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Background Estimates of overall patient health are essential to inform treatment decisions for patients diagnosed with cancer. The authors applied XWAS methods, herein referred to as "laboratory-wide association study (LWAS)", to evaluate associations between routinely collected laboratory tests and survival in veterans with prostate cancer. Methods The authors identified 133,878 patients who were diagnosed with prostate cancer between 2000 and 2013 in the Veterans Health Administration using any laboratory tests collected within 6 months of diagnosis (3,345,083 results). Using the LWAS framework, the false-discovery rate was used to test the association between multiple laboratory tests and survival, and these results were validated using training, testing, and validation cohorts. Results A total of 31 laboratory tests associated with survival met stringent LWAS criteria. LWAS confirmed markers of prostate cancer biology (prostate-specific antigen: hazard ratio [HR], 1.07 [95% confidence interval (95% CI), 1.06-1.08]; and alkaline phosphatase: HR, 1.22 [95% CI, 1.20-1.24]) as well laboratory tests of general health (eg, serum albumin: HR, 0.78 [95% CI, 0.76-0.80]; and creatinine: HR, 1.05 [95% CI, 1.03-1.07]) and inflammation (leukocyte count: HR, 1.23 [95% CI, 1.98-1.26]; and erythrocyte sedimentation rate: HR, 1.33 [95% CI, 1.09-1.61]). In addition, the authors derived and validated separate models for patients with localized and advanced disease, identifying 28 laboratory markers and 15 laboratory markers, respectively, in each cohort. Conclusions The authors identified routinely collected laboratory data associated with survival for patients with prostate cancer using LWAS methodologies, including markers of prostate cancer biology, overall health, and inflammation. Broadening consideration of determinants of survival beyond those related to cancer itself could help to inform the design of clinical trials and aid in shared decision making. Lay summary This article examined routine laboratory tests associated with survival among veterans with prostate cancer. Using laboratory-wide association studies, the authors identified 31 laboratory tests associated with survival that can be used to inform the design of clinical trials and aid patients in shared decision making.

BACKGROUND The revised 2017 European LeukemiaNet (ELN) classification (ELN-2017) of acute myeloid leukemia (AML) divides patients into 3 prognostic risk categories, with additional factors such as the fms-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) allele ratio (AR) considered for risk stratification. To the best of the authors' knowledge, the prognostic usefulness of ELN-2017 in comparison with ELN-2010 in younger patients with AML has not been validated to date. METHODS The authors performed a retrospective study on patients aged

The modified Glasgow Prognostic Score (mGPS), an inflammation-based prognostic score that uses thresholds of C-reactive protein (10 mg/L) and albumin (35 g/L), has been found to be independently prognostic of survival in patients with cancer. The objective of the current study was to establish whether the addition of a differential leukocyte count and a high-sensitivity C-reactive protein measurement enhanced the prognostic value of the mGPS.A total of 12,119 patients who had an incidental blood sample taken between 2000 and 2007 for C-reactive protein, albumin, and a differential leukocyte count as well as a diagnosis of cancer made within 2 years were identified. This group was studied for the prognostic value of neutrophil, lymphocyte, and platelet counts. In addition 2742 patients whose blood was sampled after the introduction of high-sensitivity C-reactive protein measurements were studied for the prognostic value of different thresholds.Using cancer-specific survival as an endpoint, the prognostic value of the mGPS (hazard ratio [HR], 2.61; P.001 [area under the receiver operating characteristic curve (AUC), 0.695]) was found to be improved by the addition of neutrophil and platelet counts (HR, 4.86; P.001 [AUC, 0.734]) and a high-sensitivity C-reactive protein measurement (3 mg/L) (HR, 5.77; P.001 [AUC, 0.734]).The results of the current study demonstrate that the addition of neutrophil and platelet counts, as well as a high-sensitivity C-reactive protein measurement, enhanced the prognostic value of the mGPS.

BACKGROUND: Bone marrow (BM) biopsies from patients with chronic lymphocytic leukemia (CLL) may show reticulin fibrosis at diagnosis, but its significance remains unclear. This study sought to assess the prognostic impact of BM reticulin fibrosis in patients with previously untreated CLL. METHODS: Data was reviewed from untreated CLL patients in the national Israel CLL database, followed during 1987 to 2012. All bone marrow biopsies were graded for reticulin fibrosis using a modified scoring system containing 4 grades (0-3), based on the European consensus report. Grade of reticulin fibrosis was correlated with overall survival (OS), outcome, and a number of well-recognized prognostic factors for CLL. RESULTS: The final cohort included 176 patients (122 males and 51 females). Median age was 63 years (range, 32-86 years) and the 5-year OS was 77.1%. Grade of BM reticulin fibrosis correlated with OS (P < .0001) and mortality (P = .001), and separated patients into 2 groups with different survival curves. Advanced reticulin fibrosis (grades 2-3) was associated with thrombocytopenia (platelet counts of < 100,000/mm3) (P = .025), anemia (P = .018), elevated β2-microglobulin < 4000 μg/mL (P = .048), and the presence of 11q deletion (P = .0015). CONCLUSIONS: There was a significant correlation between poor survival and grade of BM reticulin fibrosis. This staining procedure is easy to perform and can readily be added routinely when examining BM biopsies in CLL, because the findings do have prognostic implications. Cancer 2013. © 2013 American Cancer Society.

Cyclophosphamide (CY) in a total dose of 120 mg/kg was given over 2 days on one to three occasions to 12 patients with a variety of nonlymphoid solid tumors. Two of 10 patients with measurable disease had a partial response. One had embryonal rhabdomyosarcoma and the other had ovarian carcinoma. In the 20 treatment courses, the mean leukocyte count was less than 1,00O/mm3 for 7 days. Thrombocytopenia was variable with a mean nadir of 87,90O/mm3 on day 12. There were four instances of local infection, one of bacteremia, and 11 of fever of undetermined origin. Weight gain of 2 or more kg occurred after 12, and EKG changes compatible with cardiotoxicity after six courses of CY. Serial skin testing with recall antigens revealed a frequent transient loss, and in three patients a later overall gain, in responsiveness. All patients, were immunized with Vi antigen before CY, and with Vi and sheep red blood cells (SRBC) after CY. Specific immune tolerance to Vi, with a satisfactory response to SRBC, was found in six of 12 patients. Patients' responses to the lymphocytes of 2 ABO compatible normal subjects were measured in mixed lymphocyte culture (MLC) before and after CY. Patients were given 500 ml of whole blood from one of the subjects prior to CY. Following CY, the patients' responses to the blood donors' cells were not significantly lower than their responses to nondonor cells. Thus, tolerance to HL-A antigens was not demonstrable in RILC. Three patients had an increase from subnormal to normal reactivity to nondonor cells in MLC.

Twenty-five patients with Hodgkin's disease and high eosinophil counts were observed for an average of 90 months. Fluctuations in the levels of eosinophils were important in the course of observation. No relation with stages, histologic type, or evolution was noticed. Steroid-containing regimens and severe premortem conditions seemed to lower the counts. Relapse-free survival was shorter in our 25 patients than in a control group of 50 patients with Hodgkin's disease and no eosinophilia who had approximately the same stage, histologic type, and treatment of disease. However, the overall survival was somewhat better for the eosinophilic patients with stages IIIB and IV (0.1 greater than P greater than 0.05).

Pretreatment characteristics of 48 infants (under 2 years of age) with leukemia treated over a period of 18 years at a single institution were studied in relation to response to therapy, extramedullary involvement, and survival. In order to provide a basis of comparison, 45 of the infants were each paired with an older (2-9 years of age) leukemic child, who had the same race, and disease type, who was treated within the same period of time and received similar suportive care and chemotherapy, and when possible, was of the same sex. The overall median survival times of infants and their pairmates were 211 days and 445 days, respectively. Initial status of the spleen was the single significant factor in relation to the length of survival. Median survival time for infants with splenomegaly was 186 days compared to a median survival time of 414 days for infants without splenomegaly. The complete response rate was 75% for infants and 80% for the pairmates. Median duration of remission was 84 days for infants and 280 days for their pairmates. Initial peripheral leucocyte count was significantly related to the duration of remission; patients with very high leucocyte counts had the shortest remissions. The duration of remission increased throughout the period covered by this study, however, prognosis relative to pairmates remained poor. Central nervous system leukemia occurred in 44% of infants and 40% of the pairmates; incidence of CNS leukemia was much higher (70%) in infants under one year of age than in infants one year old (37%). Extramedullary leukemia occurred at other sites in 46% of the infants and 31% of the pairmates. The only pretreatment characteristic of prognostic importance for predicting extramedullary involvement was the patient's age at diagnosis.

Tumor involvement of the bone marrow in patients with Hodgkin's disease may be suspected in the presence of other manifestations of advanced disease such as fever, lymphopenia, hypoalbuminemia, mixed cellular histologic type, or Stage III or IV disease by other clinical parameters. It occurs more frequently in the older age groups. When anemia, leucopenia, and/or thrombocytopenia are present and are unrelated to recent bone marrow suppressant chemotherapy, marrow involvement is likely to be present. Bone marrow examination, done by multiple trephine biopsies, provides an adequate sampling of tissue and results in a high incidence of detection of involvement by Hodgkin's disease. This manifestation of Hodgkin's disease is associated with a relatively short survival. Aggressive combination chemotherapy is necessary to produce a significant remission.

BACKGROUND The objective of this study was to evaluate prospectively the acute and late adverse effects of taxane/carboplatin neoadjuvant chemotherapy and 3-dimensional, conformal radiotherapy in patients with locally advanced nonsmall cell lung cancer (NSCLC). METHODS Forty-two patients were entered into a nonrandomized Phase II study of continuous, hyperfractionated, accelerated radiotherapy (CHART) week-end less (CHARTWEL) to a dose of 60 grays (Gy). Three cycles of chemotherapy were given over 9 weeks before radiotherapy. Dose escalation with paclitaxel was from 150 mg/m2 to 225 mg/m2. Systemic toxicity to chemotherapy was monitored throughout. Radiation-induced, early, adverse effects were assessed during the first 9 weeks from the start of radiotherapy, and late effects were assessed from 3 months onward. Overall survival, disease-free survival, and locoregional tumor control also were monitored. RESULTS Twenty percent of patients failed to receive chemotherapy as planned, primarily because of neutropenia. The incidence of Dische Dictionary Grade ≥2 and Grade ≥3 dysphagia was 57.5% and 10%, respectively, with an average duration of 1.2 weeks and 1.5 days, respectively. By 9 weeks

BACKGROUND The objectives of the current study were to evaluate the outcome of patients ≥ 60 years with acute myeloid leukemia (AML) treated uniformly with high-dose daunorubicin containing induction and modified high-dose cytosine arabinoside containing postremission therapy, and to identify factors predictive of complete disease remission (CR) and survival. METHODS Between 1998 and 2002, the authors treated 117 newly diagnosed patients (acute promyelocytic leukemia excluded) with AML ≥ 60 years (median, 67 years; range, 60–82 years). Karyotype (Medical Research Council classification) at diagnosis was categorized as good risk (n = 3), intermediate risk (n = 69), adverse risk (n = 26), and suboptimal/not done (n = 19). A normal karyotype was seen in 41 patients and 40 (34%) had secondary AML. RESULTS The outcome of induction included the following: CR, 62 (53%); early death, 5 (4%); death during hypoplasia, 14 (12%); and resistant disease, 36 (31%). The 3-year event-free (EFS) and overall survival (OS) rates were 9% (95% confidence interval [95% CI], 3–16%) and 17% (95% CI, 9–29%), respectively. In a univariate analysis, cytogenetics, lactate dehydrogenase level, leukocyte count, and performance status were the significant factors for EFS and OS. Age was not a significant prognostic factor for either CR or survival. In a multivariate model, adverse-risk cytogenetics, previous history of myelodysplastic syndrome or antecedent hematologic disorder, and high leukocyte count (> 30 × 109/L) were independent adverse prognostic factors for survival. The impact of adverse karyotype on EFS and OS was time dependent and was observed after 50 and 150 days, respectively. CONCLUSIONS The authors concluded that candidacy for intensive therapy in older patients should be based on biologic features of disease and fitness, rather than on age. Cancer 2005. © 2005 American Cancer Society.

BACKGROUND Although pulmonary complications account for significant morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), to the authors' knowledge there are sparse data available in published literature. The authors evaluated pulmonary complications in patients with CLL and identified prognostic variables that predict hospital mortality in these patients. METHODS Clinical data were analyzed retrospectively from patients with CLL who required hospitalization for a respiratory illness at a tertiary care institution from January 1993 to December 2001. A logistic regression analysis with a backward elimination procedure was carried out to determine prognostic variables that predict hospital mortality. RESULTS There were 110 patients who were admitted on 142 occasions with a pulmonary complication. The median age was 75 years (range, 43–97 years), and the male:female ratio was 1.7:1.0. Among 142 admissions, 68% were high risk according to the Rai criteria, 68% of patients admitted had received prior therapy for CLL, and 35% had received treatment within 3 months of admission. The most common pulmonary complications were pneumonias (75%), malignant pleural effusion/and or lung infiltrate due to CLL (9%), pulmonary leukostasis (4%), Richter transformation or nonsmall cell lung carcinoma (3%), and upper airway obstruction (2%). Forty-four of 110 patients (40%) died. In multivariate analysis, admission absolute neutrophil counts ≤ 0.5 × 109/L (odds ratio, 4.6; 95% confidence interval [95% CI], 1.3–16.6) and blood urea nitrogen (BUN) levels ≥ 20 mg/dL (odds ratio, 3.0; 95% CI, 1.1–8.3) were correlated significantly with mortality. CONCLUSIONS Pneumonia was the major pulmonary complication in hospitalized patients with CLL. Severe neutropenia and high BUN levels were correlated significantly with increased mortality. Cancer 2003. © 2003 American Cancer Society.

BACKGROUND Significantly elevated telomerase activity (TA) has been found in samples from patients with almost all malignant hematologic diseases. The impact of elevated TA on the course of pediatric patients with acute myeloid leukemia (P-AML) is unknown. METHODS Using a modified polymerase chain reaction-based, telomeric repeat-amplification protocol assay, the authors measured TA in bone marrow samples from 40 patients with P-AML and, for comparison, in 65 adult patients with AML (A-AML), excluding patients with French–American–British M3 disease. The results were correlated with patient characteristics and survival. RESULTS TA in patients with P-AML was significantly lower compared with TA in patients with A-AML (P = 0.005). Patients who had P-AML with low TA had a projected 5-year survival rate of 88%, whereas patients who had P-AML with high TA had a projected 5-year survival rate of 43% (P = 0.009). Conversely, patients who had A-AML with very high TA (upper quartile) had significantly longer survival compared with patients who had A-AML with lower TA (P = 0.03). There was no correlation between complete remission rate or disease free survival and TA in P-AML or A-AML. In the A-AML group, when patients were separated by cytogenetic findings (poor prognosis vs. others), it was found that TA was significantly lower in patients with a poor prognosis, but the prognostic value of TA was not independent of cytogenetic status. CONCLUSIONS The current results suggest, that for patients with P-AML, bone marrow TA is a highly significant prognostic factor. Cancer 2003;97:2212–7. © 2003 American Cancer Society. DOI 10.1002/cncr.11313

BACKGROUND The objective of this study was to assess the natural history of the two disease courses, patient immune system tolerance, and results of therapy in human immunodeficiency virus (HIV)–infected patients with germ cell tumors (GCT). METHODS From 1985 to 1996, 34 HIV-infected men received a diagnosis of GCT. Their charts were analyzed retrospectively. RESULTS Sixteen patients had seminomas, and 18 had nonseminomatous GCTs (NSGCT); 71% had International Union Against Cancer (UICC), 1997 Stage I–II GCTs. At the time of chemotherapy, 69%, 6%, and 25% of patients with advanced NSGCT were in the International Germ Cell Consensus Classification (IGCCC) good, intermediate, and poor prognostic group, respectively. All except 1 of the 10 patients with advanced seminomas were in the IGCCC good prognostic group. At diagnosis of GCT, 85% of patients were classified as having asymptomatic HIV infection or only persistent generalized lymphadenectomy. The median CD4 cell count was 325/μL (range, 6–1125). Overall, 26 patients were given chemotherapy, but the planned dose intensity was respected in only 15 (57%) patients. Severe toxic effects included febrile neutropenia in 35% of patients. During chemotherapy, zidovudine, prophylactic granulocyte colony-stimulating factor (G-CSF), and a Pneumocystis carinii prophylaxis were given in 19%, 23%, and 35% of cases, respectively. CD4 cell count decreased in 7 (64%) of 11 patients during chemotherapy. Infradiaphragmatic radiotherapy was given in 10 cases and was clinically well tolerated. At a median follow-up of 27 months (range, 3–150), 50% of patients were alive, and only 18% of patients died of GCT. Two patients developed a non-GCT malignancy while in complete remission, namely, Hodgkin disease and an acute leukemia. CONCLUSIONS The prognosis of GCT in HIV-infected patients is mostly dictated by the HIV infection. Patients should be treated according to stage and histologic subtype, although dose reduction of chemotherapy might be necessary in approximately half of the patients. Close surveillance of neutrophil and CD4 cells counts, as well as the use of G-CSF and systematic anti-Pneumocystis carinii prophylaxis are recommended during chemotherapy. The use of highly active antiretroviral therapy during chemotherapy for GCT requires a prospective assessment. Cancer 2001;92:1460–7. © 2001 American Cancer Society.

BACKGROUND Hematopoietic growth factors (HGFs) have been used to reduce the neutropenic complications of cytotoxic chemotherapy so that higher doses may be given. The authors have previously shown that endogenous serum granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage–colony stimulating factor (GM-CSF) levels at night (p.m.) were significantly higher than those in the morning (a.m.). METHODS Twenty-four patients with soft tissue or bone sarcoma who were treated with high dose ifosfamide-based chemotherapy were enrolled in this study. Patients were randomized to either a.m. or p.m. treatment. GM-CSF was administered at a dose of 5 μg/kg/day at 10 a.m. or 10 p.m., beginning 36–48 hours after the last chemotherapy dose. GM-CSF therapy was continued until the neutrophil count exceeded 1000/mm3 for 2 consecutive days. Leukocyte, neutrophil, monocyte, and platelet counts were measured immediately before GM-CSF administration and exactly 12 hours after the first dose of GM-CSF, and every 24 hours until 3 days after the cessation of GM-CSF. RESULTS The mean duration of Grade 3–4 neutropenia was 5.3 ± 0.4 days for the a.m. treatment arm and 6.5 ± 0.3 days for the p.m. treatment arm (P = 0.017). Although the duration of neutropenia in the a.m. arm was significantly shorter than in the p.m. arm, there were no differences related to the number of febrile neutropenic episodes or the duration of antibiotic administration. Also, there were no differences in the side effects observed in the a.m. and p.m. arms. CONCLUSIONS The finding of 1.2 days' difference in the duration of Grade 3–4 neutropenia warrants further study of chronotherapy with HGFs. Cancer 2000;88:2033–6. © 2000 American Cancer Society.

BACKGROUND Chronic myelogenous leukemia (CML) represents a paradigm of the stepwise increment in disease aggressiveness, resistance to therapy, and transformation. Thrombopoietin (TPO) and its receptor, c-mpl, support the proliferation of multiple types of immature hematopoietic progenitor cells, and induce clonal growth of leukemic cells. The authors investigated whether TPO or c-mpl overexpression might correlate with progression of CML, disease aggressiveness, or response to therapy. METHODS Expression of c-mpl and TPO was measured in bone marrow samples from 208 patients with CML by Western blot analysis and solid-phase plate radioimmunoassay (used for quantification). Samples obtained from individuals without evidence of hematologic abnormalities were used as controls. RESULTS There were no significant differences in TPO or c-mpl expression among patients in different phases of CML or between patients with Philadelphia chromosome positive and negative CML. When TPO and c-mpl levels were analyzed in relation to prognostically important host and disease characteristics in early chronic phase CML, platelet and white blood cell counts demonstrated significant differences in both TPO and c-mpl expression, but age and spleen size demonstrated significant differences in TPO expression only. Responses to interferon (INF)-α-based therapy and survival were not influenced by TPO or c-mpl levels. CONCLUSIONS TPO or c-mpl overexpression did not correlate with different CML phases, suggesting that they were not involved in CML progression from early to advanced phase. Neither TPO nor c-mpl overexpression was particularly evident in any risk group, suggesting lack of correlation between their expression and disease aggressiveness. This was supported by the finding of similar response to IFN-α-based therapy and survival regardless of the level of TPO or c-mpl expression. Cancer 2000;88:570–6. © 2000 American Cancer Society.

BACKGROUND Promising results have been reported for patients with non-Hodgkin's lymphoma (NHL) receiving chronic oral etoposide. Due to the small number of patients reported, information regarding side effects is limited, and therefore warrants further evaluation. METHODS Twenty eligible patients with NHL and chronic lymphatic leukemia (CLL), resistant to or relapsed after previous protocols of polychemotherapy were treated with oral etoposide at a dosage of 50 mg/m2/day for 21 days in a 28-day cycle. Response and toxicity were evaluated according to standard criteria. RESULTS Total response was noted in 13 patients, complete response in 2 patients, and partial response in 11 patients. Two patients had stable disease and five patients had progression of disease during treatment. Seventy-five percent of patients experienced neutropenia below 1500/μL. Half acquired infection and required hospitalization. Fifty-five percent required blood transfusions. All patients needed course shortening and dosage reduction. CONCLUSIONS Chronic daily administration of oral etoposide is effective in patients with NHL and CLL. In heavily pretreated patients, myelotoxicity is severe. Therefore, modification of the schedule plan is mandatory in this group of patients. Cancer 1996;77:2313-7.

In patients with acute myeloid leukemia (AML), testing for fms-like tyrosine kinase-3 (FLT3)-internal tandem duplication (FLT3-ITD) and nucleophosmin-1 (NPM1) mutations can allow for further prognostic subclassification, but less is known about the effects of FLT3-ITD allele burden and presenting white blood cell count (WBC) within molecular subgroups.The authors retrospectively assessed 206 adult patients who had AML with an intermediate-risk karyotype and who received treatment on a uniform induction and consolidation chemotherapy regimen.The presenting WBC was a prognostic factor for survival only in patients who had an FLT3-ITD mutation. On multivariate analysis, after correcting for age, WBC, secondary AML, and blast percentage, nucleophosmin-1 (NPM1)-mutated/FLT3-ITD-negative patients had superior overall survival compared with patients in the other molecular subgroups. Patients who had FLT3-ITD mutations had an inferior overall survival compared with patients who had NPM1 wild-type/FLT3-negative disease, and patients who had low or intermediate levels of the FLT-ITD of mutant allele had overall and disease-free survival similar to those in patients who had high-level mutations.NPM1 and FLT3-ITD status, age, WBC, and secondary AML were identified as important prognostic variables that can help to risk stratify patients with AML who have intermediate-risk cytogenetics. FLT3 allele burden had no significant influence on outcomes after correcting for other variables.

Lymphoproliferative disorder of granular lymphocytes (LPGL) is an indolent process that is often associated with neutropenia. Although splenectomy, corticosteroids and cytotoxic agents have all been used to treat patients with life-threatening neutropenia, there are few data supporting their effectiveness. We describe a patient with LPGL, severe neutropenia, and a life-threatening infection who had a dramatic response after treatment with granulocyte colony-stimulating factor (G-CSF). The neutrophil count increased from less than 10 cells/microliters to more than 10,000/microliters after seven doses of G-CSF. The infection promptly healed. A review of the literature indicates that 8 of 11 patients with LPGL and severe neutropenia responded to treatment with G-CSF or granulocyte-macrophage colony-stimulating factor (GM-CSF). In view of their relative lack of toxicity and rapid onset of action, the colony-stimulating factors should be considered for initial therapy in patients with LPGL and severe neutropenia. In addition, the high rate of response achieved with colony stimulating factors suggests that in many cases, a defect in myeloid maturation rather than accelerated granulocyte removal is the cause of neutropenia.

Background. Ascites in patients with hepatocellular carcinoma (HCC) is a poorly characterized subgroup of malignancy-related ascites. Not only the underlying liver disease, but also the tumor growth and spread contributes to the ascites formation. The authors differentiated ascites in HCC from other types of ascites. Methods. The authors analyzed the ascitic fluid of 185 consecutive patients (89 liver cirrhosis, 33 HCC, 31 peritoneal carcinomatosis, 22 liver metastases, 10 spontaneous bacterial peritonitis). Resulfs. Each subgroup showed a typical pattern. Compared with the cirrhotic patients, those with HCC showed a higher frequency of positive cytologic findings (4 of 33 versus 0/89, P < 0.004), elevated fibronectin concentration (10/33 versus 8/89, P < 0.004), and elevated polymorphonuclear cell count (10/33 versus 5/89 P < 0.004). Conclusions. A significant number of patients with ascites and HCC patients showed signs of peritoneal infiltration with positive cytologic findings and increased concentration of fibronectin. Moreover, neutrocytic ascites without signs of superinfection is relatively common (30%). Cancer 1993; 72677-82.

Background A peripheral blood absolute lymphocyte count (ALC) of greater than 5 x 10(9)/l is considered the required minimum for diagnosis of chronic lymphocytic leukemia (CLL). Cases with low ALC (CLL-LLC), less than 5 x 10(9)/l, have not been included in the current staging systems, and would not be suspected of having CLL, or investigated for the disease, especially in the absence of clinical manifestations. On the other hand, the diagnostic value of the differential lymphocyte counts have not been emphasized. Methods Cell suspensions from peripheral blood of previously untreated cases of CLL-LLC (n = 12) and typical CLL (n = 189) were analyzed for immunologic evaluation of surface immunoglobulin (SIg), mouse erythrocyte rosettes, CD5, CD19, CD20, CD22, and CD2, as well as cytochemical evaluation of tartrate-resistant acid phosphatase (TRAP). The results in CLL-LLC were compared statistically with typical CLL. Results The ages of the 12 patients with CLL-LLC ranged from 47 to 84 years. The absolute lymphocyte counts ranged from 1.5 x 10(9)/l to 4.9 x 10(9)/l, and the percentage of lymphocytes in the differential leukocyte counts ranged from 52% to 93%. None of the patients had signs and symptoms of CLL or other conditions that may cause reactive lymphocytosis. CLL-LLC demonstrated similar characteristics to typical CLL, i.e., weak expression of monoclonal SIg, mouse rosette formation, positive CD5, high CD19 and CD20, negative CD22 and TRAP. No statistical differences existed between the immunologic markers or between SIg isotype distribution in the two groups. Conclusions Cases of CLL-LLC constituted 6% of B-CLL and would have been missed if immunologic investigation was not carried out because of the absence of absolute lymphocytosis and clinical manifestations of CLL. Persistent relative lymphocytosis of > or = 50% of the differential leukocyte count in older individuals (older than 50 years of age), is an indication for further investigation of CLL by immunophenotyping of peripheral blood lymphocytes and examination of bone marrow.

For the determination of cellular immunity status, mitogen-induced lymphocyte proliferation tests are used, along with measurements of cytokine secretion. The authors have established a test system with whole blood cell cultures in which they measured the following cytokines: alpha-interleukin-1 (alpha-IL-1), interleukin-2 (IL-2), gamma-interferon (tau-IFN), and alpha-tumor necrosis factor (alpha-TNF) in the supernatants by enzymoimmunologic methods. With this system, the authors tested blood samples of 72 patients with malignant melanoma, 38 patients with basal cell carcinoma, and 315 healthy control subjects. In the blood cell cultures of the patients with melanoma, significantly lower values of the lymphokines tau-IFN and IL-2 were found, compared with those of the control subjects, and the levels of the monokines alpha-IL-1 and alpha-TNF were reduced. tau-IFN values correlated with different clinical stages. In contrast, the patients with basal cell carcinoma had equal values for all four cytokines as an age-matched control group.

BACKGROUND: Lineage involvement and maturation arrest are considered to have prognostic significance in patients with myelodysplastic syndromes (MDS). However, although the prognostic value of neutropenia, thrombocytopenia, and monocytosis have been documented, little is known about the impact of eosinophils and basophils. METHODS: The authors examined the prognostic significance of eosinophils and basophils in 1008 patients with de novo MDS. Patients were enrolled from 3 centers of the Austrian-German MDS Working Group and were analyzed retrospectively. Blood eosinophils and basophils were quantified by light microscopy, and their impact on survival and leukemia-free survival was calculated by using Cox regression. RESULTS: Eosinophilia (eosinophils >350/μL) and basophilia (basophils >250/μL) predicted a significantly reduced survival (P < .05) without having a significant impact on leukemia-free survival. In multivariate analysis, eosinophilia and basophilia were identified as lactate dehydrogenase (LDH)-independent prognostic variables with International Prognostic Scoring System (IPSS)-specific impact. Although elevated LDH was identified as a major prognostic determinant in IPSS low-risk, intermediate-1 risk, and high-risk subgroups, the condition “eosinophilia and/or basophilia” was identified as a superior prognostic indicator in the IPSS intermediate-2 risk subgroup. CONCLUSIONS: The evaluation of eosinophils and basophils in patients with MDS was helpful and may complement the spectrum of variables to optimize prognostication in MDS. Cancer 2010. © 2010 American Cancer Society.

BACKGROUND Some specific chromosome abnormalities for the leukemias have been proven to be associated with the prognosis of acute nonlymphocytic leukemia (ANLL). However, most of these reports included patients treated with different protocols. Therefore, some bias has been involved in the evaluation of the prognostic factors in such reports. METHODS The authors studied the morphologic, cytogenetic, and clinical features of 136 patients (86 males and 50 females) with de novo ANLL treated with the same protocol of intensive induction chemotherapy using multivariate analyses. RESULTS Chromosome abnormalities were detected in 62.5% of the patients. The overall complete remission (CR) rate of disease was 85.5% in these patients. More than 90% of the patients with t(8;21) and pseudodiploid abnormalities achieved experienced CR. However, CR rates in the patients with abnormalities of chromosome 5 or 7 were 50%. With multivariate analyses by the type of karyotypic abnormality, CR duration and survival time of the patients with t(8;21) were longer than those of patients with normal karyotype and abnormalities of chromosome 5 or 7. Abnormalities of chromosome 5 or 7 and hyperdiploid were associated with poor prognosis. Older age and lower platelet counts also were factors contributing to shorter survival times. With the analysis with French-American-British (FAB) classification, only hypoplastic leukemia was a poor prognostic factor. CONCLUSIONS These data suggest that cytogenetic analyses plays an important role in estimating the prognosis of patients treated with intensive induction chemotherapy.

BACKGROUND: To the authors' knowledge, the literature regarding extreme leukocytosis in solid tumor patients is sparse, consisting of a few case reports and small case series. METHODS: A total of 3770 consecutive solid tumor patients with a white blood cell count>40,000/μL were retrospectively identified over a 3-year period (2005-2008). Those patients without a secondary cause of their leukocytosis were defined as having a paraneoplastic leukemoid reaction. RESULTS: A total of 758 (20%) patients with solid tumors and extreme leukocytosis were identified. The etiology of the leukocytosis was hematopoietic growth factors in 522 (69%) patients, infection in 112 (15%) patients, high-dose corticosteroids in 38 (5%) patients, newly diagnosed leukemia in 9 (1%) patients, and paraneoplastic leukemoid reaction in 77 (10%) patients. The patients diagnosed with a paraneoplastic leukemoid reaction typically had neutrophil predominance (96%) and radiographic evidence of metastatic disease (78%), were clinically stable, and had a poor prognosis; 78% either died or were discharged to hospice within 12 weeks of their initial extreme leukocyte count. All of the 8 (10%) patients who survived>1 year received effective antineoplastic therapy. CONCLUSIONS: Infection was an uncommon cause of extreme leukocytosis in patients with solid tumors. Patients with paraneoplastic leukemoid reactions typically were clinically stable despite having large tumor burdens. However, clinical outcomes were poor unless effective antineoplastic treatment was received. Cancer 2009. © 2009 American Cancer Society.

Two hundred sixty-two adult patients with Hodgkin's disease (HD) were studied. Incorporation of carbon-14-thymidine was measured in unstimulated monocyte-depleted lymphocyte cultures, and in cultures activated by concanavalin A (Con-A) before institution of therapy in all patients. Total blood lymphocytes and T-cell subsets were enumerated in the last 108 patients. Patients had significantly decreased total (CD3+, CD4+, CD8+) and relative (CD3+, CD4+) T-cell counts compared with healthy controls. Stage IV patients tended to have lower total lymphocyte and subset counts than remaining patients. However, significantly reduced total lymphocyte and CD8+ counts were only observed in comparison to patients in clinical stage II. Thirty-three percent of patients had an increased spontaneous and a decreased Con-A-induced blood lymphocyte DNA synthesis. Functional lymphocyte abnormalities were related to advanced clinical stage, high age, mixed cellularity, and lymphocyte depletion histopathology and presence of B symptoms. The 10-year survival of patients in this group was 36%, compared with 62% for the remainder. In a multivariate analysis of the whole series lymphocyte DNA synthesis was besides age the strongest predictor of prognosis. In univariate analyses of the second patient series total lymphocyte, T-cell and subset counts were related to prognosis. These relatively simple lymphocyte functional tests may help to identify young HD patients for whom intensive cytoreductive therapy with or without autologous stem cell support may be the best therapeutic option.

There have been a number of reports over the last 15 years of patients with cancer who develop both leukocytosis and hypercalcemia, particularly in patients with cancers of the oral cavity. In this study, the authors report the frequency of hypercalcemia and leukocytosis in 225 patients with oral malignancies. Ten patients (4.4%) had hypercalcemia, 11 patients (4.9%) had leukocytosis, and five (2.2%) had both hypercalcemia and leukocytosis. The occurrence of these two distinct paraneoplastic syndromes in the same patients was greater than could have been expected from chance alone (chi-square = 45.8, P less than 0.0001). This study demonstrates that although hypercalcemia and leukocytosis are relatively uncommon in oral cancers, when they do occur they are frequently associated. To the knowledge of the authors, this is the first report in which the frequency of the association hypercalcemia and leukocytosis is studied in detail in large numbers of patients with oral cancer.

BACKGROUND Although glucocorticoids are often used in cancer therapy, in particular to enhance the effectiveness of antiemetic therapy, they have been associated with impaired tumor apoptosis and an increased frequency of metastases in some reports. The current study aimed to determine whether glucocorticoid treatment had an adverse effect on outcomes in patients with ovarian carcinoma. METHODS Records of patients with ovarian carcinoma who were scheduled to receive at least six courses of systemic chemotherapy were reviewed. Patients were grouped into those who had or had not received corticosteroid medication as a part of general antiemetic prophylaxis before chemotherapy, and details of hematologic parameters during treatment and disease recurrence-free and overall survival were recorded. RESULTS Altogether, 245 patients with ovarian carcinoma had received chemotherapy. Of these, 62 had been given concurrent glucocorticoid treatment and 183 had not. The two patient groups were well balanced with respect to disease stage and other prognostic factors. Kaplan–Meier analyses showed no significant differences in survival between the groups. Patients who received glucocorticoid treatment had significantly higher leukocyte values in the days immediately after chemotherapy, higher nadir leukocyte values, and higher counts before subsequent courses of chemotherapy (P < 0.01; Levene test, t test) compared with patients who did not receive glucocorticoid treatment. As a result, the initial treatment targets were achieved significantly more often in the glucocorticoid group (P = 0.007; chi-square test). CONCLUSIONS There was no evidence that glucocorticoid treatment had a negative effect on outcomes in these patients. Glucocorticoids may exert protective effects on the bone marrow. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND Despite improvements in supportive care, death due to treatment toxicity remains a significant problem for children treated for acute leukemia. METHODS To determine the causes of and risk factors for death unrelated to refractory leukemia, to disease recurrence, or to second malignancy, the authors reviewed the records of 1011 patients with acute lymphoblastic leukemia (ALL) and 260 patients with acute myeloid leukemia (AML) treated between 1984 and 1999 and between 1983 and 2002, respectively, at St. Jude Children's Research Hospital (Memphis, TN). Data for patients who underwent stem cell transplantation were censored at the time of transplantation. RESULTS For patients with ALL, the estimated 10-year cumulative incidence of death was 2.9% ± 5.3%. Age was the only predictor of death. Patients with ALL 1–9 years old had a significantly lower risk of death than did younger or older patients (P = 0.002). For patients with AML, the estimated 5-year cumulative incidence of death was 7.6% ± 1.9%. Increasing age and increasing leukocyte count were significantly associated with increased risk of death. For patients with ALL and with AML, the incidence of death remained relatively constant during the time periods studied. Infection was the most common cause of death. CONCLUSIONS In the current study, the authors determined that children ≥ 10 years of age are at increased risk of death during therapy for ALL and AML. Cancer 2004. © 2004 American Cancer Society.

BACKGROUND Although patients with malignant disease frequently use dietary supplements, the effects of these agents with regard to chemotherapy are unclear. Therefore, the authors investigated the influence of vitamin B12, folate, and nutritional supplements on chemotherapy-induced toxicity. METHODS Women with breast carcinoma were asked to complete a questionnaire that recorded their use of dietary supplements. Blood samples were obtained for the assessment of serum vitamin B12 and folate levels before and after the first cycle of chemotherapy and for weekly complete blood counts. Toxicity was evaluated by measuring absolute neutrophil counts and the frequency and severity of oral mucositis. RESULTS Of the 49 women who submitted questionnaires, 35 (71%) took a combined total of 165 supplements. Compared with patients in a previous study (performed in 1990), patients in the current study had dramatically increased serum folate levels. Initial neutrophil count, but not type of chemotherapy, patient age, or serum vitamin B12 level, was predictive of nadir absolute neutropenia and the decrease from initial neutrophil count to nadir (Nfall). After adjusting for initial neutrophil count, Nfall was found to be lower for women who were taking supplements compared with women who were not taking supplements (P = 0.01) and for women who were taking multivitamins (P = 0.01) or vitamin E (P = 0.03). Women with serum folic acid levels < 20 ng/mL had a smaller decrease in neutrophil count after chemotherapy than did women with higher folate levels (P = 0.04). No significant association between oral mucositis and initial neutrophil count, nadir neutrophil count, Nfall, age, vitamin B12 level, or folate level was found. CONCLUSIONS The decrease in neutrophil count caused by chemotherapy was ameliorated by dietary supplementation with a multivitamin or vitamin E. In contrast, high serum folate levels were associated with the exacerbation of this decrease in neutrophil count. Cancer 2004. © 2004 American Cancer Society.

In 1983, Pretlow et al. reported one classical study of the prognostic influence of eosinophil infiltration in human colon carcinoma. Since then, very few reports have analyzed this supposed prognostic influence in this type of tumor, although there have been several reports of other types of tumors with different results. Eosinophils seem to play a central role in the immunologic defense against tumors; their activity can be induced through immunotherapy with interleukin in cases that are unresponsive to conventional therapies.To analyze the prognostic influence of eosinophils in colorectal carcinoma, the authors selected 126 patients with this type of tumor treated only with curative surgery and followed for a minimal period of 5 years. They divided these patients into 4 categories according to the number of eosinophils per high-power field (400x): 0 (Grade 1), 1-9 (Grade 2), 10-50 (Grade 3), and more than 50 (Grade 4).The results of this series confirm that high eosinophil counts are associated with a significantly better prognosis. In multivariate analysis, this factor was independent from staging, vascularization, p53 expression, and histologic grade.Eosinophil count served as a significant independent favorable prognosticator in colorectal carcinoma patients.

BACKGROUND Cranial radiation therapy (CRT) has been suggested to be a principal factor responsible for long term neurocognitive deficits in survivors of acute lymphoblastic leukemia (ALL). However, neither reduction of the irradiation dose nor the elimination of irradiation entirely appear to have abolished neurocognitive impairment in long term ALL survivors. Positron emission tomography (PET) and [18F]-fluorodeoxyglucose (FDG) can be used to quantitate cerebral glucose metabolism, a potential indicator of treatment-induced adverse central nervous system (CNS) effects. The purpose of this study was to assess whether CRT is associated with defects in cerebral glucose metabolism in long term ALL survivors. The authors also studied whether chemotherapy and/or the severity of disease have deleterious effects on glucose metabolism. METHODS Forty long-term survivors of childhood ALL were studied using FDG PET. All subjects went through an elaborate neurocognitive assessment. In 20 of these children, the prophylactic treatment of the CNS had been CRT combined with methotrexate (MTX), and it was MTX only in the remaining 20 children. RESULTS No major differences were found in the regional cerebral glucose utilization or in neurocognitive performance between the irradiated and nonirradiated groups. A high leukocyte count at the time of diagnosis was found to be associated inversely with cerebral glucose utilization. CONCLUSIONS CRT does not appear to affect cerebral glucose metabolism in long term survivors of ALL. By contrast, the association between the leukocyte count and glucose utilization implies that disease severity may be partly responsible for adverse CNS effects in long term survivors of childhood ALL. Cancer 2000;88:693–700. © 2000 American Cancer Society.

Although it is widely accepted that failure to achieve complete remission (CR) portends a poor prognosis in childhood acute lymphoblastic leukemia (ALL), there is variability in the precise definition of induction failure and, to the authors' knowledge, few published data exist regarding the outcome of patients who are slow to achieve CR.Between 1987-1995, 774 children with ALL were treated on 2 consecutive protocols and were evaluable to assess the time required to attain CR. The authors compared presenting characteristics and outcomes of patients based on their remission status after 1 month of induction chemotherapy: CR (n = 656), protracted hypoplasia (low peripheral blood counts and/or hypocellular marrow) (n = 95), and persistent leukemia (M2 or M3 bone marrow and/or evidence of extramedullary leukemia) (n = 23). The median follow-up was 5.2 years.Presenting features that predicted persistent leukemia included a leukocyte count100,000/mm3 and T-cell phenotype. Approximately 91% of patients with persistent leukemia and 100% with protracted hypoplasia eventually achieved CR. The 5-year event free survival (EFS) (95% confidence intervals [95% CI] in parentheses) for patients with persistent leukemia after 1 month was 16% (95% CI, 0%, 31%), which was significantly worse (P0.001) than that for those who achieved CR within 1 month (5-year EFS, 82%; 95% CI, 79%, 86%) and that for those with protracted hypoplasia (5-year EFS, 79%; 95% CI, 70%, 87%). For patients with persistent leukemia, there was no significant difference in survival based on bone marrow status (M2 or M3) after 1 month or on the number of induction cycles received before achieving CR.Patients with persistent leukemia at the end of 1 month of therapy have a dismal prognosis, regardless of when they subsequently achieve CR. More intensive and/or novel therapies should be considered for this subset of patients.

The combination of cisplatin, ifosfamide, and prolonged oral etoposide (PIE) was studied in patients with extensive small cell lung carcinoma (SCLC) in a Phase I trial followed by a Phase II trial to determine the maximum tolerated dose (MTD), characterize toxicity, and estimate response and median survival rates.Thirty-three patients were treated between October 1991 and December 1994. Doses for the initial cohort were cisplatin 20 mg/m2/day, ifosfamide 1500 mg/m2/day with mesna (all given intravenously on Days 1-3), and oral etoposide 50 mg/m2 on Days 4-17. This cycle was repeated every 4 weeks for up to 6 cycles. The MTD was reached for the first 9 patients. For these 9 patients and the next 24 patients, who were entered in the Phase II trial, response and survival were estimated.Dose-limiting toxicity was manifested as Grade 4 neutropenia in 3 of 3 patients (associated with fever in 2 of 3), and Grade 4 thrombocytopenia was encountered in 2 of 3 patients at the second dose level. Of 6 patients treated at the first dose level, 4 achieved targeted myelosuppression (absolute granulocyte count nadir1000), but only 1 experienced Grade 4 neutropenia, defining this level as the MTD. Grade 4 neutropenia and/or thrombocytopenia was observed in 36 (24%) of a total of 152 courses administered at or below the MTD. Nonhematologic toxicity above Grade 2 was uncommon, excluding nausea and vomiting. Overall objective response rate was 93% of 30 evaluable patients: 5 (17%) complete responses and 23 partial responses (76%). Median failure free and overall survival durations were 36 and 54 weeks, respectively.The combination of cisplatin, ifosfamide, and oral etoposide produced encouraging failure free and overall median survival rates in patients with extensive SCLC. These results warrant further evaluation of this regimen in the initial therapy of patients with limited stage disease.

Single doses of radioantibody are effective at treating single cells or small clusters of cancer cells. However, large tumor masses require either multiple doses of radioantibody or a multimodal approach to therapy using two or more therapeutic agents. Timing of the second dose in a multiple cycle scheme or the second treatment in a multimodal protocol will depend on recovery from toxicity associated with the first treatment.BALB/c mice were dosed with a maximal tolerated dose (MTD) of I-131-MN-14 anti-carcinoembryonic antigen immunoglobulin G (IgG) (250 microCi) or F(ab')2 (1.2 mCi). Mice were redosed with the MTD at one of four time points, either Day 28, 35, 42, or 49 after IgG or Day 14, 21, 28, or 35 after F(ab')2. Survival was monitored to determine the earliest time to redose without lethality. Several studies were then performed to identify an accurate measure of true myelorecovery. Mice were bled retroorbitally on the day of the first dose and at weekly intervals thereafter. Total peripheral white blood cell counts, granulocyte counts, and lymphocyte counts were determined for each animal. GR-1hi expression (percentage of positive cells) and mean channel florescence were determined by FACScan analysis of a blood sample incubated with fluorescein isothiocyanate-anti-mouse Ly-6G (GR-1). In other studies, two mice were killed weekly from a group treated with a single MTD of radioantibody. The weights of their spleens and thymus glands were determined. At that time, femoral marrow was collected from these animals and plated in Methocult M3430 methylcellulose medium (Stemcell Technologies, Vancouver, Canada), and total colony-forming cells in culture were determined. Another population of mice was used to assess normal tissue metabolic activity following radioantibody therapy by quantitating the 4-hour utilization of I-125-dUrd.The ability to redose mice with a second MTD of 1-131-IgG or F(ab')2 required 49 days and 35 days, respectively. Granulocyte and lymphocyte counts did not accurately predict myelorecovery from the first dose. Hematopoietic tissue weight, tissue metabolic activity, and marrow colony forming cells all suggested that redosing was possible 1-2 weeks before it could actually be done without lethality. Percent of cells expressing GR-1hi (60%) and absolute numbers of GR-1hi cells (1400 cells/mm3) suggested myelorecovery in most animals. A greater degree of accuracy was achieved when trends in GR-1hi expression were noted over 2 or more weeks (i.e., the absolute amount of GR-1hi had to exceed levels in untreated mice, as evidence that the hyperproliferative phase of recovery was complete).The only approach that accurately predicted the ability to retreat with myelosuppressive therapy without risk of lethality was an increase in GR-1hi-positive cells above untreated levels. Other approaches are currently being investigated, including the expression of proliferation antigens (e.g., proliferating cell nuclear antigen and Ki-67) in both murine and human samples and differentiation antigens (CD33 and CD34) in humans.

Patients with chronic myelogenous leukemia (CML) occasionally experience persistent thrombocythemia despite having adequate white blood cell (WBC) counts. Trimethylenethiophosphoramide (thiotepa) is an alkylating agent that significantly inhibits platelet production.The authors studied the effects of thiotepa in eight patients with CML with persistent thrombocythemia. All patients had adequate WBC counts while receiving therapy for leukemia. The median age of the patients was 58 years, and all had received at least 2 prior therapy regimens for CML. Thiotepa was administered by intravenous infusion at a dose of 75 mg/m2 once every 2 to 3 weeks; doses were adjusted according to hematologic response.Seven patients were evaluable for response to thiotepa. Their pretreatment median platelet count was 1215 x 10(9)/L. After receiving the first dose, 6 patients (86%) had favorable responses as the median platelet count dropped to 348 x 10(9)/L (P = 0.02). However, all the patients' platelet counts returned to near baseline values after the first course. Patients required a median of three courses to achieve stable platelet counts near the normal range. In 4 patients (57%), administration of thiotepa was discontinued because of a stable normal platelet count after a median of 7.5 courses; 1 patient was still receiving treatment at last follow-up (18 courses) and 2 patients stopped receiving treatment after their disease progressed to the blastic phase. Toxicity was mostly hematologic, with neutropenia (or = 1 x 10(9)/L) occurring during 5 of the 64 courses (8%) administered but only 1 patient's course was complicated by fever.The authors conclude that thiotepa is useful in controlling thrombocythemia in CML patients who have elevated platelet counts despite having adequate WBC counts.

The improved efficacy of imipenem over other beta-lactam antibiotics in the treatment of febrile neutropenic patients has been attributed to its broad spectrum of activity.A prospective, randomized, clinical trial was performed comparing vancomycin 1 g every 12 hours plus imipenem/cilassatin 500 mg every 6 hours and the same dose of vancomycin plus aztreonam 2 g every 6 hours for empiric treatment of febrile episodes in neutropenic patients with cancer.The imipenem regimen cured 76% of the 148 evaluable episodes compared with a 67% cure rate for the 152 episodes treated with the aztreonam regimen (p = 0.1). Most of the polymicrobial infections (77% or 10/13) treated with the imipenem responded, whereas only 38% (5/13) of these infections responded to the aztreonam regimen. Although the cost of the imipenem regimen was less than the cost of the aztreonam regimen, it was associated significantly more with skin rashes (12/194 vs 3/189, p = 0.02). In a multivariate analysis, a poor outcome was independently associated in both instances with the persistence of neutropenia and the presence of pneumonia (p0.001).Overall, in a multifactorial analysis that included efficacy, toxicity, and cost, the imipenem and aztreonam regimens were comparable.

BACKGROUND High-dose melphalan (HDM) is now a standard treatment for multiple myeloma (MM). Stem cell transplants are fast evolving as an alternative to bone marrow transplants because they are less traumatic and easier to perform. A study was undertaken to test if whole blood harvested after mobilizing peripheral blood stem cells with granulocyte-colony stimulating factor (G-CSF) reinfused as such (without stem cells being processed or concentrated through a cell separator) for rescue after HDM (dose 140–180 mg/m2) in MM accelerates hematopoietic recovery. METHODS Eight consecutive patients with MM were given HDM after receiving 4–5 courses of infusional vincristine, doxorubicin, and dexamethasone (VAD) chemotherapy. Approximately 6 weeks after the last course of chemotherapy, at the start of the procedure, G-CSF (Neupogen) was given at a dose of 10 μg/kg subcutaneously daily for 4 days to mobilize stem cells. All of the patients had brisk leukocytosis (18.4–64.6 × 109/L). On day 0 (fifth day after G-CSF), 1 L of blood was removed by phlebotomy and kept at room temperature for 24 hours. This was followed by a rapid intravenous (i.v.) bolus of melphalan at a dose of 140 mg/m2 in the first three patients, 155 mg/m2 in the 4th, 170 mg/m2 in the 5th, and 180 mg/m2 in the 6th, 7th, and 8th patients, applies to all patients along with hydration and diuresis. Twenty-four hours later, 1 L of blood previously removed was transfused back to the patient without any processing through the cell separator. The numbers of mononuclear cells reinfused was between 0.76 and 3.2 × 108/kg (mean: 1.82 × 108/kg). The number of CD 34+ cells infused in 4 patients ranged from 1.9 to 2.8 × 106/kg (mean: 2.35 × 106/kg). G-CSF was restarted on day 2 at a dose of 5 μg/kg and given daily until the granulocyte count was 0.5 × 109/L or more for 3 consecutive days. Antibiotics were given whenever a patient developed pyrexia. Platelets were transfused if below 20 × 109/L or for incidences of overt bleeding. RESULTS Granulocyte counts touched 0 between Days 6 and 10, lasting for an average of 3.4 days. Duration of granulocyte count below 0.5 × 109/L was 6.5 days (range: 5–9), and these rose to 1.0 or more × 109/L by Day 13.7 (range: 13–16). The number of platelet transfusions given per patient was 2.5 (range: 0–4). Intravenous antibiotics were used for 9 days (range: 4–12), and patients were discharged on Day 19 (range: 16–22). Follow-up ranged from 45 to 380 days. CONCLUSIONS Hematopoietic recovery was rapid in all patients, including those who received doses of melphalan higher than 140 mg/m2. This resulted in less need for platelet transfusions or antibiotics, and hospitalization was short. Our results are historically similar to conventional peripheral blood stem cell transplants but much better than autologous bone marrow transplants, indicating that whole blood after G-CSF provided sufficient progenitor cells for early engraftment. The procedure is less labor intensive insofar as it does not require separation and concentration of stem cells. It has the potential of becoming an alternative to autologous marrow and peripheral blood stem cell transplantation in patients with MM. Cancer 1996;77:1073-8.

High dose interleukin-2 (IL-2) has been found to produce durable antitumor responses in some patients, benefiting most greatly those patients with melanoma and renal cell carcinoma. In this paper, the hematologic toxicity and changes resulting from high dose IL-2 alone administered by intravenous bolus are discussed.One hundred ninety-nine consecutive patients treated with high dose IL-2 alone from January 1, 1988 to December 31, 1992 were included in this study. All patients had a diagnosis of metastatic melanoma or metastatic renal cell carcinoma and were treated at the National Cancer Institute (Bethesda, MD).Anemia, requiring erythrocyte transfusions, occurred in 14% of all treatment courses, with a median of two units of erythrocytes transfused. Severe leukopenia (1,000 leukocytes/mm3) was rare (1.5% of all patients) and was not associated with any infectious complications. Severe thrombocytopenia (30,000 platelets/mm3) occurred in 2.2% of all treatment cycles, with two patients experiencing a grade 3 hemorrhage, defined as gross blood loss, and one patient experiencing a grade 4 hemorrhage, defined as a debilitating blood loss. Defects in the coagulation pathway were common: abnormal partial thromboplastin time and prothrombin time values occurred in 64% and 25% of the treatment cycles, respectively. In addition, a mean clearance of 93% of lymphocytes from the peripheral blood was observed within 24 hours after initiating IL-2 therapy. This was followed by rebound lymphocytosis to a mean of 198% of baseline on posttreatment Day 4. There were no treatment-related deaths.During IL-2 therapy, adverse sequelae of anemia, thrombocytopenia, coagulopathy, and leukopenia were usually mild, transient and rarely limited therapy. A profound decrease in lymphocytes in the peripheral circulation occurred within 24 hours after initiating therapy, with a rebound occurring after stopping IL-2. No specific hematologic parameter was associated significantly with a patient's increased probability of responding to therapy.

Forty patients with Stage II-III breast cancer with 10 or more positive axillary nodes were treated with mastectomy followed by four cycles of standard dose CAF (cytoxan, Adriamycin, 5-FU), followed by high dose cytoxan, cisplatin, carmustine (HDCT) with autologous bone marrow transplant support (ABMT), and local-regional radiotherapy (LR XRT). During LR XRT, the hematologic toxicity experienced by these patients appeared more severe than that usually seen in patients not heavily pretreated with chemotherapy. Radiation therapy was interrupted in four patients (10%) because of thrombocytopenia and leukopenia. This observation prompted a comparison of the hematologic changes seen in this group with those seen in patients not treated previously with chemotherapy.A detailed analysis of changes in hematologic parameters during LR XRT was performed in 33 evaluable patients who received CAF-HDCT/ABMT and compared with a "control" group of 17 women who did not receive prior chemotherapy.The mean pretreatment leukocyte, platelet, and hematocrit counts were lower in the CAF-HDCT/ABMT group than in the control group, with the differences indicating statistical significance for the latter two (P = 0.17, P0.001, and P = 0.001, respectively). None of the control patients required a treatment interruption because of hematologic toxicity, whereas four of the CAF-HDCT/ABMT patients did. Among the CAF-HDCT/ABMT patients, a leukocyte count nadir of less than 2.0, a platelet nadir of less than 50,000, and a hematocrit nadir of less than 25 occurred in 12%, 19%, and 9%, respectively. The corresponding rates of control patients were 6%, 0%, and 0%, respectively. Relative to their pretreatment levels, however, both groups experienced similar declines in platelet and leukocyte counts.The higher rate of hematologic toxicity observed in the patients who previously received conventional chemotherapy plus HDCT/ABMT appears to have been due primarily to lower preradiotherapy blood counts.

High dose chemotherapy with the support of peripheral blood progenitor cells (PBPC) is increasingly used in the treatment of solid tumors. Although the best method of PBPC mobilization is still under investigation, it should be optimized for different tumor types to obtain antitumor effect and mobilizing activity. The authors report these results in terms of the number of PBPC released and the time of maximum mobilization induced by standard dose cyclophosphamide, epidoxorubicin, 5-fluorouracil (CEF) (cyclophosphamide 600 mg/m2, epidoxorubicin 60 mg/m2, 5-fluorouracil 600 mg/m2) plus granulocyte colony stimulating factor (G-CSF) in patients with breast cancer.Peripheral blood progenitor cells were studied by clonogenic assay of granulocyte macrophage colony-forming units (CFU-GM), megakaryocyte colony-forming unit (CFU-Meg) and erythrocyte burst-forming unit (BFU-E) and by flow cytometric analysis of CD34+ cells in 12 patients with early breast cancer throughout three cycles of CEF chemotherapy plus G-CSF.Colony assays and CD34+ cell determination were performed on 111 and 151 blood samples, respectively. The peak of CFU-GM and CD34+ cells occurred consistently at day 11 throughout all three cycles. At day 11 of the first cycle, the median peak values were 2223 CFU-GM/mL and 256 CD34+ cells/microL. A progressive decrease in peak value from the first to the third cycle was observed.Standard dose CEF chemotherapy plus G-CSF is a disease specific regimen allowing PBPC mobilization without any relevant toxicity. Maximum mobilization was recorded at day 11 of the first cycle.

Background. Several uncontrolled trials have suggested that dose intensity of chemotherapy is a crucial determinant of treatment outcome for patients with non-Hodgkin's lymphoma (NHL). To explore the possibility of increasing dose intensity, a dose-escalation study of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) using recombinant human granulocyte colony stimulating factor (rhG-CSF) was initiated. Methods. First, the feasibility of standard dose CHOP (750 mg/m2 cyclophosphamide intravenously [i. v.] on Day 1; 50 mg/m2 doxorubicin i. v. on Day 1; 1.4 mg/m2 vincristine i. v. on Day 1; and 100 mg/body prednisolone orally on Days 1–5) repeated biweekly at the original dose was assessed. rhG-CSF was given subcutaneously at doses of 2–5 rg/kg every day or every other day on Days 3–13. The safety of increasing the dose of cyclophosphamide during biweekly CHOP then was tested. Besides the standard dose (750 mg/m2), two dose levels of cyclphosphamide were set (1200 mg/m2 and 1500 mg/m2 in patients younger than 61 years of age, and 1200 mg/m2 in patients 61–75 years old). Results. Twenty-seven patients with NHL who had received minimal or no previous treatment were enrolled in this study. In the 750 mg/m2 group, 9 patients received 3–6 cycles of treatment (mean, 3.9 cycles), in the 1200 mg/m2 group, 10 patients received 3–6 cycles (mean, 4.8), and in the 1500 mg/m2 group, all 8 patients received 6 cycles. No significant differences among the groups were observed in the extent and the duration of neutropenia in each cycle, and a leukocyte count of more than 3000/μ1 on Day 15 was achieved in all 131 cycles. Hemoglobin values and platelet counts, however, decreased in the later cycles in the 1500 mg/m2 group. Two patients were hepatitis-B virus carriers, one of whom died of fulminant hepatitis after completion of six cycles. Another patient developed a transient increase of transaminases after the second cycle. One other patient developed Grade 4 mucositis (World Health Organization scale). The numbers of patients who achieved complete and partial responses, respectively, were 4 (50%) and 2 (25%) in the 750 mg/m2 group, 8 (80%) and 2 (20%) in the 1200 mg/m2 group, and 8 (100%) and 0 (0%) in the 1500 mg/m2 group. Conclusions. The dose of cyclophosphamide in biweekly CHOP can be increased up to 1500 mg/m2 with no increase in the incidence of treatment-related early mortalities without any organ damage in younger patients. The efficacy of this dose intensification of CHOP currently is being investigated in a multicenter prospective randomized trial using three different dose levels of cyclophosphamide.

BACKGROUND The prognosis of thymoma is related mainly to the tumor stage. The prognostic value of argyrophilic nucleolar organizer regions (AgNORs) has been demonstrated in several human neoplasias. Ninety primary thymomas were investigated retrospectively to assess whether AgNOR analysis could offer additional prognostic information. METHODS Sections from surgically resected thymomas, routinely fixed in formol and embedded in paraffin, were stained with the argyrophilic method of Ploton. The mean number of AgNORs in the nuclei of 100 tumor cells (AgNOR counts) was calculated for each case. The association between AgNOR counts and survival was assessed by means of uni- and multivariate survival analyses. RESULTS On univariate analysis, AgNOR counts were associated significantly with 5- and 10-year survival rates (95% and 90%, respectively, for thymomas with 5.58 or fewer AgNORs per cell, but only 55% and 44%, respectively, for tumors with more than 5.58 AgNORs per cell; P < 0.0001). Histologic subtypes of the American classification (P = 0.0006) and clinical stage (P < 0.0001) also were correlated with prognosis. The multivariate survival analysis showed that AgNOR counts (P = 0.001), clinical stage (P < 0.001), and age (P = 0.011) were independent prognostic variables. AgNOR counts were associated with histologic subtypes in the American (P = 0.0001) and European (P = 0.005) classifications and with the clinical stage (P < 0.0001). Moreover, thymoma cells and intermingling lymphocytes showed different numbers of AgNORs and patterns of AgNOR distribution. CONCLUSIONS Analysis of argyrophilic nucleolar organizer regions provides useful prognostic information for patients with thymomas and offers an exact evaluation of the proliferative activity of the neoplastic cells even for thymomas with prominent lymphocytic infiltration.

The authors compared the pharmacokinetics of doxorubicin when administered with and without concomitant high dose cyclosporine for multidrug resistant (MDR) tumor modulation in small cell lung cancer.Eight patients with small cell lung cancer served as their own controls and were studied first during an initial course of doxorubicin without cyclosporine, and then subsequently during a cyclosporine-modulated doxorubicin course. All patients received cyclophosphamide and vincristine in each course. Doxorubicin was administered as a 1-hour infusion after a 2-hour cyclosporine loading infusion, and cyclosporine was infused continuously for the next 48 hours. Serum concentrations of doxorubicin, doxorubicinol, and cyclosporine all were assayed by high-pressure liquid chromatography. Pharmacokinetic analysis of doxorubicin included area under the curve (AUC), clearance, apparent volume of distribution at steady state (Vss), and elimination half-life (T1/2). The percent of change and surviving fraction of leukocyte count and platelets were determined as pharmacodynamic indices.Cyclosporine modulation increased the AUC0-36 of doxorubicin by 48% (P = 0.042) and the AUC0-36 of doxorubicinol by 443% (P = 0.0001), whereas the doxorubicin clearance declined by 37% (P = 0.0495). No difference was found in the Vss or T1/2 for doxorubicin when cyclosporine was added to the regimen. The ratio of the doxorubicinol AUC0-36 to the doxorubicin AUC0-36 increased significantly with cyclosporine modulation (8.88 vs. 2.19; P = 0.001). Drug-related toxicity was also greater with the cyclosporine-modulated course of doxorubicin. A 91% reduction in the leukocyte count followed the modified course, compared with an 84% reduction following the initial course (P = 0.0074). A more prolonged and greater degree of myelosuppression was observed and a significant relationship was found between the systemic exposure to doxorubicin (defined by AUC) and the surviving fraction of the leukocyte count (r = -0.69; P = 0.006). Similarly, the reduction in the platelet count was significantly greater after the cyclosporine-modulated course (72.8%) than after the initial course (36.4%) (P = 0.0016). A significant correlation was found between the AUC of doxorubicinol and the surviving fraction of platelets (r = -0.71; P = 0.004). In addition, patients showed decreased performance status associated with significant weight loss and severe myalgias.The addition of high dose cyclosporine for MDR modulation resulted in the significant alteration of doxorubicin disposition and remarkable toxicity in all patients. The mechanisms responsible for the decreased doxorubicin clearance may include cyclosporine's ability both to interfere with P-glycoprotein in normal tissues and to selectively inhibit the cytochrome P-450 enzyme system. Further study of this potentially significant drug-drug interaction is warranted.

Standard treatment for fever during periods of chemotherapy-induced neutropenia includes hospitalization and administration of intravenous antibiotics until the patient is afebrile and no longer neutropenic. This study prospectively evaluates the safety and cost-effectiveness of early discharge of selected low risk children before recovery from neutropenia.We studied 74 children with cancer during 131 consecutive admissions for fever during a period of neutropenia. All patients initially were hospitalized and received broad-spectrum antibiotics. Intravenous antibiotic therapy was discontinued, and the patients promptly were discharged even if they had an absolute neutrophil count (ANC) of less than 500 cells/mm3 as long as they were afebrile, appeared clinically well, had negative cultures, exhibited control of local infection, and showed hematologic evidence of bone marrow recovery.Intravenous antibiotics were discontinued in 82 cases (63%) before recovery of the ANC to more than 500 cells/mm3, and 78 patients were discharged immediately. None of 70 patients discharged while neutropenic but exhibiting a rising ANC at the time of discharge developed recurrent fever and required readmission. Thirty of these children had an improving localized infection when intravenous antibiotics were discontinued and completed a course of oral antibiotics at home. The estimated mean savings in hospital charges due to early discharge was $5058 per patient.Low risk children with cancer who are hospitalized and treated for fever and neutropenia but appear clinically well may have intravenous antibiotics discontinued and be discharged safely irrespective of the ANC, as long as their granulocyte count is rising. This approach shortens hospital stays and results in considerable cost savings.

High-dose chemotherapy with autologous bone marrow transplantation has been useful in some patients with advanced breast, lymphoma, or germ cell tumors. Double-cycle high-dose chemotherapy may be able to deliver an even higher total dose within a given time period. It is important to determine whether peripheral blood stem cells and hematopoietic growth factors can diminish the hematopoietic toxicity of such a treatment.From November 1989 to May 1991, 14 patients were enrolled in two cycles of high-dose chemotherapy consisting of cyclophosphamide, 4.5 g/m2; cisplatin, 150 mg/m2; and etoposide, 900 mg/m2 in each cycle. The first five patients received peripheral blood stem cells harvested from 8-10 leukaphereses during steady state. The next nine patients, besides receiving peripheral blood stem cells mobilized by growth factors, also received either granulocyte-macrophage colony-stimulating factor (GM-CSF) at 250 micrograms/m2/day by two subcutaneous (s.c.) injections given 12 hours apart from day 6 until neutrophil recovery or granulocyte colony-stimulating factor (G-CSF) at 200 micrograms/m2 as daily s.c. injections.For the first five patients, there was a median of 14 days from the first day of absolute marrow suppression to neutrophil count exceeding 500/microliters and a median of 15 days for a platelet count exceeding 20,000/microliters. For the next nine patients, with the use of either G-CSF or GM-CSF, there was a median of 8 days for a neutrophil count exceeding 500/microliters and and a median of 11 days for a platelet count exceeding 20,000/microliters.With the use of peripheral stem cells and growth factors, high-dose chemotherapy could be given safely every 30 days with acceptable toxicity. A high complete response rate was seen in patients with nasopharyngeal carcinoma and in patients with small cell and non-small cell lung cancer who either had not received previous chemotherapy or who had responded to previous chemotherapy.

Background Both interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) have some efficacy in renal cell cancer (RCC) as single agents. Additionally, there is some evidence for additive or synergistic antitumoral activity of IL-2 and alpha-IFN in vitro and possibly in vivo. Based on these data, the authors initiated a Phase II trial with a combination of recombinant IL-2 (rIL-2) and recombinant alpha-IFN (alpha-rIFN) in advanced RCC. Methods Thirty-six assessable patients with metastatic RCC were entered in this Phase II trial using a daily alternating schedule of alpha-rIFN and rIL-2. Over a period of 14 days, the patients received daily alternating treatment with 10 x 10(6) IU/m2 of recombinant alpha-2b-interferon subcutaneously and 18 x 10(6) IU/m2 of rIL-2 as a 1-hour intravenous infusion. This treatment schedule was repeated every sixth week up to a maximum of four cycles. After the second cycle, patients were examined for response. Patients with stable disease or better received two additional cycles of therapy. Patients with progressive disease were available for other strategies. Results Thirty-six patients entered the trial and were assessable for toxic effects. Thirty of 36 patients completed at least two cycles and were assessable for response. Nine patients achieved an objective response: 2 had complete responses (CR) and 7 had partial responses (PR). Three patients had a minor response. No effect was observed in patients with local relapse or bone metastases. A relapse-free survival length of 6 months or longer was seen in both patients with CR (12, 23 + months) and in four of seven patients with PR (6, 7, 12, 12 months). The toxicity was moderate and included fever and nausea in most patients, and hypotension, fatigue, skin rash, and arthralgia in a minority of the patients. No Grade 4 and only occasionally Grade 3 toxicity was observed. Fluid retention was negligible. The monitoring of immunologic parameters showed a significant rebound lymphocytosis including cytotoxic (CD56+) cells; in responders the peak of lymphocytosis occurred up to 1 week later than in nonresponders. Peripheral lymphocytes obtained after therapy showed only a slight increase of natural killer cell and lymphokine-activated killer cell activity. During therapy, there was a great release of secondary cytokines as tumor necrosis factor-alpha, gamma-interferon, and interleukin-6, with a peak level 2-4 hours after rIL-2 infusion. Conclusions In conclusion, daily alternating administration of alpha-rIFN and rIL-2 is effective in RCC with less toxicity, and the response rate is comparable to those of other immunotherapeutic schedules, including adoptive immunotherapeutic schedules, including adoptive immunotherapy and combinations of high-dose IL-2 and alpha-IFN.