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Anas Younes

Publications and source records attributed to Anas Younes.

At least 19 recordsLinked to original sources
PubMed2007

Experience with heat shock protein-peptide complex 96 vaccine therapy in patients with indolent non-Hodgkin lymphoma.

BACKGROUND: The objective of this phase II trial was to investigate the safety and efficacy of autologous heat shock protein-peptide complex 96 (HSPPC-96) vaccines prepared from tumor specimens of patients with newly diagnosed or previously treated indolent non-Hodgkin lymphoma (NHL). METHODS: The study was for patients with indolent B-cell NHL with measurable lesions. HSPPC-96 vaccines were prepared from patients' resected tumor specimens and administered as a 25-microg intradermal injection in the absence of disease progression every week for 4 weeks and then every 2 weeks until the vaccine supply was exhausted. RESULTS: Twenty patients were enrolled in this trial. The median patient age was 59 years. Ten patients had been treated previously (median, 2 regimens; range, 1 to 7). Eighteen (90%) patients had stage III or IV disease. Autologous vaccines were successfully prepared for 17 (85%) patients and all received at least 1 dose. The treatment was very well tolerated. One patient experienced a response with biopsy-proven clearance of the lymphoma cells in 2 of the skin nodules at 3.0 months that lasted for 7.0 months. Eight patients had stable disease for 6.0 to 19.8 months. The median failure-free survival duration in patients who received vaccine therapy was 5.2 months. CONCLUSIONS: HSPPC-96 can be prepared from tumor specimens for the majority of lymphoma patients, but it had limited efficacy in inducing responses in patients with active diseases. Further studies of HSPPCs, therefore, should be considered in adjuvant settings or in combination with other immunomodulatory agents to assess survival benefit.

Aged↗
PubMed2006

K1 protein of human herpesvirus 8 suppresses lymphoma cell Fas-mediated apoptosis.

Expression of the K1 gene of human herpesvirus 8 activates nuclear factor-kappaB and induces lymph node hyperplasia and lymphomas in transgenic mice. To further delineate its role in cell survival, we determined whether K1 altered apoptosis of lymphoma cells. K1 protein is expressed in Kaposi sarcoma and primary effusion lymphoma. We retrovirally transfected BJAB lymphoma, THP-1, U937, and Kaposi sarcoma SLK cells to express K1 and a K1 mutant with the deleted immunoreceptor tyrosine-based activation motif (K1m). We challenged cells with an agonistic anti-Fas antibody, Fas ligand, irradiation, and tumor necrosis factor-related apoptosis-inducing ligand. K1 transfectants but not K1m transfectants exhibited reduced levels of apoptosis induced by the anti-Fas antibody but not apoptosis induced by the tumor necrosis factor-related apoptosis-inducing ligand or irradiation. K1 expression resulted in reduced apoptosis rates as shown in several assays. K1 induced a modest reduction in levels of Fas-associated death domain protein, and procaspase 8 recruited to the death-inducing signaling complex. Finally, K1 transfectants cleaved procaspase 8 at significantly lower rates than did K1m transfectants. K1-transfected mice, compared with vector-transfected mice, showed lower death rates after challenge with anti-Fas antibody. K1 may contribute to lymphoma development by stimulating cell survival by selectively blocking Fas-mediated apoptosis.

Antibodies↗
PubMed2006

Safety and efficacy of once-per-cycle pegfilgrastim in support of ABVD chemotherapy in patients with Hodgkin lymphoma.

The objective of this prospective study was to examine the safety and efficacy of pegfilgrastim in support of chemotherapy regimens that are administered every 14 d. Patients with Hodgkin lymphoma receiving standard ABVD (doxorubicin, bleomycin, vinblastine, and decarbazine) chemotherapy every 14 d were eligible for the study. All patients received one fixed dose of 6 mg pegfilgrastim approximately 24h after each ABVD infusion. Absolute neutrophil counts (ANCs) were measured weekly while on therapy. After completion of therapy, ANCs were measured every 3-4 months for 2 years, and every 6 months thereafter. Twenty-three patients received 115 courses (230 doses) of ABVD. Nadir ANC below 0.5 x 10(9)/L was observed only in two cases (1.1%), and ANC counts on the day of ABVD therapy below 1 x 10(9)/L was observed only once (0.4%). No neutropenic fever was observed. Two hundred and fifteen (93.5%) doses of ABVD were given on time as scheduled. Grade 3/4 bone pain was observed after 0.4% of ABVD doses, and bleomycin lung toxicity was observed in two patients. With a median follow-up of 29 months after completion of ABVD, no myelodysplastic syndrome was observed. Two patients relapsed and subsequently underwent successful stem cell collection and transplantation. Pegfilgrastim was found to be safe in support of ABVD chemotherapy that is administered every 14 d. Pegfilgrastim was also effective in maintaining ABVD dose intensity, and keeping planned dose of chemotherapy on schedule.

Adult↗
PubMed2006

The heat shock protein 90 inhibitor 17-AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9.

Mantle cell lymphoma (MCL), a distinct type of non-Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17-allylamino-17-demethoxy-geldanamycin (17-AAG), a HSP90 small molecule inhibitor, induced G(0/1) cell cycle arrest and cell death in a dose- and time-dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17-AAG may have a potential therapeutic value in patients with MCL.

Antineoplastic Agents↗
PubMed2006

Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M.D. Anderson Cancer Center.

PURPOSE: Advanced-stage follicular lymphoma is considered incurable. The pace of improvements in treatment has been slow. This article analyzes five sequential cohorts of patients with stage IV follicular lymphoma treated between 1972 and 2002. METHODS: Five consecutive studies (two were randomized trials) involving 580 patients were analyzed for overall survival (OS), failure-free survival (FFS), and survival after first relapse. A proportional hazards analysis, and subset analyses using the follicular lymphoma international prognostic index (FLIPI) score were performed. Treatment regimens included: cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin (CHOP-Bleo); CHOP-Bleo followed by interferon alfa (IFN-alpha); a rotation of three regimens (alternating triple therapy), followed by IFN-alpha; fludarabine, mitoxantrone, dexamethasone (FND) followed by IFN-alpha; and FND plus delayed versus concurrent rituximab followed by IFN-alpha. RESULTS: Improvements in 5-year OS (from 64% to 95%) and FFS (from 29% to 60%) indicate steady progress, perhaps partly due to more effective salvage therapies, but the FFS data also indicate improved front-line therapies; these observations held true after controlling for differences in prognostic factors among the cohorts. The FLIPI model adds rigor to and facilitates comparisons among the different cohorts. An unexpected finding in this study was a trend toward an apparent FFS plateau. CONCLUSION: Evolving therapy, including the incorporation of biologic agents, has led to stepwise significant outcome improvements for patients with advanced-stage follicular lymphoma. The apparent plateau in the FFS curve, starting approximately 8 to 10 years from the beginning of treatment, raises the issue of the potential curability of these patients.

Adult↗
PubMed2006

Functional expression of TRAIL receptors TRAIL-R1 and TRAIL-R2 in esophageal adenocarcinoma.

The tumour necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL/Apo2L) is a member of the TNF superfamily that preferentially induces apoptosis in cancer cells, while sparing normal cells. TRAIL induces apoptosis by interacting with its receptors TRAIL-R1 and TRAIL-R2. Recently, new humanized agonistic anti-TRAIL-R1 and anti-TRAIL-R2 antibodies have been developed, and are undergoing phase I/II clinical trails. Esophageal adenocarcinoma (EA) is associated with significantly poor outcome and is rapidly increasing in incidence in the United States and Western Europe, with virtually no effective non-surgical treatment. The aim of this study was to determine whether human EA tissue express TRAIL-R1 and/or TRAIL-R2, and whether EA cell lines Bic-1 and Seg-1 expresses functional TRAIL-R1 and/or TRAIL-R2. The expression of TRAIL-R1 and TRAIL-R2 was determined in sections from 18 human EA by immunohistochemistry (IHC). Sixteen (89%) of the EA expressed TRAIL-R1 and 17 (94%) expressed TRAIL-R2. Both cell lines were found to express TRAIL-R1 and TRAIL-R2 by western blot analysis, IHC, and flow cytometry. The fully human agonistic TRAIL-R1 (HGS-ETR1) and TRAIL-R2 (HGS-ETR2) antibodies induced apoptosis in Bic-1 and Seg-1 cells in a time and dose dependent manner. Our results show that the vast majority of primary human EA express TRAIL-R1 and TRAIL-R2 and that EA cells lines express functional TRAIL-R1 and TRAIL-R2. Targeting of these receptors by agonist monoclonal antibodies may be of therapeutic value in patients with EA.

Adenocarcinoma↗
PubMed2006

Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase, dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest and cell death.

PURPOSE: Heat shock protein 90 (HSP90) is a chaperone for several client proteins involved in transcriptional regulation, signal transduction, and cell cycle control. HSP90 is abundantly expressed by a variety of tumor types and has been recently targeted for cancer therapy. The objective of this study was to determine the role of HSP90 in promoting growth and survival of Hodgkin's lymphoma and to determine the molecular consequences of inhibiting HSP90 function by the small-molecule 17-allylamino-17-demethoxy-geldanamycin (17-AAG) in Hodgkin's lymphoma. EXPERIMENTAL DESIGN: HSP90 expression in Hodgkin's lymphoma cell lines was determined by Western blot and in primary lymph node sections from patients with Hodgkin's lymphoma by immunohistochemistry. Cell viability was determined by the 3-(4,5-dimethyl-thiazol-2yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. Apoptosis and cell cycle fractions were determined by flow cytometry. Expression of intracellular proteins was determined by Western blot. RESULTS: HSP90 is overexpressed in primary and cultured Hodgkin's lymphoma cells. Inhibition of HSP90 function by 17-AAG showed a time- and dose-dependent growth inhibition of Hodgkin's lymphoma cell lines. 17-AAG induced cell cycle arrest and apoptosis, which were associated with a decrease in cyclin-dependent kinase (CDK) 4, CDK 6, and polo-like kinase 1 (PLK1), and induced apoptosis by caspase-dependent and caspase-independent mechanisms. Furthermore, 17-AAG depleted cellular contents of Akt, decreased extracellular signal-regulated kinase (ERK) phosphorylation, and reduced cellular FLICE-like inhibitory protein levels (FLIP), and thus enhanced the cytotoxic effect of doxorubicin and agonistic anti-tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor antibodies. CONCLUSION: Inhibition of HSP90 function induces cell death and enhances the activity of chemotherapy and anti-tumor necrosis factor-related apoptosis-inducing ligand death receptor antibodies, suggesting that targeting HSP90 function might be of therapeutic value in Hodgkin's lymphoma.

Adaptor Proteins, Signal Transducing↗
PubMed2006

The HSP90 inhibitor 17-AAG synergizes with doxorubicin and U0126 in anaplastic large cell lymphoma irrespective of ALK expression.

OBJECTIVE: Heat shock protein 90 (HSP90) chaperones and maintains the molecular integrity of a variety of signal transduction proteins, including the nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) oncogenic protein, a genetic abnormality that is frequently observed in anaplastic large cell lymphoma (ALCL) cells. Here we demonstrate that HSP90 is overexpressed in primary and cultured ALK-positive and ALK-negative ALCL cells, and we evaluate the potential role of the small molecule inhibitor of HSP90, 17-allylamino-17-demethoxygeldanamycin (17-AAG) in treating ALCL. METHODS: The antiproliferative effect of 17-AAG-cultured cells was determined by MTS assay. Apoptosis and cell-cycle arrest were determined by Annexin-V/propidium iodide and propidium iodide staining, respectively, and fluorescein-activated cell sorting analysis. Expression of HSP90 was evaluated by immunohistochemistry, and molecular changes were determined by Western blot. RESULTS: Treatment of cultured ALCL cells with 17-AAG induced cell-cycle arrest and apoptosis, irrespective of ALK expression. At the molecular level, 17-AAG induced degradation of ALK and Akt proteins, dephosphorylated extracellular signal-regulated kinase, and degraded the cell-cycle regulatory protein cyclin D1 and its cyclin-dependent kinases, CDK4 and CDK6, but had a differential effect on p27 and p53 proteins. Inhibition of extracellular signal-regulated kinase phosphorylation by the mitogen activated protein kinase inhibitor U0126 induced cell death in all ALCL cell lines, and sublethal concentration 17-AAG showed synergistic antiproliferative effects when combined with U0126 or doxorubicin. CONCLUSION: Our data demonstrate that targeting HSP90 function by 17-AAG may offer a novel therapeutic strategy for ALCL, either as single-agent activity or by combining 17-AAG with conventional or targeted therapeutic schemes.

Anaplastic Lymphoma Kinase↗
PubMed2006

Pegfilgrastim administered in a single fixed dose is effective in inducing neutrophil count recovery after paclitaxel and topotecan chemotherapy in patients with relapsed aggressive non-Hodgkin's lymphoma.

Pegfilgrastim is a pegylated form of a granulocyte colony-stimulating factor with a long half-life allowing for a single administration per chemotherapy cycle. The efficacy of a single dose of pegfilgrastim in supporting severely myelosuppressive regimens in previously treated cancer patients is unknown. Patients included in the present study had recurrent or refractory aggressive non-Hodgkin's lymphoma (NHL), had received two to three prior treatment regimens, and had good performance status and marrow reserve. Patients received intravenous paclitaxel 200 mg/m(2) on day 1 and topotecan 1 mg/m(2) daily for 5 days, repeated every 21 days for at least two cycles. On day 6, patients were given a single fixed dose of pegfilgrastim (6 mg) subcutaneously. Twenty patients were evaluable for analysis. After the first course of therapy, grade 4 neutropenia developed in all 20 patients. The median time to the neutrophil nadir was 9 days. The mean +/- SD duration of grade 4 neutropenia was 3.8 +/- 1.7 days. Nineteen (95%) patients received cycle 2 on time, on day 22. Five patients developed neutropenic fever (25%), which was associated with infection in one patient. In these previously treated patients with NHL, a single dose of pegfilgrastim was effective in promoting neutrophil count recovery after paclitaxel and topotecan, and allowed patients to receive the next planned dose on time.

Adult↗
PubMed2006

Phase 2 study of fludarabine and paclitaxel in patients with recurrent low-grade non-Hodgkin's lymphoma.

Although numerous options are available for patients with recurrent low-grade non-Hodgkin's lymphoma (NHL), responses are rarely durable. We previously conducted a phase I trial of fludarabine and paclitaxel in the treatment of recurrent low-grade lymphoma. The present phase II study was performed to determine the activity of fludarabine and paclitaxel in patients with recurrent low-grade NHL. Patients with histologically confirmed recurrent low-grade NHL were treated with fludarabine 20 mg/m2/day intravenously (i.v.) on days 1-5 plus paclitaxel 50 mg/m2 given by i.v. continuous infusion over 72 h starting on day 1. Treatment was repeated at 4-week intervals for a maximum of six courses. Twenty-eight evaluable patients were entered into this phase II trial. The median age was 53 years and the median performance status (Zubrod) was 1. Twenty-two (78%) patients had grade 1 or 2 follicular lymphoma, and six patients (21%) had small lymphocytic lymphoma. The median number of prior chemotherapy regimens was 1 (range, 1-3). Objective responses occurred in 16 patients (57%); nine patients (32%) achieved a complete remission with a median duration of 32 months (range 4-84+ months), and seven patients (25%) had a partial remission. Grade 3 and 4 toxicities included neutropenia (72%), neutropenic fever (34%), infection (13%), mucositis (7%), and neuropathy (3%). The combination of fludarabine and paclitaxel has clinical activity in patients with recurrent low-grade NHL.

Adult↗
PubMed2006

Inhibition of the phosphatidylinositol-3 kinase/Akt promotes G1 cell cycle arrest and apoptosis in Hodgkin lymphoma.

Activation of the phosphatidylinositol 3-kinase (PI(3)K) pathway has been linked with tumour cell growth, survival and resistance to therapy in several cancer types. The active, phosphorylated form of Akt (pAkt) was found to be aberrantly expressed in Hodgkin lymphoma (HL)-derived cell lines and in Hodgkin-Reed-Sternberg (HRS) cells in 27 of 42 (64.3%) of primary lymph node sections of HL, indicative of PI(3)K activity. Akt phosphorylation was not associated with loss of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) expression, but with its phosphorylation in HL-cell lines, suggesting that its biological function is impaired. Akt phosphorylation was further induced by CD30 ligand (CD30L), CD40L and receptor activator of nuclear factor kappa B (RANK) ligand. The PI(3)K inhibitor LY294002 demonstrated antiproliferative effects in a dose- and time-dependent manner, which was associated with Akt dephosphorylation on Thr308 and Ser473 sites and dephosphorylation of the downstream ribosomal protein S6. LY209002 induced cell cycle arrest in the G0/G1 phase and apoptosis, which were associated with upregulation of MDM2, downregulation of cyclin D1, activation of caspase 9 and poly-ADP-ribose polymerase cleavage. The Akt inhibitor QLT394 also demonstrated antiproliferative effects in a dose- and time-dependent manner, dephosphorylated ribosomal S6 and cleaved caspase 9. Collectively, these data suggest that the aberrant activation of the PI(3)K/Akt survival pathway in HRS cells is not because of loss of PTEN expression. Our data suggest that PTEN phosphorylation and activation of CD30, CD40 and RANK may play a role in activating Akt in HRS cells.

Antigens, CD↗
PubMed2006

Novel treatment strategies for aggressive non-Hodgkin's lymphoma.

The World Health Organization has included different types of lymphoma under the aggressive category. In the US, diffuse large B-cell lymphoma is the most common aggressive lymphoma and accounts for > 30% of the 55,000 new cases diagnosed annually. Recent advances in the knowledge of the molecular biology have provided an increased understanding of the heterogeneity of non-Hodgkin's lymphoma. New treatments, especially those with the use of monoclonal antibodies, are improving both the survival and the response rate.

Antineoplastic Agents↗
PubMed2006

From Rapa Nui to rapamycin: targeting PI3K/Akt/mTOR for cancer therapy.

One of the most prominent pathways explored in the area of targeted therapy is the PI3K/Akt/mTOR pathway, which plays a central role in cell survival and proliferation. Deregulation of this pathway has been implicated in the promotion of cancer cell growth and survival. Inhibition of several steps of this pathway has been shown to confer favorable antitumor activity in a variety of cancer types. This article provides a brief analysis of the PI3K/Akt/mTOR pathway, its importance in tumor pathogenesis and the current status of preclinical and clinical studies targeting signaling components of this pathway.

Antibiotics, Antineoplastic↗
PubMed2006

Hodgkin's lymphoma: molecular targets and novel treatment strategies.

The WHO classification of Hodgkin's lymphoma (HL) distinguishes between two major subtypes, classical and nodular lymphocyte predominant HL. Approximately 95% of patients with HL will have the classical HL histology, which is characterized by the presence of rare malignant Hodgkin's and Reed-Sternberg cells among an overwhelming number of benign reactive cells. In recent years, new studies have shed more light on the biological and molecular features of Hodgkin's and Reed-Sternberg cells, providing hope that new targeted therapy may be developed to enhance the cure rate and to reduce treatment-related toxicity. In this review, the current understanding of the pathology and biology of HL will be discussed, as well as the current treatment approaches for patients with classical HL. Future treatment strategies will also be discussed based on our understanding of HL biology.

Hodgkin Disease↗
PubMed2006

Cytomegalovirus infection in patients with lymphoma: an important cause of morbidity and mortality.

BACKGROUND: Cytomegalovirus (CMV) antigenemia (CMV-A) and CMV disease (CMV-D), known causes of morbidity and mortality among patients with leukemia and recipients of hematopoietic stem cell transplantations, are described sporadically in patients with lymphoma. We sought to determine the risk factors and outcome of CMV-A and CMV-D among patients with lymphoma. PATIENTS AND METHODS: We conducted a retrospective cohort study with such patients identified between 1997 and 2003 at The University of Texas M. D. Anderson Cancer Center. Seventy-one patients with 82 episodes of CMV-A and/or CMV-D (CMV-A in 38 episodes and CMV-D in 44 episodes) were studied. RESULTS: Cytomegalovirus antigenemia and/or CMV-D were more common among patients with non-Hodgkin's lymphoma than among those with Hodgkin's disease (P = 0.01). Most CMV infectious episodes occurred in patients who had active (88%) and stage III/IV lymphoma (84%). Eleven of 65 patients (17%) with outcome data died with CMV-A and/or CMV-D. Death with CMV infection was more common among patients with CMV-D than among those with CMV-A (29% vs. 3%, respectively, P = 0.005). Predictors of death by univariate analysis included intensive care unit admission, mechanical ventilation, high antigenemia burden, relapse of CMV-A and/or CMV-D, and antiviral-associated toxicity (all P < 0.05). Multivariate analysis identified antiviral toxicity as the only independent predictor of death (P = 0.01). CONCLUSION: In an era of intense and pleiotropic immunosuppressive therapy in patients with lymphoma, CMV-A and CMV-D are significant infections. Preventive strategies might be warranted for patients at risk.

Adolescent↗
PubMed2006

Targeting lymphoma cells and their microenvironment with novel antibodies.

Novel monoclonal antibodies are currently being evaluated and have been shown to have significantly influenced the treatment of Hodgkin's and non-Hodgkin's lymphoma. It is of the utmost importance to reduce treatment-related toxicity and, hopefully, improve the cure rate of lymphoma. This is possible by using novel therapies such as monoclonal antibodies, which target tumor cells while sparing normal cells. Investigational antibody therapies include those targeting malignant cells as well as those targeting the microenvironment. Continued investigation is encouraged to combine monoclonal antibodies with other targeted therapies and incorporate their use into standards of care in the treatment of lymphoma.

Antibodies, Monoclonal↗
PubMed2005

Cytomegalovirus pneumonia in patients with lymphoma.

BACKGROUND: Even when treated with antiviral therapy, cytomegalovirus pneumonia (CMVp) is associated with high morbidity and mortality in immunocompromised patients. CMVp has been rarely reported in patients with lymphoma. METHODS: The authors reviewed the records of patients treated at The University of Texas M. D. Anderson Cancer Center (Houston, TX) between 1997 and 2003. Collected information included demographics, use of chemotherapy, or corticosteroids, concomitant infections, and outcome. RESULTS: Thirty-one patients with lymphoma with 36 episodes of CMVp were identified. The incidence of CMVp increased between 1997 and 2003 (0 of 1000 treated patients vs. 9 of 1000 treated patients; P = 0.07). Most episodes occurred in patients with non-Hodgkin lymphoma (89%). Most of the patients (92%) had received chemotherapy and corticosteroids (89%) before the onset of CMVp. Concomitant CMV antigenemia was detected in 11 (41%) of the 27 episodes in which testing was performed. In 19 episodes (53%), patients had coinfections within 90 days of the episode of CMVp. Coinfections were present at the onset of CMVp in 11 episodes (31%). The yield for CMV in bronchoalveolar lavage (BAL) specimens was higher with culture methods than with cytologic evaluation or immunohistochemical staining (P < 0.001). The number of CMV antigenemia tests performed increased fourfold over the study period. The CMV-attributed mortality rate was 30% (9 of 30 patients). Independent predictors of death by multivariate Cox regression analysis were high APACHE II score (> 16) at onset of CMVp (P = 0.02, hazards ratio [HR] = 15.5, 95% confidence interval [CI], 1.5-163.7), and development of toxicity to antivirals (P = 0.04, HR = 14.03, 95% CI, 1.2-169.1). CONCLUSIONS: The incidence of CMVp in patients with lymphoma is increasing. CMV detection in BAL specimens was better with culture methods than with cytologic or immunohistochemical methods. High APACHE II score and development of antiviral toxicity were associated with a fatal outcome.

APACHE↗