Major Disease Sites Research Articles

First Cycle Risk of Severe and Febrile Neutropenia in Cancer Patients Receiving Systemic Chemotherapy: Results from a Prospective Nationwide Study.

Introduction: Myelosuppression represents the major dose-limiting toxicity of cancer chemotherapy. This prospective, nationwide study was undertaken to better define risk of neutropenia and its complications and to develop risk models for selecting patients for appropriate supportive care.Methods: More than 3,500 patients initiating a new chemotherapy regimen have been prospectively registered at 137 randomly selected practice sites. Major disease sites include breast, lung, colorectal, ovary and lymphoma. Primary outcomes include severe neutropenia (SN; absolute neutrophil count nadir <500) and febrile neutropenia (FN) (fever/infection and nadir <1000) by cycle of treatment and overall.Results: This analysis is based on the first 2,361 patients treated to date including 924 (39%) age ≥65. Severe neutropenia was documented in 28% and FN in 16% across all cancer categories. The proportion of patients with ANC <500 over the first four cycles of treatment include: colorectal (8%); lung (18%); ovary (23%); lymphoma (27%) and breast (37%). Likewise, the proportion of patients with FN during the first four cycles include: colorectal (7%); lung (11%); ovary (13%); lymphoma (18%) and breast (20%). As shown in the table, approximately half of the initial episodes of ANC <500 and FN over four cycles of treatment occurred in cycle 1.Neutropenic Events By Cycle (% Patients)Primary OutcomeCycle 1 (N=2361)Cycle 2 (N=2032)Cycle 3 (N=1724)Cycle 4 (N=1246)Total (N=2361)Any SN16111011481st Cycle SN1664228Any FN8651201st Cycle FN843116The proportion of initial episodes of severe neutropenia that occur in cycle 1 include: colorectal (67%); lung (59%); ovary (44%); lymphoma (62%) and breast (70%). Likewise, the proportion of initial episodes of FN occurring in cycle 1 include: colorectal (53%); lung (60%); ovary (57%); lymphoma (56%) and breast (58%).Conclusions: Rates of severe and febrile neutropenia vary with tumor type. The initial episode of severe or febrile neutropenia is most likely to occur during the first cycle of chemotherapy across all major cancer types.

Protein phosphatase 2C dephosphorylates and inactivates cystic fibrosis transmembrane conductance regulator.

cAMP-dependent phosphorylation activates the cystic fibrosis transmembrane conductance regulator (CFTR) in epithelia. However, the protein phosphatase (PP) that dephosphorylates and inactivates CFTR in airway and intestinal epithelia, two major sites of disease, is not certain. We found that in airway and colonic epithelia, neither okadaic acid nor FK506 prevented inactivation of CFTR when cAMP was removed. These results suggested that a phosphatase distinct from PP1, PP2A, and PP2B was responsible. Because PP2C is insensitive to these inhibitors, we tested the hypothesis that it regulates CFTR. We found that PP2Calpha is expressed in airway and T84 intestinal epithelia. To test its activity on CFTR, we generated recombinant human PP2Calpha and found that it dephosphorylated CFTR and an R domain peptide in vitro. Moreover, in cell-free patches of membrane, addition of PP2Calpha inactivated CFTR Cl- channels; reactivation required readdition of kinase. Finally, coexpression of PP2Calpha with CFTR in epithelia reduced the Cl- current and increased the rate of channel inactivation. These results suggest that PP2C may be the okadaic acid-insensitive phosphatase that regulates CFTR in human airway and T84 colonic epithelia. It has been suggested that phosphatase inhibitors could be of therapeutic value in cystic fibrosis; our data suggest that PP2C may be an important phosphatase to target.

CFTR-like Chloride Channels in Non-ciliated Bronchiolar Epithelial (Clara) Cells

Distal airways are believed to be a major site of disease in cystic fibrosis. The product of the CF gene, CFTR, is expressed in non-ciliated bronchiolar epithelial (Clara) cells. Clara cells in primary culture are capable of Cl−secretion which can be stimulated by cAMP and extracellular nucleotides. We used the patch clamp technique to look for Cl−channels in the apical membrane of rabbit Clara cells. In cell-attached patches, we recorded Cl−channels with a conductance for outward currents of 7.5 ± 0.4 pS (n = 10) and for inward currents of 3.2 ± 0.5 pS (n = 10); these channels typically exhibited slow kinetics and were not inhibited by the Cl−channel blockers NPPB and DIDS. Channel activity was not noticeably dependent on pipette potential. Addition of chlorophenylthio-cyclic AMP (cpt-cAMP) to the bath increased the percentage of cell-attached patches with active channels (33.8% vs 56.7%; p< 0.05) and the channel open probability (0.49 ± 0.03 vs 0.84 ± 0.02; p< 0.05). Extracellular ATP increased the percentage of cell-attached patches with active channels (28.7% to 50.0%; p< 0.05) but had no significant effect on the channel open probability (0.62 ± 0.07 vs 0.60 ± 0.06). In conclusion, rabbit non-ciliated bronchiolar epithelial cells express low-conductance Cl−channels that share many similarities with the CFTR-related Cl−channel and are regulated by cAMP and extracellular ATP.

Radiographic manifestations of AIDS related lymphoma in the thorax

Intrathoracic disease in AIDS-related lymphoma (ARL) produces a range of radiographic appearances. This study aimed to determine the frequency, distribution and characteristics of these appearances. The case notes and findings on imaging of 116 consecutive cases of ARL were reviewed retrospectively. In 52 cases there were abnormalities present on chest imaging (chest radiography or chest CT scanning). In 20 patients abnormalities were judged to be due to lymphomatous involvement and in 15 cases the thorax was the major site of disease. Correlation with biopsy results from thoracic disease (9), other disease (5), or evidence of response to treatment (6) was made. The most frequent imaging findings were pleural or intrapulmonary masses (7), frequently peripheral and sometimes with cavitation. In one case this simulated mycetoma formation. Pleural effusions and mediastinal lymph nodes were also frequently present, either alone or in combination. AIDS-related lymphoma uncommonly involves the chest as a major site of disease. A pleural or intrapulmonary mass with cavitation may represent the only site of disease and in these cases CT guided biopsy is likely to provide the histological diagnosis.

A Phase II Trial of Zeniplatin in Metastatic Melanoma

A third-generation platinum analogue, zeniplatin, was administered at a dose of 145 mg/m2 intravenously over 60-90 minutes every 21 days as the initial chemotherapy to 21 patients with metastatic melanoma. Prehydration and mannitol diuresis was introduced after the first 7 patients. There were 17 males and 4 females. The median age was 52 (range: 29-81). ECOG performance status was 0 in 10 patients, 1 in 8 patients and 2 in 3 patients. Major disease sites were lymph nodes, skin, lung, liver, and bone. Patients received a median of 2 cycles (range: 1-7). Two patients achieved partial responses. One with nodal disease progressed after 166 days and the other with buccal mucosal disease after 142 days. A third patient showed partial regression of nodal disease but developed cerebral metastases. Gastrointestinal toxicity included WHO grade 3 vomiting in 8 patients and nausea in 2. Antiemetics were used, but ondansetron was not available. WHO grade 3 hematologic toxicities included neutropenia in 8 patients and anemia and thrombocytopenia in 1 patient. Thrombocytosis was seen in 35% of courses. Dosage reduction was required in 15% of courses and escalation in 5% of courses. Three patients developed phlebitis related to the infusion. One patient developed a reversible rise in serum creatinine, but, unlike other studies, no severe nephrotoxicity was reported. Zeniplatin demonstrated only modest activity in melanoma with significant gastrointestinal and hematologic toxicity.

Treatment of pre-menopausal advanced breast cancer with goserelin--a long-acting luteinizing hormone releasing hormone agonist.

Twenty-two pre-menopausal evaluable patients with advanced breast cancer (median age 39 years; ER positive 19, unknown three; prior adjuvant chemotherapy 16) were treated with the LHRH agonist goserelin depot (Zoladex). Serum levels of 17 beta-estradiol and progesterone were suppressed by goserelin within 3-4 weeks of therapy, while serum leuteinizing hormone and follicle stimulating hormone titers remained in the low level of the normal range. Complete or partial response was documented in seven of 22 cases (32%) and occurred in all major sites of disease. Tumor response was documented in women regularly menstruating at the start of therapy. Median time to disease progression was 23 weeks; median duration of response was 64 weeks; overall survival was 141 weeks. Zoladex was well tolerated: only hot flushes in 82% and reversible cutaneous pigmentation in the site of injection in 45% of the patients were observed. In our experience the activity of Zoladex was comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.

Medical Castration with Zoladex: A Conservative Approach to Premenopausal Breast Cancer

For almost a century surgical castration represented the initial standard therapy for metastatic breast cancer in premenopausal women with hormone dependent tumors. Today the suppression of ovarian function can also be obtained by the administration of supraphysiologic doses of luteinizing hormone releasing hormone (LHRH) agonists. From April 1987 to February 1989, 23 premenopausal patients with advanced breast cancer (median age 39 years, range 28-52, ER positive 20, unknown 3; prior chemotherapy 17) were treated with the LHRH agonist goserelin depot (Zoladex) at the dose of 3.6 mg. every 4 weeks. Twenty-two patients were evaluable. Serum levels of 17 beta estradiol, progesterone, FSH and LH were suppressed by goserelin and fell to postmenopausal values within 8 weeks of therapy in 77% of cases. Complete response (CR) plus partial response (PR) was documented in 7 of 22 (32%) and occurred in all major sites of disease. Five patients achieved CR (soft tissue 3, viscera 2). Response rate was higher in patients not previously treated with chemotherapy (4/6). In the present series, all responses were seen in women greater than 35 years old, regularly menstruating at the start of treatment. Time to progression for the entire case series was 22 weeks and for responders 64 weeks. Oophorectomy was performed after disease progression in four patients without success. Goserelin was well tolerated. Local cutaneous dyschromia occurred in 45% and hot flushes in 82%. Treatment efficacy of goserelin is comparable to that of oophorectomy, without the psychological trauma and the morbidity related to surgical castration.

MR imaging appearance of childhood adrenoleukodystrophy with auditory, visual, and motor pathway involvement.

Childhood adrenoleukodystrophy is an X chromosome-linked disorder characterized by progressive demyelination of cerebral white matter and adrenal insufficiency. Magnetic resonance (MR) imaging was performed in 15 patients with symptomatic disease and three with presymptomatic disease. MR imaging findings were abnormal only in symptomatic patients. Major sites of disease were the occipital, parietal, and temporal lobes, with all patients showing involvement of occipital lobes, optic radiations, and splenium of the corpus callosum. Follow-up images obtained in four patients demonstrated a posterior-to-anterior progression of disease. Correlation of results from MR imaging with those from evoked potential studies indicated that MR imaging was the method of choice for detecting demyelination of visual, auditory, and motor systems in adrenoleukodystrophy.

Mitoxantrone as first-salvage chemotherapy in relapsed breast cancer.

Mitoxantrone was administered at the dose of 14 mg/m2 i.v. every 3 weeks to 25 consecutive women with measurable progressive disease who relapsed after adjuvant CMF and endocrine therapy. The treatment plan consisted in the delivery of 6 cycles, unless disease progression or severe toxicity occurred. All patients were evaluable for drug response and toxicity. One patient achieved complete remission and 6 partial remission, for a total response rate of 28%. Objective tumor response was observed in all major sites of disease. The median time to achieve remission was 3 months. The median duration of response was 7 months (range, 5-39+), and the median survival for the entire group was 10 months (range, 3-39+). Results were influenced only by the duration of disease-free status from the end of adjuvant CMF chemotherapy. In fact, all tumor responses were documented in woman with free intervals exceeding 1 year (7 of 17 or 41%). Treatment was generally well tolerated, with 10 patients developing leukopenia at some time during treatment. Only 2 patients received less than 75% of the projected dose because of granulocytopenia. Complete alopecia occurred in only 2 cases. Three patients developed a fall greater than 15% in left ventricular ejection fraction, but no episode of congestive heart failure was observed. We conclude that mitoxantrone is an effective and safe drug which can be utilized in women relapsing after adjuvant CMF.

31. Outcome-assessment of Radiological Optimizing Algorithms for Five Major Disease Sites

31. Outcome-assessment of Radiological Optimizing Algorithms for Five Major Disease Sites

Hodgkinʼs disease complicated by nephrotic syndrome

The clinical course of a 14-year-old boy who developed biopsy-proven minimal change nephrotic syndrome (MCNS) prior to institution of therapy for Hodgkin's disease (HD), mixed cellularity histologic subtype, is presented. In the first week of radiotherapy to the major site of disease in the neck, BUN and creatinine levels rose to 98 mg% and 8.4 mg%, respectively. During the second week of treatment, levels gradually decreased becoming normal in the third week. Body weight gradually decreased in the second week of radiotherapy, falling rapidly in the third and fourth week when diuresis was greatest. Although urine protein concentration fell initially, the concentration remained 1 + or more for 10 weeks following radiotherapy. Following radiotherapy to the neck, staging laparotomy demonstrated a single focus of Hodgkin's disease in the spleen. Radiotherapy was given to the splenic pedicle: six courses of multiagent chemotherapy (MOPP) followed. The boy remains free of any evidence of either HD or MCNS 33 + months from the time of the diagnosis. Circulating lymphocytes showed normal responses to stimulation by phytohemaglutinin, Concanavalin A, and pokeweed mitogens. The patient's monocyte-macrophage-mediated antibody-dependent cellular cytotoxicity (ADCC) was low both prior to and following radiotherapy. Lymphocyte-mediated ADCC was normal at both of these times.

Morphological and cytochemical characterization of cells infiltrating mouse lungs after influenza infection.

To initiate evaluation of the cell-mediated immunological response to influenza virus in a major site of disease, lung cells were obtained by transpleural lavage from lungs of uninfected mice and from those infected 3 or 6 days previously with 5 50% mouse infectious doses (MID(50)) of avirulent (P3) or virulent (P9) influenza A Hong Kong (H3N2) virus. The number of cells recovered by lavage was dependent on the dose, time after inoculation, and the type of virus used for inoculation. Although lavage pools were shown to contain peripheral blood leukocytes, this contamination was shown to be consistently less than 5% of the total leukocytes harvested. Among the ca. 0.75 x 10(6) lavage cells obtained from each uninfected mouse, about 90% were macrophages or lymphocytes in approximately equal proportion. T, B, and null (lyphocytes lacking theta or surface immunoglobulin markers) lymphocytes averaged 23, 9, and 7% of cells in these suspensions, respectively. After infection with either P3 or P9 virus, increased numbers of activated macrophages and lymphoblasts were observed. The major change during P3 infection was an increase in absolute numbers of null lymphocytes. In contrast, during P9 infection, T and B lymphocytes and macrophages progressively increased in absolute numbers while null cells decreased. These data suggest that cell-mediated immunological responses to influenza virus occur in the lung during infection, but that the responses to virulent and avirulent variants may differ both qualitatively and quantitatively.