Imipenem/cilastatin therapy of infections in cancer patients

Imipenem/cilastatin was administered during 153 febrile episodes occurring in cancer patients and the response rate was 68%. Considering only documented infections the response rate was 71%. Patients who received imipenem as initial therapy had a higher response rate than patients who received it after failing other antibiotics (77% versus 68%). The overall response rates for septicemias and pneumonias were 75% and 58%. Among the 57 gram-negative infections 77% responded, but the response rate was substantially higher if imipenem was used as initial therapy (94% versus 69%). The poorest response rate was observed when imipenem was given as secondary therapy for Pseudomonas infections (50%), but most of these patients had failed to respond to other appropriate antibiotics. The only serious side effect was seizures which occurred in ten patients, although eight of them had other predisposing factors. Imipenem appears to be a useful antibiotic for treatment of infections, even in neutropenic cancer patients.     

Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease

Risk for late onset Alzheimer disease (LOAD) and plasma amyloid beta levels (Abeta42; encoded by APP), an intermediate phenotype for LOAD, show linkage to chromosome 10q. Several strong candidate genes (VR22, PLAU, IDE) lie within the 1-lod support interval for linkage. Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD. To pursue these associations, we analyzed the same haplotypes for association with plasma Abeta42 in 24 extended LOAD families and for association with LOAD in two independent case-control series. One series (MCR, 188 age-matched case-control pairs) did not show association (p=0.64) with the six haplotypes in the 276-kb region spanning three genes (IDE, KNSL1, and HHEX) previously shown to associate with LOAD. The other series (MCJ, 109 age-matched case-control pairs) showed significant (p=0.003) association with these haplotypes. In the MCJ series, the H4 (odds ratio [OR]=5.1, p=0.003) and H2(H7) haplotypes (OR=0.60, p=0.04) had the same effects previously reported. In this series, the H8 haplotype (OR=2.7, p=0.098) also had an effect similar as in one previous case control series but not in others. In the extended families, the H8 haplotype was associated with significantly elevated plasma Abeta42 (p=0.02). In addition, the H5(H10) haplotype, which is associated with reduced risk for AD in the other study is associated with reduced plasma Abeta42 (p=0.007) in our family series. These results provide strong evidence for pathogenic variant(s) in the 276-kb region harboring IDE that influence intermediate AD phenotypes and risk for AD.     

Intra‐arterial blood pressure reading in intensive care unit patients in the lateral position

Background. Routine lateral turning of patients has become an accepted standard of care to prevent complications of immobility. The haemodynamic and oxygenation effects for patients in both lateral positions (45°) are still a matter of debate. We aimed to study the effect of these positions on blood pressure, heart rate and oxygenation in a general intensive care population. Design. Observational study. Method. Twenty stable intensive care unit patients had intra‐arterial blood pressure recordings in the supine and lateral positions with the correction of hydrostatic height compared with a fixed reference point (phlebostatic level). A multilevel model was used to analyse the data. Results. Mean arterial pressure readings in the lateral positions were, on average, 5 mmHg higher than in the supine position (p < 0·001). There were no significant differences between mean arterial pressure recordings in the left and right lateral position (p = 1·0). No important differences in oxygenation and heart rate were observed. After correction for covariates, the effects persisted. Conclusion. Our study demonstrated an increase, albeit small, in blood pressure in the lateral positions. No major differences between the left and right lateral position were found. No important differences in oxygenation and heart rate were observed. Relevance to clinical practice. Turning haemodynamically stable patients in the intensive care unit has no important effects on blood pressure measurements when continuous hydrostatic height correction is applied.     

Outcomes and cost of deep venous thrombosis among patients with cancer

BACKGROUND: Although deep venous thrombosis (DVT) often complicates the clinical course in patients with cancer, few studies of the outcomes of DVT in this population have been published. Furthermore, the cost of DVT is largely undescribed. We herein report the largest study of DVT in this population to date. METHODS: We reviewed the medical records of 529 consecutive cancer patients in whom DVT developed from January 1, 1994, through December 31, 1997, and followed up these patients through December 31, 2000, for outcomes. The cost of hospitalization was obtained from our hospital's cost-accounting system and inflated to 2002 US dollars using the Consumer Price Index for Medical Care. Logistic regression was used to identify factors that were associated with a high risk of poor outcomes. RESULTS: The most common complication of DVT was bleeding, which occurred in 13% of patients. Pulmonary embolus occurred in 4%. Five patients (1%) died of complications of DVT and 5 (1%) of complications of anticoagulation. Recurrence of DVT was common (17% overall), particularly among those who had inferior vena cava filters (32%; P<.001) or a previous episode of DVT (P =.03). All but 4 patients were hospitalized for initial anticoagulation therapy, for a mean of 11 days. The mean cost of hospitalization was 2002 US $20 065. CONCLUSIONS: Among patients with cancer, DVT frequently is associated with serious clinical outcomes. Its treatment is resource intensive and costly. More effective agents and less costly management strategies could have a significant impact on the outcomes and cost of DVT in this population.     

Prospective randomized trial of antibiotic prophylaxis in acute leukemia

Patients undergoing initial remission induction chemotherapy for acute leukemia in a protected environment unit were randomly assigned to parenteral antibiotic prophylaxis or oral and parenteral antibiotic prophylaxis. Complete remissions were obtained in 82 percent of the 45 patients receiving oral and parenteral antibiotic prophylaxis and 76 percent of the 41 patients receiving parenteral antibiotic prophylaxis. Approximately 20 percent of the patients in both groups have had a continuous complete remission for more than five years. The episodes of fever of unknown origin and major infection were significantly more common in patients receiving parenteral antibiotic prophylaxis, although the episodes of local infection were similar in both groups. The duration of remission and survival was similar in both groups. Hence, the oral and parenteral antibiotic regimen was more effective for infection prophylaxis, but had no effect on response to antileukemic chemotherapy.     

Bone marrow histopathology of patients with severe aplastic anaemia before treatment and at follow-up

Pretreatment bone marrow biopsies of 63 patients with severe aplastic anaemia (SAA) who were not transplanted and of whom 55 received ATG, were evaluated according to the amount and character of residual haematopoiesis ('genuine' aplasia/intermediate/hypoplastic myelodysplasia (MD], inflammatory infiltrate (Te Velde & Haak, 1977, grade I/II/III), and number of mast cells (normal or slightly increased/increased). Of 61 evaluable biopsies, 47 were 'genuine' aplastic, 11 intermediate and three hypoplastic MD. Inflammatory infiltrates were graded as III in 36/60 evaluable biopsies, as II in 21 and I in three. A moderate to marked increase of mast cells was seen in 19/61. Of grade III patients, 86% had a less than 90 d interval between diagnosis and administration of ATG, versus 50% of grade I/II patients (P less than 0.01). No other correlations with pretreatment characteristics were found. No significant prognostic value for survival or response to ATG of any of these three criteria has been identified. More patients with grade III inflammation tended to show adequate recovery at 4 and 6 months after ATG. Stem cell damage, not identifiable morphologically, and/or impairment of accessory cells might play a major role in eventual outcome of SAA patients. Thirty-five patients are currently alive, median 3.8 years (up to 12.4) after ATG. Follow-up bone marrow aspirates and biopsies of 32 patients were evaluable and none showed normal haematopoiesis. One patient revealed persistent aplasia. Of the remaining 31, haematopoiesis was decreased in 14 and increased in eight. All had dyserythropoiesis, 28 dysplastic myelopoiesis and in 16/29 with evaluable megakaryocytes, dysmegakaryopoiesis was found. Sixteen patients had normo- to hypercellular bone marrows with two dysplastic cell lines (consistent with myelodysplastic syndrome (MDS) according to the FAB-group). The prognostic impact of the dysplastic abnormalities found in these patients needs longer follow-up. Close observation is indicated in view of the previously recognized, albeit uncommon, evolution of SAA to MDS/acute non-lymphocytic leukaemia.     

Ultrastructural study shows morphologic features of apoptosis and para-apoptosis in megakaryocytes from patients with idiopathic thrombocytopenic purpura

To investigate whether altered megakaryocyte morphology contributes to reduced platelet production in idiopathic thrombocytopenic purpura (ITP), ultrastructural analysis of megakaryocytes was performed in 11 ITP patients. Ultrastructural abnormalities compatible with (para-)apoptosis were present in 78% +/- 14% of ITP megakaryocytes, which could be reversed by in vivo treatment with prednisone and intravenous immunoglobulin. Immunohistochemistry of bone marrow biopsies of ITP patients with extensive apoptosis showed an increased number of megakaryocytes with activated caspase-3 compared with normal (28% +/- 4% versus 0%). No difference, however, was observed in the number of bone marrow megakaryocyte colony-forming units (ITP, 118 +/- 93/105 bone marrow cells; versus controls, 128 +/- 101/105 bone marrow cells; P =.7). To demonstrate that circulating antibodies might affect megakaryocytes, suspension cultures of CD34+ cells were performed with ITP or normal plasma. Morphology compatible with (para-)apoptosis could be induced in cultured megakaryocytes with ITP plasma (2 of 10 samples positive for antiplatelet autoantibodies). Finally, the plasma glycocalicin index, a parameter of platelet and megakaryocyte destruction, was increased in ITP (57 +/- 70 versus 0.7 +/- 0.2; P =.009) and correlated with the proportion of megakaryocytes showing (para-) apoptotic ultrastructure (P =.02; r = 0.7). In conclusion, most ITP megakaryocytes show ultrastructural features of (para-) apoptosis, probably due to action of factors present in ITP plasma.