Granulocyte colony-stimulating factor versus placebo in addition to penicillin G in a randomized blinded study of gram-negative pneumonia sepsis: analysis of survival and multisystem organ failure.

Sepsis is a common cause of morbidity and mortality. Neutrophils are the major defense against bacterial invasion, and granulocyte colony-stimulating factor (G-CSF) augments both neutrophil number and function. In our study, 160 rabbits were inoculated transtracheally with 0.5 mL of a solution containing 10(4) colony forming units per milliliter of Pasteurella multocida. Twenty-four hours later, chest x-rays and quantitative blood cultures demonstrated pneumonia and bacteremia. Therapy was then begun with penicillin G and either recombinant human G-CSF (rG-CSF; 5 to 8 micrograms/kg subcutaneously) or placebo every day for 5 days. Arterial blood gases and 23 other parameters of organ function were performed before inoculation and serially thereafter. All rabbits underwent histologic examination of organs at the time of septic death or when sacrificed on day 6. A total of 149 rabbits survived long enough to initiate therapy. A significant increase in leukocytes by day 4 was found in the rG-CSF-treated group. There was a trend towards improved survival in the rG-CSF group (77% v 67%; P = .13, n = 149). Analysis of pretreatment variables revealed sepsis-induced leukopenia (< or = 2,800/microL) as the only predictor of significantly improved survival with rG-CSF treatment (57% v 39%; P = .04, n = 73). The majority of the survival benefit occurred within the first 24 hours of treatment. This was before the time that a significant difference in mean white blood cell (WBC) count was observed between the study groups, making intravascular leukocytosis an unlikely explanation for the survival advantage in the rG-CSF group. No significant difference in laboratory variables reflecting organ function was demonstrated between the groups. Histologic grading of inflammation (0, normal, to 6, necrosis) in seven organs revealed that the surviving rabbits had mild but statistically significant increased inflammation in the liver, spleen, and noninoculated lung in the rG-CSF versus placebo groups (liver: 2.6 v 1.5, P < or = .0001; spleen: 3.2 v 2.3, P < or = .0001; and noninoculated lung: 2.9 v 2.5, P = .04). Administration of rG-CSF, in addition to penicillin G, in immune competent rabbits with gram-negative sepsis complicated by leukopenia significantly improved survival over antibiotics alone. The administration of rG-CSF in early sepsis for a short therapeutic duration was not associated with any clinically evident toxicity. Clinical trials using rG-CSF in septic patients with leukopenia are indicated.

Immunomorphologic analysis of bone marrow biopsies after treatment with 2-chlorodeoxyadenosine for hairy cell leukemia.

Treatment of hairy cell leukemia with 2-chlorodeoxyadenosine (2-CdA) induces complete remissions in 85% of patients. Complete remission has been defined as the absence of hairy cells in the bone marrow after routine morphologic examination. To determine if hairy cells could be detected in complete remission bone marrows using immunohistochemical techniques with antibodies L26 (CD20) and DBA.44, 154 bone marrow biopsies performed between 3 months and 25 months after therapy were studied. Of the biopsies, 50% exhibited staining with L26 and/or DBA.44 in five or more cells with morphologic features of hairy cells. Minimal residual disease was usually less than 1% of the total cellular population. DBA.44-positive cells were demonstrated in 91% of the biopsies, although in 48% of these the morphologic features of the positive cells were not sufficiently distinctive for hairy cells. The proportion of biopsies with residual hairy cells was similar over the 25 months of follow up, indicating a relatively stable amount of residual disease. Immunomorphologic analysis is a more sensitive method for detecting residual hairy cells than morphology alone. Although further follow up is necessary to determine the clinical significance of the L26/DBA.44-positive staining in cells with and without distinctive morphologic features of hairy cells, we conclude that many patients in a stable clinical remission may have residual hairy cells.

Acute lymphoid leukemia associated with Maffucci's syndrome.

PURPOSE: Maffucci's syndrome is a nonhereditary congenital disorder associated with multiple enchondromas, soft tissue hemangiomas, or lymphangiomas. It carries an associated high risk of the development of malignant neoplasms, particularly sarcomatous transformation of an enchondroma, as well as other malignant mesodermal and nonmesodermal neoplasms. Hematopoietic malignancies arising in Maffucci's syndrome are exceedingly rare. We report the case of a 14-year-old girl with Maffucci's syndrome who developed acute lymphoid leukemia. PATIENTS AND METHODS: The patient presented at 18 months of age with enchondromatosis. Maffucci's syndrome was established at 10 years of age after the appearance of multiple hemangiomas. RESULTS: At 14 years of age the patient developed fatigue, frequent nosebleeds, easy bruising, and weight loss, with circulating blasts in the peripheral blood. Bone marrow examination showed replacement of marrow spaces with leukemic blasts. Immunohistochemical and flow cytometric findings were consistent with a diagnosis of acute lymphoblastic leukemia with myeloid antigen expression. CONCLUSIONS: The occurrence of acute leukemia in a patient with Maffucci's syndrome may represent predisposition to yet another malignancy and reflect further expression of a generalized mesodermal dysplasia in these patients. It also emphasizes the need for aggressive surveillance in patients with Maffucci's syndrome.

Prognostic implications of a bone marrow histopathologic classification system in mycosis fungoides and the Sézary syndrome.

BACKGROUND: The authors devised a histopathologic classification system for interpreting bone marrow biopsy materials in patients with mycosis fungoides and the Sézary syndrome and correlated histopathologic findings with clinical stage and outcome. METHODS: Bone marrow specimens from 90 consecutively staged patients were examined for lymphoid infiltrates, benign or cytologically atypical lymphoid aggregates, and large or cytologically transformed cells. RESULTS: Thirty-seven (41%) marrows were involved, two with diffuse lymphomatous infiltrates and 35 with lymphoid aggregates. Twelve of the 35 had lymphoid aggregates consisting of cytologically normal-appearing lymphocytes, and 23 had aggregates composed of cytologically atypical lymphocytes. Eleven patients had greater than 5% large cytologically transformed cells. Patients with infiltrative disease or cytologically atypical aggregates had an inferior survival compared with those with cytologically normal lymphocytes (P2 = 0.0042), and patients with aggregates consisting of cytologically normal lymphocytes had a survival comparable with that of patients with uninvolved marrows (P2 = 0.33). Whereas most patients with cytologically atypical marrows had advanced skin and lymph node involvement, 28% had early skin stage. Bone marrow eosinophilia was noticed in 38% of patients and was not consistently associated with peripheral blood eosinophilia or clinical stage. CONCLUSIONS: These results suggest that patients with cytologically atypical lymphoid aggregates or diffuse lymphomatous infiltration of the marrow have an inferior survival regardless of clinical stage, whereas those with lymphoid aggregates consisting of cytologically normal-appearing lymphocytes have a survival indistinguishable from that of patients without lymphoid aggregates.

Splenic metastasis in hairy cell leukemia.

BACKGROUND: Splenic metastasis is uncommon and usually occurs in the setting of widespread visceral metastasis. Splenic metastasis as an initial manifestation of disease and sole site of metastasis has not been reported previously. METHODS: The authors describe a patient with hairy cell leukemia (HCL) with the unexpected finding of metastatic adenocarcinoma in the spleen. Direct inspection at the time of laparotomy and subsequent radiographic studies did not show a primary or additional metastatic tumor. Eventually, he manifested evidence of pulmonary and hepatic metastases and died with fungal sepsis. RESULTS: The splenectomy specimen showed HCL and metastatic adenocarcinoma. Immunohistochemical studies showed adenocarcinoma with diffuse cytoplasmic staining for prostate-specific antigen and focally positive results with prostatic acid phosphatase antigen. Postmortem examination 9 months later showed HCL and widespread metastatic adenocarcinoma. No primary tumor was identified, and multiple tissue blocks of the prostate had negative findings for tumor. CONCLUSIONS: The immunohistologic features of the metastatic adenocarcinoma were interpreted as prostatic in origin. The pattern of isolated metastatic disease in the absence of primary tumor appears to represent another possible atypical disease presentation of prostatic cancer. Hairy cell-induced structural and immunologic alterations within the splenic microenvironment may have contributed to this unique clinical presentation.

Cytomegalovirus-infected cells express Leu-M1 antigen. A potential source of diagnostic error.

The authors examined cytomegalovirus (CMV)-infected tissues and Hodgkin's Disease (HD) cases with immunohistochemical assays for Leu-M1 and CMV. The cytologic characteristics were correlated with immunostaining patterns. Cytomegalovirus-infected cells in lymph node, lung, and esophagus sections showed Cowdry type A inclusions, and many had granular cytoplasmic inclusions. All infected cells showed nuclear staining with an anti-CMV antibody. Leu-M1 reacted with CMV-infected cells in cytoplasmic areas, particularly near the nucleus simulating the characteristic staining pattern of Reed-Sternberg (R-S) cells. Cytoplasmic staining intensified as the intranuclear inclusions increased in size. Reed-Sternberg cells showed characteristic Leu-M1 positivity along the cell membrane and golgi zone. At times, Leu-M1 staining of CMV-infected cells was indistinguishable from that of R-S cells. None of the R-S cells reacted with the antibody to CMV. Recognition of the reactivity of Leu-M1 with CMV-infected cells is important in avoiding misdiagnosis of CMV lymphadenitis as HD.

Perineal leiomyosarcoma.

Perineal leiomyosarcomas are rare aggressive tumors for which the therapy remains to be defined. These tumors may be extensively infiltrating and therapy may require radical surgery. The problems encountered in treating these tumors are similar to those for retroperitoneal sarcomas. Namely, delay in diagnosis, lack of distinct anatomic boundaries, and close proximity to and encroachment on multiple organs prevents resection with adequate surgical margins. We discuss the current literature and present our management of perineal leiomyosarcomas.