Papers by Constantin Yiannoutsos
BackgroundWe investigated the association between CYP2B6 polymorphisms and efavirenz drug resista... more BackgroundWe investigated the association between CYP2B6 polymorphisms and efavirenz drug resistance among women living with HIV started on anti-retroviral therapy during pregnancy and with high viremia during post-partum.MethodsThis was a cross sectional study. Women between 6-12 weeks post-partum with viral load >1000 copies/ml were eligible. Sanger sequencing to detect resistant mutations and host genotyping were performed. We categorized efavirenz metabolizer genotype according to the AIDS clinical trials group algorithm as slow, intermediate and extensive; and compared efavirenz resistance among the metabolizer genotypes.Results Over a one-year period (July 2017-July 2018), three hundred and thirty two women were screened of whom 112 (34.8%) had viral load ≥1000 copies/ml of whom 62 had whole blood available for genotyping. Fifty-nine of these women had both viral resistance and human host genotypic results. We observed a higher frequency of efavirenz resistance among slow m...
AIDS, 2016
Objective-To describe patterns of suboptimal immune recovery (SO-IR) and associated HIVrelated-il... more Objective-To describe patterns of suboptimal immune recovery (SO-IR) and associated HIVrelated-illnesses during the first 5 years following first-line antiretroviral therapy (ART) initiation across seven ART sites in East Africa. Design-Retrospective analysis of data from seven ART clinical sites (three Uganda, two Kenya and two Tanzania). Methods-SO-IR was described by proportions of ART-treated adults with CD4 + cell counts less than 200, less than 350 and less than 500 cells/μl. Kaplan-Meier survival analysis techniques were used to assess predictors of SO-IR, and incident rates of HIV-related illnesses at CD4 + cell counts less than 200, 200-350, 351-499, and >500 cells/μl, respectively. Results-Overall 80 843 adults initiated non-nucleoside reverse transcriptase inhibitor-based first-line ART; 65% were women and median CD4 + cell count was 126 [interquartile range (IQR), 52-202] cells/μl. Cumulative probability of SO-IR <200 cells/μl, <350 cells/μl and <500 cells/μl,
Journal of acquired immune deficiency syndromes (1999), 2014
Noncommunicable diseases (NCDs) account for a growing burden of morbidity and mortality among peo... more Noncommunicable diseases (NCDs) account for a growing burden of morbidity and mortality among people living with HIV in low- and middle-income countries (LMICs). HIV infection and antiretroviral therapy interact with NCD risk factors in complex ways, and research into this "web of causation" has so far been largely based on data from high-income countries. However, improving the understanding, treatment, and prevention of NCDs in LMICs requires region-specific evidence. Priority research areas include: (1) defining the burden of NCDs among people living with HIV, (2) understanding the impact of modifiable risk factors, (3) evaluating effective and efficient care strategies at individual and health systems levels, and (4) evaluating cost-effective prevention strategies. Meeting these needs will require observational data, both to inform the design of randomized trials and to replace trials that would be unethical or infeasible. Focusing on Sub-Saharan Africa, we discuss dat...
Clinical Genitourinary Cancer, 2014
Biomarkers to identify patients with metastatic prostate cancer who are destined to have a shorte... more Biomarkers to identify patients with metastatic prostate cancer who are destined to have a shorter response to testosterone suppression are limited. In a cohort of 63 patients, failure to suppress markers of bone turnover while receiving therapy was associated with a shorter time to progression. This suggests that more durable antieprostate cancer activity is associated with less cancer-associated bone turnover. Background: Elevated markers of bone turnover are prognostic for shorter survival in castration-resistant prostate cancer. We aimed to determine the prognostic value of bone turnover markers in metastatic hormone-sensitive prostate cancer. Patients and Methods: Markers of bone turnover (urine deoxypyridinoline [DPD] and N-telopeptide, serum bone alkaline phosphatase (AP), and osteocalcin [OC]) from baseline and after 6 months of study were assessed in men enrolled in a prospective metastatic prostate cancer trial with androgen deprivation therapy (ADT) with or without risedronate (ClinicalTrials.gov, NCT00216060). Results: Serum samples were collected from 63 patients with bone involvement and a median follow-up of 39.7 months. A multivariate model using Cox regression-which included prostate-specific antigen (PSA) nadir, bisphosphonate treatment, and extent of metastases-showed that suppression of bone turnover markers after 6 months of therapy compared with baseline was significantly associated with longer skeletal-related event (SRE)-free survival. ADT without bisphosphonate therapy was also associated with a decline in markers of bone turnover, presumably resulting from direct anticancer activity. Elevated baseline bone turnover markers were not prognostic. Conclusion: Failure to suppress bone turnover while receiving ADT, even when otherwise responding to therapy, may identify patients with hormone-sensitive metastatic prostate cancer who are destined for a shorter time to SREs and progression.
The Oncologist, 2007
Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide an... more Thalidomide has direct antimyeloma and immunomodulatory effects. In addition, both thalidomide and metronomic chemotherapy inhibit angiogenesis. The synergy of such a combination may decrease toxicity while maintaining efficacy. The Hoosier Oncology Group conducted a phase II trial of oral cyclophosphamide (50 mg b.i.d. for 21 days), thalidomide (200 mg/day), and prednisone (50 mg q.o.d.) (CTP) per 28-day course in patients with relapsed multiple myeloma (MM). Of the 37 patients enrolled, 16 had prior stem cell transplantation. The median follow-up time was 25.3 months (95% confidence interval [CI] 23.2–27.7). Of 35 patients treated, 22 patients (62.9%) responded: 7 (20.0%) complete responses, 2 (5.7%) near-complete responses, and 13 (37.1%) partial responses. Eight patients (22.9%) had stable disease, and three (8.6%) had disease progression. Two patients withdrew from the study early due to reasons unrelated to progression or toxicity and were treated as nonresponders. The median ...
NeuroImage, 2004
Objective: Differences in diagnostic criteria and methods have led to mixed results regarding the... more Objective: Differences in diagnostic criteria and methods have led to mixed results regarding the metabolite pattern of HIV-associated brain injury in relation to neurocognitive impairment. Therefore, a multicenter MRS consortium was formed to evaluate the neurometabolites in HIV patients with or without cognitive impairment. Methods: Proton magnetic resonance spectroscopy (MRS) at shortecho time (30 ms) was assessed in the frontal white matter, basal ganglia, and parietal cortex of 100 HIV patients [61 with AIDS dementia complex (ADC) and 39 neuroasymptomatic (NAS)] and 37 seronegative (SN) controls. Results: Compared to SN, NAS had higher glial marker myoinositol-to-creatine ratio (MI/Cr) in the white matter (multivariate analyses, adjusted P = 0.001), while ADC showed further increased MI/Cr in the white matter and basal ganglia (both P b 0.001), and increased choline compounds (Cho)/Cr in white matter (P = 0.04) and basal ganglia (P b 0.001). Compared to NAS, ADC showed a reduction in the neuronal marker N-acetyl compound (NA)/Cr in the frontal white matter (P = 0.007). CSF, but not plasma, viral load correlated with MI/Cr and Cho/Cr in white matter and NAA/Cr in parietal cortex. HIV infection and aging had additive effects on Cho/Cr and MI/Cr in the basal ganglia and white matter. Conclusions: The results suggest that glial activation occurs during the NAS stages of HIV infection, whereas further inflammatory activity in the basal ganglia and neuronal injury in the white matter is associated with the development of cognitive impairment. Aging may further exacerbate brain metabolites associated with inflammation in HIV patient and thereby increase the risk for cognitive impairment.
Molecular Cancer Therapeutics, 2007
The design of novel targeted or combination therapies may improve treatment options for pancreati... more The design of novel targeted or combination therapies may improve treatment options for pancreatic cancer. Two targets of recent interest are nuclear factor-κB (NF-κB) and cyclooxygenase (COX), known to be activated or overexpressed, respectively, in pancreatic cancer. We have previously shown that parthenolide, a proapoptotic drug associated with NF-κB inhibition, enhanced the growth suppression of pancreatic cancer cells by the COX inhibitor sulindac in vitro. In the present study, a bioavailable analogue of parthenolide, LC-1, and sulindac were evaluated in vivo using a xenograft model of human pancreatic cancer. Treatment groups included placebo, low-dose/high-dose LC-1 (20 and 40 mg/kg), low-dose/high-dose sulindac (20 and 60 mg/kg), and low-dose combination LC-1/sulindac (20 mg/kg each). In MiaPaCa-2 xenografts, tumor growth was inhibited by either high-dose sulindac or LC-1. In BxPC-3 xenografts, tumor size was significantly reduced by treatment with the low-dose LC-1/sulinda...
Journal of Neuroinflammation, 2013
Background: Neopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal flu... more Background: Neopterin, a biomarker of macrophage activation, is elevated in the cerebrospinal fluid (CSF) of most HIV-infected individuals and decreases after initiation of antiretroviral therapy (ART). We studied decay characteristics of neopterin in CSF and blood after commencement of ART in HIV-infected subjects and estimated the set-point levels of CSF neopterin after ART-mediated viral suppression. Methods: CSF and blood neopterin were longitudinally measured in 102 neurologically asymptomatic HIV-infected subjects who were treatment-naïve or had been off ART for ≥ 6 months. We used a non-linear model to estimate neopterin decay in response to ART and a stable neopterin set-point attained after prolonged ART. Seven subjects with HIV-associated dementia (HAD) who initiated ART were studied for comparison. Results: Non-HAD patients were followed for a median 84.7 months. Though CSF neopterin concentrations decreased rapidly after ART initiation, it was estimated that set-point levels would be below normal CSF neopterin levels (<5.8 nmol/L) in only 60/102 (59%) of these patients. Pre-ART CSF neopterin was the primary predictor of set-point (P <0.001). HAD subjects had higher baseline median CSF neopterin levels than non-HAD subjects (P <0.0001). Based on the non-HAD model, only 14% of HAD patients were predicted to reach normal levels. Conclusions: After virologically suppressive ART, abnormal CSF neopterin levels persisted in 41% of non-HAD and the majority of HAD patients. ART is not fully effective in ameliorating macrophage activation in CNS as well as blood, especially in subjects with higher pre-ART levels of immune activation.
Journal of Clinical Oncology, 2004
Purpose To identify prognostic variables and outcomes in patients with primary mediastinal nonsem... more Purpose To identify prognostic variables and outcomes in patients with primary mediastinal nonseminomatous germ cell tumor (PMNSGCT) with postchemotherapy resection of persistent cancer. Patients and Methods Forty-seven consecutive patients with residual cancer after resection of PMNSGCT were retrospectively reviewed. Univariate comparisons were performed. Results At diagnosis, 43 patients had elevated serum tumor markers (STMs), and 20 had extramediastinal disease. At resection, 21 patients had elevated STMs. After resection, 26 patients had germ cell tumors (GCT), 12 had malignant transformation of teratoma with elements of non-GCT, and nine had both GCT and non-GCT. Sixteen of 47 patients continuously have no evidence of disease (NED). This includes eight of 26 patients with GCT histology and two of 12 patients with non-GCT histology. Of 27 patients with mediastinal-only disease at presentation, 14 have continuously NED. Of 20 patients with extramediastinal disease at presentatio...
Journal of Clinical Oncology, 2008
Purpose Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III... more Purpose Concurrent chemoradiotherapy is standard treatment for patients with inoperable stage III non–small-cell lung cancer (NSCLC). A phase II study by the Southwest Oncology Group using consolidation docetaxel after cisplatin (P), etoposide (E), and radiation (XRT) resulted in a median survival time (MST) of 26 months. This randomized phase III trial evaluated whether consolidation docetaxel was responsible for this improved survival. Patients and Methods Eligible patients had stage IIIA or IIIB NSCLC, baseline performance status of 0 to 1, forced expiratory volume in 1 second ≥ 1 L, and less than 5% weight loss. Patients received P 50 mg/m2 intravenously (IV) on days 1, 8, 29, and 36 and E 50 mg/m2 IV on days 1-5 and 29-33 concurrently with chest XRT to 59.40 Gy. Patients who did not experience progression were randomly assigned to docetaxel 75 mg/m2 IV every 21 days for three cycles versus observation. The primary end point was to compare overall survival (Kaplan-Meier analysis...
Journal of Clinical Oncology, 2006
Purpose Surgical resection is standard therapy in stage I non–small-cell lung cancer (NSCLC); how... more Purpose Surgical resection is standard therapy in stage I non–small-cell lung cancer (NSCLC); however, many patients are inoperable due to comorbid diseases. Building on a previously reported phase I trial, we carried out a prospective phase II trial using stereotactic body radiation therapy (SBRT) in this population. Patients and Methods Eligible patients included clinically staged T1 or T2 (≤ 7 cm), N0, M0, biopsy-confirmed NSCLC. All patients had comorbid medical problems that precluded lobectomy. SBRT treatment dose was 60 to 66 Gy total in three fractions during 1 to 2 weeks. Results All 70 patients enrolled completed therapy as planned and median follow-up was 17.5 months. The 3-month major response rate was 60%. Kaplan-Meier local control at 2 years was 95%. Altogether, 28 patients have died as a result of cancer (n = 5), treatment (n = 6), or comorbid illnesses (n = 17). Median overall survival was 32.6 months and 2-year overall survival was 54.7%. Grade 3 to 5 toxicity occu...
Expert Review of Anticancer Therapy, 2008
Stereotactic body radiation therapy has emerged as a novel oncologic therapy and experience with ... more Stereotactic body radiation therapy has emerged as a novel oncologic therapy and experience with the use of stereotactic body radiation therapy for the treatment of early-stage non-small-cell lung cancer has grown over the last 10 years. This article reviews the radiobiologic, physical/technical and clinical aspects of stereotactic body radiation therapy for early-stage non-small-cell lung cancer. The literature is also reviewed.
Biology of Blood and Marrow Transplantation, 2006
has acceptable short-term survival, it is important to report longer outcome durations and delaye... more has acceptable short-term survival, it is important to report longer outcome durations and delayed complications. In this report, retrospective analyses after transplantation from 2 centers from 1985 to 2003 were evaluated. Sixty-nine patients were evaluated, median age 33 years (16-75), 43 men and 26 women, 55 had nodular sclerosing HD, 7-lymphocyte predominant, 6-mixed cellular HD, and 1-unknown subtype. Conditioning regimens consisted of TBI/ Cyclophosphamide in 11 patients, CBV in 38, BEAM/BEAC in 16, and Busulfan/Cyclophosphamide in 4. Forty-nine patients received peripheral stem cells (PSC), 17 received bone marrow (BM), and 3 received PSC plus BM. Seven patients (10%) had early mortality (Ͻ100 days) directly attributable to the transplant procedure. Four were cardiac-related and two due to infection. Long-term nondisease related mortality occurred in 16% secondary to MDS/ AML, cardiac, respiratory, and infectious-related causes. Thirtyseven patients are alive, 30 patients have died, and 2 are lost to follow-up. The OS at 5 years was 49% and 21% at 10-years, respectively, while DFS at 5 years was 41% and 33% at 10 years, respectively, indicating that patients were dying of other causes late after transplantation. No difference in OS and DFS was noted according to disease status at transplantation (CR vs active disease), gender, or PSC vs BM. However, significant differences were noted in OS (P Ͻ .05) and DFS (P Ͻ .05) according to sensitivity to salvage therapy administered prior to transplantation. Achievement of CR after transplantation had a significant effect on OS. At the median follow-up of 32 months, the OS is 83%, with a predicted OS at 10 years of 68%. Failure to achieve CR after transplantation was associated with reduced OS, with 38% alive at 32 months, and all died by 10 years post-transplant. In conclusion, autologous transplantation offers a good long-term survival option for patients with relapsed/resistant HD. However, if CR is not attained after transplantation, alternative therapies should be pursued, because long-term outcomes for this patient group is dismal.
Annals of Oncology, 2005
Background: Recombinant human angiostatin (rhAngiostatin) functions as a potent inhibitor of angi... more Background: Recombinant human angiostatin (rhAngiostatin) functions as a potent inhibitor of angiogenesis. This study combined rhAngiostatin with a standard chemotherapy regimen in patients with advanced non-small-cell lung cancer (NSCLC). Patients and methods: Eligible patients had chemotherapy-naïve stage IIIB (with pleural effusion) or IV NSCLC, performance status (PS) 0 or 1, no history of bleeding, brain metastasis or requirements for anti-coagulation. Patients received carboplatin (AUC 5) intravenously and paclitaxel (175 mg/m 2) intravenously day 1 + subcutaneous rhAngiostatin at either 15 mg or 60 mg twice daily. Cycles were repeated every 3 weeks, for up to six cycles. Patients without progression after completing at least four cycles were continued on maintenance rhAngiostatin until disease progression. Results: Patient characteristics (n = 24) were: 16 males, median age 66 years (range 45-78), 54% PS 1, 83.3% stage IV and 62.5% adenocarcinoma. Grade 3/4 toxicities included: fatigue 47.8%, neutropenia 39.1%, dyspnea 39.1%, vascular 26.1% and infection 17.4%. The overall response rate was 39.1%, 39.1% stable disease and 21.7% progressive disease. Median time to progression was 144 days, and 1-year survival was 45.8%. Conclusions: rhAngiostatin in combination with paclitaxel and carboplatin is feasible and results in a high disease control rate in patients with advanced NSCLC.
Annals of Neurology, 1999
Background: Human immunodeficiency virus (HIV) infection is associated with abnormal high-density... more Background: Human immunodeficiency virus (HIV) infection is associated with abnormal high-density lipoprotein (HDL) particles. We evaluated whether HIV infection and antiretroviral treatment promotes changes in cholesterol distribution among subpopulations of HDL particles of defined sizes. Methods: HDL particles were isolated from 78 HIV infected patients and fractionated by gel permeation chromatography to obtain five subpopulations. Thirty-six patients were antiretroviral treatment naïve, while 42 patients were treated with efavirenz or protease inhibitors. Uninfected individuals were also included as controls. Results: The distribution of cholesterol across HDL particle sizes was affected by HIV infection itself. Antiretroviral therapy reduced these alterations; only minor changes in small and very small HDL particles were observed in treated patients (ps0.01). Untreated patients with low CD4q T cell counts had less cholesterol in medium (ps0.006), small (ps0.04) and very small (ps0.03) HDL particles. Treated patients with high CD4q T cell counts had less cholesterol in the largest HDL particles (ps0.04), with overall particle distributions resembling those observed in uninfected participants.
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, Jan 15, 2018
Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the ... more Progressive multifocal leukoencephalopathy (PML) is a severe demyelinating disease caused by the polyomavirus JC (JCV) affecting subjects with impaired immune system. While JCV-DNA detection in cerebrospinal fluid (CSF) is diagnostic of PML, the clinical significance of plasma JCV-DNA is still uncertain. We retrospectively analyzed plasma samples drawn from patients with PML close to disease onset, and controls without PML. In PML patients, we compared plasma JCV DNA detection and levels to: JCV DNA in the other biological samples, clinical and laboratory parameters and patients' survival. JCV-DNA was detected in plasma of 49/103 (48%) patients with PML (20/24, 83%, HIV-negative; 29/79, 37%, HIV-positive) and of 4/144 (3%) controls without PML (0/95 HIV-negative; 4/49, 8%, HIV-positive), yielding a diagnostic sensitivity and specificity of, respectively, 48% and 97% (83% and 100% in HIV-negative; 37% and 92% in HIV-positive). Among 16 PML patients with undetectable CSF JCV-DNA, ...
To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol ... more To determine whether the preclinical antitumor and antiangiogenic activity of 2-methoxyestradiol can be translated to the clinic. Experimental Design: Men with hormone-refractory prostate cancer were enrolled into this phase II randomized, double-blind trial of two doses of oral 2-methoxyestradiol capsules (400 and 1,200 mg/d) given in 4-week cycles. Pharmacokinetic sampling was done on day 1of cycles 1and 2 and trough samples were obtained weekly. Results: Thirty-three men were accrued between February and September 2001. The notable toxicity related to therapy was one grade 2 and two grade 3 episodes of liver transaminase elevation, which resolved with continued treatment in two patients. There were two cases of deep venous thromboses. The drug had nonlinear pharmacokinetic, rapid conversion to 2-methoxyestrone and f85% conjugation. Trough plasma levels of unconjugated 2-methoxyestradiol and 2-methoxyestrone were f4 and 40 ng/mL, respectively. Prostate-specific antigen declines between 21% and 40% were seen in seven patients in the 1,200 mg group and in one patient in the 400 mg group. The higher-dose group showed significantly decreased prostatespecific antigen velocity (P = 0.037) and compared with the 400 mg dose had a longer median time to prostate-specific antigen progression (109 versus 67 days; P = 0.094) and time on study (126 versus 61 days; P = 0.024). There was a 2.5-and 4-fold increase in sex hormone-binding globulin for the 400 and 1,200 mg dose levels, respectively, at days 28 and 56. Conclusion: 2-Methoxyestradiol is well tolerated and, despite suboptimal plasma levels and limited oral bioavailability with this capsule formulation, still showed some anticancer activity at 1,200 mg/d.
JAIDS Journal of …
Winstone M. Nyandiko, MBChB, MMed,* Samuel Ayaya, MBChB, MMed,* Esther Nabakwe, MBChB, MMed,* Con... more Winstone M. Nyandiko, MBChB, MMed,* Samuel Ayaya, MBChB, MMed,* Esther Nabakwe, MBChB, MMed,* Constance Tenge, MBChB, MMed,* John E. Sidle, MD,† Constantin T. Yiannoutsos, PhD,†‡ Beverly Musick, MS,† Kara Wools-Kaloustian, MD,† and William M. ...
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Papers by Constantin Yiannoutsos