Part Of Combination Therapy Research Articles

Undetected toxicity risk in pharmacogenetic testing for dihydropyrimidine dehydrogenase.

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.

Nanoparticle delivery of HIF1α siRNA combined with photodynamic therapy as a potential treatment strategy for head-and-neck cancer

Combination therapy has become a major strategy in cancer treatment. We used anisamide-targeted lipid–calcium–phosphate (LCP) nanoparticles to efficiently deliver HIF1α siRNA to the cytoplasm of sigma receptor-expressing SCC4 and SAS cells that were also subjected to photodynamic therapy (PDT). HIF1α siRNA nanoparticles effectively reduced HIF1α expression, increased cell death, and significantly inhibited cell growth following photosan-mediated photodynamic therapy in cultured cells. Intravenous injection of the same nanoparticles into human SCC4 or SAS xenografted mice likewise resulted in concentrated siRNA accumulation and reduced HIF1α expression in tumor tissues. When combined with photodynamic therapy, HIF1α siRNA nanoparticles enhanced the regression in tumor size resulting in a ~40% decrease in volume after 10 days. Combination therapy was found to be substantially more effective than either HIF1α siRNA or photodynamic therapy alone. Results from caspase-3, TUNEL, and CD31 marker studies support this conclusion. Our results show the potential use of LCP nanoparticles for efficient delivery of HIF1α siRNA into tumors as part of combination therapy along with PDT in the treatment of oral squamous cell carcinoma.

Results of surgical treatment of cervical cancer patients of childbearing age

The world marked increase in the incidence of cervical cancer in young women, especially from 29 to 45 years old. Analysis showed that in patients with preserved ovarian function, not only the effectiveness of the treatment, but also the quality of life. It is associated with the acceleration, earlier puberty and the onset of sexual activity. In recent years more and more widely used radical surgery with preservation of the ovaries and the abduction of the radiation castration and preservation of reproductive function. In the National Cancer Research Centre of the Ministry of Health of the Republic of Uzbekistan analyzed the results of surgical treatment of 204 patients with cervical cancer younger. Age of patients from 23 to 45 years, that is, in the most hard-working, reproductive period. In our study patients met principally with exophytic – 82 (40.2 %) and 68 (33.3 %) еndophytic growth cervical tumors. Histological in 197 (96.6 %) patients with squamous cervical cancer patients with 7 (3.4%). Adenocarcinoma of cervical cancer. Handard examination of the patient are further adapted to determine the level of sex hormones (estradiol, progesterone), determination of the tumor marter CA-125 levels of calcium and phosphate in the blood. 112 patients from the main group and the combined complex therapy surgical treatment with organ-component (conservation and ovarian transposition). The first group included 112 (55.1 %) patients, who as part of combination therapy was performed and complex surgical treatment of ovarian transposition. The second group included 92 (44.9%) patients who as part of combination therapy and complex surgery performed without ovarian transposition. Each group was divided into 3 subgroup included patients with stage process T1b–2aN0M0. Which performs the combined radiotherapy. The second subgroups included patients with stage process that runs systemic chemotherapy, surgery, combined radiotherapy. The third group included patients with stage process that runs endoarterial regional prolonged chemotherapy + surgery + combined radiotherapy. In phases of dynamic monitoring of patient evaluated the effectiveness of treatment as well as studied T2bN0–1M0 the quality of life of a young body. Quality of life of patient in the dynamics of observation was determined by the American system MENQOL.

Role of ascorbic acid and tocopherol in the prevention and treatment of diseases from the standpoint of evidence-based medicine

The role of vitamin C and vitamin E in the prevention and treatment of diseases is analyzed from the standpoint of evidence-based medicine. The high provision of a patient with the vitamins has a therapeutic and preventive impact on the development and course of a number of diseases. Furthermore, when additionally prescribing the vitamins as part of combination therapy, it is necessary to take into account possible drug interactions, including those due to the inducing effect of the above antioxidants on cytochrome P450 3A4.

Allergic/infusion reactions reported with cetuximab and rituximab

Results 940 articles met criteria, including 167 and 83 for C and R, respectively, describing 19,861 and 5064 mAb-treated patients. AIRs were reported in 1694 (8.5%) and 647 (12.3%) C and R patients, but these numbers may be low as some articles only reported grade 3/4 or severe reactions. Various terms were used to describe AIRs (eg, anaphylaxis [AX], allergic reaction [AR], hypersensitivity reaction [HR], infusion reaction [IR]), so it was often difficult to distinguish the type of AIR. Some AIRs were reported as grade 4 HRs but not specifically noted as AX. Also, it was hard to attribute an AIR to a specific agent when the mAb was part of combination therapy. Grade 3/4 AIRs were noted in 633 (3.2%) and 215 (4.2%) C and R patients. AX specifically was noted in 88 (0.4%) and 64 (1.3%) C and R patients. Among C patients, 13 fatalities were attributed to AIRs, with none in the R group. Conclusions Although a well-known adverse event, the magnitude of AIRs with C and R still may be underappreciated. The presence of the galactose-galactose epitope in mAbs produced in murine cell lines, as with C, contributes to AIRs. The frequency of AIRs was likely underestimated in this review due to limited reporting in the medical literature and varied classification. Various AIR terms were used interchangeably, sometimes within a single article. Grade 4 AIRs were not always labeled as AX. Grade 3/4, AX, or fatal AIRs were rare but are clinically significant when they occur. Management of AIRs often was not reported, nor was the incidence of delayed AIRs, which may have been unknown. This suggests a need for more standardized reporting of AIRs. Appropriate steps for prevention/treatment of AIRs should be taken when these mAbs are utilized. Readily available therapies for the treatment of AIRs may be helpful (eg, epinephrine autoinjectors); however, these products are not indicated for patients at risk for delayed AIRs.

Denileukin Diftitox (Ontak) as Maintenance Therapy for Peripheral T-Cell Lymphomas: Three Cases with Sustained Remission.

Peripheral T-cell lymphomas (PTCL) are rare but markedly aggressive forms of non-Hodgkin's lymphoma (NHL). They carry a poor prognosis, with current therapeutic approach being generally ineffective. The most employed first-line treatment is CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone), which still results in high rates of relapses. Denileukin diftitox is a fusion protein combining the cytotoxic portion of the diphtheria toxin and the receptor-binding domain of the interleukin-2 (IL-2) molecule, thereby targeting cells expressing the IL-2 receptor, including both T-cell and B-cell lymphomas. It has been approved for the treatment of cutaneous T-cell lymphomas, and it has documented activity in PTCL both as a single agent and as part of combination therapy. This report documents three cases of PTCL where denileukin diftitox has been used as long-term maintenance therapy after complete remission was achieved. While the overall survival rate of patients with advanced stage, refractory PTCL is generally poor (with median overall survival of 5.5 months), the three patients described in this report are all experiencing an ongoing complete remission for more than four years.

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

An Open-Label, Dose Escalation, Multi-Center Phase 1 Study of PRLX 93936, an Agent Synthetically Active Against the Activated Ras Pathway, in the Treatment of Relapsed or Relapsed and Refractory Multiple Myeloma

Current therapy for Parkinson's disease

The main goal of therapy for Parkinson's disease (PD) is to correct dopamine deficiency in the nigrostriatal system. Levodopa preparations and dopamine receptor agonists (DRAs) that are prescribed with regards to patient age and disease severity are mainly used now. Notwithstanding the fact that levodopa preparations are the gold standard of therapy, their long-term use gives rise to complications as motor fluctuations and drug-induced dyskinesias. The currently available DRAs are the drugs of choice for the therapy of early-stage PD as they are as effective as levodopa preparations. In extensive-stage PD, DRAs are used to enhance the therapy and correction of developed motor fluctuations and dyskinesias. Pramipexole is one of the most commonly used representatives of non-ergoline DRAs. The paper analyzes the efficacy of the medication used as both monotherapy and part of combined therapy, its effect on tremor and depression in PD. A novel extended-release formulation of pramipexole is considered separately. Both immediate- and extended-release pramipexole formulations contain the same active ingredient and have the same dopamine-receptor interaction profile, but differ in the tablet release rate of the active ingredient. The advantages of the novel formulation are its more steady-state plasma concentration and 24-hour action, which ensures continuous dopaminergic stimulation of postsynaptic receptors to prevent and treat already developed motor complications. The once-daily extended-release formulation of the drug makes its treatment regimen easier and patient compliance higher.

In vitro combination therapy using low dose clotrimazole and photodynamic therapy leads to enhanced killing of the dermatophyte Trichophyton rubrum.

BackgroundSuperficial infections of the skin and mucous membranes caused by dermatophyte fungi are amongst the most common and challenging infections to treat. Previously we demonstrated the phototoxic effects of photodynamic therapy (PDT) towards Trichophyton rubrum, using a green laser to photoactivate Rose Bengal (RB). The aim of this study was to evaluate whether we could; (1) achieve a similar effect using an inexpensive light-emitting diode (LED) to photoactivate RB and (2) to evaluate whether our PDT regime could be combined with standard antifungal drug therapy and increase its effectiveness.MethodsWe designed and built our own inexpensive green (530 nm) LED source and tested its efficacy as part our RB-PDT regime in vitro against T. rubrum. We also examined the potential benefits of incorporating PDT as part of combination therapy and whether the order in which this was done had an impact. First we subjected spore suspensions to sub-inhibitory concentrations of a number of antifungal agents (CLT, MCZ and TRB) for 72 hours followed by RB-PDT. Secondly we subjected spore suspensions to sub-inhibitory PDT followed by drug treatment and evaluated if there were any changes to the minimum inhibitory concentrations (MICs) of the drugs tested.ResultsThe optimal conditions for photoinactivation of T. rubrum using RB-PDT alone were 140 μM of RB and 24 J/cm2 of LED (equating to a 30-minute exposure). These parameters also caused a 100% reduction in the viability of the pathogenic yeast Candida albicans and the model fungus Saccharomyces cerevisiae. By combining our RB-PDT regime as an adjunct to antifungal drugs we were able to dramatically reduce the exposure times. Treatment of spore suspensions using a sub-inhibitory dose of clotrimazole (CLT) followed by RB-PDT, this order was critical, significantly reduced the exposure times required to achieve 100% inhibition of T. rubrum to 15 minutes as compared to RB-PDT alone.ConclusionsThe combination of antifungal drug and RB-PDT represents an attractive alternative to the current antifungal therapies used to treat superficial fungal diseases. Our approach has the potential to reduce treatment times and drug dosages which can also reduce drug toxicity and improve patient compliance.Electronic supplementary materialThe online version of this article (doi:10.1186/s12866-014-0261-z) contains supplementary material, which is available to authorized users.

Abstract 3097: TSLP regulates expression of genes involved in cell survival in a preclinical xenograft model of CRLF2 B-ALL

Abstract A subset of children with B cell precursor acute lymphoblastic leukemia (B-ALL) are at high risk for relapse and death. Gene expression profiles in these high-risk B-ALLs is similar to that of Philadelphia chromosome-positive ALL. Approximately half of these Ph-like B-ALL are characterized by genetic defects resulting in overexpression of CRLF2. This defect occurs 5 times more commonly in Hispanic children than others and thus is a significant biological component of pediatric cancer health disparities. CRLF2, together with the IL-7Rα, forms a receptor complex that is activated by the cytokine, TSLP. Receptor complex activation leads to JAK-STAT5 phosphorylation. The activating JAK mutations found in some CRLF2 B-ALL led to speculation that TSLP stimulation is not a factor in CRLF B-ALL. However, we and others have found that TSLP increases STAT5 phosphorylation in CRLF2 B-ALL cells, including those with JAK defects. Our next step was to evaluate the role of TSLP-CRLF2 interactions in vivo in the human-mouse xenograft model. However, mouse TSLP is species-specific and does not activate the human TSLP receptor complex that includes CRLF2. Thus, traditional xenograft models do not provide the TSLP-CRLF2 interactions that may contribute to high risk CRLF2 B-ALL. We engineered immune-deficient NOD/SCID IL-2Rγ null (NSG) mice to express human TSLP (hTSLP+ mice), as well as control mice that lack the TSLP cytokine (hTSLP- mice). Then we used this hTSLP+/- xenograft model system to evaluate the in vivo effects of TSLP on transplanted CRLF2 B-ALL cells harboring a JAK defect (MUTZ5 cell line). Transplanted mice were euthanized at 5 weeks and bone marrow (BM) was harvested. Evaluation of BM by flow cytometry showed that approximately half of the human leukemia cells were apoptotic in mice without TSLP while apoptosis was virtually absent in CRLF2 B-ALL cells harvested from hTSLP+ mice. Next we used Ingenuity Pathway Analysis to identify functions and pathways regulated by TSLP. Primary CRLF2 B-ALL cells were transplanted into hTSLP+ and hTSLP- mice. Whole genome microarray performed on primary human leukemia cells isolated from BM of xenograft mice identified 280 genes that were upregulated and 281 genes that were downregulated (> 2 fold up or downregulated; p<.05) in leukemia cells from hTSLP+ as compared to hTSLP- mice. Ingenuity Pathway Analysis of changes in gene expression identified “Cell Death and Survival” as the “Molecular and Cellular Function” most impacted by TSLP (34 genes differentially regulated).These data suggest that TSLP-induced CRLF2 signaling may contribute to leukemia cell survival in vivo in CRLF2 B-ALL. Current studies are aimed at identifying TSLP-regulated genes that can be therapeutically targeted as a part of combination therapy to successfully treat CRLF2 B-ALL and reduce the cancer health disparities for children with this disease. Citation Format: Olivia L. Francis, Ruijun Su, Shannalee R. Martinez, Ineavely Baez, Terry-Ann Milford, Ross Fisher, Christopher L. Morris, Xiaobing Zhang, Valeri Filippov, Sinisa Dovat, Kimberly J. Payne. TSLP regulates expression of genes involved in cell survival in a preclinical xenograft model of CRLF2 B-ALL. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3097. doi:10.1158/1538-7445.AM2014-3097

Management of scars: updated practical guidelines and use of silicones.

Hypertrophic scars and keloids resulting from surgery, burns, trauma and infection can be associated with substantial physical and psychological distress. Various non-invasive and invasive options are currently available for the prevention and treatment of these scars. Recently, an international multidisciplinary group of 24 experts on scar management (dermatologists; plastic and reconstructive surgeons; general surgeons; physical medicine, rehabilitation and burns specialists; psychosocial and behavioural researchers; epidemiologists; beauticians) convened to update a set of practical guidelines for the prevention and treatment of hypertrophic and keloid scars on the basis of the latest published clinical evidence on existing scar management options. Silicone-based products such as sheets and gels are recommended as the gold standard, first-line, non-invasive option for both the prevention and treatment of scars. Other general scar preventative measures include avoiding sun exposure, compression therapy, taping and the use of moisturisers. Invasive treatment options include intralesional injections of corticosteroids and/or 5-fluorouracil, cryotherapy, radiotherapy, laser therapy and surgical excision. All of these options may be used alone or as part of combination therapy. Of utmost importance is the regular re-evaluation of patients every four to eight weeks to evaluate whether additional treatment is warranted. The amount of scar management measures that are applied to each wound depends on the patient's risk of developing a scar and their level of concern about the scar's appearance. The practical advice presented in the current guidelines should be combined with clinical judgement when deciding on the most appropriate scar management measures for an individual patient.

Profile and potential of ixabepilone in the treatment of pancreatic cancer.

The management of metastatic pancreatic adenocarcinoma is a challenge for medical oncologists because of both the aggressive nature of the disease and the relative paucity of effective systemic treatments with activity against this type of tumor. In the effort to discover new agents and combinations that may augment the therapeutic arsenal available for the management of this cancer, early phase clinical trials have been performed using ixabepilone, an epothilone B analog, with promising results. Targeting the microtubule system with certain taxanes in the management of pancreatic adenocarcinoma has been validated; ixabepilone also targets the microtubule system, interfering with it in an alternate manner from the taxane mechanism. Ixabepilone has demonstrated activity in cancers that have become taxane-resistant as well as those that never had any demonstrable taxane susceptibility. The available data for the use of ixabepilone in the management of pancreatic adenocarcinoma are limited but promising. Single-arm studies have demonstrated both clinical efficacy and tolerable toxicity for the use of ixabepilone as monotherapy. The trial data available for ixabepilone used as a part of combination therapy are similar: it has been paired with chemotherapy (carboplatin, irinotecan) and biologic therapy (dasatinib, sunitinib) at the Phase I level to treat solid tumors in general, again with tolerable side effects and a suggestion of benefit. A single Phase II study has evaluated combination therapy with ixabepilone in the management of patients with pancreatic cancer, pairing it with cetuximab with clinical benefit. Although these trials are promising with regard to addition of ixabepilone to the slim armamentarium for management of pancreatic cancer, further work is still to be done. Importantly, this work bears the burden of not only validating the clinical benefit of ixabepilone, but also of determining whether this benefit is enhanced in any way by combination therapy, and where ixabepilone fits in the sequence of management for patients with metastatic pancreatic cancer.

Enteral Feeding as a Part of Combination Treatment in a Patient after Small Intestine Transplantation

Objective: to describe the first experience with an enteral feeding regimen used as part of combination therapy in a patient after small intestine transplantation (SIT). Materials and methods. The results of treatment in a 48year-old male after heterotopic SIT for short bowel syndrome were given. The extent of the graft was 250 cm. The combination treatment aimed to restore graft functions and included immunosuppressive, infusion, transfusion, antibacterial, antiviral, and detoxification therapies and parenteral and enteral feeding (EF). Our elaborated EF regimen was divided into 3 steps: 1) early enteral therapy (on day 1) using a monomeric saline enteral solution and a specialized formula containing pharmaconutrients (glutamine, antioxidants, and tributyrine); 2) incorporation of a semielemental formula (on day 5); 3) use of polymeric formulas and clinical nutrition. Laboratory, ultrasound, radiological, and endoscopic monitoring and biopsy were performed. Results. The combination treatment using stepwise EF could satisfy a patient's protein-energy needs. Restoration of histological structures in the graft mucosa was observed during morphological examination on day 7. At enteroscopy, the intestinal mucosa was pink with prominent villi, motility, and bile-colored chyme. On day 7, there was a 150-ml self-colored stool. Data confirmed that the intestinal graft restored absorption and parietal digestion. On day 30, the patient was switched to polymeric formulas and curative diet. By the discharge from hospital, on day 86, his body mass index was 23.1 kg/m 2 . Conclusion. The positive treatment results in the patient became possible after SIT due to improvement of surgical techniques, current immunosuppression, and a comprehensive approach to treating him in the postoperative period. Our elaborated stepwise EF regiment is an important component of combination therapy after SIT and facilitates the restoration of the major functions of the transplanted intestine and its preparation for the assimilation of polysubstrate formulas and natural foods.

Bedaquiline: a review of human pharmacokinetics and drug-drug interactions

Bedaquiline has recently been approved for the treatment of pulmonary multidrug-resistant tuberculosis (TB) as part of combination therapy in adults. It is metabolized primarily by the cytochrome P450 isoenzyme 3A4 (CYP3A4) to a less-active N-monodesmethyl metabolite. Phase I and Phase II studies in healthy subjects and patients with drug-susceptible or multidrug-resistant TB have assessed the pharmacokinetics and drug-drug interaction profile of bedaquiline. Potential interactions have been assessed between bedaquiline and first- and second-line anti-TB drugs (rifampicin, rifapentine, isoniazid, pyrazinamide, ethambutol, kanamycin, ofloxacin and cycloserine), commonly used antiretroviral agents (lopinavir/ritonavir, nevirapine and efavirenz) and a potent CYP3A inhibitor (ketoconazole). This review summarizes the pharmacokinetic profile of bedaquiline as well as the results of the drug-drug interaction studies.

The Phosphoinositide 3-Kinase α Selective Inhibitor BYL719 Enhances the Effect of the Protein Kinase C Inhibitor AEB071 in GNAQ/GNA11-Mutant Uveal Melanoma Cells

G-protein mutations are one of the most common mutations occurring in uveal melanoma activating the protein kinase C (PKC)/mitogen-activated protein kinase and phosphoinositide 3-kinase (PI3K)/AKT pathways. In this study, we described the effect of dual pathway inhibition in uveal melanoma harboring GNAQ and GNA11 mutations via PKC inhibition with AEB071 (sotrastaurin) and PI3K/AKT inhibition with BYL719, a selective PI3Kα inhibitor. Growth inhibition was observed in GNAQ/GNA11-mutant cells with AEB071 versus no activity in wild-type cells. In the GNAQ-mutant cells, AEB071 decreased phosphorylation of myristoylated alanine-rich C-kinase substrate, a substrate of PKC, along with ERK1/2 and ribosomal S6, but persistent AKT activation was present. BYL719 had minimal antiproliferative activity in all uveal melanoma cell lines, and inhibited phosphorylation of AKT in most cell lines. In the GNA11-mutant cell line, similar effects were observed with ERK1/2 inhibition, mostly inhibited by BYL719. With the combination treatment, both GNAQ- and GNA11-mutant cell lines showed synergistic inhibition of cell proliferation and apoptotic cell death. In vivo studies correlated with in vitro findings showing reduced xenograft tumor growth with the combination therapy in a GNAQ-mutant model. These findings suggest a new therapy treatment option for G-protein-mutant uveal melanoma with a focus on specific targeting of multiple downstream pathways as part of combination therapy.

Tu2022 Optimizing Outcomes of Complex Ventral Hernia Repairs Using a Sandwich Reconstruction Technique With Novel Hybrid-VAC Closure

Introduction: Esophageal cancer remains a highly lethal malignancy with a low overall survival rate. In recent years, Western countries have seen a rapid increase in the incidence of esophageal adenocarcinoma. We have already demonstrated the effectiveness of cyclooxygenase-2 controlled conditionally replicative adenoviruses (CRAd) in esophageal adenocarcinoma cell lines in both in vitro and in vivo models. We now hypothesize that CRAds designed to express interferon alpha (IFN) could provide for increased cell killing capabilities. Additionally, when used as part of combination therapy with chemotherapy and radiation we hope to exploit IFN's properties as a chemoradiotherapy sensitizer to overcome barriers of conventional regimens for esophageal adenocarcinoma. Methods: An infectivity enhanced IFN-expressing CRAd was designed and generated (5/3 Cox2 CRAd ΔE3 ADP IFN). Crystal violet assays were used to determine the in vitro cytocidal effects of the virus across multiple esophageal cancer cell lines (OE19, OE33, and TE7) when compared to three control vectors. Furthermore, the IFN-expressing CRAd was used in conjunction with varying doses of cisplatin and radiation as part of a combination regimen. Results: Genetic modification of the virus capsid (Ad5/Ad3) was used to overcome esophageal adenocarcinoma's low expression of the primary adenovirus receptor and improve infectivity. The virus was also armed with the adenoviral death protein (ADP) to maximize adenoviral spread. At low viral titers, the IFN-expressing CRAd had a much improved cytocidal effect compared to its otherwise identical counterpart that expressed luciferase instead of IFN. Furthermore, the IFN-expressing CRAd had an equivalent cytocidal effect as a non-selective IFN-expressing virus at later time points. The IFN-expressing CRAd also greatly outperformed the standard control adenovirus (Ad5 Wt). The combination of the IFN-expressing CRAd with chemoradiation outperformed all monotherapy treatments (virus alone, chemotherapy alone, radiation alone) across all cell lines tested. Of note, when chemotherapy and radiation were tested in the OE19 cell line, increasing concentrations of cisplatin (up to 9 μM) and doses of radiation (up to 16 Gy) were unable to yield a complete cytocidal effect. Importantly, it was not until the addition of the IFN-expressing CRAd to the chemoradiotherapy regimen that total cancer cell death was achieved. Conclusion: We have demonstrated that an IFN-expressing CRAd has a potent cytocidal effect across multiple esophageal cancer cell lines. When used as part of a combination regimen with chemotherapy and radiation, the IFN-expressing CRAd affords greatly increased cancer cell death. Given these promising results, we are currently testing the IFN-expressing CRAd in an in vivo setting.

Tu2021 Interferon Expressing Oncolytic Adenovirus for Esophageal Cancer

Introduction: Esophageal cancer remains a highly lethal malignancy with a low overall survival rate. In recent years, Western countries have seen a rapid increase in the incidence of esophageal adenocarcinoma. We have already demonstrated the effectiveness of cyclooxygenase-2 controlled conditionally replicative adenoviruses (CRAd) in esophageal adenocarcinoma cell lines in both in vitro and in vivo models. We now hypothesize that CRAds designed to express interferon alpha (IFN) could provide for increased cell killing capabilities. Additionally, when used as part of combination therapy with chemotherapy and radiation we hope to exploit IFN's properties as a chemoradiotherapy sensitizer to overcome barriers of conventional regimens for esophageal adenocarcinoma. Methods: An infectivity enhanced IFN-expressing CRAd was designed and generated (5/3 Cox2 CRAd ΔE3 ADP IFN). Crystal violet assays were used to determine the in vitro cytocidal effects of the virus across multiple esophageal cancer cell lines (OE19, OE33, and TE7) when compared to three control vectors. Furthermore, the IFN-expressing CRAd was used in conjunction with varying doses of cisplatin and radiation as part of a combination regimen. Results: Genetic modification of the virus capsid (Ad5/Ad3) was used to overcome esophageal adenocarcinoma's low expression of the primary adenovirus receptor and improve infectivity. The virus was also armed with the adenoviral death protein (ADP) to maximize adenoviral spread. At low viral titers, the IFN-expressing CRAd had a much improved cytocidal effect compared to its otherwise identical counterpart that expressed luciferase instead of IFN. Furthermore, the IFN-expressing CRAd had an equivalent cytocidal effect as a non-selective IFN-expressing virus at later time points. The IFN-expressing CRAd also greatly outperformed the standard control adenovirus (Ad5 Wt). The combination of the IFN-expressing CRAd with chemoradiation outperformed all monotherapy treatments (virus alone, chemotherapy alone, radiation alone) across all cell lines tested. Of note, when chemotherapy and radiation were tested in the OE19 cell line, increasing concentrations of cisplatin (up to 9 μM) and doses of radiation (up to 16 Gy) were unable to yield a complete cytocidal effect. Importantly, it was not until the addition of the IFN-expressing CRAd to the chemoradiotherapy regimen that total cancer cell death was achieved. Conclusion: We have demonstrated that an IFN-expressing CRAd has a potent cytocidal effect across multiple esophageal cancer cell lines. When used as part of a combination regimen with chemotherapy and radiation, the IFN-expressing CRAd affords greatly increased cancer cell death. Given these promising results, we are currently testing the IFN-expressing CRAd in an in vivo setting.

Improved Sustained Virological Response Following Treatment with Pegylated-Interferon Alpha-2b Compared with Alpha-2a, Both with Ribavirin, for Chronic Hepatitis C Infection with Genotypes 2 and 3

Purpose: The optimal formulation of pegylated interferon a (PEG-IFa) as a part of combination therapy with ribavirin (RBV) is uncertain for patients infected with hepatitis C Genotypes 2 and 3. Methods: A multivariate analysis of prospectively collected treatment data from two tertiary centres on 351 treatment na?ve HCV Genotype 2 or 3 patients who received PEG-IFa-2a or b plus ribavirin. Results: Univariate analyses demonstrate that PEG-IFa-2b based on regimens achieved a higher sustained virological response (SVR) than PEG-IFa-2a (77.9% versus 62.0%, P = 0.0012). On multivariate analyses, PEG-IFa-2b appeared superior to PEG-IFa-2a with an odds ratio (OR) and 95% confidence interval (CI95) for SVR of 2.19 (CI95 1.35-3.52, P = 0.0005). Genotype was a significant predictor of outcome in the multivariate model with 80% of Genotype 2 but only 67.7% of Genotype 3 subjects achieving SVR (OR 2.66 [CI95 1.35-5.92]). Increasing age was negatively associated with SVR (OR 0.97 [CI95 0.94-0.99]). Some of the differences in SVR are explained by higher relapse rates with PEG-IFa-2a (P = 0.009). Conclusions: PEG-IFa-2b and RBV achieve higher SVR rates than PEG-IFa-2a and RBV in Genotypes 2 and 3 chronic HCV infections. There is less relapse with PEG-IFa-2b. Genotype 2 infections are considerably easier to cure. SVR is higher in younger patients. These findings should influence a choice of PEG-IFa in the era of direct acting anti-viral drugs in therapy of Genotypes 2 and 3.

Oncolytic viruses in head and neck cancer: a new ray of hope in the management protocol.

This paper intends to highlight the different types of oncolytic viruses (OVs), mechanism of tumor specificity, its safety, and various obstacles in the design of treatment and combination therapy utilizing oncotherapy. Search was conducted using the internet-based search engines and scholarly bibliographic databases with key words such as OVs, head and neck cancer, viruses, oral squamous cell carcinoma, and gene therapy. Revolutionary technologies in the field of cancer treatment have gone through a series changes leading to the development of innovative therapeutic strategies. Oncolytic virotherapy is one such therapeutic approach that has awaited phase III clinical trial validation. OVs are self-replicating, tumor selective and lyse cancer cells following viral infection. By modifying the viral genome, it is possible to direct their toxicity toward cancer cells. Viruses that are used for treatment of head and neck cancer are either naturally occurring or genetically modified. OVs are tumor selective and potential anticancer agents. Virotherapy may become the standard of care and part of combination therapy in the management of head and neck cancer in the future.

Ceftolozane/Tazobactam: A Novel Cephalosporin/β-Lactamase Inhibitor Combination with Activity Against Multidrug-Resistant Gram-Negative Bacilli

Ceftolozane is a novel cephalosporin currently being developed with the β-lactamase inhibitor tazobactam for the treatment of complicated urinary tract infections (cUTIs), complicated intra-abdominal infections (cIAIs), and ventilator-associated bacterial pneumonia (VABP). The chemical structure of ceftolozane is similar to that of ceftazidime, with the exception of a modified side-chain at the 3-position of the cephem nucleus, which confers potent antipseudomonal activity. As a β-lactam, its mechanism of action is the inhibition of penicillin-binding proteins (PBPs). Ceftolozane displays increased activity against Gram-negative bacilli, including those that harbor classical β-lactamases (e.g., TEM-1 and SHV-1), but, similar to other oxyimino-cephalosporins such as ceftazidime and ceftriaxone, it is compromised by extended-spectrum β-lactamases (ESBLs) and carbapenemases. The addition of tazobactam extends the activity of ceftolozane to include most ESBL producers as well as some anaerobic species. Ceftolozane is distinguished from other cephalosporins by its potent activity versus Pseudomonas aeruginosa, including various drug-resistant phenotypes such as carbapenem, piperacillin/tazobactam, and ceftazidime-resistant isolates, as well as those strains that are multidrug-resistant (MDR). Its antipseudomonal activity is attributed to its ability to evade the multitude of resistance mechanisms employed by P.aeruginosa, including efflux pumps, reduced uptake through porins and modification of PBPs. Ceftolozane demonstrates linear pharmacokinetics unaffected by the coadministration of tazobactam; specifically, it follows a two-compartmental model with linear elimination. Following single doses, ranging from 250 to 2,000mg, over a 1-h intravenous infusion, ceftolozane displays a mean plasma half-life of 2.3h (range 1.9-2.6h), a steady-state volume of distribution that ranges from 13.1 to 17.6L, and a mean clearance of 102.4mL/min. It demonstrates low plasma protein binding (20%), is primarily eliminated via urinary excretion (≥92%), and may require dose adjustments in patients with a creatinine clearance <50mL/min. Time-kill experiments and animal infection models have demonstrated that the pharmacokinetic-pharmacodynamic index that is best correlated with ceftolozane's in vivo efficacy is the percentage of time in which free plasma drug concentrations exceed the minimum inhibitory concentration of a given pathogen (%fT >MIC), as expected of β-lactams. Two phaseII clinical trials have been conducted to evaluate ceftolozane±tazobactam in the settings of cUTIs and cIAIs. One trial compared ceftolozane 1,000mg every 8h (q8h) versus ceftazidime 1,000mg q8h in the treatment of cUTI, including pyelonephritis, and demonstrated similar microbiologic and clinical outcomes, as well as a similar incidence of adverse effects after 7-10days of treatment, respectively. A second trial has been conducted comparing ceftolozane/tazobactam 1,000/500mg and metronidazole 500mg q8h versus meropenem 1,000mg q8h in the treatment of cIAI. A number of phaseI and phaseII studies have reported ceftolozane to possess a good safety and tolerability profile, one that is consistent with that of other cephalosporins. In conclusion, ceftolozane is a new cephalosporin with activity versus MDR organisms including P.aeruginosa. Tazobactam allows the broadening of the spectrum of ceftolozane versus β-lactamase-producing Gram-negative bacilli including ESBLs. Potential roles for ceftolozane/tazobactam include empiric therapy where infection by a resistant Gram-negative organism (e.g., ESBL) is suspected, or as part of combination therapy (e.g., with metronidazole) where a polymicrobial infection is suspected. In addition, ceftolozane/tazobactam may represent alternative therapy to the third-generation cephalosporins after treatment failure or for documented infections due to Gram-negative bacilli producing ESBLs. Finally, the increased activity of ceftolozane/tazobactam versus P.aeruginosa, including MDR strains, may lead to the treatment of suspected and documented P.aeruginosa infections with this agent. Currently, ceftolozane/tazobactam is being evaluated in three phaseIII trials for the treatment of cUTI, cIAI, and VABP.