Deglacial pulses of deep-ocean silicate into the subtropical North Atlantic Ocean.

Growing evidence suggests that the low atmospheric CO2 concentration of the ice ages resulted from enhanced storage of CO2 in the ocean interior, largely as a result of changes in the Southern Ocean. Early in the most recent deglaciation, a reduction in North Atlantic overturning circulation seems to have driven CO2 release from the Southern Ocean, but the mechanism connecting the North Atlantic and the Southern Ocean remains unclear. Biogenic opal export in the low-latitude ocean relies on silicate from the underlying thermocline, the concentration of which is affected by the circulation of the ocean interior. Here we report a record of biogenic opal export from a coastal upwelling system off the coast of northwest Africa that shows pronounced opal maxima during each glacial termination over the past 550,000 years. These opal peaks are consistent with a strong deglacial reduction in the formation of silicate-poor glacial North Atlantic intermediate water (GNAIW). The loss of GNAIW allowed mixing with underlying silicate-rich deep water to increase the silicate supply to the surface ocean. An increase in westerly-wind-driven upwelling in the Southern Ocean in response to the North Atlantic change has been proposed to drive the deglacial rise in atmospheric CO2 (refs 3, 4). However, such a circulation change would have accelerated the formation of Antarctic intermediate water and sub-Antarctic mode water, which today have as little silicate as North Atlantic Deep Water and would have thus maintained low silicate concentrations in the Atlantic thermocline. The deglacial opal maxima reported here suggest an alternative mechanism for the deglacial CO2 release. Just as the reduction in GNAIW led to upward silicate transport, it should also have allowed the downward mixing of warm, low-density surface water to reach into the deep ocean. The resulting decrease in the density of the deep Atlantic relative to the Southern Ocean surface promoted Antarctic overturning, which released CO2 to the atmosphere.

ICSH guidelines for the standardization of bone marrow specimens and reports.

The bone marrow examination is an essential investigation for the diagnosis and management of many disorders of the blood and bone marrow. The aspirate and trephine biopsy specimens are complementary and when both are obtained, they provide a comprehensive evaluation of the bone marrow. The final interpretation requires the integration of peripheral blood, bone marrow aspirate and trephine biopsy findings, together with the results of supplementary tests such as immunophenotyping, cytogenetic analysis and molecular genetic studies as appropriate, in the context of clinical and other diagnostic findings. Methods for the preparation, processing and reporting of bone marrow aspirates and trephine biopsy specimens can vary considerably. These differences may result in inconsistencies in disease diagnosis or classification that may affect treatment and clinical outcomes. In recognition of the need for standardization in this area, an international Working Party for the Standardization of Bone Marrow Specimens and Reports was formed by the International Council for Standardization in Hematology (ICSH) to prepare a set of guidelines based on preferred best practices. The guidelines were discussed at the ICSH General Assemblies and reviewed by an international panel of experts to achieve further consensus.

Gemtuzumab ozogamicin (MylotargTM) is infrequently associated with sinusoidal obstructive syndrome/veno-occlusive disease.

BACKGROUND: Gemtuzumab ozogamicin (GO) is approved for the treatment of older adults with acute myeloid leukemia in first relapse. Several reports have suggested an association between GO administration and hepatic veno-occlusive disease (VOD), which has recently been termed sinusoidal obstructive syndrome (SOS). However, the majority of these studies were done in patients who had undergone high-dose therapy with stem cell transplantation or when GO was administered in combination with other cytotoxic chemotherapy. PATIENTS AND METHODS: We performed a retrospective review of all patients treated at our institution with single-agent GO, either as initial therapy or in the relapsed and refractory setting. All patients were planned to receive GO 9 mg/m2 in two doses, 14 days apart. We reviewed liver function tests before and after administration and analyzed hepatic injuries in the context of patients' other comorbid conditions. Patients were classified as experiencing liver toxicity if their liver function(s) abnormality lasted for > 7 days, as documented by repeated serum studies. RESULTS: Forty-seven patients were analyzed. Response rate (27.2%) and median duration of response (6 months) were comparable to other reports. All patients were assessable for liver toxicity, of which 23 (48%) had elevation of at least one of their liver function tests (alanine aminotransferase, aspartate aminotransferase, total bilirubin or alkaline phosphatase). Elevations in liver function test(s) were noted at a median of 14 days (range 7-175 days). Eight patients had other comorbid conditions that could explain their liver abnormality, making the incidence of direct GO-induced liver injury 31%. However, only one patient had radiographic and clinical evidence suggesting SOSVOD. CONCLUSIONS: When administered using the recommended dose and schedule, GO has little association with VODSOS if given as a single agent. In this retrospective review, the incidence of GO-related SOSVOD is as low as 2%.

Southward migration of the intertropical convergence zone through the Holocene.

Titanium and iron concentration data from the anoxic Cariaco Basin, off the Venezuelan coast, can be used to infer variations in the hydrological cycle over northern South America during the past 14,000 years with subdecadal resolution. Following a dry Younger Dryas, a period of increased precipitation and riverine discharge occurred during the Holocene "thermal maximum." Since approximately 5400 years ago, a trend toward drier conditions is evident from the data, with high-amplitude fluctuations and precipitation minima during the time interval 3800 to 2800 years ago and during the "Little Ice Age." These regional changes in precipitation are best explained by shifts in the mean latitude of the Atlantic Intertropical Convergence Zone (ITCZ), potentially driven by Pacific-based climate variability. The Cariaco Basin record exhibits strong correlations with climate records from distant regions, including the high-latitude Northern Hemisphere, providing evidence for global teleconnections among regional climates.

Increased bone marrow angiogenesis in B cell chronic lymphocytic leukemia.

Recent studies have shown that angiogenesis may be involved in the pathogenesis of hematopoietic malignancies, apart from its well-characterized role in the growth and metastasis of solid tumors. In this study, we quantified the degree of angiogenesis in B cell chronic lymphocytic leukemia (B-CLL) by measuring the microvessel density and hotspot density in bone marrow trephine biopsy sections with B-CLL involvement (n = 12) and compared it to normal bone marrow sections (n = 11). The B-CLL samples had a mean microvessel count/high power field (hpf) of 7.64 while the control samples had a mean microvessel count/hpf of 2.11 (P = 0.0001). The mean hotspot density in the B-CLL sections (14.83/hotspot) was also significantly higher (P = 0.0008) than the mean hotspot density in control bone marrow sections (7.09/hotspot). Both the microvessel density and hotspot density correlated positively with the clinical stage of the B-CLL patients. In a separate cohort of B-CLL patients, the median urine level of the angiogenic peptide, basic fibroblast growth factor (2216.5 pg/g, n = 14), was significantly higher (P = 0.0001) than the bFGF level in normal controls (1,084 pg/g, n = 58). These results indicate that angiogenesis may be involved in the pathogenesis of B-CLL.

Rapid changes in the hydrologic cycle of the tropical Atlantic during the last glacial.

Sedimentary time series of color reflectance and major element chemistry from the anoxic Cariaco Basin off the coast of northern Venezuela record large and abrupt shifts in the hydrologic cycle of the tropical Atlantic during the past 90,000 years. Marine productivity maxima and increased precipitation and riverine discharge from northern South America are closely linked to interstadial (warm) climate events of marine isotope stage 3, as recorded in Greenland ice cores. Increased precipitation at this latitude during interstadials suggests the potential for greater moisture export from the Atlantic to Pacific, which could have affected the salinity balance of the Atlantic and increased thermohaline heat transport to high northern latitudes. This supports the notion that tropical feedbacks played an important role in modulating global climate during the last glacial period.

Lymphoid aggregates in bone marrow mimic residual lymphoma after rituximab therapy for non-Hodgkin lymphoma.

Rituximab is a novel anti-CD20 monoclonal antibody used in the treatment of relapsed low-grade non-Hodgkin lymphoma. To determine the impact of this therapy on the interpretation of posttherapy specimens, we reviewed the pretherapy and posttherapy bone marrow and peripheral blood morphologic and flow cytometric findings for 20 patients who received rituximab. Nine patients had a total of 13 posttherapy bone marrow specimens; all were positive for lymphoma before therapy. After therapy, 11 of 13 posttherapy bone marrow specimens were interpreted as positive or suggestive of lymphoma based on routine H&E-stained sections. However, immunohistochemical and/or flow cytometric immunophenotyping showed that 6 of the 11 cases were negative for lymphoma; the lymphoid infiltrates were composed entirely of T cells without B cells. We report that posttherapy bone marrow specimens from patients treated with rituximab may mimic residual lymphoma if examined by morphologic features alone. Familiarity with this finding and the use of ancillary immunophenotypic studies will aid in the accurate interpretation of posttherapy specimens.

Technetium-99m sulfur colloid scanning and correlative magnetic resonance imaging in patients with hairy cell leukemia and hypocellular bone marrow biopsies after 2-chlorodeoxyadenosine.

It has been observed that some patients in complete remission (CR) after 2-chlorodeoxyadenosine (2-CdA) for hairy cell leukemia (HCL) have hypocellular bone marrow biopsies despite normal peripheral blood cell counts. This discrepancy between bone marrow cellularity and peripheral blood cell counts suggests the possibility of abnormal sites of hematopoiesis. To determine sites of hematopoiesis, 11 radionuclide scans using technetium-99m (99mTc) sulfur colloid were performed in eight patients. Although no single, pattern was observed on the 99mTc sulfur colloid scans, two of the eight patients, both with virtually aplastic marrows, had multiple areas of increased uptake in the distal appendicular skeleton, suggesting abnormal sites of hematopoiesis. The same two patients had magnetic resonance imaging (MRI), which confirmed the abnormal sites of hematopoiesis.

Minimal residual disease in patients with hairy cell leukemia in complete remission treated with 2-chlorodeoxyadenosine or 2-deoxycoformycin and prediction of early relapse.

The purine nucleoside analogues 2-chlorodeoxyadenosine (2-CdA) and 2'-deoxycoformycin (2'-DCF) induce complete remission (CR) in the majority of patients with hairy cell leukemia. However, minimal residual disease (MRD) has been detected in bone marrow core biopsies using immunohistochemical techniques in patients achieving CR by conventional criteria. This study was designed to compare the prevalence of MRD with each agent in patients in CR by using conventional criteria and the relapse-free survival for patients with and without MRD. Bone marrow biopsies from 39 patients treated with a single cycle of 2-CdA and 27 patients treated with multiple cycles of 2'-DCF were studied. The monoclonal antibodies anti-CD20, DBA.44, and anti-CD45RO were used to evaluate the paraffin-embedded bone marrow core biopsies for MRD. Five of 39 patients (13%) treated with 2-CdA had MRD, as compared to 7 of 27 patients (26%) treated with 2'-DCF (two-tailed P = 0.21). Relapse has occurred in two of the five patients with MRD after 2-CdA treatment and in four of the seven patients with MRD after 2'-DCF treatment. In total, 6 of the 12 patients (50%) with MRD have relapsed, whereas 3 of 54 patients (6%) without MRD have relapsed, and 2 patients have died without evidence of relapse. The estimated 4-year relapse-free survival among patients with MRD is 55% (+/- 15%, SE), compared to 88% (+/- 5%, SE) among patients without MRD (two-tailed P = 0.0023). The prevalence of MRD detected in a subset of patients in CR after either 2-CdA or 2'-DCF treatment did not differ significantly. However, the presence of MRD is associated with an increased risk of relapse.

Treatment of hairy-cell leukemia: current views.

Although hairy-cell leukemia (HCL) is uncommon, remarkable progress has been made in the treatment of patients with this disease. Because of their unique mechanisms of action, the purine analogs, 2'-deoxycoformycin (2'-DCF) and 2-chlorodeoxyadenosine (2-CdA), are naturally targeted to lymphocytes and are cytotoxic to both resting and dividing cells. Both of these agents induce durable complete remissions (CRs) in the overwhelming majority of patients. Remarkably, equally high rates of durable CR are achieved in both untreated and previously treated patients. Furthermore, patients with large tumor burdens fare as well as those with minimal disease. Therefore, these agents have emerged as the treatments of choice for all patients with hairy-cell leukemia and have supplanted earlier treatments such as splenectomy and interferon-alpha (IFN-alpha). Since a single 7-day cycle of 2-CdA leads to excellent outcomes and is associated with few toxicities other than culture-negative fever, this agent is particularly attractive and may offer some advantages. However, given the indolent natural history of HCL, long-term follow-up study will be required to determine if one purine analog offers a survival advantage over the other.

CD5- small B-cell leukemias are rarely classifiable as chronic lymphocytic leukemia.

Expression of the CD5 antigen by neoplastic cells often is considered a diagnostic criterion for B-cell chronic lymphocytic leukemia (B-CLL). However, published series frequently include a number of CD5- cases. We studied the spectrum of CD5- B-cell lymphoproliferative disorders presenting with leukemia involvement and reassessed the prevalence of CD5- B-CLL. We immunophenotyped 192 cases of clonal, small lymphocytic, B-cell disorders involving peripheral blood or bone marrow. Of these, 41 CD5- cases were further analyzed, correlating the immunophenotypic findings with pathologic material and clinical data. Only 3 CD5- cases were classified as CD5- B-CLL. These 3 cases had features unusual for B-CLL, including bright surface immunoglobulin expression, bright CD20 expression, and absence of CD23 expression (2 cases) or Richter syndrome (1 case). The remainder of the CD5- cases consisted of hairy cell leukemia, hairy cell variant, prolymphocytic leukemia, follicular center cell lymphoma, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma (SMZL), small lymphocytic lymphoma with marrow fibrosis, and lymphoma, not further classified. Eight cases remained unclassified, but some displayed features of SMZL. CD5- lymphoproliferative disorders of peripheral blood or bone marrow are unlikely to be CLL and often are classified more appropriately as non-Hodgkin lymphoma in the leukemia phase.

Detecting disseminated Mycobacterium avium complex infections in HIV-positive patients. The usefulness of bone marrow trephine biopsy specimens, aspirate cultures, and blood cultures.

Disseminated Mycobacterium avium complex (MAC) infections are common in patients with acquired immunodeficiency syndrome (AIDS). These patients frequently seek care with fever accompanied by generalized systemic symptoms and undergo bone marrow biopsy. It is our practice to stain all bone marrow trephine biopsy specimens from patients infected with HIV for acid-fast bacilli (AFB). We evaluated this practice by comparing the sensitivity and turnaround time for detection of MAC by biopsy specimen staining, bone marrow aspirate culture, and blood culture. Bone marrow trephine biopsy specimens with corresponding bone marrow aspirate and blood cultures from 86 HIV-positive patients were reviewed. Of the 86 patients, 30 had positive results for disseminated MAC infection, and all 30 of those patients had positive blood cultures. Bone marrow aspirate cultures identified 17 MAC-positive cases, and AFB staining of the biopsy specimen identified 9. The mean times to detection of MAC positivity were 1.1 days for AFB staining of the biopsy specimen, 19 days for bone marrow aspirate culture, and 16 days for blood culture. While AFB staining of biopsy specimens was the least sensitive of the detection methods, it was useful for the rapid diagnosis of disseminated MAC infection, allowing for prompt initiation of antimycobacterial therapy in one third of patients.

Secondary abnormalities of chromosome 6q in B-cell chronic lymphocytic leukemia: a sequential study of karyotypic instability in 51 patients.

Although karyotypic abnormalities are well documented in B-cell chronic lymphocytic leukemia (B-CLL), few sequential cytogenetic studies have been done. In this study, peripheral blood lymphocytes from fifty-one patients with B-CLL were sequentially karyotyped over a mean interval of 13.8 months (range, one to 51 months). Cytogenetic clones were detected in 33/51 patients (66%) on initial study, including 17 patients with structural abnormalities of chromosome 13q14, and three patients with trisomy 12. Karyotypic evolution was documented in 22/51 patients (43%). The most common secondarily acquired chromosome aberrations were structural abnormalities of the long arm of chromosome 6 involving the region of 6q21-q24 (six patients). Four patients each had acquired structural abnormalities of 1q, 3p, 12q, and 13q. Disease progression, as measured by advance in Rai stage or death from the disease, was observed more often in the clonal evolution group than in the karyotypically stable group (11/22 vs. 5/29; P = 0.017). Patients with secondary abnormalities of 6q had a significantly decreased progression-free survival interval compared with other patients in the study (P = .023). The authors conclude that clonal karyotypic evolution is common in B-CLL, and that clonal evolution correlates with clinical disease progression. Furthermore, the poor outcomes previously attributed to CLL with 6q abnormalities may be related to the clonal acquisition of these abnormalities over time. Future studies should focus on the relevant genetic events underlying the clinical progression observed with karyotypic evolution of B-CLL.

Enhanced detection of malignant lymphoma in cerebrospinal fluid by multiparameter flow cytometry.

Immunophenotyping by flow cytometry has not been widely applied to cerebrospinal fluid (CSF) analysis. We attempted to optimize flow cytometric detection of malignant lymphoma in CSF samples by the routine use of 3- and 4-color flow cytometry, with specific selection of lymphoid cells by fluorescence vs 90 degrees light scatter gating. Thirty-six consecutive CSF samples were immunophenotyped by flow cytometry, and the results were compared with those of standard microscopic examination. Lymphoid events were adequate for analysis in 27 of the 36 samples. Each of the 9 unsuccessful samples was more than 24 hours old at analysis or contained fewer than 1 x 10(4) total cells (< or =1 cell/microL). Lymphoma was detected in 10 of the remaining 27 cases. Six lymphomas were detected by morphology and flow cytometry, 1 only by morphologic examination, and 3 only by flow cytometry. Therefore, the combination of flow cytometry and morphologic examination enhanced the detection by 43% over morphologic examination alone. Flow cytometry permitted the detection of lymphoid clones totaling less than 1% of total cells. Multicolor flow cytometry is a rapid and sensitive technique that enhances detection of lymphoma in paucicellular CSF samples. Given the great sensitivity of flow cytometry, future studies will be necessary to assess the significance of detecting small lymphoid clones in this setting.

Isolated 13q14 abnormalities and normal karyotypes are associated with typical lymphocyte morphology in B-cell chronic lymphocytic leukemia.

Peripheral blood lymphocyte morphology and karyotype were correlated across the spectrum of cytogenetic abnormalities in 78 previously karyotyped cases of B-cell chronic lymphocytic leukemia (CLL). Cases were classified according to French-American-British morphologic criteria as typical CLL or CLL, mixed-cell type; the latter category was divided into CLL with a mixture of small and large cells and CLL with increased prolymphocytes (CLL/PL). Other leukemic lymphoproliferative disorders were excluded from this analysis. CLL cases with normal karyotypes were more likely to demonstrate typical morphology than those with clonal abnormalities (P = .042). In addition, all six cases containing isolated 13q14 abnormalities had typical morphology, compared with six of 16 other isolated abnormalities (P = .009), including one of seven cases of isolated trisomy 12. In contrast with the cases of isolated 13q14 changes, only seven of 17 cases with 13q14 as part of complex abnormalities had typical morphology (P = .012). Trisomy 12 was associated with mixed-cell morphology, particularly CLL/PL, consistent with previous reports. We conclude that isolated 13q14 abnormalities and normal karyotype are associated with typical CLL morphology, while other clonal abnormalities, including trisomy 12, are associated with mixed-cell morphology. These results further support the concept of distinct CLL subgroups based on karyotype. Furthermore, the association of trisomy 12 and complex abnormalities with mixed-cell morphology may have implications for clonal evolution in CLL.

Relapse of hairy cell leukemia after 2-chlorodeoxyadenosine: long-term follow-up of the Northwestern University experience.

Although 2-chlorodeoxyadenosine (2-CdA) is effective in inducing complete remissions (CRs) in the majority of patients with hairy cell leukemia (HCL), neither the actual relapse rate, the clinical factors that may predict relapse, the long-term outcome, nor the response rate to re-treatment at relapse has been clearly determined. Fifty-two consecutive patients with previously untreated or treated HCL were treated with 2-CdA at a dose of 0.1 mg/kg/d by continuous intravenous infusion for 7 days. Of 50 assessable patients, 40 (80%) achieved CR, and 9 (18%) achieved partial remission (PR). A total of 7 patients (14%) have relapsed, at a median duration of 24 months (range, 12 to 44). Of the 7 relapsed patients, 5 were re-treated with a second cycle of 2-CdA; 2 achieved a second CR and 3 attained a PR. The progression-free survival (PFS) rate is 72% at 4 years for all 52 patients and 83% for patients achieving CR. The overall survival (OS) rate is 86% at 4 years. Only prior therapy was predictive of relapse. The majority of patients achieve durable CRs with a single cycle of 2-CdA. The relapse rate is low and the long-term prognosis is excellent. The few patients who relapse can attain second remissions after re-treatment with 2-CdA.