Cancer Cell Membrane-Biomimetic Nanoparticles Based on Gelatin and Mitoxantrone for Synergetic Chemo-Photothermal Therapy of Metastatic Breast Cancer.

The purpose of this paper is to develop a cancer cell membrane biomimetic nanodrug delivery system (NDDS) to achieve an enhanced chemo-photothermal synergistic antitumor effect. The biomimetic NDDSs are composed of mitoxantrone (MIT)-loaded gelatin nanoparticles and IR820-encapsulated 4T1 cancer cell membrane-derived vesicles. The biomimetic NDDS displayed excellent stability and photothermal conversion efficiency. Compared to naked nanoparticles, the cell membrane-coated nanoparticles improved 4T1 cell uptake through homologous targeting and effectively reduced internalization of macrophages. In vivo photothermal imaging results further showed that the NDDS could be enriched at the tumor site for 48 h and could raise the temperature of the tumor area to 60 °C within 5 min under 808 nm laser irradiation. Finally, NDDS successfully inhibited primary tumor growth (over 89% inhibition) and significantly inhibited lung metastasis. This study may provide a new strategy for personalized chemotherapy-photothermal combination therapy of metastatic breast cancer using tumor cell membranes from cancer patients as drug carriers.

Calcium-phosphate homeostasis in secondary progressive multiple sclerosis patients during mitoxantrone therapy.

OBJECTIVES: To assess calcium-phosphate parameters in SPMS patients treated with mitoxantrone (MTX). METHODS: Thirty eight SPMS patients eligible for MTX therapy in the Department of Neurology in Zabrze, Poland were enrolled in a prospective study from March 2016 to November 2019. The parameters of serum calcium-phosphate metabolism and the neurological status according to the Expanded Disability Status Scale (EDSS) were assessed. In patients with hypovitaminosis D, vitamin D (VitD) supplementation was introduced (4000 IU/day for 1 month and later 2000 IU /day). RESULTS: Most patients were women [57.89%]. The mean age [years] was 56.11 (±7.74). The median time from diagnosis to inclusion day (ID) was 7.50 [4.00-14.00] [years]. Due to VitD supplementation, an increase in serum VitD was observed during the study. 84.21% of patients presented with hypovitaminosis D before MTX treatment compared to 47.37% after treatment. Before MTX therapy, none of the patients underwent surgical repair of the fracture compared to 42.11% of patients after MTX treatment (p < 0.01). DISCUSSION: Deficiency of VitD was observed at the baseline in most SPMS patients eligible for MTX therapy. Due to adverse reactions to MTX treatment, this therapy requires patient compliance, cautious drug administration and monitoring during the therapy.

The impact of oral arsenic and all-trans-retinoic acid on coagulopathy in acute promyelocytic leukemia.

The aim of our study was to evaluate the impact of oral arsenic (the realgar-indigo naturalis formula, RIF) and all-trans retinoic acid (ATRA) on coagulopathy in acute promyelocytic leukemia (APL) compared with intravenous arsenic trioxide (ATO) and ATRA during induction. Mitoxantrone was added to all the patients at a dose of 1.4mg/m2 per day for 5-7 days. D-dimer levels, prothrombin time (PT), fibrinogen (Fbg) levels and the platelet count were comparably analyzed among 83 newly diagnosed APL patients treated with RIF (n=45) or with ATO (n=38). Since induction therapy with RIF and ATRA, the median levels of Fbg, PT and platelets were recovered to the normal range within 4days, 10days and 28days, respectively. The last day of platelet and plasma transfusion was day 12 (range: 0-24 days) and day 3 (range: 0-27 days), respectively. Among the 42 patients with a disseminated intravascular coagulation (DIC) score=4, the consumption of transfused platelets was less in the RIF group than that in the ATO group (P=0.037). In the 17 patients with a DIC score <4, prompt recovery of Fbg levels (P=0.028) was observed in the RIF group compared with that in the ATO group (P=0.401). RIF and ATO showed similar effects on the recovery of coagulopathy in APL patients. RIF had a potential beneficial effect in accelerating the recovery of thrombocytopenia and hypofibrinogenemia for subclinical DIC patients.

Multi-functional magnetic nanoparticles as an effective drug carrier for the controlled anti-tumor treatment.

Because of the complications and mutability of cancers, combination of chemotherapy and other therapy with multi-mechanisms would be a bright future for the treatment of cancer. Thus, development of multi-functional tumor-targeted drug delivery systems with two or more than two functions should be of great significance. In the study, the Fe3O4@C nanoparticles linked with thermoresponsive copolymer (MTC-NPs) were synthesized, after that, the magnetic properties and photothermal effects of MTC NPs were evaluated. Compared to the pure water, MTC-NPs absorbed more energy and transform it into heat under the 808 nm laser irradiation, and the temperature could increase over 60℃. In addition, the grafted copolymer with coil-to-globule transition acts as a gatekeeper for the temperature-controlled release of mitoxantrone molecules. The super paramagnetic behavior of MTC-NPs certified by the hysteresis loop gives a negligible coercivity at room temperature. Both in vitro and in vivo studies confirmed that the synergistic combination of magnetic targeting, drug controlled release, and thermochemotherapy improve the anti-tumor efficacy with lower side effects. This nanoparticle is a great potential drug carrier in anti-tumor drugs, which can improve the effect of hyperthermia, increase target distribution in tumor, and enhance curative effect for tumor while reducing normal tissue toxicity.

Análisis de impacto presupuestal de tecnologías para el manejo complementario de quimioterapia en Colombia / Budget impact analysis of technologies for the complementary management of chemotherapy in Colombia

INTRODUCCIÓN: El análisis de impacto presupuestal (AIP) de los medicamentos quimioterapéuticos para el tratamiento de cáncer en Colombia, se desarrolló en el marco del mecanismo técnico científico para la ampliación progresiva del Plan de Beneficios en Salud con cargo a la UPC (PBSUPC) y la definición de la lista de exclusiones, establecido en el artículo 15 de la Ley 1751 de 2015. La quimioterapia tiene un gran impacto en el tratamiento oncológico, la cual es indispensable por su valor terapéutico en varios tipos de cáncer. Esta tecnología puede ser usada sola o junto con otros tratamientos, tales como la cirugía o la radioterapia. La quimioterapia engloba a una gran variedad de fármacos y su objetivo es destruir las células tumorales con el fin de lograr la reducción de la enfermedad, los medicamentos empleados en este tipo de tratamiento se les denomina fármacos antineoplásicos. Cada tipo de tumor canceroso tiene una determinada sensibilidad a estos medicamentos, por lo tanto, es frecuente que el mismo fármaco se pueda emplear en el tratamiento de distintos tumores, variando las dosis o asociándolo a otros fármacos distintos. La quimioterapia puede ser administrada con fines curativos o para aliviar los síntomas y prolongar la supervivencia. La forma de administración de la quimioterapia es por ciclos y esto se logra alternando los periodos de tratamiento con periodos de descanso. Un ciclo es, por lo tanto, el periodo de administración del tratamiento y el de descanso hasta la siguiente administración. El objetivo de este análisis de impacto presupuestal (AIP) es estimar el esfuerzo financiero necesario para la adopción de la quimioterapia en el tratamiento de pacientes con cáncer en Colombia, en un horizonte temporal de tres años. Este documento está conformado por cuatro secciones: en la primera se identifican las tecnologías a evaluar, en la segunda sección se especifica la perspectiva, horizonte temporal y la población sobre la cual se realizó el AIP; en la sección tres se detallan los costos utilizados en el modelo, además de los escenarios planteados por los investigadores; por último, en la sección cuatro se exponen los resultados en los diferentes escenarios planteados Este documento describe la metodología desarrollada para realizar el análisis de impacto presupuestal de 21 tecnologías para el manejo quimioterapéutico del cáncer en Colombia Este informe, sigue los lineamientos propuestos en el Manual para la Elaboración de Análisis de Impacto Presupuestal y en Manual de Participación y Deliberación publicados por IETS. Insumos y método: Esta sección presenta los supuestos, parámetros y métodos utilizados para el modelo de estimación del impacto presupuestal describiendo la siguiente información: Perspectiva: La perspectiva de este AIP es la del tercer pagador el cual en nuestro contexto es el Sistema General de Seguridad Social en Salud (SGSSS). Horizonte temporal: El horizonte temporal de este AIP en el caso base corresponde a un año. Adicionalmente se reportan las estimaciones del impacto presupuestal para los años 2 y 3, bajo el supuesto de inclusión en el PBS en el año 1. Población total: Para el desarrollo de este AIP se parte de la población general afiliada al SGSSS colombiano sin distinción de sexo o edad. ESCENARIOS: Se consideró para la formulación de los escenarios de adopción de las tecnologías evaluadas los siguientes aspectos: 1. Los medicamentos evaluados no son alternativas terapéuticas para las patologías observadas, estas tecnologías sanitarias hacen parte de los protocolos de tratamiento con evidencia científica suficiente que garantizan su efectividad y seguridad clínica y que actualmente se encuentran en las opciones de tratamiento utilizados en la práctica clínica colombiana. 2. Al ser esquemas de tratamiento que hacen parte de protocolos estandarizados de aplicación, sí alguno de los medicamentos es sujeto de recobros ante ADRES, este trámite puede generar barreras de acceso al tratamiento hasta que se efectué la respectiva aprobación. Por lo tanto, no hay certeza de la efectividad clínica si los esquemas de tratamiento son suministrados de forma parcial o incompleta. 3. La elección del esquema de tratamiento obedece a criterios clínicos y a las características evaluadas en el paciente, no se espera una sustitución entre los diferentes esquemas sí se realiza un cambio en el mecanismo de financiamiento. 4. La adopción de las tecnologías evaluadas en este AIP no se espera que se modifiquen de manera importante, debido a que estas tecnologías hacen parte integral de los esquemas de tratamiento y su incorporación en la práctica clínica habitual en el contexto internacional y nacional, data de aproximadamente 10 a 5 años. Tambieén son parte de las opciones de primera línea de tratamiento para estadios tempranos, avanzados y localmente avanzados del paciente diagnosticado con câncer. De acuerdo a las anteriores consideraciones, al incorporar los medicamentos evaluados al PBS con cargo a la UPC, se espera la misma composición del mercado con la adopción de los nuevos medicamentos en el 100% de los tratamientos esperados en la siguiente anualidad. Los resultados esperados en el sistema de salud, en este cambio de financiamiento, se esperan obtener en dos puntos: a) En una mejor oportunidad de acceso a los esquemas de tratamiento en el SGSSS (25). b) En una mejora en la cobertura efectiva de los tratamientos de quimioterapia en pacientes con diagnóstico de cáncer. RESULTADOS: Se muestra el resultado consolidado para las ventiun tecnologías objeto del Análisis de Impacto Presupuestal. La tecnología que genera un mayor impacto es Oxaliplatino, con un valor por persona de $2.363.250,76 usada en 3170 pacientes, para un total de $7.491.504.923,90. El Megestrol es la tecnología con menor impacto, con un costo por persona de $ 383.791,06 y siendo usada en 34 pacientes, tiene un valor total de $ 13.048.896,00. La tretinoina es la tecnología más económica por paciente, con un valor de $ 97.996,50, es usada en 242 personas para un total de $ 23.715.153,00. DISCUSIÓN: En la práctica actual existe un volumen amplio de recobros en el caso de estos medicamentos por usos UNIRS. En algunos casos, los cambios en el mercado farmacéutico, ya sea por el retiro de medicamentos o la llegada de ellos, hace que se modifique indicaciones ya existentes en los registros y que pueden llegar a impactar estos. usos, por ejemplo aquellos casos en los que existe la indicación antineplásico y se cambian por indicaciones especificas, que pueden no considerar condiciones de salud de baja incidencia. Como se ha caracterizado con anterioridad, el mercado de tecnologías sanitarias que se encuentran incluidas al plan de beneficios en salud con cargo a la UPC difiere sustancialmente al mercado de tecnologías sanitarias aún no financiadas por dicho mecanismo. La existencia de las Empresas Administradoras de Planes de Beneficios (EAPB) presume la existencia de un actor que al maximizar su beneficio, es un buen negociador que en cumplimiento de los principios del SGSSS, llega a un precio de equilibrio que maximiza el beneficio social. En cambio, los medicamentos que son sujetos a recobros al ADRES presume un precio fuera de aquel nivel en donde se maximiza al beneficio social, en la medida que no hay una función clara de monopsonio que coteje y negocie un precio de adquisición. En algunos casos puede llegar asumir sobrecostos que las EAPB al ser intermediarias, no tienen incentivos para efectuar un adecuado control. Con el objetivo de estimar el resultado de la incorporación de estos medicamentos al PBS con cargo a la UPC, se asumieron dos escenarios en los cuales la población objetivo del AIP se consideró constante y se asumieron los siguientes supuestos: En el primer escenario se asume que los precios observados en recobros serán el promedio de todas las transacciones de compra en la siguiente anualidad. En el segundo escenario los precios promedio de adquisición de los medicamentos evaluados, corresponden al promedio observado en SISMED como predictor de los precios de equilibrio que pueden generar las EAPB como ente negociador. Se asume que, en promedio, las EAPB son negociadores eficientes que se acercan a un precio de equilibrio que maximiza el bienestar social. Se asume que la población objetivo corresponde al total de posibles pacientes que requieren las tecnologías sanitarias en evaluación, sin que exista demanda insatisfecha para estos esquemas de tratamiento. Para su cálculo, como se presenta en la tabla 09 de los servicios prestados durante el año 2015 y recobrados al FOSYGA en los años 2015 y 2016, se calculó un valor per-cápita de acuerdo con el identificador (cedula de ciudadanía anonimizada) registrado en cada recobro. Luego, este valor es indexado a precios 2016 con el IPC reportado por el DANE a diciembre 31 del año 2015. Este valor será el comparador del precio calculado para cada uno de los medicamentos a partir de SISMED 2016.

Effect of melatonin supplementation on plasma lipid hydroperoxides, homocysteine concentration and chronic fatigue syndrome in multiple sclerosis patients treated with interferons-beta and mitoxantrone.

UNLABELLED: Multiple sclerosis (MS) prevalence is higher in geographic regions with less sunlight exposure. Melatonin participates in the effects of sunlight in healthy individuals and could play a role in MS pathophysiology. Melatonin crosses the blood-brain barrier and exerts antioxidative, immunomodulatory, and anti-inflammatory effects. Chronic fatigue syndrome concerns 80 - 90% MS patients. The pathophysiology of chronic fatigue syndrome is unknown, however activation of immune, inflammatory, oxidative and nitrosative stress mechanisms and plasma lipid peroxide elevation was reported. Homocysteine increases plasma lipid hydroperoxides levels. The aim was to determine the effect of melatonin supplementation on chronic fatigue syndrome in MS patients and evaluate plasma lipid hydroxyperoxides (LHP) and homocysteine concentrations as a potential biochemical fatigue biomarkers. Into a case-control prospective study 102 MS patients divided according receiving immunomodifying MS treatment into groups: RRMS-pretreated, RRMS-INF-beta, SP/PPMS-mitoxantrone, RRMS-relapse were enrolled. Patients were supplemented with melatonin over 90 days. Plasma LHP, homocysteine concentration, brain MRI and fatigue score were examined. Results show that LHP concentrations were significantly higher in all studied MS groups vs. CONTROLS: In all MS patient groups melatonin application resulted in significant decrease in plasma LHP concentrations. Plasma homocysteine concentration was similar in healthy people, RRMS-pretreated, RRMS-INF-beta and SP/PP-MS-mitoxantrone groups. However, in the RRMS-relapse group plasma levels of homocysteine were significantly higher compared to the RRMS-pretreated group. There were no significant differences in plasma homocysteine concentration in the studied groups before and after melatonin application. The fatigue score was significantly lower in RRMS pretreated group compared to RRMS-INF-beta and SP/PP MS-mitoxantrone treated patients. Plasma lipid hydroxyperoxides could be potential biochemical chronic fatigue syndrome biomarker in MS patients and homocysteine could be a potential marker of acute phase of MS. Melatonin exerts beneficial effects in MS patients based on its' proved antioxidative properties.

Influence of melatonin supplementation on serum antioxidative properties and impact of the quality of life in multiple sclerosis patients.

The relationship between the prevalence of multiple sclerosis (MS) and sunlight's ultraviolet radiation was proved. Oxidative stress plays a role in the pathogenic traits of MS. Melatonin possesses antioxidative properties and regulates circadian rhythms. Several studies have reported that the quality of life is worse in patients with MS than in healthy controls, with a higher prevalence of sleep disturbances, depression and fatigue. The aim of study was to evaluate 5 mg daily melatonin supplementation over 90 days on serum malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity and its' influence on impact of the quality of life of MS patients. A case-control prospective study was performed on 102 MS patients and 20 controls matched for age and sex. The EDSS, MRI examinations and Multiple Sclerosis Impact Scale (MSIS-29) questionnaire was completed. Marked increase in serum MDA concentration in all MS patients groups was observed and after melatonin treatment decreased significantly in interferons-beta and glatiramer acetate-treated groups, but not in mitoxantrone-treated group. A significant increase in SOD activity compared to controls only in glatiramer acetate-treated group was observed. After 3 months melatonin supplementation the SOD activity increased compared to initial values in interferons beta-treated groups. A significant increase in both MSIS-29-PHYS and MSIS-29-PSYCH items mean scores only in the MX group as compared to other groups was observed. There were no significant differences in mean MSIS-29-PHYS was observed before and after melatonin therapy. Melatonin supplementation caused a decrease in mean MSIS-29-PSYCH scores compared to initial values in interferons beta-treated groups. Finding from our study suggest that melatonin can act as an antioxidant and improves reduced quality in MS patients.

Mitoxantrone for multiple sclerosis.

BACKGROUND: This is an updated Cochrane review of the previous published version.Mitoxantrone (MX) has been shown to be moderately effective in reducing the clinical outcome measures of disease activity in multiple sclerosis (MS) patients. OBJECTIVES: The main objective was to assess the efficacy and safety of MX compared to a control group in relapsing-remitting (RRMS), progressive relapsing (PRMS) and secondary progressive (SPMS) MS participants. SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (June 2012) and reference lists of articles. We also undertook handsearching and contacted trialists and pharmaceutical companies. SELECTION CRITERIA: Randomised, double-blinded, controlled trials (RCTs) comparing the administration of MX versus placebo or MX plus steroids treatment versus placebo plus steroids treatment were included. DATA COLLECTION AND ANALYSIS: The review authors independently selected articles for inclusion. They independently extracted clinical, safety and magnetic resonance imaging (MRI) data, resolving disagreements by discussion. Risk of bias was evaluated to assess the quality of the studies. Treatment effect was measured using odds ratios (OR) with 95% confidence intervals (CI) for the binary outcomes and mean differences (MD) with 95% CI for the continuous outcomes. If heterogeneity was absent, a fixed-effect model was used. MAIN RESULTS: Three trials were selected and 221 participants were included in the analyses. MX reduced the progression of disability at two years follow-up (proportion of participants with six months confirmed progression of disability (OR 0.30, 95% CI 0.09 to 0.99 and MD -0.36, 95% CI- 0.70 to -0.02; P = 0.04)). Significant results were found regarding the reduction in annualised relapse rate (MD -0.85, 95% CI -1.47 to -0.23; P = 0.007), the proportion of patients free from relapses at one year (OR 7.13, 95% CI 2.06 to 24.61; P = 0.002) and two years (OR 2.82, 95% CI 1.54 to 5.19; P = 0.0008), and the number of patients with active MRI lesions at six months or one year only (OR 0.24, 95% CI 0.10 to 0.57; P = 0.001). Side effects reported in the trials (amenorrhoea, nausea and vomiting, alopecia and urinary tract infections) were more frequent in treated patients than in controls, while no major adverse events have been reported. These results should be considered with caution because of the heterogeneous characteristics of included trials in term of drug dosage, inclusion criteria and quality of included trials. Moreover, it was not possible to estimate the long-term efficacy and safety of MX. AUTHORS' CONCLUSIONS: MX shows a significant but partial efficacy in reducing the risk of MS progression and the frequency of relapses in patients affected by worsening RRMS, PRMS and SPMS in the short-term follow-up (two years). No major neoplastic events or symptomatic cardiotoxicity related to MX have been reported; however studies with longer follow-up (not included in this review) have raised concerns about the risk of systolic disfunction (˜12%) and therapy-related acute leukaemias (0.8%), which are increasingly reported in the literature.MX should be limited to treating patients with worsening RRMS and SPMS and with evidence of persistent inflammatory activity after a careful assessment of the individual patients' risk and benefit profiles. Assessment should also consider the present availability of alternative therapies with less severe adverse events.

Photosensitizing and radiosensitizing effects of mitoxantrone: combined chemo-, photo-, and radiotherapy of DFW human melanoma cells.

This study evaluated the effects of mitoxantrone (MX), an antitumor agent, as a sensitizer to both photodynamic and radiation therapy in DFW human melanoma cells. Cells were incubated with MX at different concentrations for 90 min and then exposed to non-coherent light at different fluence rates and/or X-ray ionizing radiation at different dose rates. Combinatorial effects of this chemo-, photo-, and radiotherapy were also evaluated. MX had no significant effects on viability at moderate doses but had a strong cytotoxic effect on cancer cells when used as a photosensitizer. MX also acted as a potent radiosensitizer. We observed a dose-dependent effect on cell viability in cells exposed to MX in combination with phototherapy and radiotherapy. Strong synergistic effects were observed for combinations of two or more treatment methods, which, in some cases, induced complete cell death. Thus, a combination of ionizing radiation with MX-mediated photodynamic therapy could serve as a new method for cancer therapy with fewer adverse side effects.

Biochemical and pharmacological effects of mitoxantrone and acetyl-L-carnitine in mice with a solid form of Ehrlich tumour.

BACKGROUND: Dysfunction of the carnitine system in non-tumour tissue following anticancer therapy has been reported. In this setting, supplementation with carnitine derivatives might increase the general metabolic activity of normal cells so that they might better withstand the adverse effects of chemotherapy aimed at tumour cells. Here we investigated the effect of acetyl-L-carnitine (ALC) alone and in combination with the antineoplastic agent mitoxantrone (MX) in an animal cancer model. METHODS: The effects of MX and MX-ALC were assessed based on gain or loss of body weight and on local growth of a solid form of Ehrlich tumour inoculated into mice. We also performed biochemical analyses like serum activities of some enzymes signalling the functioning of the liver, aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Total protein, albumin and bilirubin were also determined in serum. Under favourable conditions, the Ehrlich tumour readily forms metastases, and this is the reason why we performed histological studies of samples of both the liver and heart in order to identify changes that may have mediated the observed effect of the treatment. In addition to those studies, the survival time of treated animals against controls was also noted. RESULTS: MX monotherapy was associated with lower body weight gain, fewer metastases, smaller tumour size, and lower dissemination. ALC alone promoted survival, but had no potentiating effect on MX therapy in terms of survival. Serum biochemistry changes associated with MX-ALC treatment consisted of a significant (p < 0.05) increase in AST with MX at 6 or 9 mg·kg(-1) plus ALC 200 mg·kg(-1) and a significant (p < 0.05) reduction in total protein compared to the corresponding MX group; serum albumin and bilirubin remained unchanged. CONCLUSION: ALC in combination with MX, regardless of the dose of MX, led to higher occurrences of metastases with dissemination to the kidneys, lungs, heart, and mediastinum compared to MX treatment alone. These histological findings indicate that ALC is inappropriate to combine with MX in the treatment of a solid cancer. The protective effect of ALC in combination therapy with the cytostatic drug MX was not supported in this study by our findings that the agent did not improve the therapeutic outcomes of MX therapy.

Effect and prognostic analysis of treatment for acute myeloid leukemia using Chinese drugs combined with chemotherapy.

OBJECTIVE: To observe the clinical efficacy of Chinese drugs combined with chemotherapy in the treatment of acute myeloid leukemia (AML) and to investigate the prognostic relevance of the main parameters in AML treated with integrative medicine. METHODS: Forty AML patients hospitalized at the authors hospital were treated with Chinese drugs and chemotherapy. The routine examination, immunophenotype and karyotype analyses were carried out. The clinical efficacy was observed and the prognostic factors were analyzed. RESULTS: (1) Clinical efficacy: Twenty patients had complete remission (CR), with the CR rate being 50.0%. Among these patients, the CR rate was 73.9% (17/23) in de novo AML and 17.6% (3/17) in secondary or refractory AML, respectively. The median disease free survival (DFS) was 6 months (2-32 months) and median overall survival (OS) was 7 months (1-36 months). (2) Analysis of prognostic factors: Aging (> 60 years) and hepatosplenomegaly or extramedullary leukemia did not affect the treatment outcome. Patients with lower white blood cell (WBC) counts (<4.0x10(9)/L) had a significantly higher CR rate (P<0.01). Secondary or refractory AML was associated with a lower CR rate and shorter OS (P<0.01,P<0.05). Expression of CD34 was an adverse factor for obtaining CR (P<0.05) and survival in both DFS and OS (P<0.05,P<0.01). The expression of CD56 was significantly associated with a lower CR rate (P<0.05), but did not affect DFS and OS. Twenty-three (57.5%) out of 40 cases had chromosomal abnormalities. The CR rate was decreased and both DFS and OS shortened stepwise from the cases with favorable cytogenetics to those with intermediate and unfavorable cytogenetics (P<0.01). CONCLUSIONS: The combined treatment of Chinese drugs with chemotherapy has a predominant effect in de novo AML. Secondary or refractory AML, expression of CD34 and CD56, and unfavorable cytogenetics were the main factors of poor prognosis in AML.

HIV and anal cancer outcomes: a single institution's experience.

PURPOSE: The purpose of this study is to identify the effect of HIV status on outcome of treatment for squamous-cell carcinoma of the anal canal. METHODS: A retrospective review was performed on all patients with squamous-cell carcinoma of the anal canal treated at a single academic institution between January 1996 and December 2006. RESULTS: Our search identified 87 (21 HIV-positive) patients who had invasive squamous-cell cancer. The median follow-up was 38 months. Eighty-five percent of HIV-negative patients and 81 percent of HIV-positive were identified as complete responders at 6 weeks after completion of combined modality therapy. Eight percent of HIV-negative and 29 percent of HIV-positive patients developed recurrent disease after 6 months (P = 0.0009). Overall survival for HIV-negative and HIV-positive patients was 71 percent and 73 percent, respectively. CONCLUSIONS: HIV-positive patients respond equally to combined modality therapy but have recurrences more frequently than patients who are HIV negative. Overall survival in these two groups is equivalent.

Identification of novel antipoxviral agents: mitoxantrone inhibits vaccinia virus replication by blocking virion assembly.

The bioterror threat of a smallpox outbreak in an unvaccinated population has mobilized efforts to develop new antipoxviral agents. By screening a library of known drugs, we identified 13 compounds that inhibited vaccinia virus replication at noncytotoxic doses. The anticancer drug mitoxantrone is unique among the inhibitors identified in that it has no apparent impact on viral gene expression. Rather, it blocks processing of viral structural proteins and assembly of mature progeny virions. The isolation of mitoxantrone-resistant vaccinia strains underscores that a viral protein is the likely target of the drug. Whole-genome sequencing of mitoxantrone-resistant viruses pinpointed missense mutations in the N-terminal domain of vaccinia DNA ligase. Despite its favorable activity in cell culture, mitoxantrone administered intraperitoneally at the maximum tolerated dose failed to protect mice against a lethal intranasal infection with vaccinia virus.

Complete remissions in chemotherapy of lung cancer models induced in mice by asbestos.

Chemotherapy trials were run with mice bearing transplants of carcinomas originally induced from fetal mouse lung cells by asbestos. After treatments with a nitrosourea (PCNU), mice bearing transplants of a large-cell carcinoma (ASB XIV) had complete remissions (CR) in 13 of 20 animals on a 15 mg/kg regimen, in 6 of 20 on an 8 mg/kg regimen, and in none of 10 on a 4 mg/kg regimen. With comparable total doses, treatment was most effective when PCNU was given in a few large doses. In groups where CRs occurred, continued PCNU treatment of animals without CRs prolonged survival but yielded no additional CRs. No CRs of ASB XIV occurred in 80 mice treated with eight other anticancer agents or in 50 controls injected with 0.9% NaCl solution. In mice bearing transplants of a squamous cell carcinoma (ASB XIII), treatments with PCNU were followed by CRs in 3 of 38 animals on 15 mg/kg regimens and in 3 of 28 animals on 8 mg/kg regimens. In groups of 6 mice fed a retinoid (Ro 10-9359) and treated with PCNU, CRs of ASB XIII occurred in 3 animals in each of two trials and in none in a third trial. Ro 10-9359 inhibited growth of transplants of squamous cell carcinoma LC 12 that had been induced from fetal mouse lung cells by a polycyclic hydrocarbon. In trials of four other anticancer agents vs. ASB XIII, CRs occurred only with cyclophosphamide (CPA). There were 7 CRs among 8 mice treated with CPA 100 mg/kg x 3, no CRs in 10 after 100 mg/kg x 2, one CR in 8 after 50 mg/kg x 3, and no CRs in 6 after 50 mg/kg x 4. With the 50 mg/kg x 4 regimen of CPA and 7.5 mg/kg PCNU on the same days, there were 5 CRs in 8 mice. As a single agent, aziridinylbenzoquinone (AZQ) increased life span but gave no CRs. There were CRs of ASB XIII in all of 8 mice after toxic combined therapy with PCNU and AZQ. There were no CRs in 66 control mice bearing ASB XIII.

A nurse-led, patient-centred mitoxantrone service in neurology.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system for which there is no known cure. There are licensed treatments available to influence the disease course, but for a small group of patients, progression of the disease may continue at an alarming rate. Mitoxantrone, a cytotoxic agent normally used in the treatment of cancer, has been shown to reduce disease activity in patients who have this more aggressive form of MS. However, the immunosuppressive action and side-effect profile of mitoxantrone mean that this drug should be used with caution. This article describes a MS nurse-led initiative where an evidence-based, integrated care pathway was designed to ensure a safe, high-quality service provision for this select patient group.

[Radiation and concomitant chemotherapy after surgery for breast cancer]. / Irradiation et chimiothérapie concomitante après chirurgie pour cancer du sein.

In breast cancer, radiation therapy improves local control rate and survival. When chemotherapy and radiation are indicated the sequencing of the two treatments is still controversial. Several studies have suggested that adjuvant radiotherapy could be safely delayed until adjuvant chemotherapy was completed. Other studies, most of them retrospective, pointed out that a delay in the initiation of radiotherapy to give chemotherapy first, will result in a increased rate of local recurrence. Concomitant administration of the two treatments is an alternative. Pilot studies have suggested the feasibility of simultaneous administration using selected regimen as CMF or FNC. A randomized phase III trials has been conducted to compare sequential treatment with chemotherapy first and radiation versus concomitant treatments. Preliminary results of this study are presented.

Chemotherapy of prostate cancer: present and future.

The role of chemotherapy in prostate cancer continues to evolve. In men with symptomatic androgen-independent prostate cancer, significant reduction in pain and analgesic requirements are achievable with mitoxantrone and glucocorticoid combinations compared with glucocorticoids alone. However, survival rates are not improved. Taxane-based combinations with estramustine phosphate or other new agents show promise. Prostate-specific antigen response rates with these combinations appear to be 1.5 to 2 times more frequent than with mitoxantrone-based combinations. Randomized trials of taxane versus mitoxantrone-based therapies are underway. New agents and applications of current agents in adjuvant settings should be explored if survival in men with prostate cancer is to be improved.

[Adjuvant and additive therapy for cancer of the pancreas]. / Adjuvante und additive Therapie beim Pankreaskarzinom.

Recent advances have been made in the treatment of pancreas cancer. Specialized pancreas centres have reported an increasing rate of resections with reduced postoperative mortality. On account of the highly aggressive nature of pancreas cancer, there is a great challenge in identifying effective therapy concepts for advanced stages of the cancer as well as for the development of resection-associated measures. As large-scale, randomised, controlled studies are lacking, the additive therapy concepts after resection do not have a sufficiently scientific basis. The ESPAC-1 study, which included 600 patients, surpassed all previous studies on adjuvant therapy for pancreas cancer. This study has shown,for example, that the most promising adjuvant chemotherapy with 5-fluorouracil and folic acid leads to an equal if not better result than the multimodal regimen. This regimen can be superseded with the use of Gemcitabine, which will be evaluated in the ESPAC-3 study that includes 990 patients from various European countries including Germany, as well as from Canada and Australia. Participation in the large, phase-3 study therefore plays a key role in the continued development of the management of pancreas cancer.

Experience with methotrexate, 5-fluorouracil, and leucovorin (MFL): a first line effective, minimally toxic regimen for metastatic breast cancer.

Thirty-two women with untreated metastatic breast cancer were treated with 100 mg/M2 i.v. methotrexate (MTX), 600 mg/M2 5-fluorouracil (5FU) and leucovorin 15 mg orally every 6 hr, 24 hr after MTX (MFL) on days 1 and 8 every 28 days. Stratification was according to sites of metastases (mets), adjuvant (adj), chemotherapy (CTX), and/or hormonal therapy or no adj therapy (Tx). Treatment continued until documented radiographic or clinical disease was in progression. Toxicity was mild, consisting of only minimal elevations of transaminases and mild cytopenias. There was no pulmonary toxicity. There were no hospitalizations, treatment delays or cessations for toxicity. One patient with skeletal mets had a complete response and 7 had partial responses. The overall median progression free survival (PFS) was 13.8 months (mos). Eighteen patients with skeletal mets had PFS from 7-70 mos (median 15.9). Five patients with lung mets only had PFS from 6-20 mos (median 9.8 mos). Patients with liver alone or with other visceral mets showed progression within 2-5 mos. However, patients with bone and visceral mets without liver involvement had PFS from 8-50 mos (median 20.5). Of 21 adj Tx failures the median PFS was 8.8 mos (2-94). Six who received adj CTX had a median PFS of 7.6 mos (3-12) and 4 tamoxifen (tam) failures a median PFS of 11 mos (8-15). Eleven patients who received adj CTX+tam had a median PFS of 8.5 mos (2-94). Six patients received tam at adj failure and MFL at progression. These six had a median PFS of 19.8 mos (8-50). The patients (six, who received no prior adj Tx) had a median PFS of 24.3 (8-70). MFL is as effective in achieving clinical remissions in metastatic breast cancer, is inexpensive and is far less toxic than other CTX regimes. MFL should strongly be considered as first line Tx.