Utilizing Video-Assisted Retroperitoneal Debridement for Retroperitoneal Abscess Following Penetrating Trauma.

Retroperitoneal abscess as a sequela of penetrating trauma can pose a difficult clinical scenario for surgeons and literature to inform decision making is sparse. It is logical to follow a "step-up" approach applied to other etiologies of infected retroperitoneal fluid collections, such as infected pancreatic necrosis and perinephric abscess. Video-assisted retroperitoneal debridement (VARD) is a well-established approach in infected pancreatic necrosis when surgical debridement is warranted. Minimally invasive retroperitoneal approaches have emerged in a broadening range of etiologies and specialties. We describe our experience utilizing VARDs in two patients that developed retroperitoneal abscesses following gunshot injuries to bowel and proximal urinary system. Both failed a conservative approach including antibiotic and percutaneous drains. Rapid improvement and subsequent discharge were observed within days of VARD procedure. We believe VARD to be a viable approach to post-trauma retroperitoneal abscesses when surgical drainage is indicated, and anatomy is favorable.

Nonclinical safety assessment of engineered T cell therapies.

Over the last decade, immunotherapy has established itself as an important novel approach in the treatment of cancer, resulting in a growing importance in oncology. Engineered T cell therapies, namely chimeric antigen receptor (CAR) T cells and T cell receptor (TCR) T cell therapies, are platform technologies that have enabled the development of products with remarkable efficacy in several hematological malignancies and are thus the focus of intense research and development activity. While engineered T cell therapies offer promise in addressing currently intractable cancers, they also present unique challenges, including their nonclinical safety assessment. A workshop organized by HESI and the US Food and Drug Administration (FDA) was held to provide an interdisciplinary forum for representatives of industry, academia and regulatory authorities to share information and debate on current practices for the nonclinical safety evaluation of engineered T cell therapies. This manuscript leverages what was discussed at this workshop to provide an overview of the current important nonclinical safety assessment considerations for the development of these therapeutic modalities (cytokine release syndrome, neurotoxicity, on-target/off-tumor toxicities, off-target effects, gene editing or vector integration-associated genomic injury). The manuscript also discusses approaches used for hazard identification or risk assessment and provides a regulatory perspective on such aspects.

Antitumor Potency of an Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy, Lisocabtagene Maraleucel in Combination With Ibrutinib or Acalabrutinib.

Chimeric antigen receptor (CAR) T-cell therapy is a promising treatment for patients with CD19 B-cell malignancies. Combination strategies that improve CAR T-cell potency, limit tumor environment-mediated immune dysfunction, and directly reduce tumor burden may increase the potential for durable clinical benefit of CAR T-cell therapy. Lisocabtagene maraleucel (liso-cel) is a product therapy candidate being tested in patients with relapsed/refractory non-Hodgkin lymphoma or chronic lymphocytic leukemia. This study assessed the in vitro and in vivo functionality of CAR T cells transduced to express the anti-CD19 CAR of liso-cel in combination with ibrutinib or acalabrutinib. In prolonged stimulation assays, the presence of ibrutinib or acalabrutinib improved the CAR T-cell effector function. RNA-Seq analysis and surface marker profiling of these CAR T cells treated with ibrutinib but not acalabrutinib revealed gene expression changes consistent with skewing toward a memory-like, type 1 T-helper, Bruton tyrosine kinase phenotype. Ibrutinib or acalabrutinib improved CD19 tumor clearance and prolonged survival of tumor-bearing mice when used in combination with CAR T cells. A combination of the defined cell product therapy candidate, liso-cel, with ibrutinib or acalabrutinib is an attractive approach that may potentiate the promising clinical responses already achieved in CD19 B-cell malignancies with each of these single agents.

Cytokines in CAR T Cell-Associated Neurotoxicity.

Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell-associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.

Chimeric Antigen Receptor T Cell-Mediated Neurotoxicity in Nonhuman Primates.

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell-mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/µL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell-mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan-T cell encephalitis.Significance: We provide the first immunologically relevant, nonhuman primate model of B cell-directed CAR T-cell therapy-mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750-63. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

Local Delivery of OncoVEXmGM-CSF Generates Systemic Antitumor Immune Responses Enhanced by Cytotoxic T-Lymphocyte-Associated Protein Blockade.

Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using a murine version of the virus, we characterized local and systemic antitumor immune responses driving efficacy in murine syngeneic models.Experimental Design: The activity of talimogene laherparepvec was characterized against melanoma cell lines using an in vitro viability assay. Efficacy of OncoVEXmGM-CSF (talimogene laherparepvec with the mouse granulocyte-macrophage colony-stimulating factor transgene) alone or in combination with checkpoint blockade was characterized in A20 and CT-26 contralateral murine tumor models. CD8+ depletion, adoptive T-cell transfers, and Enzyme-Linked ImmunoSpot assays were used to study the mechanism of action (MOA) of systemic immune responses.Results: Treatment with OncoVEXmGM-CSF cured all injected A20 tumors and half of contralateral tumors. Viral presence was limited to injected tumors and was not responsible for systemic efficacy. A significant increase in T cells (CD3+/CD8+) was observed in injected and contralateral tumors at 168 hours. Ex vivo analyses showed these cytotoxic T lymphocytes were tumor-specific. Increased neutrophils, monocytes, and chemokines were observed in injected tumors only. Importantly, depletion of CD8+ T cells abolished all systemic efficacy and significantly decreased local efficacy. In addition, immune cell transfer from OncoVEXmGM-CSF-cured mice significantly protected from tumor challenge. Finally, combination of OncoVEXmGM-CSF and checkpoint blockade resulted in increased tumor-specific CD8+ anti-AH1 T cells and systemic efficacy.Conclusions: The data support a dual MOA for OncoVEXmGM-CSF that involves direct oncolysis of injected tumors and activation of a CD8+-dependent systemic response that clears injected and contralateral tumors when combined with checkpoint inhibition. Clin Cancer Res; 23(20); 6190-202. ©2017 AACR.

Tumor necrosis factor, tumor necrosis factor inhibition, and cancer risk.

OBJECTIVE: Tumor necrosis factor (TNF) is a highly pleiotropic cytokine with multiple activities other than its originally discovered role of tumor necrosis in rodents. TNF is now understood to play a contextual role in driving either tumor elimination or promotion. Using both animal and human data, this review examines the role of TNF in cancer development and the effect of TNF and TNF inhibitors (TNFis) on malignancy risk. RESEARCH DESIGN: A literature review was performed using relevant search terms for TNF and malignancy. RESULTS: Although administration of TNF can cause tumor regression in specific rodent tumor models, human expression polymorphisms suggest that TNF can be a tumor-promoting cytokine, whereas blocking the TNF pathway in a variety of tumor models inhibits tumor growth. In addition to direct effects of TNF on tumors, TNF can variously affect immunity and the tumor microenvironment. Whereas TNF can promote immune surveillance designed to eliminate tumors, it can also drive chronic inflammation, autoimmunity, angiogenesis, and other processes that promote tumor initiation, growth, and spread. Key players in TNF signaling that shape this response include NF-κB and JNK, and malignant-inflammatory cell interactions, each of which may have different responses to TNF signaling. Focusing on rheumatoid arthritis (RA) patients, where clinical experience is most extensive, a review of the clinical literature shows no increased risk of overall malignancy or solid tumors such as breast and lung cancers with exposure to TNFis. Lymphoma rates are not increased with use of TNFis. Conflicting data exist regarding the risks of melanoma and nonmelanoma skin cancer. Data regarding the risk of recurrent malignancy are limited. CONCLUSIONS: Overall, the available data indicate that elevated TNF is a risk factor for cancer, whereas its inhibition in RA patients is not generally associated with an increased cancer risk. In particular, TNF inhibition is not associated with cancers linked to immune suppression. A better understanding of the tumor microenvironment, molecular events underlying specific tumors, and epidemiologic studies of malignancies within specific disease indications should enable more focused pharmacovigilance studies and a better understanding of the potential risks of TNFis.

Immunomodulation and lymphoma in humans.

Observational and clinical studies have associated increased cancer risks with primary or acquired immunodeficiencies, autoimmunity, and use of immunotherapies to treat chronic inflammation (e.g. autoimmunity) or support organ engraftment. Understanding of the relationship between immune status and cancer risk is generally grounded in two juxtaposing paradigms: that the immune system protects the host via surveillance of tumors and oncogenic viruses (e.g. immunosurveillance model) and that chronic inflammation can augment tumor growth and metastasis (inflammation model). Whereas these models support a role of immune status in many cancers, they are insufficient to explain the disproportionate increase in B-cell lymphoma risk observed across patient populations with either chronic immunosuppression or inflammation. Evaluation for the presence of Epstein-Barr virus (EBV) in lymphomas obtained from various populations demonstrates a variable role for the virus in lymphomagenesis across patient populations. An evaluation of the DNA alterations found in lymphomas and an understanding of B-cell ontogeny help to provide insight into the unique susceptibility of lymphocytes, primarily B-cells, to oncogenic transformation. EBV-independent B-cell oncogenic transformation is driven by chronic antigenic stimulation due to either inflammation (as seen in patients with autoimmune disease or a tissue allograft) or to unresolved infection (as seen in immunosuppressed patients), and the transformation arises as a result of DNA damage from genomic recombination and mutation during class switching and somatic hypermutation. This model explains the increased background rate of lymphoma in some patients with autoimmunity, and highlights the challenge of resolving the confounding that occurs between disease severity and use of targeted immunotherapies to treat chronic inflammation. The ability to distinguish between disease- and treatment-related risk of lymphoma and an appreciation of the etiology of B-cell transformation is central to an improved risk assessment by scientists, clinicians and regulators, including the approval, labeling, and chronic use of immunotherapies.

Critical analysis of an oncolytic herpesvirus encoding granulocyte-macrophage colony stimulating factor for the treatment of malignant melanoma.

Oncolytic viruses that selectively lyse tumor cells with minimal damage to normal cells are a new area of therapeutic development in oncology. An attenuated herpesvirus encoding the granulocyte-macrophage colony stimulating factor (GM-CSF), known as talimogene laherparepvec (T-VEC), has been identified as an attractive oncolytic virus for cancer therapy based on preclinical tumor studies and results from early-phase clinical trials and a large randomized Phase III study in melanoma. In this review, we discuss the basic biology of T-VEC, describe the role of GM-CSF as an immune adjuvant, summarize the preclinical data, and report the outcomes of published clinical trials using T-VEC. The emerging data suggest that T-VEC is a safe and potentially effective antitumor therapy in malignant melanoma and represents the first oncolytic virus to demonstrate therapeutic activity against human cancer in a randomized, controlled Phase III study.

Interleukin-21 enhances rituximab activity in a cynomolgus monkey model of B cell depletion and in mouse B cell lymphoma models.

Rituximab, a monoclonal antibody targeting CD20 on B cells, is currently used to treat many subtypes of B cell lymphomas. However, treatment is not curative and response rates are variable. Recombinant interleukin-21 (rIL-21) is a cytokine that enhances immune effector function and affects both primary and transformed B cell differentiation. We hypothesized that the combination of rIL-21 plus rituximab would be a more efficacious treatment for B cell malignancies than rituximab alone. We cultured human and cynomolgus monkey NK cells with rIL-21 and found that their activity was increased and proteins associated with antibody dependent cytotoxicity were up-regulated. Studies in cynomolgus monkeys modeled the effects of rIL-21 on rituximab activity against CD20 B cells. In these studies, rIL-21 activated innate immune effectors, increased ADCC and mobilized B cells into peripheral blood. When rIL-21 was combined with rituximab, deeper and more durable B cell depletion was observed. In another series of experiments, IL-21 was shown to have direct antiproliferative activity against a subset of human lymphoma cell lines, and combination of murine IL-21 with rituximab yielded significant survival benefits over either agent alone in xenogeneic mouse tumor models of disseminated lymphoma. Therefore, our results do suggest that the therapeutic efficacy of rituximab may be improved when used in combination with rIL-21.

Preclinical safety, pharmacokinetics, and pharmacodynamics of recombinant human interleukin-21 in cynomolgus macaques (Macaca fascicularis).

Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (≤3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis) once daily for 5 days, followed by 9 nondosing days (1 cycle) for ≤4 cycles. The rIL-21 pharmacokinetics was dose-dependent. Accumulation was not observed after repeated dosing, consistent with the short elimination half-life (t (1/2,λz); 0.4-0.8 hours). Safety findings included cyclical anemia and thrombocytopenia, clinical pathology changes consistent with acute-phase response, leukocyte infiltrates in hepatic sinusoids, and sporadic serum transaminase elevations (typically <3 times upper-limit of normal); all were reversible upon cessation of treatment. Decreased pharmacodynamic responses with time corresponded to the development of anti-rIL-21 antibodies; effects varied among individuals and were dose-dependent. These studies demonstrated rIL-21 to be generally well-tolerated when administered to cynomolgus monkeys, and all adverse effects were reversible upon treatment cessation. However, development of anti-rIL-21 antibodies may limit the use of this species in long-term studies.

Safety assessment of immunomodulatory biologics: the promise and challenges of regulatory T-cell modulation.

Regulatory T-cell (T(reg)) modulation is developing as an important therapeutic opportunity for the treatment of a number of important diseases, including cancer, autoimmunity, infection, and organ transplant rejection. However, as demonstrated with IL-2 and TGN-1412, our understanding of the complex immunological interactions that occur with T(reg) modulation in both non-clinical models and in patients remains limited and appears highly contextual. This lack of understanding will challenge our ability to identify the patient population who might derive the highest benefit from T(reg) modulation and creates special challenges as we transition these therapeutics from non-clinical models into humans. Thus, in vivo testing in the most representative animal model systems, with careful progress in the clinic, will remain critical in developing therapeutics targeting T(reg) and understanding their clinical utility. Moreover, toxicology models can inform some of the potential liabilities associated with T(reg) modulation, but not all, suggesting a continued need to explore and validate predictive models.

ICH S9: Developing anticancer drugs, one year later.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 is the first international regulatory guidance document devoted to a specific therapeutic area, highlighting its importance in harmonizing regulatory expectations for the nonclinical development of therapeutics designed to treat advanced cancer. ICH S9 successfully outlines the core requirements for the nonclinical development of novel oncology therapeutics, and the unique risk-benefit considerations for expediting drug development to treat these most grievous diseases. However, development companies and regulatory agencies have had limited opportunity to apply this guidance, so our collective experience in developing therapeutics under the guidance is limited. Discussed here are several key areas of ambiguity in the guidance, including identification of the patient population, selection of the initial safe dose for first-in-human trials, and requirements for nonclinical recovery data.

Alterations in regulatory T-cells: rediscovered pathways in immunotoxicology.

In addition to the effector T-cells subsets, T-cells can also differentiate into cells that play a suppressive or regulatory role in adaptive immune responses. The cell types currently identified as regulatory T-cells (T(regs)) include natural or thymic-derived T(regs), T-cells which express Foxp3(+)CD25(+)CD4(+) and can suppress immune responses to autoreactive T-cells, as well as inducible T(regs), that are generated from naïve T-cells in the periphery after interaction with antigens presented by dendritic cells. Inducible T(regs) include T(H)3 cells, T(r)1 cells, and Foxp3(+)-inducible T(regs). T(regs) have been shown to be critical in the maintenance of immune responses and T-cell homeostasis. These cells play an important role in suppressing responses to self-antigens and in controlling inappropriate responses to non-self-antigens, such as commensal bacteria or food in the gut. For example, depletion of CD4(+)CD25(+) T(regs) from mice resulted in the development of multi-organ autoimmune diseases. CD4(+)CD25(+) T(regs) and/or IL-10-producing T(r)1 cells are capable of suppressing or attenuating T(H)2 responses to allergens. Moreover, adoptive transfer of CD4(+)CD25(+) T(regs) from healthy to diseased animals resulted in the prevention or cure of certain autoimmune diseases, and was able to induce transplantation tolerance. Clinical improvement seen after allergen immunotherapy for allergic diseases such as rhinitis and asthma is associated with the induction of IL-10- and TGFß-producing T(r)1 cells as well as FoxP3-expressing IL-10 T-cells, with resulting suppression of the T(H)2 cytokine milieu. Activation, expansion, or suppression of CD4(+)CD25(+) T(regs) in vivo by xenobiotics, including drugs, may therefore represent a relevant mechanism underlying immunotoxicity, including immunosuppression, allergic asthma, and autoimmune diseases.

Cadmium induced p53-dependent activation of stress signaling, accumulation of ubiquitinated proteins, and apoptosis in mouse embryonic fibroblast cells.

The tumor suppressor oncoprotein, p53, is a critical regulator of stress-induced growth arrest and apoptosis. p53 activity is regulated through the ubiquitin proteasome system (UPS) with stress-induced disruption leading to increased accumulation of p53, resulting in growth arrest. In the present study, we investigate the role of p53 to determine sensitivity to cadmium (Cd) and whether induction of stress signaling responses and perturbation of the UPS are involved in Cd-induced cytotoxicity and apoptosis. We treated synchronously cultured p53 transgenic mouse embryonic fibroblasts, both wild-type p53+/+ and knockout p53-/- cells, with cadmium chloride (Cd, 0.5-20µM) for 24 h. Cd-induced cytotoxicity was assessed by cellular morphology disruption and neutral red dye uptake assay. Proteins in the stress signaling pathway, including p38 mitogen-activated protein kinase (MAPK) and stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK); ubiquitination, such as high-molecular weight of polyubiquitinated proteins (HMW-polyUb); and apoptotic pathways, were all measured. We found that Cd induced p53-dependent cytotoxicity in the p53+/+ cells, which exhibited a twofold greater sensitivity. We observed a dose-dependent stimulation of p38 MAPK and SAPK/JNK phosphorylation that corresponded to accumulation of HMW-polyUb conjugates and lead to the induction of apoptosis, as evidenced by the elevation of cleaved caspase-3. Our study suggests that Cd-mediated cytotoxicity and induction of stress signaling responses, elevated accumulation of HMW-polyUb conjugates, and resulting apoptosis are all dependent on p53 status.

Carcinogenicity assessments of biotechnology-derived pharmaceuticals: a review of approved molecules and best practice recommendations.

An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling.

Resistencia bacteriana en cuidados intensivos y tendencia actual: Departamento de Cuidados Críticos, Servicio de Cuidados Intensivos del Hospital Nacional Guillermo Almenara Irigoyen, Essalud, Lima, Perú, 2004-2006 / Antimicrobial resistance in an intensive care unit and current trends: Critical Care Department, Intensive Care Service of Guillermo Almenara Irigoyen National Hospital, EsSalud, Lima. Peru, 2004-2006

Introducción: se describe y analiza el comportamiento de los microorganismos más frecuentes en el Servicio de Cuidados Intensivos (UCI) del Hospital Guillermo Almenara Irigoyen, y su sensibilidad/resistencia a los antibióticos. Material y método: se identifica gérmenes y la técnica de susceptibilidad empleada, realizado mediante el sistema automatizado Micro Scan Walk Away 96 y paneles MIC Combo NUC entre el periodo 2004 y 2006 de los pacientes hospitalizados en el servicio de Cuidados Intensivos. Resultados: el Acinetobacter spp. presentó frecuencia creciente, a través de los años de estudio con incremento de su resistencia a los carbapenem en el lapso de tres años desde un 0 por ciento en el 2004 hasta cerca del 40 por ciento en el 2006. Los gérmenes más frecuente en vías respiratorias fueron el S. aureus, P. aeruginosa y Acinetobacter y en hemocultivos el S. aureus, Candida sp y el S. epidermides. S. aureus fue el germen más común en la UCI. Las cepas de S. aureus oxacilino resistentes en la UCI, variaron del 93 por ciento al 100 por ciento en el ultimo año del estudio. P. aeruginosa y el Acinetobacter son bacterias con resistencia creciente tanto a los antibióticos tradicionales como a los modernos. Conclusiones: la explosión de infección resistente a antibióticos continúa a nivel mundial y por otro lado la declinación en investigación y desarrollo de nuevos antibióticos hacen sombrío el futuro principalmente de las infecciones graves y más aun en el epicentro de la resistencia como es el área de cuidados intensivos. Ya que los pacientes de UCI tiene alta tasa de complicaciones infecciosas y son expuestos a antibióticos de amplio espectro, la emergencia de resistencia antimicrobiana ha hecho que el uso apropiado de antibióticos sea un objetivo.

Introduction: This is a description and analysis of the behavior of most frequently isolated microorganisms in the Intensive Care Unit (ICU) of Gullermo Alemnara-Irigoyen Hospital in Lima. Antimicrobial susceptibility/resistance patterns were also analyzed. Material and method: Microorganisms were isolated and their antimicrobial susceptibility patters were assessed using a Micro Scan Walk Away 96 automatic system and Combo NUC panels for determining minimal inhibitory concentrations (MIC) in patients hospitalized in the ICU during the period between 2004 and 2006. Results: Acinetobacter spp. were increasingly isolated, and their resistance to carbapenem antimicrobials rose in a three-year period, from 0 per cent in 2004 to nearly 40 per cent in 2006. Most frequently isolated microorganisms in the respiratory tract were: S. aureus, P. aeruginosa, and Acinetobacter spp.; and S. aureus, Candida spp., and S. epidermidis were the most frequently isolated pathogens in blood cultures. Overall, S. aureus was the most commonly isolated microorganism in the ICU. Oxacillin-resistant S. aureus strains in the ICU had a 93 per cent to 100 per cent frequency in the last year of the study. P. aeruginosa and Acinetobacter spp. have increasing resistance to both traditional and modern antibiotics. Conclusions: The pandemic of antibiotic resistant infections all over the world, and the decline in research and development of new antibacterial compounds may lead us to a somber future, particularly in cases of severe infections, especially in places most affected by antibiotic resistance, such as the ICUs. Since ICU patients have a high rate of infectious complications and considering they are exposed to wide-spectrum antibiotics, this emergence of antibiotic resistance stresses the urgent need for the appropriate use of antimicrobial agents.

Adverse consequences of immunostimulation.

The therapeutic uses of immunostimulatory agents are generally in the treatments of infections or cancer. The traditional example of vaccination is one form of immunostimulation used in the prevention of pathogenic infections or cancer (e.g., human papillomavirus vaccine). Recombinant cytokines are increasingly used to stimulate immune system function. For example, interferon-alpha (IFNalpha) and interleukin (IL)-2 have been used to treat chronic hepatitis C virus infection and metastatic melanoma, respectively. In contrast, monoclonal antibodies are used to target malignant cells for elimination via antibody-dependent cytotoxicity mechanisms or apoptosis, including the anti-CD20 monoclonal antibody rituximab and the anti-CD56 monoclonal antibody alemtuzumab used in the treatment of B-cell malignancies, and the anti-erb2 receptor antibody trastuzumab used in the treatment of breast cancer. Finally, immunostimulation may develop via modulation of pathways involved in immune system regulation. For example, the anti-CD28 monoclonal antibody TGN1412 was developed as an agonist of regulatory T-cells for treatment of T-cell-mediated chronic inflammatory diseases or leukemias. A panel was convened to discuss potential toxicities associated with immunostimulation. At the Immunotoxicology IV meeting in 2006, a panel, moderated by Dr. Robert House (Dynport Vaccine Co., Frederick, MD), included Drs. Gary Burleson (Burleson Research Technologies, Inc., Raleigh, NC), Kenneth Hastings (US FDA, Center for Drug Evaluation and Research [CDER], Rockville, MD), Barbara Mounho (Amgen, Thousand Oaks, CA), Rafael Ponce (ZymoGenetics, Inc., Seattle, WA), Mark Wing (Huntington Life Sciences, Cambridgeshire, United Kingdom), Lauren Black (Navigators Consulting, Sparks, NV) and Anne Pilaro (US FDA, CDER, Rockville, MD). This paper reviews the major identified toxicities associated with immunostimulation, including the acute phase response, cell and tissue abnormalities/injury, cytokine release/cytokine storm, tumor lysis syndrome, vascular leak, and autoimmunity that were discussed by this panel.

Duration of chronic toxicity studies for biotechnology-derived pharmaceuticals: is 6 months still appropriate?

For chronic use biotechnology-derived pharmaceuticals, toxicity studies of 6 months have generally been accepted for regulatory approval. This review assessed the data for 23 approved biotechnology-derived pharmaceuticals to determine whether the studies conducted were predictive of human safety and whether there is new data from approved products indicating that longer than 6 months is necessary. This assessment involved three approaches; whether new toxicities were identified at >6 months, similarity of findings between 6 months and shorter studies and predictivity of clinical adverse events. In two cases there were apparently new findings in studies >6 months. On examination however, one of these cases was a well established risk with foreign protein administration to animals (adalimumab). For insulin aspart, the 12 month study identified tumors not seen in shorter term studies, however, determination of carcinogenic potential is not a goal of chronic toxicity studies and is addressed by separate studies. In most cases the toxicology studies were predictive of common clinical adverse reactions, but were poorly predictive of rare clinical events or some serious adverse reactions. Although specific circumstances may require a longer study, this review indicates no new data is available to refute the utility of 6 month studies to support chronic clinical dosing with biotechnology-derived pharmaceuticals.

Toxicity as a result of immunostimulation by biologics.

The immune system has evolved highly effective mechanisms of surveillance and defense against foreign pathogens, and is also thought to act in surveillance and suppression of cancer. Thus, a predominant goal of immune system-based therapies is to normalize or enhance the host immune response in the areas of infectious disease and oncology. This review considers general approaches used for therapeutic immunostimulation, alterations in immune response mechanisms that occur with these treatments and the syndromes that commonly arise as a result of these changes. Because nonclinical studies of these therapies are conducted in animal models as the basis for predicting potential human toxicities, this review also considers the value of nonclinical testing to predict human toxicity.