Fragmentomic analysis of circulating tumor DNA-targeted cancer panels.

BACKGROUND: The isolation of cell-free DNA (cfDNA) from the bloodstream can be used to detect and analyze somatic alterations in circulating tumor DNA (ctDNA), and multiple cfDNA-targeted sequencing panels are now commercially available for Food and Drug Administration (FDA)-approved biomarker indications to guide treatment. More recently, cfDNA fragmentation patterns have emerged as a tool to infer epigenomic and transcriptomic information. However, most of these analyses used whole-genome sequencing, which is insufficient to identify FDA-approved biomarker indications in a cost-effective manner. PATIENTS AND METHODS: We used machine learning models of fragmentation patterns at the first coding exon in standard targeted cancer gene cfDNA sequencing panels to distinguish between cancer and non-cancer patients, as well as the specific tumor type and subtype. We assessed this approach in two independent cohorts: a published cohort from GRAIL (breast, lung, and prostate cancers, non-cancer, n = 198) and an institutional cohort from the University of Wisconsin (UW; breast, lung, prostate, bladder cancers, n = 320). Each cohort was split 70%/30% into training and validation sets. RESULTS: In the UW cohort, training cross-validated accuracy was 82.1%, and accuracy in the independent validation cohort was 86.6% despite a median ctDNA fraction of only 0.06. In the GRAIL cohort, to assess how this approach performs in very low ctDNA fractions, training and independent validation were split based on ctDNA fraction. Training cross-validated accuracy was 80.6%, and accuracy in the independent validation cohort was 76.3%. In the validation cohort where the ctDNA fractions were all <0.05 and as low as 0.0003, the cancer versus non-cancer area under the curve was 0.99. CONCLUSIONS: To our knowledge, this is the first study to demonstrate that sequencing from targeted cfDNA panels can be utilized to analyze fragmentation patterns to classify cancer types, dramatically expanding the potential capabilities of existing clinically used panels at minimal additional cost.

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial.

BACKGROUND: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. PATIENTS AND METHODS: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. RESULTS: In the OSP (n = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n = 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade ≥3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1∗28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1∗1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n = 1/11; 9.1% ORR). CONCLUSIONS: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Detection and Characterization of Xanthomonas vasicola pv. vasculorum (Cobb 1894) comb. nov. Causing Bacterial Leaf Streak of Corn in the United States.

Bacterial leaf streak of corn (Zea mays) recently reached epidemic levels in three corn-growing states, and has been detected in another six states in the central United States. Xanthomonas vasicola was identified as the causal agent of this disease. A multilocus sequence alignment of six housekeeping genes and comparison of average nucleotide identity from draft genome sequence were used to confirm phylogenetic relationships and classification of this bacteria relative to other X. vasicola strains. X. vasicola isolates from Nebraska and South Africa were highly virulent on corn and sugarcane and less virulent on sorghum but caused water-soaking symptoms that are typical of X. vasicola infection on the leaves of all three hosts. Based on host range and phylogenetic comparison, we propose the taxonomic designation of this organism to X. vasicola pv. vasculorum ( Cobb 1894 ) comb. nov. Polymerase chain reaction-based diagnostic assays were developed that distinguish X. vasicola pv. vasculorum and X. vasicola pv. holcicola from each other and from other Xanthomonas spp.

Experimental determination of third-order elastic constants of diamond.

To determine the nonlinear elastic response of diamond, single crystals were shock compressed along the [100], [110], and [111] orientations to 120 GPa peak elastic stresses. Particle velocity histories and elastic wave velocities were measured by using laser interferometry. The measured elastic wave profiles were used, in combination with published acoustic measurements, to determine the complete set of third-order elastic constants. These constants represent the first experimental determination, and several differ significantly from those calculated by using theoretical models.

High rate of early virological failure with the once-daily tenofovir/lamivudine/nevirapine combination in naive HIV-1-infected patients.

BACKGROUND: The combination of one non-nucleoside reverse transcriptase inhibitor (NNRTI) with two nucleoside reverse transcriptase inhibitors is a validated first-line antiretroviral (ARV) therapy. The once-daily combination of lamivudine, tenofovirDF and nevirapine has not been evaluated in a clinical trial. METHODS: Randomized, open-label, multicentre, non-inferiority trial comparing lamivudine, tenofovirDF and nevirapine once daily (Group 2) with zidovudine/lamivudine and nevirapine twice daily (Group 1), in naive HIV-1-infected patients with a CD4 count <350/mm(3). We planned to enroll 250 patients. RESULTS: As of May 2006, 71 patients had been enrolled (35 in Group 1 and 36 in Group 2) and an unplanned interim analysis was done. The groups were comparable at baseline: median CD4 count was 195 and 191/mm(3) and median plasma viral load was 4.9 log(10) and 5.01 log(10), respectively, in Groups 1 and 2. Eight early non-responses (22.2%) were observed, all in Group 2, while two later viral rebounds occurred. Resistance genotypes for the nine Group 2 failing patients showed the mutations M184V/I (n = 3), K65R (n = 6), one or more NNRTI resistance mutations in all cases. At baseline, the nine Group 2 patients who failed had higher median plasma viral load (5.4 log(10)) and lower median CD4 count (110/mm(3)) than the other Group 2 patients (4.7 log(10), P = 0.002 and 223/mm(3), P = 0.004). Nevirapine trough concentrations were not different between the two groups, nor between patients with full viral suppression or those who failed in Group 2. Due to slow recruitment, and those results, the steering committee decided to stop the trial at 12 months. CONCLUSIONS: In ARV-naive HIV-1-infected patients, the once-daily lamivudine, tenofovirDF and nevirapine regimen resulted in a high rate of early virological failures. The reasons for the failures remain unclear.

Isoprinosine and Imuthiol, two potentially active compounds in patients with AIDS-related complex symptoms.

Isoprinosine and Imuthiol are immunomodulators with a unique effect on T-cells. The possibility of using them in treating patients with acquired immunodeficiency syndrome related complex (ARC) was initially examined regarding their in vitro effects on peripheral blood mononuclear cells. In six ARC patients Isoprinosine (100 micrograms/ml) and Imuthiol (10 pg/ml) induced in vitro an early chromatin activation as measured by nuclear refringency test and potentiated phytohemagglutinin (5 micrograms/ml) in the same 20-min assay in the absence of fetal calf serum. In all patients an early phytohemagglutinin induced chromatin dispersion was observed with a dose related response before interleukin 2 production can occur. Isoprinosine and Imuthiol increased significantly both the percentage and the absolute number of T4+ cells when peripheral blood mononuclear cells were incubated for 4 days in RPMI supplemented with 10% fetal calf serum. No changes in T8+ cells were noted. Three homosexual ARC patients were then treated p.o. with Imuthiol (5-10 mg/kg/week) for 4 to 6 months. Without any deleterious effect a clinical improvement (in terms of adenopathy and opportunistic infection regression) and restoration of the response to recall antigens were observed in all three patients. One patient with less than 500 T4+ lymphocytes/mm3 exhibited a complete restoration of OKT profiles. In such patients clinical and immunological effects of Isoprinosine have already been reported by others. Altogether these preliminary results indicate that more data should be obtained on the effects of these two agents in ARC patients.

Long-term hypokalemia in acute myeloid leukemia.

A 48-year-old man suffering from acute myeloid leukemia presented a hypokalemia that persisted almost constantly during 18 months despite total hematological remission. The renal investigation demonstrated a hypokalemic nephropathy with an impairment of urinary concentrating function. Light and electron microscopy showed renal lesions related to potassium depletion. We did not observe specific lesions explaining the renal potassium wasting. Metabolic studies showed persistent hyperkaluresis, which appeared to be the main kaliopenic factor. We also found hypomagnesemia and changes of the renin-aldosterone system. We observed a hyperreninism, probably due to hypokalemia and a slight hyperaldosteronism, which could have been one of the kaluretic agents.

[Hepatitis A seroprevalence in HIV-infected patients]. / Séroprévalence de l'hépatite A chez des patients infectés par le VIH.

OBJECTIVE: The authors had for aim to prospectively study the hepatitis A seroprevalence of an HIV-infected population, followed-up in an outpatient clinic (CISIH Strasbourg). DESIGN: Blood tests were performed on all patients from September 2003 to March 2004 to screen for hepatitis A (total antibodies with Elisa). RESULTS: The overall seroprevalence was 219/514 (56.6%), similar in male and female patients. It increased with age, especially in European patients (P = 0.003). The seroprevalence was lower in European subjects: 46.3% (while it reached 100% in sub-Saharan Africans), the prevalence was similar whatever the HIV risk group (46% in homosexual as well as in heterosexual patients, 44% in intravenous drug users). Hepatitis B or C co-infection did not increase the seroprevalence of hepatitis A. The hepatitis A seroprevalence was similar in various CD4 T cell count categories. CONCLUSIONS: Our results stress the utility of hepatitis A serology in HIV-infected patients (more than 50% of European patients are non immune), and the importance of assessing hepatitis A vaccination.

High hepatitis C viraemia and impaired antibody response in patients coinfected with HIV.

OBJECTIVE: To compare hepatitis C virus (HCV) load in patients infected with HCV alone and those coinfected with HIV, and to evaluate the antibody response to HCV in the case of HIV infection. DESIGN: Patients coinfected with both HCV and HIV have been shown to develop hepatic changes more rapidly, which may be due to an interaction between HCV and HIV. In a prospective study, serum samples were taken from 150 patients. METHODS: Using reverse transcription followed by polymerase chain reaction and the branched DNA assay, we detected HCV RNA in 75 patients coinfected with HIV and HCV and in 75 patients infected with HCV alone. The HIV RNA was also quantified by the branched DNA assay and the p24 antigenaemia was determined by enzyme-linked immunosorbent assay. The immune response to HCV was studied in the 150 patients by the use of third generation recombinant immunoblot assay (RIBA). RESULTS: Although a comparable number of patients had detectable HCV viraemia in both groups, HCV RNA was quantifiable in 79% of HIV-positive patients and in only 43% of HIV-negative patients (P < 10(-5)), and the mean HCV RNA level was much higher in the HIV-positive group than in the HIV-negative group (P < 10(-7)). The quantity of HCV RNA did not correlate with the CD4 count, p24 antigenaemia or HIV RNA level. The analysis of RIBA showed 14.7% indeterminate or negative results in the HIV-positive group and only 4% indeterminate results in the HIV-negative group. HIV-positive patients had reactivity to less antigen bands than HIV-negative patients (P < 10(-3)), and they had a weaker reactivity to c100, c33c and NS5 antigen bands than HIV-negative patients. CONCLUSION: Our results show that in the case of HIV infection, the HCV RNA levels are strongly increased, but HCV load is not linked to the immunosuppression induced by HIV; therefore, the present data do not support the hypothesis of a direct interaction between HIV and HCV.

Zidovudine plus interferon-alpha versus zidovudine alone in HIV-infected symptomatic or asymptomatic persons with CD4+ cell counts > 150 x 10(6)/L: results of the Zidon trial. Zidon Study Group.

OBJECTIVE: To evaluate the efficacy and safety of zidovudine (ZDV) and lymphoblastoid interferon (IFN)-alpha combination therapy compared with ZDV monotherapy in HIV-infected subjects with CD4+ cell counts between 150 and 500 x 10(6)/l. DESIGN: Open, randomized controlled trial with subjects stratified by the Centers for Disease Control and Prevention (CDC) 1986 classification of HIV disease (group II/III or IV). The study was amended to a sequential design in February 1992 to allow interim analyses to be conducted. SETTING: Outpatient clinics in 45 hospitals in Europe, Australia and Canada. PARTICIPANTS: A total of 402 previously untreated subjects with symptomatic HIV infection (CDC group IV) and CD4+ count 150-500 x 10(6)/l or asymptomatic HIV infection (CDC group II/III) with CD4+ count 150-350 x 10(6)/l. INTERVENTIONS: ZDV 250 mg twice daily with or without 3 MU subcutaneous injections of lymphoblastoid IFN-alpha three times per week. MAIN OUTCOME MEASURES: Time to development of a study endpoint defined as: progression from CDC group II/III to group IV, group IV non-AIDS to AIDS, or group IV AIDS to a second AIDS-defining condition; also CD4+ count to < 50 x 10(6)/l on two occasions at least 1 month apart or HIV-related death irrespective of CDC group on entry. RESULTS: There was no reduction in the rate of disease progression for patients receiving ZDV plus IFN-alpha compared with patients receiving ZDV alone. No major differences between the groups were seen for CD4+ counts or percentages, or p24 antigenaemia. In a subset of 70 patients, a similar proportion from both dose groups showed evidence of ZDV resistance after 48 weeks of treatment. More adverse experiences were seen in the ZDV/IFN-alpha group. CONCLUSIONS: Combination therapy with low dose lymphoblastoid IFN-alpha and ZDV revealed no clinical benefit compared with ZDV monotherapy.

Impact of protease inhibitors on AIDS-defining events and hospitalizations in 10 French AIDS reference centres. Fédération National des Centres de Lutte contre le SIDA.

OBJECTIVE: To assess the clinical and economic consequences of the use of protease inhibitors in the treatment of HIV infection. DESIGN: Multicentric, observational, retrospective cohort study. SETTING: Ten AIDS reference centres in France. PATIENTS: All patients followed in each centre from September 1995 through October 1996. MAIN OUTCOME MEASURES: AIDS-defining events, death, health-care resources use, administration of antiretroviral therapy. RESULTS: Data from 7749 patients in 10 centres showed a drop in hospitalization days by 35%, new AIDS cases by 35%, and deaths by 46%. In the same period, the proportion of patients receiving antiretrovirals rose from 36 to 53% including highly active antiretroviral therapy (HAART), which rose from 0.3 to 18%. Overall cost evaluation showed a slight increase of monthly treatment cost of US$ 12 per patient. Comparison of the three centres that used HAART earliest to the three centres that used it latest showed a clear benefit to early HAART with a drop in hospitalization days by 41%, new AIDS cases by 41% and deaths by 69%. The proportion of patients with HAART rose to 27% and monthly health-care cost decreased by US$ 248852 (i.e., by US$ 101 per patient per month). Late prescribing centres experienced a less marked effect with a drop in hospitalization days by 22%, new AIDS cases by 31%, and deaths by 32.5%. Proportion of patients with HAART rose to 12% and monthly health-care costs increased by US$ 113578 (i.e., by US$ 38 per patient per month). CONCLUSIONS: This study supports the extensive use of HAART in HIV-infected patients.

Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study.

BACKGROUND: Fat distribution abnormalities have been reported in patients treated with various antiretroviral drug regimens. The LIPOCO study is an ongoing observational study of unselected HIV-infected patients which aims to better characterize such disorders and their metabolic correlations. METHODS: Cross-sectional analysis of data collected at baseline in the first 154 male patients included. Investigators divided patients into four predetermined clinical categories of fat distribution: lipoatrophy, obesity, mixed condition and normal. Body composition (tetrapolar bioelectrical impedance analysis and skinfold thickness), fat distribution [computed tomography (CT) scan], plasma glucose and insulin concentrations both fasting and during an oral glucose tolerance test and endocrine and lipid profile were measured and compared between the four groups. RESULTS: Patients in the lipoatrophy group had significantly decreased abdominal and mid-thigh subcutaneous fat area values and elevated levels of plasma triglycerides. Patients in the obese and mixed groups had significantly increased intra-abdominal fat area values and elevated levels of plasma insulin and C-peptide. The CT scans identified some patients with isolated subcutaneous fat accumulation but no other alterations in fat distribution and no insulin resistance. Visceral adipose tissue measured by CT scan was positively correlated with fasting insulin and the sum of insulin levels (P < 0.0001). Fasting insulin as well as the sum of insulin levels were negatively correlated with the delta HIV-RNA (log(10)). In a multivariate logistic regression model, the use of stavudine significantly correlated with fat wasting in both nucleoside reverse transcriptase inhibitor and protease inhibitor groups: odds ratio (OR), 413 [95% confidence interval (CI), 5.2-999; P = 0.0068] and OR, 2.08 (95% CI, 0.92-7.0; P = 0.058) respectively, when compared with the use of zidovudine. Neither lamivudine or didanosine use, nor the use of protease inhibitors were significantly associated with fat distribution abnormalities or fat wasting. CONCLUSIONS: These preliminary results suggest that three major types of fat distribution abnormalities may occur in isolation or in association in HIV-infected patients undergoing active antiretroviral therapy: a fat depletion or 'lipoatrophy' syndrome which might be related to the use of stavudine; a mixed or fat redistribution syndrome related to an unusual side-product of effective virus control; and a subcutaneous adiposity syndrome reflecting increase in caloric intake.

A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy.

OBJECTIVE: To compare body composition, body fat distribution and insulin secretion in patients taking nucleoside reverse transcriptase inhibitor (NRTI) therapy. DESIGN AND SETTING: Cross-sectional study in three French AIDS clinical centres. PATIENTS: Forty-three HIV-infected patients on long-term NRTI therapy including stavudine (n = 27) or zidovudine (n = 16) and 15 therapy-naive HIV-infected patients (control group). MAIN OUTCOME MEASURES: Fat wasting was assessed by physical examination and body composition by bioelectrical impedance. Regional fat distribution was estimated using caliper measurements of skinfold thickness at four sites and evaluated by computed tomography at abdominal and mid-thigh level. Fasting glucose, insulin, C-peptide, triglyceride, cholesterol, free fatty acid, testosterone, follicle stimulating hormone, luteinizing hormone, cortisol levels, CD4 cell count and HIV viral load were determined. Daily total caloric and nutrient intake were evaluated. RESULTS: The zidovudine group and the control group had similar body composition and regional fat distribution. Stavudine therapy was associated with a significantly lower percentage of body fat (12.9% versus 15.2% in the zidovudine group; P < 0.05), markedly decreased subcutaneous to visceral fat ratio (0.90 +/- 0.63 versus 1.92 +/- 1.34, P < 0.01) and higher mean intake of fat and cholesterol (P < 0.01). Fasting plasma glucose, insulin and C-peptide levels were similar among the three groups. Triglyceride levels were significantly higher in the stavudine group than in the controls (P < 0.05), but did not differ between the stavudine and the zidovudine group or between the zidovudine and the control group. Free fatty acids tended to be higher in the stavudine group but the difference did not reach statistical significance. Lipodystrophy was observed clinically in 17 (63%) patients taking stavudine, and in three (18.75%) patients taking zidovudine after a median time of 14 months. The relative risk of developing fat wasting was 1.95 in the stavudine group as compared with the zidovudine group (95% confidence interval, 1.18-3.22). Five out of 12 patients had a major or mild improvement in their lipodystrophy after stavudine was discontinued. CONCLUSION: Lipodystrophy may be related to long-term NRTI therapy, particularly that including stavudine.

Filgrastim to treat neutropenia and support myelosuppressive medication dosing in HIV infection. G-CSF 92105 Study Group.

BACKGROUND: Patients with HIV infection frequently experience disease or treatment-related myelosuppression leading to neutropenia. Neutropenia often leads to dose-reduction or discontinuation of important myelosuppressive therapy. OBJECTIVE: To examine the efficacy and safety of filgrastim for reversing neutropenia and determine the effect of this on use of myelosuppressive medications. DESIGN: Open-label, non-comparative, multicentre study in 200 HIV-positive patients with neutropenia [absolute neutrophil count (ANC) < 1.0 x 10(9)/l]. Filgrastim was started at 1 microgram/kg/day subcutaneously for 28 days. This initial treatment phase was followed by a maintenance phase, using 300 micrograms on 1-7 days/week. In both phases the dose of filgrastim was adjusted to achieve an ANC of 2-5 x 10(9)/l. RESULTS: Filgrastim reversed neutropenia in 98% of patients (ANC > or = 2 x 10(9)/l), with a median time to reversal of 2 days (range 1-16) and a median dose of 1 microgram/kg/day (range 0.5-10). Most patients (96%) achieved reversal of neutropenia with a filgrastim dose of < or = 300 micrograms/day (< or = 1 vial/day). Normal ANCs were then maintained with a median of 1 microgram/kg/day (range 0.22-10.6) during the treatment phase and 3 x 300 micrograms vials/week (range 1-7) during the maintenance phase. Ganciclovir, zidovudine, co-trimoxazole and pyrimethamine were the drugs most frequently considered to be causing neutropenia, and 83% of patients received one or more of these in the study. Filgrastim allowed > 80% of patients to increase or maintain dose-levels of these four medications or add them to their therapy. The number of these four medications received per patient increased by > 20% during filgrastim therapy. Filgrastim was well tolerated. CD4, CD8 and total lymphocyte counts all increased slightly, and there was no difference in HIV-1 p24 antigen levels. CONCLUSION: Filgrastim rapidly reverses neutropenia and maintains normal ANC in patients with HIV infection. This allows greater use of myelosuppressive medications without the potentially life-threatening complications of neutropenia.

Monocular acuity norms for the Teller Acuity Cards between ages one month and four years.

PURPOSE: To derive norms for monocular grating acuity and interocular acuity differences that are appropriate for clinical applications using the acuity card procedure (ACP) and Teller Acuity Cards (TAC). METHODS: Monocular acuities were measured in 460 children in 12 age groups between 1 month and 4 years. Inclusion criteria were term birth, good general health and normal development, normal eyes, and cycloplegic refraction within specific limits. Each child was tested by two ACP testers who were aware of TAC spatial frequency but not grating location during testing. RESULTS: Three monocular tests were completed in the first session in 99% of children. Median time to complete the tests of both eyes ranged from 3.2 to 8.4 minutes. Monocular acuity norms were calculated using 95% and 99% prediction limits. The new norms spanned higher spatial frequencies than the preliminary ACP norms between ages 1 month and 18 months but were similar between 24 and 36 months. The lower normal 2.5% limits were similar to lower limits of other normative studies. The interocular acuity difference was zero or 0.5 octave in 99% of subjects of all ages. Acuities obtained by the same tester on different days and by different testers on the same day were within 0.5 octave in at least 90% of subjects, comparable to previous studies. CONCLUSIONS: This study provides monocular acuity norms that are appropriate for clinical settings in which the ACP and TAC are used and should replace the preliminary ACP norms.

Decreased membrane "fluidity" of T lymphocytes from untreated patients with Hodgkin's disease.

Plasma membrane "fluidity" of peripheral blood T lymphocytes from untreated patients with Hodgkin's disease (HD) and healthy controls was studied using the fluorescent probes 1,6-diphenyl-1,3,5-hexatriene (DPH) and 1-(4(trimethylamino)phenyl)-6-phenyl-1,3,5-hexatriene (TMA-DPH). In 13 consecutive patients a significant increase of T lymphocyte plasma membrane microviscosity was observed with both DPH and TMA-DPH. These alterations seemed unrelated to the cholesterol (Chol) and phospholipid (PL) content of HD T lymphocytes since the Chol/PL ratio was comparable in both HD and control cells. Since prostaglandin E2 (PGE2) from monocytic origin has been claimed to be responsible for the impairment of cell-mediated immunity (CMI) associated with HD, we studied the effect of exogeneously added PGE2 (0.1 microM) on control subjects T lymphocyte membrane "fluidity". Using the fluorescent probe DPH and the spin labelled fatty acid probe 16 NMS for electron paramagnetic resonance study, we observed a PGE2-induced fluidization of control T lymphocyte membranes which is specifically located in the inner part of the plasma membrane, whereas the plasma membrane surface seemed unaffected by PGE2 as judged by the TMA-DPH probe. Thus, PGE2 does not appear to be responsible for the alterations of T lymphocyte membranes observed in HD. Intrinsic alterations and/or other mediators might be involved.

Membrane markers, karyotypic abnormalities, ultrastructure and functional properties of lymphocytes in a case of 'D-cell' chronic lymphatic leukemia.

D cells are lymphocytes bearing both receptors for the third complement component and the ability to form spontaneous rosettes with SRBC. We report the case of a patient with a D-cell chronic lymphatic leukemia who presented a long evolution without treatment and whose leukemic cell characteristics have been extensively studied. Cytogenetic analysis showed numerous karyotypic abnormalities among leukemic cells; all metaphases were hypodiploid and arranged in four different clones; seven marker chromosomes were present. The cells were found to bear human T-cell specific antigen, the T helper/inducer phenotype, HLA-A and HLA-B determinants, but no HLA-DR antigens. They displayed a high proliferative response to PHA and Con A, no response to PWM stimulation, and possibly the capacity of allogeneic stimulation in the mixed lymphocyte culture system. Assays for cell-mediated cytotoxicity in the CML system, and for K and NK activities were negative.

A life-threatening tracheal localization of lymphoma in a patient with AIDS.

Lymphoma is a frequent complication of HIV infection, but we report a rare localization in the subglottic tracheal area. A case of tracheal stenosis due to lymphoma in an HIV-infected patient is presented. The main complaint was severe dyspnea. Chemotherapy was ineffective but radiotherapy improved the patient's condition and increased the caliber of the tracheal lumen.

Assessing the role of case mix in cesarean delivery rates.

OBJECTIVE: Implicit in comparisons of unadjusted cesarean rates for hospitals and providers is the assumption that differences result from management practices rather than differences in case mix. This study proposes a method for comparison of cesarean rates that takes the effect of case mix into account. METHODS: All women delivered of infants at our institution from December 1, 1994, through July 31, 1995, were classified according to whether they received care from community-based practitioners (N=3913) or from the hospital-based practice that serves a higher-risk population (N=1556). Women were categorized according to both obstetric history (nulliparas, multiparas without a previous cesarean, multiparas with a previous cesarean) and the presence of obstetric conditions influencing the risk of cesarean delivery (multiple birth, breech presentation or transverse lie, preterm, no trial of labor for a medical indication). We determined the percent of women in each parity-obstetric condition subgroup and calculated a standardized cesarean rate for the hospital-based practice using the case mix of the community-based practitioners as the standard. RESULTS: The crude cesarean rate was higher for the hospital-based practice (24.4%) than for the community-based practitioners (21.5%), a rate difference of 2.9% (95% confidence interval=0.4%, 5.4%; P=.02). However, the proportion of women falling into categories conferring a high risk of cesarean delivery (multiple pregnancy, breech presentation or transverse lie, preterm, no trial of labor permitted) was twice as high for the hospital-based practice (24.4% hospital, 12.1% community). The standardization indicates that if the hospital-based practitioners had the same case mix as community-based practitioners, their overall cesarean rate would be 20.1%, similar to the 21.5% rate of community providers (rate difference=-1.4%, 95% confidence interval =-3.1%, 0.3%; P=.11). CONCLUSION: Standardization for case mix provides a mechanism for distinguishing differences in cesarean rates resulting from case mix from those relating to differences in practice. The methodology is not complex and could be applied to facilitate fairer comparisons of rates among providers and across institutions.