Virotherapy: From single agents to combinatorial treatments.

Virotherpay is emerging as a promising strategy against cancer, and three oncolytic viruses (OVs) have gained approval in different countries for the treatment of several cancer types. Beyond the capability to selectively infect, replicate and lyse cancer cells, OVs act through a multitude of events, including modification of the tumour micro/macro-environment as well as a complex modulation of the anti-tumour immune response by activation of danger signals and immunogenic cell death pathways. Most OVs show limited effects, depending on the viral platform and the interactions with the host. OVs used as monotherapy only in a minority of patients elicited a full response. Better outcomes were obtained using OVs in combination with other treatments, such as immune therapy or chemotherapy, suggesting that the full potential of OVs can be unleashed in combination with other treatment modalities. Here, we report the main described combination of OVs with conventional chemotherapeutic agents: platinum salts, mitotic inhibitors, anthracyclines and other antibiotics, anti-metabolites, alkylating agents and topoisomerase inhibitors. Additionally, our work provides an overview of OV combination with targeted therapies: histone deacetylase inhibitors, kinase inhibitors, monoclonal antibodies, inhibitors of DNA repair, inhibitors of the proteasome complex and statins that demonstrated enhanced OV anti-neoplastic activity. Although further studies are required to assess the best combinations to translate the results in the clinic, it is clear that combined therapies, acting with complementary mechanisms of action might be useful to target cancer lesions resistant to currently available treatments.

Evaluation of a new staging classification and a Peritoneal Surface Disease Severity Score (PSDSS) in 229 patients with mucinous appendiceal neoplasms with or without peritoneal dissemination.

INTRODUCTION: Most classifications of mucinous appendiceal neoplasms (MAN) do not take into consideration the type of primary tumor or the burden of peritoneal disease. MATERIALS AND METHODS: We conducted a retrospective evaluation of 229 patients with MAN. The severity of their disease was analyzed with the Peritoneal Surface Disease Severity Score (PSDSS) on a five-point scale that included: (1) the primary appendiceal tumor, (2) the type of peritoneal dissemination, and (3) the burden of disease. Overall survival was analyzed according to five tiers of estimated disease severity based on the above parameters. RESULTS: There were 19, 67, 59, 43, and 41 patients with PSDSS 0, I, II, III, and IV, respectively. One hundred seventy-three patients underwent cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Overall survival was 80.0 months in this group with 5-year survival of 100%, 79.2%, 23.3%, and 6.9% in patients with PSDSS I, II, III, and IV, respectively (P < 0.001). On multivariate analysis, sex and PSDSS stage were identified as independent predictors of survival. CONCLUSIONS: The PSDSS appears to be an important prognostic indicator in patients with MANs with or without peritoneal dissemination and may improve selection of patients for appropriate therapy from the time of diagnosis.

Mitomycin C versus 5-fluorouracil as an adjunctive treatment for trabeculectomy: a meta-analysis of randomized clinical trials.

Mitomycin C (MMC) and 5-fluorouracil (5-FU) are the most frequently utilized adjuvant therapies in trabeculectomy (TRAB), but there is no general consensus as to the direct comparative efficacy and safety of these two adjuvants. In this study, the authors conducted a meta-analysis to compare the efficacy and safety of augmenting TRAB with MMC or 5-FU. A systematic review with meta-analysis was conducted and five randomized controlled clinical trials comparing MMC versus 5-FU as adjunctive therapies were identified, totaling 416 participants. A lower pooled mean IOP and higher complete and qualified success rates were observed in the MMC arm than in the 5-FU arm. Epithelial corneal defects were the unique complication reported more frequently with 5-FU compared to MMC treatment. Compared to TRAB with 5-FU, TRAB with MMC was associated with higher rates of complete and qualified surgical success and was not associated with increased incidences of postoperative complications.

Treatment of idiopathic membranous nephropathy.

Immunosuppressive treatment of patients with idiopathic membranous nephropathy (iMN) is heavily debated. The controversy is mainly related to the toxicity of the therapy and the variable natural course of the disease-spontaneous remission occurs in 40-50% of patients. The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis provides guidance for the treatment of iMN. The guideline suggests that immunosuppressive therapy should be restricted to patients with nephrotic syndrome and persistent proteinuria, deteriorating renal function or severe symptoms. Alkylating agents are the preferred therapy because of their proven efficacy in preventing end-stage renal disease. Calcineurin inhibitors can be used as an alternative although efficacy data on hard renal end points are limited. In this Review, we summarize the KDIGO guideline and address remaining areas of uncertainty. Better risk prediction is needed to identify patients who will benefit from immunosuppressive therapy, and the optimal timing and duration of this therapy is unknown because most of the randomized controlled trials were performed in low-risk or medium-risk patients. Alternative therapies, directed at B cells, are under study. The discovery of anti-M type phospholipase A2 receptor-antibodies is a major breakthrough and we envisage that in the near future, antibody-driven therapy will enable more individualized treatment of patients with iMN.

Effect of mitomycin C on revision endoscopic dacryocystorhinostomy.

OBJECTIVE: The objectives of the study were to compare the outcome and success rate of revision endoscopic dacryocystorhinostomy (EN-DCR) with or without use of adjunctive mitomycin C (MMC) in cases with dacryocystorhinostomy (DCR) failure. METHODS: Thirty-six consecutive adult patients underwent revision EN-DCR. The patients were divided into 2 groups. In group 1 (18 patients), a neurosurgical cottonoid soaked in MMC at 0.5 mg/mL was placed at the osteotomy site for 5 minutes (using canalicular silicone intubation tube). In the other group (18 patients), standard endoscopic dacryocystorhinostomy technique was used without MMC (using canalicular silicone intubation tube). Successful DCR was defined as relief of symptoms (resolution of epiphora and absence of discharge) as demonstrated by saline irrigation at the last postoperative visit. RESULTS: The EN-DCR procedure with adjunctive MMC was successful in 16 (88.88%) cases. The mean follow-up was 11.5 months (7-19 months). No significant complications were encountered. In the control group, the EN-DCR was successful in 10 patients (55.55%). The mean follow-up was 12.7 months (6-22 months). The difference between the 2 groups was statistically significant (P < 0.05). CONCLUSIONS: Recurrent nasolacrimal duct obstruction after primary DCR is mainly due to reclosure of the nasolacrimal stoma and osteotomy site with granulation tissue. Adjunctive use of intraoperative MMC seems to be a safe adjuvant that could help in increasing the success rates of revision EN-DCR surgery.

Sézary syndrome: immunopathogenesis, literature review of therapeutic options, and recommendations for therapy by the United States Cutaneous Lymphoma Consortium (USCLC).

Sézary syndrome (SS) has a poor prognosis and few guidelines for optimizing therapy. The US Cutaneous Lymphoma Consortium, to improve clinical care of patients with SS and encourage controlled clinical trials of promising treatments, undertook a review of the published literature on therapeutic options for SS. An overview of the immunopathogenesis and standardized review of potential current treatment options for SS including metabolism, mechanism of action, overall efficacy in mycosis fungoides and SS, and common or concerning adverse effects is first discussed. The specific efficacy of each treatment for SS, both as monotherapy and combination therapy, is then reported using standardized criteria for both SS and response to therapy with the type of study defined by a modification of the US Preventive Services guidelines for evidence-based medicine. Finally, guidelines for the treatment of SS and suggestions for adjuvant treatment are noted.

Polycythemia vera: plethora, from prehistory to present.

The term polycythemia (literally, "many blood cell disease") and its obsolete synonym, erythremia, postdate Robert Hooke's 17th century discovery of cells, but the concept of a clinically problematic excess of blood was formulated in antiquity. Observation of plethoric patients by clinicians of the Hippocratic school informed the classical humoral framework that dominated theoretical constructs of human disease for more than a thousand years. In the golden era of disease description at the end of the 19th century, the idiopathic entity polycythemia rubra vera (PRV) was first described and distinguished from secondary and relative polycythemia (red cell excess not caused by a primary bone marrow disorder, and artifactual red cell excess caused by plasma volume contraction, respectively). This review traces some of the principal events in the history of polycythemia vera (PV) as a discrete clinical entity.

In vitro evaluation of dimethane sulfonate analogues with potential alkylating activity and selective renal cell carcinoma cytotoxicity.

We identified five structurally related dimethane sulfonates with putative selective cytotoxicity in renal cancer cell lines. These compounds have a hydrophobic moiety linked to a predicted alkylating group. A COMPARE analysis with the National Cancer Institute Anticancer Drug Screen standard agent database found significant correlations between the IC50 of the test compounds and the IC50 of alkylating agents (e.g., r = 0.68, P < 0.00001 for chlorambucil). In this report, we examined whether these compounds had activities similar to those of conventional alkylating agents. In cytotoxicity studies, chlorambucil-resistant Walker rat carcinoma cells were 4- to 11-fold cross-resistant to the test compounds compared with 14-fold resistant to chlorambucil. To determine effects on cell cycle progression, renal cell carcinoma (RCC) line 109 was labeled with bromodeoxyuridine prior to drug treatment. Complete cell cycle arrest occurred in cells treated with an IC90 dose of NSC 268965. p53 protein levels increased as much as 5.7-fold in RCC line 109 and as much as 20.4-fold in breast cancer line MCF-7 following an 18-hour drug exposure. Finally, DNA-protein cross-links were found following a 6-hour pretreatment with all compounds. Thus, the dimethane sulfonate analogues have properties expected of some alkylating agents but, unlike conventional alkylating agents, appear to possess activity against RCC.

Brostallicin: a new concept in minor groove DNA binder development.

Brostallicin is a bromoacryloyl derivative of distamycin A, which has shown very promising preclinical activity against a variety of human tumors both in vitro and in vivo. The drug has a limited toxicity towards bone marrow precursor cells in vitro resulting in a therapeutic index much higher than those achieved with other distamycin A derivatives. It retains activity against cancer cells resistant to alkylating agents, topoisomerase I inhibitors and cells with mismatch repair deficiency. Brostallicin has a peculiar mechanism of action involving activation upon binding to glutathione (GSH) catalyzed by glutathione-S-transferase (GST). As a consequence, cells expressing relatively high GST/GSH levels are more susceptible to treatment with brostallicin. Considering that increased levels of GST/GSH are often found in human tumors, this could represent an advantage for the drug in the clinic. Initial clinical studies indicate the tolerability of the drug and allow the determination of the optimal dose for subsequent studies. Some partial response were obtained in these initial phase I studies. Altogether, the results suggest brostallicin to be a new promising anticancer agent with a new mechanism of action. It also raises the possibility to use it in combination with other anticancer drugs currently used.

Polycythemia vera: a review.

Polycythemia vera (PV) is a clonal stem cell disorder characterized by increased erythrocyte production. Its etiology is not fully understood, and hemorrhage, thrombosis, and hyperviscosity may occur at any time during the course of this disorder. Treatment depends on the most affected cell type, duration and severity of the condition, and patient age. PV treatment can involve phlebotomy, administration of myelosuppressive agents, and biologic therapy. The inconsonant nature of the disease and complications related to its various treatments present nursing care challenges. Nurses must work with patients with PV to ensure compliance with treatment, teach awareness of disease- and treatment-related complications, and provide needed support.

An "evidence-based" survey of therapeutic options for IgA nephropathy: assessment and criticism.

BACKGROUND: Immunoglobulin A (IgA) nephropathy is a worldwide disease that causes end-stage renal failure in 15% to 20% of patients within 10 years of the apparent onset of disease and in 30% to 40% of individuals within 20 years. Severity of renal lesions, serum creatinine level, and severe proteinuria are adverse prognostic indicators. No specific treatment has been established, but several approaches have been experimented. METHODS: We reviewed the literature and evaluated the quality of published randomized trials using standard methods and the quality of their reporting according to the revised version of the Consolidated Standards for Reporting Trials Statement. Meta-analyses of randomized trials on the efficacy of steroid treatment, cytotoxic agents, and fish oils on the outcome of renal function and daily proteinuria in patients with IgA nephropathy were performed. RESULTS: Only 10 randomized trials were available and included in the review. Their quality was very poor, and a limited amount of data was reported. Cytotoxic agents seem beneficial on both renal function (relative risk, 0.38; 95% confidence interval [CI], 0.22 to 0.66) and daily proteinuria (weighted mean difference [WMD], -1.16; 95% CI, -2.18 to -0.14) in patients with moderate to severe renal damage, steroids act mainly on proteinuria (WMD, -0.50; 95% CI, -0.78 to -0.21), and fish oils do not imply a particular benefit. This statement is based on the very limited and poor available published evidence. CONCLUSION: Only a few randomized trials, of low quality and inadequately reported, are available relating to treatment of IgA nephropathy. More properly designed and reported trials are necessary to reach a definitive assessment of this matter.

Effect of alpha-tocopherol on hepatocarcinogenesis in transforming growth factor-alpha (TGF-alpha) transgenic mice treated with diethylnitrosamine.

To examine the potentially chemopreventive effects of alpha-tocopherol on hepatocarcinogenesis, we fed the transgenic mice line MT42, which overexpresses transforming growth factor-alpha (TGF-alpha) and which has been established as having a high incidence of liver tumor, with different concentrations of alpha-tocopherol and examined the hepatic tumorigenesis of these mice. At 3 weeks of age, MT42 male mice received a single intraperitoneal injection of diethylnitrosamine (DEN), 5 mg/kg body weight, to initiate the formation of liver tumors. The mice were divided into three groups: group A, control diet (20 mg/kg of alpha-tocopherylacetate); group B, deficient diet (less than 1 mg/kg); group C, supplemented diet (500 mg/kg). Neoplastic change was determined at 40 weeks of age. The incidence of adenomas (p < 0.05), the maximum tumor size (p < 0.01), the mean relative liver weight (p < 0.01), and the proliferating cell nuclear antigen (PCNA) labeling indices of the non-tumor sites (p < 0.01) of group B were significantly higher than those of group C. No toxic effects of alpha-tocopherol were found. Alpha-tocopherol-deficient diet accelerated the hepatocarcinogenesis of TGF-alpha transgenic mice treated with DEN. At best, these data demonstrate that alpha-tocopherol-deficiency is not beneficial for prevention of hepatocarcinogenesis in this model. Alpha-tocopherol may be useful for the chemoprevention for liver cancer.

Innovative treatment approaches for rheumatoid arthritis. Cyclosporin, leflunomide and nitrogen mustard.

Cyclosporin A (CSA) Cyclosporin inhibits IL-2 release and T-cell activation and, secondarily, affects B-cell function. It also inhibits bone resorption, at least in vitro. This drug's bio-availability averages 25-35% but is highly variable. Food and grapefruit juice enhance bio-availability and newer formulations may make its absorption more reliable. It is highly concentrated in fatty tissues and red blood cells but does not cross the blood-brain barrier. CSA is metabolized to numerous metabolites by the liver and its elimination half-life is 6-12 hours in the absence of severe liver disease. Biliary excretion accounts for 94% of CSAs elimination. Because it is highly metabolized, its metabolism can be inhibited by other drugs (e.g. ketoconazole and erythromycin) or its metabolism can be induced (e.g. anticonvulsants). Cyclosporin is more effective than placebo for the treatment of rheumatoid arthritis and as effective as other antirheumatics. There is potential for the use of CSAs in DMARD combinations. The principal toxicities of cyclosporin are gastro-intestinal and renal, with the latter being of more concern. Leflunomide (LF). Leflunomide may be a pyrimidine synthesis inhibitor, although tyrosine kinase inhibitor may also be part of its mechanism of action. Its active metabolite is excreted renally to a large degree, with a prolonged elimination half-life of about 11 days. Since LF is activated by liver metabolism, renal failure may have less effect on kinetics than severe liver disease. Early data on efficacy indicate efficacy at 10-25 mg/day, although more well-controlled data is necessary. Toxicity relates to the skin, liver and GI tract, although some degree of weight loss was also found. Nitrogen mustard (NM). Nitrogen mustard is an alkylating agent whose pharmacokinetics are poorly understood. Small, open studies in RA indicate that NM has a potential for relatively rapid response (1-2 weeks) but, clearly, much work remains to be done. As an alkylating agent, GI and hematological toxicities are of greatest concern.

Effects of levamisole, DTC and low-dose mechlorethamine on humoral response of SRBC-immunized rabbits exposed to cold stress.

The experiments were carried out on normothermal rabbits and rabbits exposed to cold stress (hypothermia). The animals of the latter group were submerged in ice-water for 20 s and then placed in a freezer at -15 degrees C for 8 min until their body temperature dropped by 3 degrees C. Both the normothermal and hypothermal rabbits were immunized i.p. with 3 ml of 10% sheep red blood cells (SRBC). Levamisole (2 mg/kg), DTC (sodium diethyldithiocarbamate, 20 mg/kg) or mechlorethamine (mustine; 5 micrograms/kg) were injected i.v. three times at 24-h intervals. The number of PFC, total (19S + 7S) and 2-mercapthoethanol resistant (7S) serum haemagglutination titres were determined. It was found that, in normothermal rabbits, all three agents potentiated the number of plaque-forming cells (PFC); the impact of DTC was the strongest, while the weakest influence was observed for mechlorethamine. Furthermore, DTC increased anti-SRBC haemagglutinin titre, whereas mechlorethamine did not. Levamisole, on the other hand, reduced total serum haemagglutinin titre. Cold stress reduced humoral response to SRBC, which was reflected in the decreased number of PFC and serum haemagglutination titres (19S + 7S and 7S). Each agent showed a different way of action. Pretreatment with DTC prevented the immunosuppression caused by cold stress, while levamisole and mechlorethamine only reduced the immunosuppressive effect.

[The action of amino acid di[2-haloethyl]hydrazides on DNA synthesis in normal and tumor cells and on the cell cycle kinetics in mice with melanoma B-16]. / Deistvie di-[2-galoétil]gidrazidov aminokislot na sintez DNK v normal'nykh i opukholevykh kletkakh i kinetiku kletochnogo tsikla u myshei s melanomoi B-16.

A comparative study was carried out with two alkylating agents IMB-MM and IMB-97 which are di-(2-halogenoethyl) hydrazides of amino acid derivatives. They have been found to exert a high activity towards wide spectrum of experimental tumours. Both agents caused inhibition of incorporation of 3H-thymidine into DNA of melanoma B16, marrow, intestinal mucosa, spleen and liver cells of mice with tumours. A maximal inhibition of DNA synthesis in all tissues was observed 24 h after the single doses of drugs. However 96 h later this effect was removed excluding the tumour cells. The cytofluorimetric study have shown that IMB-MM, like sarcolysine, caused an accumulation of tumour cells in G2/M phase of cell cycle, while IMB-97 increased accumulation of S-phase cells. The difference in phase sensitivity of tumour cells towards IMB-MM and IMB-97 is due to the differences in aminoacid carriers of di-(2-halogenethyl) hydrazide groups.

Single-agent chemotherapy for advanced adenocarcinoma of the lung. A review.

Systemic therapy with cytostatic agents has been widely used in the management of inoperable adenocarcinoma of the lung (ACL). However, chemotherapy for this tumor type remains experimental, and the prognosis is still poor. Thus, the literature on single-agent chemotherapy was reviewed in order to establish critical background material for the planning and evaluation of future studies. Only vindesine, dibromodulcitol, doxorubicin and hexamethylmelamine have displayed overall response rates exceeding 10% in randomized studies. Several of the most promising agents with response rates above 20% in non-randomized studies, i.e., 5-fluorouracil, mitomycin C, vinblastine and ifosfamide, have not been adequately evaluated in randomized trials in ACL. There is no published evidence to suggest the superiority of single-agent chemotherapy over the best supportive treatment, with respect either to survival or to quality of life. There are considerable methodological problems in designing, executing, analyzing and reporting these studies. Some of the problems could be solved by use of the internationally accepted guidelines for reporting results of cancer treatment, which might make more rapid progress possible.

Cysteamine protects against diarrhoea induced by castor oil. This protective effect can be potentiated by SH-alkylator treatment.

Cysteamine given orally or subcutaneously protects against diarrhoea induced by castor oil. Pretreatment with N-EM, an SH-alkylator, does not influence the occurrence of diarrhoea. Furthermore, N-EM pretreatment does not influence the protective effect of loperamide or difenoxilate. However, N-EM pretreatment potentiates the protective effects of cysteamine or indomethacin against diarrhoea. These findings indicate that sulfhydryl-sensitive processes may also be involved in the mechanisms of diarrhoea.

MOPC-315 murine plasmacytoma as a model anticancer screen for human multiple myeloma.

The murine tumor MOPC-315 plasmacytoma was studied as a model for human multiple myeloma. Plasmacytoma cells (10(6)) were injected iv into BALB/c mice, and 14 days later a single ip dose of the anticancer agent to be tested was administered at a dose that would result in 10% toxicity within 30 days (LD10). Increases in life-span and cures resulting from the LD10 dose were the parameters assessed. The response of this MOPC-315 plasmacytoma model to a variety of anticancer agents demonstrated good correlation with clinically active agents. A number of investigational agents were found to be highly active and potential candidates for clinical phase II studies.