Monoclonal antibody therapy in the treatment of non-Hodgkin lymphoma.
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Biomedical subjects
Publications and source records attributed to J P Gockerman.
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BACKGROUND: To address the feasibility and outcome of moderate dose intensification with granulocyte-colony stimulating factor (G-CSF) for patients with aggressive non-Hodgkin lymphoma (NHL), the Cancer and Leukemia Group B (CALGB) conducted two studies evaluating dose-escalated cyclophosphamide and etoposide in the cyclophosphamide, doxorubicin, vincristine, prednisone, etoposide (CHOPE) regimen. METHODS: Eligibility criteria included histologically documented, diffuse small cleaved, diffuse mixed, diffuse large cell, or immunoblastic lymphoma, Stage III--IV or bulky Stage II disease, and an ECOG performance status of 0--1. CALGB 8852, a group-wide study, accrued 227 patients: 120 patients in the pilot study to determine the maximum tolerated dose (MTD) without G-CSF and 107 in the pilot study of dose-escalated CHOPE with G-CSF. CALGB 8854, a limited-institution, Phase I study, enrolled 38 patients and determined the MTD of CHOPE with G-CSF to be used in CALGB 8852. The MTD in both studies was defined as the dose at which 50% of patients had 1) Grade 4 neutropenia or thrombocytopenia lasting 7 days or more, or 2) Grade 3--4 hemorrhage or nonhematologic toxicity (excluding alopecia, nausea, and emesis), or 3) were prevented from receiving 100% of drug on Day 22. RESULTS: The MTD of CHOPE without G-CSF was cyclophosphamide 1000 mg/m(2) on Day 1 and etoposide 100 mg/m(2) on Days 1--3 with doxorubicin 50 mg/m(2) on Day 1, vincristine 1.4 mg/m(2) (maximum, 2 mg) on Day 1, and prednisone 100 mg on Days 1--5. With the addition of G-CSF at 200 microg/m(2) on Days 5--19, the MTD was cyclophosphamide 1500 mg/m(2) and etoposide 160 mg/m(2) on Days 1-3 with standard doses of doxorubicin, vincristine, and prednisone. Increasing the dose of G-CSF from 200 microg/m(2) to 400 microg/m(2) did not allow for further dose escalation. The primary toxicity in all cohorts was neutropenia. Four toxic deaths occurred on CALGB 8852. The 5-year failure free survival (FFS) and overall survival (OS) rates for eligible patients on CALGB 8852 were 31% (95% confidence interval [95%CI], 23--39) and 48% (95%CI, 40--57), respectively. The 5-year FFS and OS rates for eligible patients on CALGB 8854 were 34% (95%CI, 17--52) and 51% (95%CI, 33--70), respectively. CONCLUSIONS: Moderate dose escalation with G-CSF is feasible. However, response and survival rates of patients who receive dose-escalated CHOPE, even with the addition of G-CSF, appear similar to the rates reported with standard-dose CHOP.
Cytomorphology in conjunction with immunophenotypic characterization is becoming increasingly used for the primary diagnosis of non-Hodgkin's lymphomas (NHL). This combination is especially advantageous for the diagnosis of intra-abdominal and intrathoracic lymphomas, since unlike superficial lesions, open biopsy of deep-seated tissues is more invasive and more costly, and is associated with a higher risk. We report the cytologic and immunophenotypic features of intra-abdominal NHL obtained by fine-needle aspiration (FNA). Twenty-two cases of intra-abdominal lesions obtained by image-guided FNA where flow cytometry was also performed were reviewed. Of the 22 studied cases, 7 were classified as large-cell lymphoma, 5 as follicular center-cell lymphoma, 2 as small noncleaved-cell lymphoma, 2 as lymphoplasmacytoid lymphoma, one as small lymphocytic lymphoma, and one as marginal-zone lymphoma. In the remaining 4 cases where the immunophenotypic pattern was not definitive, the cytomorphologic features were of small cleaved cells in 3 cases and of mixed small cleaved and large cells in one case. We successfully classified 9 of the 10 patients on whom histologic confirmation was obtained. The successful primary classification of most intra-abdominal non-Hodgkin's lymphomas can be done with a combination of cytology and flow cytometry, and this can be the initial approach in patients with deep-seated lesions. Diagn. Cytopathol. 1999;21:98-104.
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A case of malignant melanoma presenting as a mediastinal mass without an extrathoracic primary is reported. Microscopically the tumor appeared consistent with malignant melanoma, with the presence of focal melanin pigment in large epithelioid cells. Fontana stain confirmed the presence of melanin pigment. Immunohistochemical staining further suggested melanoma, with the tumor cells expressing a HMB45+, S100+ and cytokeratin-phenotype. Electron microscopy showed an abundance of melanosomes confirming the diagnosis of malignant melanoma.
An azotemic patient benefited from diagnostic magnetic resonance imaging (MRI) in the evaluation of his renal mass. This led to suspicion of lymphoma, and provided guidance for percutaneous biopsy. Chemotherapy was then initiated, and an unnecessary nephrectomy was avoided. After a year of follow-up, evolution was stable and renal function significantly improved.
We report two patients with acute myeloid leukemia (AML) following therapy for malignant glioma; one was a young women treated heavily with alkylating agents for glioblastoma and the other a young man treated with high doses of procarbazine, lomustine, and vincristine (PCV) for anaplastic astrocytoma. We found 26 other examples of therapy related leukemia in adult and pediatric brain tumor patients. Including our two, there were 12 patients with malignant glioma; median interval from treatment to diagnosis of AML was 31 months. Nine adult malignant glioma patients all received nitrosoureas, some as the sole form of chemotherapy. No definite cases occurred after radiotherapy alone. Based upon analogy with other cancers, the cumulative dose of chemotherapy, especially alkylating agents, is the major risk factor for development of secondary AML. Agents implicated include carmustine (BCNU), lomustine (CCNU), and procarbazine. Conventional radiotherapy appears not to confer additional risk. Progressive macrocytosis, early dose reductions for thrombocytopenia, and refractory anemia may provide early diagnostic clues. Current glioma therapy is leukemogenic but the number of patients who survive the interval required to induce AML is small; nevertheless, the identification of chemosensitive types of glioma, and subgroups of patients who derive the most benefit from chemotherapy, may result in increasing numbers of patients at risk of long term complications. If regimens such as PCV continue to prove valuable in neurooncology the risk of leukemia will require integration into the clinical decision process. A search for more effective therapy with minimal mutagenicity remains critical.
Metastatic tumor is one of several etiologies of space-occupying masses in the orbit that accounts for 1%-13% of all orbital masses (1). In the adult patient population, breast cancer is the most common tumor to metastasize to the orbit followed by metastases from the lung, prostate and gastrointestinal tract (2). It is rare for carcinoid tumors to metastasize to the eye or to the orbit. Carcinoid tumors arise from Kulchitsky cells that originate in the neural crest. Histologically, these tumors resemble, but are not as aggressive as, adenocarcinomas. Most carcinoids arise in the gastrointestinal tract or the lung. The most common site for carcinoid metastases is the liver. On anatomical imaging studies, such as CT and magnetic resonance imaging, metastatic orbital carcinoid tumors appear as nonspecific tumor masses. Carcinoid tumors have an affinity for uptake of the radiopharmaceutical 131I-metaiodobenzylguanidine (MIBG) (3). We report a case of a patient with a known carcinoid tumor who developed a left orbital mass that demonstrated abnormal uptake of 131I-MIBG indicative of metastatic carcinoid tumor to the orbit.
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Primary central nervous system lymphoma (PCNSL) almost always remains confined to the nervous system. We report a patient with well documented PCNSL who responded to treatment, but subsequently developed pathologically confirmed systemic metastases without repeated local failure 35 months after initial diagnosis. In a review of the world's literature we identified 5 other cases of PCNSL with histologically confirmed antemortem systemic metastases and a total of 62 cases of central nervous system (CNS) lymphoma in some way associated with extraneural lymphoma. These cases are classified and discussed. Clinicians caring for PCNSL patients must remain alert to the possibility of systemic metastasis, especially as local control of PCNSL improves.
Freshly isolated acute non-lymphocytic leukemia (ANLL) cells were treated with the nitric oxide (NO)-liberating compounds sodium nitroprusside or S-nitrosoacetyl penicillamine and analyzed for viability, growth, and differentiation at 3-5 days. NO decreased the viability and the growth of freshly isolated ANLL cells in vitro. NO treatment significantly increased expression of CD14 in blast cells from patients with M5 ANLL, and increased at least one differentiation parameter in M4 or M5 cells. It had little or no effect on parameters of differentiation in other ANLL cells. We conclude that in vitro culture with NO decreases the growth and viability of most freshly isolated ANLL cells. NO also induces the differentiation of ANLL cells with a monocytic phenotype.
BACKGROUND: Advanced stage Hodgkin's disease (HD) usually is treated with combination chemotherapy with or without supplemental irradiation. The risk of significant acute and long term toxicity when the chemotherapy regimen contains alkylating agents has provided the impetus for the development of systemic combinations that do not include alkylating agents. This trial was designed to assess the toxicity and efficacy of a regimen of etoposide, vinblastine, and doxorubicin (EVA) as part of a combined modality approach in patients with moderate to high risk HD. METHODS: This was a prospective pilot study that included 26 previously untreated patients. They received 6 cycles of EVA, and complete responders received low dose (1500-2500 cGy) involved field radiation. RESULTS: Four patients were hospitalized for sepsis during chemotherapy. Complete response was achieved in 54% of patients, and 46% patients experienced induction failures. Two year failure-free survival is 44%, while 2 year overall survival is 86%. Median follow-up is 27 months. CONCLUSIONS: The EVA regimen is no more efficacious than other programs already in use and may be less so. It also is potentially leukemogenic because of the presence of etoposide. New combinations that do not contain etoposide should be explored in therapy programs for advanced HD in the hopes of discovering an efficacious treatment program that has minimal long term side effects.
Paraneoplastic nervous system syndromes are being identified with increasing frequency because of greater physician awareness and the availability of serodiagnostic tests for some syndromes. Frequently, paraneoplastic syndromes develop in the setting of an indolent, limited stage, or otherwise occult malignancy. As a result, the paraneoplastic disorder often becomes the most disabling part of a patient's disease. Effective treatment appears to require early identification. For these reasons, the ability to diagnose a paraneoplastic syndrome, follow its course, and treat it successfully are important. The authors describe four patients with neurologic paraneoplastic syndromes and identical magnetic resonance imaging abnormalities. Three patients responded to immunosuppressive or immunomodulatory therapy, and in one, corresponding radiographic improvement was documented. Strategies for early diagnosis and options for treatment of paraneoplastic nervous system disorders are discussed.
The activity of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in the treatment of primary central nervous system lymphoma (PCNSL) prior to radiotherapy was studied in six patients. Primary lesions were reduced by 80% or more on contrast-enhancing cross-sectional area in four patients and to a lesser extent in two others after two cycles of chemotherapy. The primary lesion sites demonstrated no contrast enhancement in the three patients who completed four cycles of therapy. However, concurrent with response at the primary disease sites, multiple lesions occurred at distant, noncontiguous CNS parenchymal sites in five patients after two to four cycles of chemotherapy. Median survival was 8.5 months for the six enrolled patients and 16.5 months for the four patients completing craniospinal radiotherapy. PCNSL is highly responsive to standard systemic non-Hodgkin's lymphoma chemotherapy regimens, but the pattern and rapidity of relapse suggest mechanisms of failure including inherent or rapidly evolving antineoplastic drug resistance and perhaps limited drug delivery to occult sites of disease in the brain.
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Progressive thrombocytopenia may develop in as many as 5% of patients receiving heparin anticoagulation. In these patients, the risk of thromboembolic complications as well as continued thrombocytopenia necessitates discontinuation of heparin and initiation of an alternative anticoagulant when indicated. The heparinoid Lomoparan (Org 10172) is a mixture of several non-heparin low molecular weight glycosaminoglycans with proven anticoagulant efficacy that is generally non-reactive with platelets in the presence of plasma from patients with heparin induced thrombocytopenia, whereas standard heparin will induce platelet aggregation. We evaluated the role of heparinoid as a potential alternative anticoagulant in patients with heparin induced thrombocytopenia. During a 6 month period, we identified six patients with heparin induced thrombocytopenia who required an alternative parenteral anticoagulant, four as primary treatment for specific medical problem, and two as anticoagulation during a necessary surgical procedure. Heparinoid was used successfully in both medical and surgical patients requiring parenteral anticoagulation. In no case was there an exacerbation of the thrombocytopenia nor thromboembolic complications while on heparinoid therapy. Three of our patients sustained hemorrhagic complications, predominantly in the post-surgical setting in association with elevated anti-factor Xa levels and additional anticoagulant agents. We feel that these results confirm the utility of heparinoid anticoagulation in a select subset of patients with heparin induced thrombocytopenia who require continued parenteral anticoagulation.
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An ocular toxic reaction presenting as conjunctivitis or keratitis develops in a significant number of patients who are treated with high-dose cytosine arabinoside (ara-C). Although eye drops containing glucocorticoid reportedly decrease the incidence, they do not totally eliminate this side effect. In comparing this technique with artificial tears, both were found to be equally effective. The primary mechanism by which eye drops decrease ocular toxic reactions associated with high-dose ara-C is presumably due to dilution of intraocular concentrations of ara-C.