Agnogenic myeloid metaplasia associated with Klinefelter syndrome: a case report.

Klinefelter syndrome is the most commonly diagnosed sex chromosome disorder among males. It is usually associated with 47 chromosomes, including two Xs and one Y. The formal cytogenetic designation for Klinefelter syndrome is 47, XXY; the extra sex chromosome is due to meiotic chromosomal nondisjunction. Increased risk of various malignant diseases has been recognized among patients with different congenital chromosomal abnormalities. Since the early 1960s, numerous reports have appeared of an increased risk of malignant neoplasms among patients with Klinefelter syndrome. Evidence suggests a correlation with increased incidences of germ cell tumors and breast cancers. Whether these patients are at an increased risk of hematologic malignant disease, especially acute leukemia, is still uncertain. This report describes a patient with agnogenic myeloid metaplasia and Klinefelter syndrome, an association not previously reported.

A phase II trial of edatrexate, vinblastine, adriamycin, cisplastin, and filgrastim (EVAC/G-CSF) in patients with non-small-cell carcinoma of the lungs: a North Central Cancer Treatment Group Trial.

Edatrexate is an antifolate agent with improved in vitro antineoplastic activity as compared with methotrexate. A Mayo phase I trial of edatrexate (E), vinblastine (V), doxorubicin (Adriamycin) (A), cisplatin (C), and filgrastim (GCSF), (EVAC-GCSF) showed promising antineoplastic activity in non-small-cell lung cancer (NSCLC) (Colon-Otero G, et al. Cancer J Sci Am 1997;3:297-302) leading to a phase II trial of this regimen, the results of which are reported here. A total of 34 patients with stage IIIB or IV measurable or evaluable NSCLC were entered in this North Central Cancer Treatment Group phase II study. Treatment consisted of edatrexate 100 mg/m2 intravenously on day 1 and cisplatin 30 mg/m2/d on day 1 and day 2 followed by vinblastine 3 mg/m2 intravenously and doxorubicin 30 mg/m2 intravenously on day 2. Filgrastim was given at 300 microg subcutaneously daily from day 4 to day 18 or until an absolute neutrophil count of 2,000/mm3 or more was obtained. Cycles were repeated every 21 days until either progression or the development of intolerable toxicity. Sixteen of 34 evaluable patients responded to therapy, for a response rate of 47.1% with a 95% CI of 30.3% to 63.8%. Median time to disease progression was 132 days, median survival time was 219 days, and the estimated 1-year survival was 41.2% (95% CI of 27.6-61.5%). The EVAC/G-CSF regimen has significant antineoplastic activity as seen by the response rates for patients with NSCLC. However, this study had significant myelosuppressive toxicity; 56% patients had grade III or higher leukopenia with three treatment-related deaths observed. In addition, Quality of Life assessments indicate that patients experienced an overall decline in quality of life during the course of treatment. These mitigating factors need to be considered regarding further evaluation of this regimen in this patient population.

The prednisone dosage in the CHOP chemotherapy regimen for non-Hodgkin's lymphomas (NHL): is there a standard?

PURPOSE: Discrepancies in the quoted prednisone dosages in the regimens reported as the only standard CHOP regimen stimulated our interest in reviewing the medical literature regarding this issue and to assess whether practicing hematologists and oncologists in the U.S. are aware of the different dose schedules of prednisone in the published CHOP programs. METHODS: Sixteen textbooks and chemotherapy reference books were reviewed. A MEDLINE search of English-language articles published between January 1970 and December 1998 was performed. An eight-point questionnaire was sent via e-mail with responses obtained from 421 hematology/oncology physicians in the U.S. RESULTS: Sixteen textbooks and chemotherapy reference books reviewed quoted only one prednisone dosage as part of the standard CHOP regimen; the prednisone dosages quoted as standard varied between publications. More than 4,000 eligible non-Hodgkin's lymphoma patients have been treated with the CHOP chemotherapy as part of 43 different clinical trials reviewed. The dosages of prednisone and prednisolone used varied among six different levels. Thirty percent (127/421) of practicing U.S. physicians were not aware of the existence of more than one prednisone dose schedule as part of the CHOP regimen. The three most frequently used dosages are 100 mg/days 1-5 (67%), 100 mg/m(2)/days 1-5 (17%), and 60 mg/m(2)/days 1-5 (13%). CONCLUSIONS: Discrepancies in steroid dosages used as part of the reported standard CHOP regimens are common and not well recognized in the medical literature nor by practicing U.S. hematologists/oncologists. Based on this study, a prednisone dose of 100 mg/day for five days should be considered the standard dose.

Lymphomas in patients with connective tissue disease. Comparison of p53 protein expression and latent EBV infection in patients immunosuppressed and not immunosuppressed with methotrexate.

Cell cycle dysregulation as measured by p53 protein expression and latent Epstein-Barr (EBV) infection are important in the pathogenesis of lymphoma, particularly in immunosuppressed patients. Although latent EBV commonly is detected in lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate, p53 protein expression has not been reported. We compared the immunohistologic expression of p53 protein and the incidence of latent EBV infection in lymphomas arising in patients with connective tissue disease treated and not treated with methotrexate. Increased p53 staining was detected in 10 of 11 lymphomas arising in patients after methotrexate therapy vs 5 of 11 in patients not treated with methotrexate. Latent EBV was detected in 7 of 13 lymphomas arising in patients after methotrexate therapy vs 2 of 11 in patients not treated with methotrexate. Concordant p53 expression and latent EBV were detected in 5 of 7 lymphomas arising after treatment with methotrexate, including 1 that regressed after methotrexate therapy was withdrawn. These findings suggest that cell cycle dysregulation and EBV-related transformation are important in the pathogenesis of lymphomas arising in patients with connective tissue disease who are immunosuppressed with methotrexate.

Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver.

PURPOSE: Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS: Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS: Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION: Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.

A dose-seeking trial of edatrexate in combination with vinblastine, adriamycin, cisplatin, and filgrastim (EVAC/G-CSF) in patients with advanced malignancies: promising antineoplastic activity against non-small cell lung carcinomas.

PURPOSE: To determine the maximum tolerated dose, toxicities, and potential antitumor activity of edatrexate (E), an antifolate agent with enhanced in vitro antitumor activity as compared with methotrexate (M), when given in combination with vinblastine, doxorubicin, cisplatin, and filgrastim (G-CSF) to patients with advanced malignancies. PATIENTS AND METHODS: Thirty-seven patients with advanced malignancies were treated with escalating doses of edatrexate in combination with vinblastine (V), doxorubicin (A), cisplatin (C), and filgrastim (EVAC/G-CSF) following three different subsequently developed schedules. Schedule 1 was patterned after the MVAC regimen, a combination chemotherapy program with activity against different epithelial malignancies, and consisted of E, 40 mg/m2/day, days 1/15/22; V, 3 mg/m2/day, days 2/15/22; A, 30 mg/m2/ day, day 2; C, 70 mg/m2/day, day 2; repeated every 28 days. Schedules 2 and 3 were designed to avoid observed dose-limiting toxicity on schedule 1 consisting of transient elevation of serum creatinine levels and delayed myelosuppression. Schedule 2 consisted of E, 40 or 60 mg/ m2/day, days 1 and 15; V, 3 mg/m2/day, days 2 and 15; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 28 days. Schedule 3 consisted of E, 60 to 120 mg/m2/day, day 1; V, 3 mg/m2/day, day 2; A, 30 mg/m2/day, day 2; C, 30 mg/m2/day, days 1 and 2; cycled every 21 days. Filgrastim 5 micrograms/kg/day was given to all patients subcutaneously until the absolute neutrophil count was greater than 10,000/microL postnadir. Three patients were treated on schedule 1, 10 on schedule 2 (four at an E dose of 40 mg/m2/day and six at an E dose of 60 mg/m2/day), and 24 on schedule 3 (six at each of the following E dosages: 60, 80, 100, and 120 mg/m2/day). RESULTS: Dose-limiting toxicities of grade 3 to 4 leukopenia and transient elevation of serum creatinine values were observed in two of three patients treated on schedule 1. A dose-limiting toxicity of grade 3 to 4 leukopenia was noted in two of six patients treated on schedule 2 at an edatrexate dose of 60 mg/m2/day. Two of six patients treated on schedule 3 at an edatrexate dose of 120 mg/m2/day had a dose-limiting toxicity of grade 3 stomatitis (one patient) and grade 3 cytopenia (one patient). Nineteen of 37 patients with evaluable or measurable disease had a response to treatment (response rate 51%, 95% confidence intervals = 35%-67%). Nine of 15 patients with metastatic non-small cell lung cancer responded, including one complete remission (response rate 60%, confidence intervals = 35%-85%). A median survival of 517 days (confidence interval = 163-808 days) and a 1-year survival rate of 60% (confidence interval = 35%-85%) was seen in patients with advanced non-small cell lung cancer. CONCLUSIONS: The maximum tolerated dose and the recommended phase II dose of edatrexate is 100 mg/m2/day when administered as part of the EVAC/G-CSF program following schedule 3. Promising antineoplastic activity against non-small cell lung carcinomas was observed, and a phase II study is planned.

Evaluation of a somatostatin analog in the treatment of lymphoproliferative disorders: results of a phase II North Central Cancer Treatment Group trial.

PURPOSE: Malignant cells from non-Hodgkin's lymphomas (NHL) have been shown to express the somatostatin receptor on their cell surface and most NHL are visible on somatostatin radioscintigraphy scans. This provided the rationale to conduct a phase II trial of a somatostatin analog in patients with B- and T-cell lymphoproliferative disorders. PATIENTS AND METHODS: Sixty-one patients with measurable or assessable lymphoproliferative disorders (31 stage III or IV low-grade NHL; 21 chronic lymphocytic leukemia [CLL]; and nine cutaneous T-cell NHL [CTCL]) were enrolled. Patients were treated with somatostatin 150 micrograms subcutaneously (SQ) every 8 hours for 1 month. Patients with stable or responding disease received 2 additional months of therapy; those who responded after 3 months were treated for an additional > or = 3 months. RESULTS: Sixty patients were assessable for toxicity and 56 for response. There were no complete remissions. In the low-grade NHL group, 36% (10 of 28 patients; 95% confidence interval [CI], 19% to 56%) had a partial remission. Forty-four percent (four of nine; 95% CI, 14% to 79%) of patients with CTCL had a partial response. No patients with CLL had a partial remission. Among 45 patients with stable disease or a partial remission, the mean time to progression (TTP) was 10.9 months (median, 6.2; range, 1.6 to 48.5). The drug was well tolerated, with the most common side effects being diarrhea and hyperglycemia. CONCLUSION: Somatostatin at a dose of 150 micrograms every 8 hours is well tolerated and has activity in low-grade NHL.

Primary lymphoma of the spinal cord.

Non-Hodgkin's lymphomas arising in the spinal cord are extremely rare. Only eight single case reports have been well confirmed in the literature. Herein we describe a 59-year-old woman with symptoms attributable to a spinal cord lesion. Physical examination revealed neurologic deficits but no evidence of tumor elsewhere. Although several imaging studies were performed, only magnetic resonance imaging with use of gadolinium revealed the exact site and extent of the lesion. Laminectomy and direct examination of the spinal cord disclosed a discolored region at the level of the 11th thoracic vertebra. A biopsy specimen was obtained, and pathologic examination revealed an intermediate grade, mixed cell lymphoma of T-cell origin. Radiotherapy was administered to the lesion and adjacent region of the spinal cord with use of 6-MV photons and an anteroposterior-posteroanterior technique; the total dose was 45 Gy in 23 fractions. No chemotherapy was given. After 3 years of follow-up, the neurologic signs and symptoms were stable, and repeated magnetic resonance imaging with use of gadolinium showed no residual tumor. In addition to the case report, we review the literature on primary lymphomas of the central nervous system and discuss treatment recommendations.

Paraneoplastic pemphigus: a case of prolonged survival.

OBJECTIVE: To describe a patient with severe, recalcitrant mucous membrane erosions and chronic lymphocytic leukemia. DESIGN: We present a case report and a literature review of paraneoplastic pemphigus. MATERIAL AND METHODS: Immunofluorescence studies and immunoprecipitation confirmed the presence of autoantibodies characteristic of paraneoplastic pemphigus in the patient's serum. RESULTS: Our patient lived almost 8 years after the onset of paraneoplastic pemphigus, the longest time that anyone with this disease is known to have survived. CONCLUSION: The clinical course of paraneoplastic pemphigus tends to be rapid and fatal despite immunosuppressive therapy. Long-term survival is uncommon.

Bone marrow aspirate immunofluorescent and bone marrow biopsy immunoperoxidase staining of plasma cells in histologically occult plasma cell proliferative marrow disorders.

Immunofluorescent staining (immunofluorescence bone marrow aspirate) and immunoperoxidase staining (immunoperoxidase bone marrow biopsy) were compared in 26 patients with plasma cell dyscrasia and less than 10% marrow plasma cells. Their clinical diagnoses included monoclonal gammopathy of undetermined significance (13 patients), treated multiple myeloma (four patients), multiple myeloma with less than 10% marrow plasma cells (two patients), primary systemic amyloidosis (two patients), monoclonal gammopathy of undetermined significance with neuropathy (two patients), angiofollicular lymph node hyperplasia (two patients, all with the POEMS [polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes] syndrome), and primary (amyloidosis) amyloid neuropathy (one patient). The percentage of plasma cells was greater than 5% in 23% of patients and less than or equal to 5% in 77% of patients. With immunofluorescence bone marrow aspirate and immunoperoxidase bone marrow biopsy, light-chain restriction was demonstrated in 84% of all cases and accurately determined in 96% of all cases as shown by serum and urine paraprotein analysis or tissue amyloid typing. Monoclonal populations of plasma cells can be readily identified with immunofluorescence bone marrow aspirate and immunoperoxidase bone marrow biopsy in most patients with paraproteins and marrow plasmacytoses not diagnostic of multiple myeloma.

Refractory thrombocytopenia. A myelodysplastic syndrome that may mimic immune thrombocytopenic purpura.

The French-American-British classification scheme of myelodysplastic syndromes includes a category of refractory cytopenia that includes refractory thrombocytopenia (RTC). Because dysmegakaryopoiesis manifesting as an isolated cytopenia can be difficult to identify morphologically and because it may be accompanied by megakaryocytic hyperplasia, RTC may be confused with idiopathic thrombocytopenic purpura. A review of 1,220 cases of myelodysplastic syndromes at Mayo Clinic Jacksonville and Mayo Clinic Rochester from 1979 to 1990 yielded 9 cases (0.7%) of isolated thrombocytopenia (RTC) associated with clonal chromosome abnormalities. Review of 319 marrow chromosome analyses performed at the cytogenetics laboratory at Mayo Clinic Rochester from 1979 to 1990 for patients with low platelet count yielded two additional cases of RTC (0.6%). Of the 11 RTC cases, 3 previously had been misdiagnosed as idiopathic thrombocytopenic purpura. All patients had oval macrocytes in peripheral blood smears and abnormal megakaryocyte morphology in bone marrow aspirates, lacked antiplatelet antibodies, and did not have splenomegaly on clinical examination. The most common clonal chromosome abnormalities involved chromosomes 3, 5, 8, or 20. Steroid therapy was ineffective. Clinical and laboratory findings can establish the diagnosis of RTC and allow the physician to avoid recommending inappropriate therapy (steroids or splenectomy) for these patients.

Granulocyte-macrophage colony-stimulating factor. Preliminary observations on the influences of dose, schedule, and route of administration in patients receiving cyclophosphamide and carboplatin.

BACKGROUND: In an attempt to learn how best to administer granulocyte-macrophage colony-stimulating factor (GMCSF), the authors performed a Phase I study of this agent. They were interested in the influences of dose, schedule, and route of administration on the effects of GMCSF in patients receiving standardized 1-day regimens of cyclophosphamide (CYCLO) and carboplatin (CBDCA). METHODS: Between June 1988 and March 1991, 57 patients with advanced cancer received GMCSF in association with CYCLO 1 g/m2 plus CBDCA 225-700 mg/m2. After the first dose escalation to 300 mg/m2 of CBDCA, patients who had previously received chemotherapy or radiation therapy were excluded. GMCSF was administered in three different doses, five different schedules, and by two different routes. Altogether, 17 different treatment groups were observed. In addition, 24-hour GMCSF serum concentration curves were charted in four patients. RESULTS: Using four sequential groups of three patients each who had received myelosuppressive treatment, treatment with CYCLO 1 g/m2 and CBDCA 225 mg/m2, the apparent superiority of daily subcutaneous injection over 30-minute daily IV infusion of GMCSF was demonstrated graphically. Subsequently, the authors observed apparent enhancement of GMCSF effects beyond those produced by the initially selected 20-day basic 10 micrograms/kg daily SC regimen beginning 2 days after chemotherapy. When administered SC every 12 hours for 14 days beginning the day after chemotherapy, GMCSF appeared to ameliorate the severity of both leukopenia and thrombocytopenia. These effects permitted escalation of the CBDCA dose to 700 mg/m2 (with 1 g/m2 of CYCLO) before cytotoxic tolerance limits were reached. Graphic small group comparisons suggest that GMCSF given SC in doses of 5 micrograms/kg twice daily may produce comparable leukocyte and platelet support after chemotherapy with lower toxicity than occurs from higher doses. Prechemotherapy priming with GMCSF twice daily for an additional 4 days (days -6 to -3) seems to ameliorate postchemotherapy cytopenias further but at the cose of some increased risk of GMCSF toxicity. Although most of the toxic effects of moderate-dose GMCSF are controlled by antihistamines and ibuprofen, oral glucocorticoids (e.g., prednisone, 10 mg twice daily during the second week of GMCSF administration) may be required in patients with serositis, pulmonary infiltrates, or severe skin eruptions. CONCLUSIONS: Our observations suggest that GMCSF should be administered SC in doses of approximately 5 micrograms/kg every 12 hours for 10-14 days beginning the day after chemotherapy. Prechemotherapy priming with these same doses for four additional days (days -6 to -3) may additionally ameliorate postchemotherapy leukopenia and thrombocytopenia, but with increased risk of toxicity.

A practical approach to the differential diagnosis and evaluation of the adult patient with macrocytic anemia.

The most common causes of macrocytic anemias in the adults are (1) alcoholism, (2) liver diseases, (3) hemolysis or bleeding, (4) hypothyroidism, (5) folate or vitamin B12 deficiency, (6) exposure to chemotherapy and other drugs, and (7) myelodysplasia. A carefully obtained history and examination with evaluation of a peripheral blood smear and reticulocyte count should be performed in most patients with macrocytosis. Serum vitamin B12 and folate levels, serum thyroid studies, liver function studies, and bone marrow aspirate and biopsy with cytogenetic analysis are frequently required to confirm a diagnosis suspected on the basis of the initial evaluation.

How to diagnose bleeding disorders.

Patients with problems of hemostasis are not uncommon in the primary care setting. The bleeding history provides critical information that helps in guiding evaluation of these patients. Results of frequently used screening tests of coagulation can be abnormal in patients who have no significant hemostatic defect and can be normal in patients who do have one.

Inhibition of hemopoietic growth factor-induced proliferation by adenosine diphosphate-ribosylation inhibitors.

The effects of adenosine diphosphate (ADP) ribosylation inhibitors on hematopoietic growth factor-induced proliferation were examined. Significant inhibition of interleukin-3 (IL-3), colony-stimulating factor 1, and lung conditioned media-induced clonal agar growth of normal murine hematopoietic cells by 10 mmol/L nicotinamide (NAM), 10 mmol/L 3-aminobenzamide (3AB), and 5 mmol/L N1-methylnicotinamide (1MN) was noted. Nicotinic acid, a related compound that does not inhibit ADP ribosylation, failed to inhibit the growth factor-mediated proliferation. NAM (10 mmol/L), 3AB (10 mmol/L), and 1MN (5 mmol/L) also prevented IL-3 and phorbol ester-stimulated 3H-thymidine incorporation into the IL-3-responsive FDC-P1 cell line. Exposure of FDC-P1 cells to 10 mmol/L NAM led to a significant decrease in nuclear poly-(ADP-ribose) levels. Exposure of FDC-P1 cells to 5 mmol/L 1MN did not affect the interaction of the phorbol ester receptor, protein kinase-C (PK-C), with the cell membrane as determined by assay of phorbol ester binding in cytosol and membrane preparations. Nor did it affect the catalytic activity of PK-C as determined by assaying the in vitro phosphorylation of histone H1 by cytosolic kinase preparations from FDC-P1 as well as EL4 thymoma cells. 1MN markedly enhanced the inhibitory effects of phorbol esters on DNA synthesis of EL4 cells even at concentrations (1.25 mmol/L) that had no effects on DNA synthesis in the absence of phorbol esters. Our findings demonstrate that (a) active ADP ribosylation inhibitors interfere with growth factor-induced proliferation of murine hematopoietic cells and (b) the inhibition occurs at a step that follows the activation and translocation of PK-C and is more closely linked to DNA synthesis.

Preoperative evaluation of hemostasis in patients with congenital heart disease.

The incidence of abnormal results of coagulation tests and the risks for postoperative hemorrhage were assessed in 235 patients with congenital heart disease. Preoperatively, the prothrombin time, partial thromboplastin time, activated partial thromboplastin time, thrombin time, or platelet count was abnormal in 45 of the 235 patients (19%), a significantly higher incidence than that expected in a normal population (P less than 0.002). Prolonged values for the prothrombin time or the partial thromboplastin time or activated partial thromboplastin time were seen most frequently. Further evaluation in eight of the patients with prolonged prothrombin time or partial thromboplastin or activated partial thromboplastin time showed decreased levels of either factor VII or IX in six of them, suggesting that impaired vitamin K-dependent carboxylation is commonly present. Normal results of preoperative coagulation tests do not exclude the presence of a major bleeding diathesis (von Willebrand's disease was later diagnosed in a patient with such findings). The use of blood products during subsequent cardiac operations was not significantly different in patients with normal or abnormal test results. Two of the three patients who required reoperation and were found to have a nonsurgical cause of bleeding had abnormalities in two or more of the preoperative coagulation tests. This finding suggests that abnormal results of preoperative coagulation tests may be predictive of defective hemostasis in the postoperative period.

Peripheral T-cell lymphoma simulating Hodgkin's disease with initial bone marrow involvement.

In a patient who had fever and cytopenias but no peripheral lymphadenopathy, bone marrow biopsy revealed findings consistent with Hodgkin's disease. Subsequently lymph node biopsy specimens showed lymphoma with features more consistent with peripheral T-cell lymphoma. The clinical features of this patient were those that have been ascribed to an atypical clinical form of Hodgkin's disease. This case illustrates the inadequacy of bone marrow examination as the sole criterion for establishing an initial diagnosis of Hodgkin's disease, particularly in relationship to the newly recognized pleomorphic variants of T-cell malignant lymphoma.