed using human embryonic kidney (HEK) cells stably transfected with human DAT. The cells were exposed to 4% isoflurane for 1 h while the location of DAT was observed with fluorescent confocal microscopy. RESULTS: The [18F]FECNT binding potential in rhesus monkeys decreased by 63 +/- 6% (SEM, n = 5) when isoflurane was increased from 1 to 2% as compared with no significant change (0.7 +/- 2.5%; SEM, n = 5) when the isoflurane concentration was not changed (P < 0.001). No difference in DAT staining between isoflurane-treated and control rats was apparent from visual inspection, and quantitative Western blot analyses showed no significant change in total DAT protein. After isoflurane treatment, focal puncta of intense fluorescence was visible inside the HEK cells. CONCLUSIONS: The experiments indicate that DAT is trafficked into the cell by isoflurane without changing the total amount of DAT in the striatum. The PET data are consistent with this finding, provided that intracellular DAT acquires a conformation that has low affinity for [18F]FECNT. Thus, [18F]FECNT appears to be an excellent agent for measuring plasma membrane-expressed DAT and evaluating DAT trafficking.
Anesthetics, Inhalation↗
Feasibility and correlates of arsenic trioxide combined with ascorbic acid-mediated depletion of intracellular glutathione for the treatment of relapsed/refractory multiple myeloma.
Patients with multiple myeloma (MM) invariably relapse with chemotherapy-resistant disease, underscoring the need for new agents that bypass these resistance mechanisms. We have reported that ascorbic acid (AA) enhances the activity of arsenic trioxide (As(2)0(3)) against drug-resistant MM in vitro by depleting intracellular glutathione (GSH). These data led us to open a National Cancer Institute/Cancer Therapy Evaluation Program-sponsored Phase I/II trial of As(2)0(3) + AA for relapsed/refractory MM. We now present the completed Phase I component of this trial. The primary objective of the trial's Phase I component was to assess whether the addition of AA affected the well-described toxicity profile of As(2)0(3) alone. Correlative studies were undertaken of As(2)0(3) and AA pharmacokinetics, the ability of AA to deplete intracellular GSH in vivo, and the development of arsenic resistance. Six patients with stage IIIA relapsed/refractory myeloma were studied. We found that 0.25 mg/kg/day As(2)O(3) + 1,000 mg/day AA could be given for 25 days (over a 35-day period) without dose-limiting toxicity. One episode of grade 3 hematological toxicity (leukopenia) and no grade 3 nonhematological toxicities (in particular, cardiac) were observed. The coadministration of AA did not alter the pharmacokinetics of As(2)0(3), and elevated AA levels were associated with decreased intracellular GSH. Serial in vitro studies demonstrated continued sensitivity of patient myeloma cells to As(2)0(3) + AA. Two patients (both with thalidomide-refractory disease) had partial responses; four patients had stable disease. In conclusion, we have found that As(2)0(3) + AA has acceptable toxicity and that there is promising evidence of activity in refractory/relapsed myeloma.
Adult↗
Phenylephrine and norepinephrine increase dopamine transporter ligand binding in striatum.
PURPOSE: 8-(2-[18F]fluoroethyl)-2 beta-carbomethoxy-3beta-(4-chlorophenyl)nortropane ([18F]FECNT) is a radiotracer for positron emission tomography (PET) used to trace the location and binding potential (BP) of the dopamine transporter (DAT). We tested the hypothesis that adrenergic receptor agonists increase the BP of [18F]FECNT for the DAT. PROCEDURES: Anesthetized monkeys were scanned twice to determine the ligand BP at baseline and during administration of phenylephrine (3-6 microg/kg/min) or norepinephrine (0.5-1 microg/kg/min). Standard immunohistochemistry and immunoblot analyses were performed in rats to determine if the quantity of DAT changed with phenylephrine. [18F]FECNT uptake in human embryonic kidney (HEK) cells, stably transfected with DAT cDNA, was measured by gamma scintillation counting during phenylephrine. RESULTS: The PET measured BP of [18F]FECNT increased by 50% and 45% during the phenylephrine and norepinephrine infusion, respectively. The immunohistochemistry and immunoblot analyses did not show a difference in total DAT. CONCLUSION: Adrenergic agonists increase the BP of [18F]FECNT in monkey striatum.
Adrenergic Agonists↗