Eric J. Seifter

Intravascular lymphomatosis: a clinicopathologic study of 10 cases and assessment of response to chemotherapy.

PURPOSE We report a clinicopathologic study of 10 cases of intravascular lymphomatosis (IVL) seen at a single institution, and assess the response to chemotherapy in these patients, as well as those collected from a literature review. PATIENTS AND METHODS The clinical, pathologic, and immunophenotypic features of 10 cases of IVL diagnosed at the Johns Hopkins Hospital since 1977 were studied. Follow-up information was obtained in each case by consultation with the treating physician. In addition, cases of IVL reported previously in which patients were treated with chemotherapy and for which follow-up data were available at the time of publication were reviewed. RESULTS In the present series of 10 cases, the most common clinical features were fever of unknown origin (FUO), mental status changes, and rash. Diagnostic specimens were obtained from a variety of sources, including brain, skin, prostate, liver, kidney, and gallbladder. All of the four patients treated with combination chemotherapy are alive and two have achieved long-term survival (48 and 45 months, respectively); the remaining two are alive and in complete remission (CR) after short follow-up duration of 6 months. Among 35 patients reported in the literature who received chemotherapy (including four from this series), 43% attained a CR and were free of disease at the time of publication. None of the three patients in our series who received localized therapy (surgery with or without radiation therapy) is alive (mean survival duration, 9 months). For the three patients diagnosed at postmortem examination, the mean interval between onset of symptoms and death was 3 months, and disease was widespread. CONCLUSION These findings suggest that IVL represents a high-grade non-Hodgkins lymphoma (NHL) with a propensity for systemic dissemination, and that CR and long-term survival may result in patients treated with aggressive combination chemotherapy.

Immunoablative High-Dose Cyclophosphamide without Stem-Cell Rescue for Refractory, Severe Autoimmune Disease

High-dose cytotoxic therapy followed by autologous stem-cell transplantation has been proposed as a novel treatment for severe autoimmune disease [1, 2]. This approach was prompted by autoimmune animal models that demonstrated marked improvement or complete eradication of autoimmune disease after syngeneic marrow transplantation [3, 4]. In addition, allogeneic marrow transplantation (performed chiefly for aplastic anemia) has been reported to eradicate concurrent autoimmune disease [5, 6]. Allogeneic marrow transplantation is not routinely used to treat autoimmune disease because of substantial associated morbidity and mortality. Although interest in the use of high-dose cytotoxic therapy followed by autologous stem-cell transplantation to treat autoimmune disease is increasing, disease progresses or relapses early in many patients [7, 8]. It is unclear whether reappearance of the disease after autologous transplantation results from failure of high-dose therapy to eradicate autoaggressive lymphocytes, reinfusion of autoaggressive lymphocytes with the autograft, or renewed challenge from the autoantigen [7, 8]. However, the success of syngeneic transplantation in animal models and allogeneic transplantation in patients with autoimmune diseases suggests that high-dose cytotoxic therapy may be sufficient to eradicate autoaggressive lymphocytes [8]. We previously found that the immunoablative doses of cyclophosphamide used for transplantation can induce durable, complete remission (median follow-up > 10 years) without stem-cell rescue in most patients with severe aplastic anemia [9]. Because most cases of aplastic anemia result from immune suppression of hematopoiesis [10], high-dose cyclophosphamide without the addition of other cytotoxic immunosuppressive agents seems to ablate the autoaggressive lymphocytes. We also reported that high-dose cyclophosphamide spared hematopoietic stem cells because full hematopoietic recovery occurred [9]. Hematopoietic stem cells express high levels of aldehyde dehydrogenase, an enzyme responsible for cellular resistance to cyclophosphamide, and are therefore resistant to the cytotoxic effects of cyclophosphamide [11, 12]. We investigated the efficacy of high-dose cyclophosphamide without stem-cell rescue in patients with various severe autoimmune diseases. Methods Treatment Schedule Our study was approved by the institutional review boards of Johns Hopkins University and Hahnemann University. After giving informed consent, eight patients (Table 1 and Table 3) with refractory autoimmune disorders received cyclophosphamide (50 mg/kg of body weight per day) intravenously for 4 consecutive days. Granulocyte colony-stimulating factor therapy (5 g/kg per day) was started 6 days after the last dose of cyclophosphamide and was continued until the absolute neutrophil count reached 109 cells/L. Inclusion in the study required failure of two previous therapies. Patients were excluded if their cardiac ejection fraction was less than 0.45, their serum creatinine level was greater than 176.8 mol/L, or they were older than 70 years of age. Red blood cell transfusions were administered to patients with a hematocrit less than 0.25, and platelet transfusions were given to patients with platelet counts less than 20 109 cells/L or clinically significant bleeding. Complete remission required the absence of any clinical or serologic evidence of disease. Complete remission from lupus nephritis was defined as fewer than 10 dysmorphic erythrocytes per high-powered field, absence of cellular casts, and excretion of less than 1 g of protein per day without doubling of the serum creatinine level [13]. For patients with systemic lupus erythematosus, daily activity indices [14] were measured at 3-month intervals. Table 1. Patient Characteristics and Response to High-Dose Cyclophosphamide Table 3. Table 1. Continued Selected Case Reports Patient 1 was a 64-year-old man with a 35-year history of rheumatoid arthritis treated with prednisone and gold. The Felty syndrome had been diagnosed 3 years earlier when the patient developed a perirectal abscess and profound neutropenia (neutrophil count < 0.2 109 cells/L). Examination of bone marrow showed hypercellularity with myeloid maturation arrest. The patient was treated with myeloid growth factors and steroids but showed no response. He required frequent hospitalizations for recurrent infections. Before the patient received high-dose cyclophosphamide, he was positive for antineutrophil antibodies, the neutrophil count was 0.1 109 cells/L, the rheumatoid factor level was elevated, complement levels were depressed, and the Karnofsky score [15] was 40%. The patient tolerated high-dose cyclophosphamide well and had few side effects other than alopecia; he achieved a neutrophil count greater than 0.5 109 cells/L by day 15, and infections (perirectal abscess, pneumonia, and sinusitis) that were present at the time of treatment resolved. Two units of red blood cells and five platelet transfusions were required. The patient is in complete remission 21 months after treatment and has normal peripheral blood counts, has normal complement levels, and is negative for antineutrophil antibodies. He has not been receiving any immunosuppressive agents for more than 15 months. Patient 6 was a 23-year-old woman in whom lupus was diagnosed at 12 years of age after she presented with the Raynaud phenomenon and stomatitis. She later developed severe proteinuria, hyperlipidemia, polyarthralgia, and an extensive skin rash. Renal biopsy performed 4 years before initiation of high-dose cyclophosphamide therapy showed membranous nephropathy. The patient required hospitalization for lupus flares three to four times per year despite treatment with methylprednisolone (4 mg/d), hydroxychloroquine (400 mg/d), azathioprine (150 mg/d), and pulse-dose cyclophosphamide. Before high-dose cyclophosphamide therapy began, the hematocrit was 0.27, the leukocyte count was 2.8 109 cells/L, the platelet count was 278 109 cells/L, and the erythrocyte sedimentation rate was 104 mm/h. Anti-DNA antibodies were present at a titer of 1:320, the C3 level was 0.41 g/L, and the 24-hour urine protein level was 2 g. The patient tolerated high-dose cyclophosphamide well; side effects were alopecia and febrile neutropenia. A neutrophil count greater than 0.5 109 cells/L was reached on day 18, and only six units of red blood cells and three platelet transfusions were needed. The patient is in continuous complete remission 12 months after treatment; the erythrocyte sedimentation rate is 20 mm/h, no anti-DNA antibodies are present, the C3 level is 1.49 g/L, and the 24-hour urine protein level is 86 mg. Immunosuppressive therapy has been tapered to 1 mg of prednisone daily. Results High-dose cyclophosphamide was well tolerated and was associated with rapid hematologic recovery in all eight patients despite their poor medical condition at time of treatment. Four patients were hospitalized for complications of their autoimmune disease, and four patients were being treated for active infections at the time of cyclophosphamide therapy; the median Karnofsky score was 40% (range, 20% to 70%). The median time to achievement of a neutrophil count greater than 0.5 109 cells/L was 17 days (range, 11 to 22 days), and the median time to the last platelet transfusion was 16 days (range, 12 to 33 days). All patients experienced complete alopecia, and six patients required antibiotics for febrile neutropenia. No patient developed hemorrhagic cystitis or mucositis. Patients 2 and 4 eventually died of complications of autoimmune disease. Patient 2, who was treated for autoimmune hemolytic anemia, died of complications of immune thrombocytopenic purpura, which was not present when she was treated with high-dose cyclophosphamide. Autoimmune hemolytic anemia remained in complete remission until the patients death, 16 months after cyclophosphamide therapy. Patient 4 achieved brief remission of immune thrombocytopenic purpura and died of her disease 8 months later. Six patients remain alive, and five (patients 1, 3, 6, 7, and 8) have no symptomatic manifestations of their disease. In addition, four patients have no laboratory or clinical evidence of disease (Table 2). Patient 3, who has the Evans syndrome, shows continued improvement in blood counts; prednisone therapy is being tapered to 10 mg every other day. Patient 3 has been independent of transfusion for more than 10 months and has a normal hemoglobin level and a platelet count of 66 109 cells/L. One of the patients with lupus achieved complete remission; the other still has clinical and serologic evidence of the disease but continues to improve 14 months after treatment. Patient 7, who has the Felty syndrome, is in complete remission 3 months after cyclophosphamide therapy. Patient 10, who has chronic inflammatory demyelinating polyneuropathy, had progressive upper- and lower-extremity paralysis and was unable to walk. Plasmapheresis, intravenous immunoglobulin, and pulse-dose cyclophosphamide therapy had proven ineffective. Three months after therapy with high-dose cyclophosphamide, he has no neurologic manifestations, is not receiving immunosuppressive therapy, and can walk normally. Table 2. Laboratory Results* Discussion Most immunoablative therapy for severe autoimmune disease uses autologous stem-cell rescue after high-dose therapy with cyclophosphamide in combination with other immunosuppressive agents [8]. Although our study was small and the follow-up was relatively short, the results indicate that high-dose cyclophosphamide alone can be effective therapy for some patients with severe autoimmune disease. In addition, our study confirms that high-dose cyclophosphamide (50 mg/kg per day for 4 days) spares hematopoietic stem cells; the kinetics of bone marrow recovery after high-dose cyclophosphamide therapy without stem-cell rescue are similar to those of engraftment after autol

National Institutes of Health State-of-the-Science Conference: role of active surveillance in the management of men with localized prostate cancer.

National Institutes of Health (NIH) Consensus and State-of-the-Science Statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality, 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session, 3) questions and statements from conference attendees during open discussion periods that are part of the public session, and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of NIH or the U.S. government. The statement reflects the panel’s assessment of medical knowledge available at the time the statement was written. Thus, it provides a “snapshot in time” of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research. The following statement is an abridged version of the panel’s report, which is available in full at http://consensus.nih.gov/2011/prostatefinalstatement.htmNational Institutes of Health (NIH) Consensus and Stateof-the-Science Statements are prepared by independent panels of health professionals and public representatives on the basis of 1) the results of a systematic literature review prepared under contract with the Agency for Healthcare Research and Quality, 2) presentations by investigators working in areas relevant to the conference questions during a 2-day public session, 3) questions and statements from conference attendees during open discussion periods that are part of the public session, and 4) closed deliberations by the panel during the remainder of the second day and morning of the third. This statement is an independent report of the panel and is not a policy statement of NIH or the U.S. government. The statement reflects the panel’s assessment of medical knowledge available at the time the statement was written. Thus, it provides a “snapshot in time” of the state of knowledge on the conference topic. When reading the statement, keep in mind that new knowledge is inevitably accumulating through medical research. The following statement is an abridged version of the panel’s report, which is available in full at http: //consensus.nih.gov/2011/prostatefinalstatement.htm In 2011, more than 240 000 men are projected to receive a diagnosis of prostate cancer and 33 000 are projected to die of this condition. More than 2.5 million men in the United States are long-term survivors of prostate cancer. Men with a strong family history of prostate cancer and African American men are at increased risk for prostate cancer. Most cases of prostate cancer are localized at diagnosis and detected as a result of screening with prostatespecific antigen (PSA) testing. Most of these screendetected cases of cancer are low risk and are unlikely to cause death. The natural history of prostate cancer has changed dramatically in the past 3 decades because of PSA screening. Although most cases of prostate cancer are slowgrowing and unlikely to spread, most men receive immediate treatment with surgery or radiation. These therapeutic strategies are associated with shortand long-term complications, including impotence and urinary incontinence. Only a few men choose observational strategies, thereby delaying the initiation of curative therapy or avoiding it completely. Given the high prevalence of low-risk prostate cancer, the roles of active surveillance and other observational strategies as alternatives to immediate treatment need to be clarified. The National Cancer Institute, the Centers for Disease Control and Prevention, and the NIH Office of Medical Applications of Research convened a State-of-the-Science Conference on 5 to 7 December 2011 to assess the available scientific evidence about active surveillance for men with localized prostate cancer. The conference, which addressed 5 key questions, was informed by a formal evidence report commissioned through the Agency for Healthcare Research and Quality, data presented by speakers, and input from attendees.

High-dose cytotoxic therapy and bone marrow transplantation for relapsed Hodgkin's disease.

Patients with Hodgkins disease who have failed two or more chemotherapy regimens or who have relapsed after an initial chemotherapy-induced remission of less than 12 months are seldom cured with conventional salvage therapies. We studied the effect of high-dose cytoreductive therapy followed by bone marrow transplantation in 50 such patients with relapsed Hodgkins disease. Twenty-one patients with histocompatibility locus antigen (HLA)-matched donors had allogeneic marrow transplants, one patient received marrow from an identical twin, and 28 patients without a matched donor received autologous grafts purged with 4-hydroperoxycyclophosphamide. Busulfan plus cyclophosphamide was the preparative regimen for the 25 patients who had received extensive prior irradiation, and the other 25 patients received cyclophosphamide plus total body irradiation. The overall actuarial probability of event-free survival at 3 years was 30%, with a median follow-up of 26 months. The event-free survival following transplantation was influenced by the number of chemotherapy failures and the patients response to conventional salvage therapy prior to transplant. The 16 patients who were transplanted at first relapse, while still responsive to standard therapy, had a 64% actuarial probability of event-free survival at 3 years. Age, presence of extranodal disease, preparative regimen, and type of graft (autologous v allogeneic) were not significant prognostic factors. The majority of transplant-related deaths were from interstitial pneumonitis; inadequate pulmonary function, multiple prior chemotherapy regimens, and prior chest irradiation all appeared to increase the transplant-related mortality. These results suggest a role for marrow transplantation in a subset of patients with relapsed Hodgkins disease who are unlikely to be otherwise cured but are still responsive to conventional-dose cytoreductive therapy.

Long-Term Results of Blood and Marrow Transplantation for Hodgkin's Lymphoma

PURPOSE To evaluate the long-term outcome after allogeneic (allo) and autologous (auto) blood or marrow transplantation (BMT) in patients with relapsed or refractory Hodgkins lymphoma (HL). PATIENTS AND METHODS We analyzed the outcome of 157 consecutive patients with relapsed or refractory HL, who underwent BMT between March 1985 and April 1998. Patients <or= age 55 with HLA-matched siblings were prioritized toward allo BMT. The median age was 28 years (range, 13 to 52 years) for the 53 allo patients and 30.5 years (range, 11 to 62 years) for the 104 auto patients. RESULTS The median follow-up after BMT for surviving patients was 5.1 years (range, 1 to 13.8 years). For the entire group, the probabilities of event-free survival (EFS) and relapse at 10 years were 26% (95% confidence interval [CI], 18% to 33%) and 58% (95% CI, 48% to 69%), respectively. According to multivariate analysis, disease status before BMT (sensitive relapse if responding to conventional-dose therapy or resistant disease if not) (hazard ratio [HR] = 0.39, P < .0001) and date of BMT (HR = 0.93, P = .004) were independent predictors of EFS, whereas only disease status (HR = 0.35, P < .0001) influenced relapse. There was a trend for probability of relapse in sensitive patients to be less after allo BMT at 34% (range, 8% to 59%) versus 51% (range, 36% to 67%) for the auto patients (HR = 0.51, P = .17). There was a continuing risk of relapse or secondary acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) for 12 years after auto BMT, whereas there were no cases of secondary AML/MDS or relapses beyond 3 years after allo BMT. CONCLUSION There seems to be a clinical graft-versus-HL effect associated with allo BMT. Allo BMT for HL also seems to have a lower risk of secondary AML/MDS than auto BMT. Thus, allo BMT warrants continued study in HL.

Metastatic breast carcinoma presenting as a large pulmonary embolus: case report and review of the literature.

Involvement of the pulmonary vasculature by carcinoma of the breast typically occurs in the form of microscopic tumor emboli involving the small arteries, arterioles, or capillaries. Obstruction of a large pulmonary artery by a tumor embolus has not been reported. We describe a patient with a history of breast carcinoma diagnosed 5 years previously who sought treatment for dyspnea and a large mass in the right pulmonary artery suggestive of a pulmonary embolus. After failure of both systemic and intraarterial thrombolytic therapy, a biopsy of the mass was obtained, which revealed adenocarcinoma of the breast. Systemic chemotherapy with doxorubicin and cyclophosphamide was initiated and resulted in the complete resolution of her symptoms.