RESUMEN

INTRODUCCIÓN: Cuadro clínico: El cáncer colorrectal es una neoplasia maligna del colon o del recto. Según la Organización Mundial de la Salud es la tercera neoplasia más frecuente y la segunda neoplasia con mayor mortalidad. En el año 2020, el Observatorio Global de Cáncer de la Agencia Internacional para la Investigación en Cáncer (GLOBOCAN) reportó 1 931 590 casos nuevos de cáncer colorrectal en todo el mundo y una incidencia estandarizada por edad de 19.6 por 100 000 personas-año. En cuanto a la mortalidad, en todo el mundo se reportó 935 173 muertes atribuibles a cáncer colorrectal y una incidencia de mortalidad estandarizada por edad de 9 por 100 000 personas-año. En América Latina, se reportó un total de 103 954 nuevos casos de cáncer colorrectal, una incidencia estandarizada por edad de 18.5 por 100 000 personasaño, 52 013 muertes atribuibles a cáncer colorrectal y una incidencia de mortalidad estandarizada por edad de 8.9 por 100 000 personas-año. En Perú, para el año 2019, se reporta una prevalencia de cáncer colorrectal de 2.1 por 100 000 y una incidencia de 0.3 por 100 000 entre las personas menores de 20 años. Entre los peruanos con cáncer colorrectal menores de 20 años de edad se reportó 5.04 años de vida saludable perdidos (AVISA) por 100 000 y 0.19 años vividos con discapacidad (AVD) por 100

Asunto(s)

Humanos , Preescolar , Niño , Adolescente , Neoplasias Colorrectales/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Capecitabina/efectos adversos , Fluorouracilo/efectos adversos , Irinotecán/efectos adversos , Oxaliplatino/efectos adversos , Metástasis de la Neoplasia/tratamiento farmacológico , Evaluación en Salud/economía , Eficacia , Análisis Costo-Beneficio/economía

RESUMEN

Transient receptor potential (TRP) channels are involved in the development of oxaliplatin-induced neuropathic pain, a frequent and debilitating side effect of cancer therapy. Here we explored whether oxaliplatin-induced changes in the expression of TRP channels, as well as the development of pain-related behaviours, differed between male and female animals. Adult rats were injected with oxaliplatin or saline and mechanical and cold allodynia were evaluated using Von Frey and Choi Tests. The mRNA levels of TRPV1, TRPM8 and TRPA1 were assessed in lumbar ganglia and spinal cord by using real time RT-PCR. Oxaliplatin administration induced mechanical and cold hypersensitivity and allodynia in both sexes, with more severe responses to cold stimulation detected in females. Oxaliplatin also induced a significant increase in the expression of TRPV1, TRPM8 and TRPA1 in lumbar dorsal root ganglia. Interestingly, while TRPV1 and TRPA1 upregulation showed no sex difference, the increase in TRPM8 mRNA levels was more pronounced in female ganglia, correlating with the increased sensitivity to innocuous cold stimuli observed in females. TRPV1 and TRPM8 were also found to be upregulated in the spinal cord of animals of both sexes. Our results reveal previously undescribed changes in the expression of TRP channels occurring in peripheral ganglia and spinal cord of both male and female oxaliplatin-treated animals, with some of these changes exhibiting sex-related differences that could underlie the development of sex-specific patterns of pain-related behaviours.

Asunto(s)

Neuralgia , Canales Catiónicos TRPM , Canales de Potencial de Receptor Transitorio , Animales , Frío , Síndromes Periódicos Asociados a Criopirina , Femenino , Ganglios Espinales/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Neuralgia/metabolismo , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/metabolismo , Oxaliplatino/efectos adversos , ARN Mensajero/metabolismo , Ratas , Canal Catiónico TRPA1/metabolismo , Canales Catiónicos TRPM/metabolismo , Canales de Potencial de Receptor Transitorio/metabolismo

RESUMEN

Almost 90% of patients develop pain immediately after oxaliplatin (OXA) treatment. Here, the impact of aging on OXA-induced acute peripheral neuropathy and the potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) as a new therapeutic strategy were evaluated. In Swiss mice, the oxidative damage and its influence on Mg2+-ATPase and Na+, K+-ATPase activities were investigated. The relationship between the reactive oxygen species (ROS) and nitrate and nitrite (NOx) levels, the activity of glutathione peroxidase (GPx), and superoxide dismutase (SOD) with the development of OXA-induced acute peripheral neuropathy was also studied. In this study, it was evidenced that OXA-induced acute peripheral neuropathy was exacerbated by aging through increased oxidative damage as well as Na+, K+-ATPase, and Mg+2-ATPase inhibition. 4-PSQ reversed hypersensitivity induced by OXA and aging-aggravated by reducing ROS and NOx levels, through modulation of GPx and SOD activities. 4-PSQ partially reestablish Na+, K+-ATPase activity, but not Mg 2+-ATPase activity. Locomotor and exploratory activities were not affected. This study is the first of its kind, providing new insight into the aging impact on mechanisms involved in OXA-induced acute peripheral neuropathy. Also, it provides evidence on promising 4-PSQ effects on this condition, mainly on aging.

Asunto(s)

Adenosina Trifosfatasas , Enfermedades del Sistema Nervioso Periférico , Envejecimiento , Animales , Humanos , Ratones , Oxaliplatino/efectos adversos , Estrés Oxidativo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Quinolinas , ATPasa Intercambiadora de Sodio-Potasio

RESUMEN

PURPOSE: The randomized PANAMA trial investigated the efficacy of panitumumab (Pmab) when added to maintenance therapy with fluorouracil and folinic acid (FU/FA) in patients with RAS wild-type metastatic colorectal cancer. METHODS: Following first-line induction therapy with six cycles of FU/FA and oxaliplatin plus Pmab, responding patients (stable disease or partial or complete remission) were randomly assigned (1:1, open-label) to maintenance treatment with either FU/FA plus Pmab or FU/FA alone. The primary objective was to demonstrate superiority of progression-free survival (PFS, time from random assignment until progression or death) in favor of FU/FA plus Pmab with a hazard ratio (HR) of 0.75, a power of 80%, and a significance level of 10%. Secondary end points included overall survival, objective response rate of maintenance therapy, and toxicity. Survival end points were analyzed by the Kaplan-Meier method and compared by log-rank test and Cox regressions. Dichotomous variables were compared by Fisher's exact test; odds ratios were indicated when appropriate. The trial is registered with ClinicalTrials.gov (NCT01991873). RESULTS: Overall, 248 patients were randomly assigned and received maintenance therapy with either FU/FA plus Pmab (125 patients) or FU/FA alone (123 patients). At data cutoff, with 218 events (of 218 needed), PFS of maintenance therapy was significantly improved with FU/FA plus Pmab (8.8 months v 5.7 months; HR, 0.72; 80% CI, 0.60 to 0.85; P = .014). Overall survival (event rate 54%) numerically favored the FU/FA plus Pmab arm (28.7 months v 25.7 months; HR, 0.84; 95% CI, 0.60 to 1.18; P = .32). Objective response rates were 40.8% in patients receiving FU/FA plus Pmab versus 26.0% in patients receiving FU/FA alone (odds ratio, 1.96; 95% CI, 1.14 to 3.36; P = .02). The most frequent Common Terminology Criteria for Adverse Event grade ≥ 3 event during maintenance therapy was skin rash (7.2%). CONCLUSION: In RAS wild-type metastatic colorectal cancer, maintenance therapy with FU/FA plus Pmab induced a significantly superior PFS compared with FU/FA alone. If active maintenance therapy is aspired following induction therapy with FU/FA and oxaliplatin plus Pmab, FU/FA plus Pmab appears to be the most favorable option.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Colorrectales/tratamiento farmacológico , Fluorouracilo/uso terapéutico , Genes ras , Leucovorina/uso terapéutico , Oxaliplatino/uso terapéutico , Panitumumab/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Femenino , Fluorouracilo/efectos adversos , Alemania , Humanos , Leucovorina/efectos adversos , Quimioterapia de Mantención , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos , Oxaliplatino/efectos adversos , Panitumumab/efectos adversos , Supervivencia sin Progresión , Factores de Tiempo

RESUMEN

Oxaliplatin-induced neurotoxicity is expressed as a dose-limiting peripheral sensory neuropathy (PSN). Cannabinoid substances have been investigated for the analgesic effect. This study aimed to investigate the role of cannabinoid receptors in oxaliplatin-associated PSN. Swiss male mice received nine oxaliplatin injections (2 mg/kg, i.v.). Mechanical and thermal nociceptive tests were performed for 56 days. CB1, CB2, and c-Fos expression were assessed in dorsal root ganglia (DRG), spinal cord (SC), trigeminal ganglia (TG), spinal trigeminal nucleus caudalis (Sp5C), and periaqueductal gray (PAG). Iba-1 expression was assessed in DRG and ATF3 in TG. Cannabidiol (10 mg/kg, p.o.) or a CB1/CB2 non-selective agonist (WIN 55,212-2; 0.5 mg/kg, s.c.) or AM251 (CB1 antagonist) or AM630 (CB2 antagonist) (3 mg/kg, i.p.) were injected before oxaliplatin. Oxaliplatin increased CB1 in DRG, SC, TG, Sp5C, and ventrolateral PAG, with no interference in CB2 expression. Cannabidiol increased CB1 in DRG, reduced mechanical hyperalgesia and c-Fos expression in DRG and SC. Additionally, WIN 55,212-2 increased CB1 in DRG, reduced mechanical hyperalgesia, cold allodynia and c-Fos expression in DRG and SC. CB1 blockage hastened the cold allodynia response, but the CB2 antagonist failed to modulate the oxaliplatin-induced nociceptive behavior. Oxaliplatin also increased Iba-1 in DRG, suggesting immune response modulation which was reduced by cannabidiol and enhanced by AM630. The modulation of the endocannabinoid system, through the CB1 receptor, attenuates the oxaliplatin-associated PNS. The activation of the endocannabinoid system could be considered as a therapeutic target for controlling oxaliplatin-associated neuropathy.

Asunto(s)

Endocannabinoides/metabolismo , Nocicepción/efectos de los fármacos , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Receptor Cannabinoide CB1/agonistas , Animales , Técnica del Anticuerpo Fluorescente , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/patología , Ganglios Espinales/fisiopatología , Masculino , Ratones , Oxaliplatino/antagonistas & inhibidores , Dimensión del Dolor , Enfermedades del Sistema Nervioso Periférico/metabolismo , Receptor Cannabinoide CB1/metabolismo , Prueba de Desempeño de Rotación con Aceleración Constante

RESUMEN

The object of this study was to evaluate the relationship between oxidative damage induced by oxaliplatin (OXA) and the therapeutic potential of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) in kidney of mice. Mice received OXA (10 mg/kg) or vehicle intraperitoneally (days 0 and 2). Oral administration of 4-PSQ (1 mg/kg) or vehicle was performed on days 2 to 14. On day 15 the animals were euthanized and the kidneys and blood were collected. The effect of OXA and (or) 4-PSQ on urea, thiobarbituric acid reactive species, nonprotein thiol (NPSH), and protein carbonyl (PC) levels were investigated. Moreover, renal superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), glutathione S-transferase (GST), δ-aminolevulinic acid dehydratase (δ-ALA-D), and Na+,K+ ATPase activities were evaluated. Our findings revealed an increase on urea levels and significant renal oxidative damage in OXA-induced mice. OXA exposure increased SOD, GPx, and GST activities and caused a reduction on NPSH levels and CAT and GR activities. Na+,K+ ATPase and δ-ALA-D activities were reduced by OXA. 4-PSQ decreased plasmatic urea levels and renal oxidative damage. SOD, GPx, CAT, GR, and Na+,K+ ATPase activities were restored by 4-PSQ. 4-PSQ may be a good prototype for the treatment of OXA-induced renal injury.

Asunto(s)

Antioxidantes/farmacología , Enfermedades Renales/prevención & control , Oxaliplatino/efectos adversos , Quinolinas/farmacología , Animales , Antineoplásicos/toxicidad , Catalasa/metabolismo , Glutatión Peroxidasa/metabolismo , Glutatión Transferasa/metabolismo , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Superóxido Dismutasa/metabolismo

RESUMEN

Chemotherapy-Induced Peripheral Neuropathy (CIPN) is a common, difficult-to-treat, and dose-limiting side effect associated with Oxaliplatin (OXA) treatment. In this study, we evaluated the effect of three antioxidants - namely N-acetylcysteine, α-lipoic acid and vitamin E - upon nociceptive parameters and antitumor efficacy of OXA in a tumor-bearing Swiss mice model. Oral treatment with antioxidants inhibited both mechanical and cold allodynia when concomitantly administrated with OXA (preventive protocol), as well as in animals with previously established CIPN (therapeutic protocol). OXA increased Reactive Oxygen Species (ROS) production and lipoperoxidation, and augmented the content of pro-inflammatory cytokines (IL-1ß and TNF-α) and expression of the astrocytic marker Gfap mRNA in the spinal cord. Antioxidants decreased ROS production and lipoperoxidation, and abolished neuroinflammation in OXA-treated animals. Toll-like receptor 4 (Tlr4) and inflammasome enzyme caspase-1/11 knockout mice treated with OXA showed reduced levels of pro-inflammatory cytokines (but not oxidative stress) in the spinal cord, which were associated with resistance to OXA-induced mechanical allodynia. Lastly, antioxidants affected neither antitumor activity nor hematological toxicity of OXA in vivo. The herein presented results are provocative for further evaluation of antioxidants in clinical management of chemotherapy-induced peripheral neuropathy. PERSPECTIVE: This study reports preventive and therapeutic efficacy of orally administrated antioxidants (N-acetylcysteine, α-lipoic-acid and Vitamin-E) in alleviating oxaliplatin-induced peripheral neuropathy in tumor-bearing mice. Antioxidants' anti-nociceptive effects are associated with inhibition of ROS-dependent neuroinflammation, and occur at no detriment of OXA antitumor activity, therefore indicating a translational potential of these compounds.

Asunto(s)

Antineoplásicos/efectos adversos , Antioxidantes/farmacología , Hiperalgesia , Neoplasias/tratamiento farmacológico , Enfermedades Neuroinflamatorias , Oxaliplatino/efectos adversos , Estrés Oxidativo/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico , Médula Espinal , Animales , Modelos Animales de Enfermedad , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/prevención & control , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Enfermedades Neuroinflamatorias/inducido químicamente , Enfermedades Neuroinflamatorias/tratamiento farmacológico , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/prevención & control , Médula Espinal/efectos de los fármacos , Médula Espinal/inmunología , Médula Espinal/metabolismo , Receptor Toll-Like 4

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/terapia , Oxaliplatino/efectos adversos , Trombocitopenia/inducido químicamente , Quimioterapia Adyuvante/efectos adversos , Colectomía , Neoplasias Colorrectales/sangre , Neoplasias Colorrectales/patología , Femenino , Fluorouracilo/efectos adversos , Humanos , Leucovorina/efectos adversos , Persona de Mediana Edad , Compuestos Organoplatinos/efectos adversos , Trombocitopenia/sangre , Trombocitopenia/diagnóstico , Trombocitopenia/inmunología

RESUMEN

BACKGROUND/OBJECTIVES: The incidence of pancreatic cancer is increasing in developed countries. The incorporation of new therapies, to the first-line treatment of patients with good performance status led to better survival in clinical trials. However, there is a wide variability in their use and some concerns about the treatment of elderly patients who were not included in the clinical trials. METHODS: This is a retrospective multicenter study. Data from consecutive patients diagnosed with metastatic pancreatic cancer (mPC) treated with FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) were analysed to evaluate efficacy (overall survival-OS) and toxicity. RESULTS: A total of 119 patients were included. 49.6% were treated with FFX and 50.4% with GNP in first-line. The median OS was 12 months with no statistically significant differences between both regimens (12.7 m for FFX vs 10.2 m for GnP). Elevated Ca 19.9 levels and neutrophil-lymphocyte ratio (NLR) increased the risk of death. Patients who received both regimens in first/second line had a median OS longer than 15 months whichever the sequence. 32 patients (27%) were older than 70-y. 54% patients received a second-line treatment, 56% in the FFX group and 44% in the GnP group. The median OS for patients older than 70 was 9.5 m versus 12.3 m for patients younger than 70. Progression of the disease was the cause of death in 67.6% of the patients. CONCLUSIONS: In our setting, the use of FFX and GnP for treating mPC is quite similar, but superiority could not be demonstrated for any of the schemes in the first line. OS was determined by basal levels of Ca 19.9 and NLR. Patients receiving both regimens in first/second line whichever the sequence, exhibited the best survival rates. In our series, elderly patients had poorer survival rates.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Causas de Muerte , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Progresión de la Enfermedad , Femenino , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Irinotecán/efectos adversos , Irinotecán/uso terapéutico , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Oxaliplatino/efectos adversos , Oxaliplatino/uso terapéutico , Paclitaxel/efectos adversos , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/patología , Estudios Retrospectivos , Tasa de Supervivencia , Gemcitabina

RESUMEN

There is an increasing incidence of hepatotoxicity induced by oxaliplatin (OXA); therefore, researchers' attention has been drawn to therapeutic alternatives that may decrease OXA-induced hepatotoxicity. Studies indicate that oxidative stress plays a major role in OXA-induced liver injury. As several pharmacological effects of 7-chloro-4-(phenylselanyl) quinole (4-PSQ) involve its antioxidant action, the hypothesis that this organoselenium compound could be promising for the treatment or prevention of hepatotoxicity induced by treatment with OXA was investigated. To test this hypothesis, male Swiss mice received OXA (10 mg·kg-1) on days 0 and 2, followed by oral administration of 4-PSQ (1 mg·kg-1) on days 2 to 14. 4-PSQ reduced the plasma aspartate, and alanine aminotransferase activity increased by exposure to OXA. The histopathological examination of the liver showed that 4-PSQ markedly improved OXA-induced hepatic injury. In addition, treatment with 4-PSQ reduced the oxidation of lipids and proteins (thiobarbituric acid reactive species levels and protein carbonyl content) and attenuated the increase of hepatic catalase and glutathione peroxidase activity caused by OXA. The inhibition of hepatic δ-aminolevulinic dehydratase activity induced by OXA was reverted by 4-PSQ. In conclusion, results indicate that 4-PSQ may be a good therapeutic strategy for attenuating OXA-induced liver damage.

Asunto(s)

Hígado/efectos de los fármacos , Hígado/metabolismo , Oxaliplatino/efectos adversos , Quinolinas/química , Quinolinas/farmacología , Animales , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones

RESUMEN

INTRODUCTION: Platinum compounds are frequently used for the treatment of colorectal cancer as initial chemotherapy. Oxaliplatin is a third-generation platinum used for the treatment of stage III colorectal cancer and is associated with hypersensitivity reactions. The incidence of hypersensitivity reaction is approximately 12%, with 1-2% of patients developing moderate to severe reactions. CASE REPORT: A 54-year-old male patient with stage III B colon cancer was diagnosed and chemotherapy with oxaliplatin was indicated by the oncology service. Within 20 min of the first cycle of oxaliplatin, he developed dyspnea, laryngeal spam, foreign body sensation in the throat, nausea, and diarrhea; therefore, the infusion of oxaliplatin was suspended, and intramuscular epinephrine was administered and intravenous hydrocortisone along with chlorpheniramine with adequate resolution of symptoms.Management and outcome: Intradermal skin test performed at the concentration of 5 mg/ml (dilution 1:100) was positive. Due to the symptoms presented we decided to perform desensitization to oxaliplatin (total dose: 250 mg) with three bags-12 steps protocol with an initial concentration dose of 1/100 of the total dose in a course of 5.56 h with no hypersensitivity reactions. DISCUSSION: Approximately 50% of patients who are exposed to oxaliplatin may have hypersensitivity despite premedication. Desensitization protocol induces tolerance to a drug temporarily and is dependent on continuous exposure.

Asunto(s)

Antineoplásicos/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Desensibilización Inmunológica/métodos , Hipersensibilidad a las Drogas/terapia , Oxaliplatino/efectos adversos , Antiinflamatorios/uso terapéutico , Antineoplásicos/uso terapéutico , Clorfeniramina/uso terapéutico , Epinefrina/uso terapéutico , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Humanos , Hidrocortisona/uso terapéutico , Tolerancia Inmunológica , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia/tratamiento farmacológico , Oxaliplatino/uso terapéutico

RESUMEN

In this study, the deposition of platinum in oxaliplatin (OXA)-exposed mice and the effects of the oxidative damage on the central nervous system were investigated. The relationship between the reactive species (RS) levels as well as the expression and activity of enzymes, such as catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD) and acetylcholinesterase (AChE), in the development of peripheral neuropathy after OXA exposure, was evidenced. The effects of 7-chloro-4-(phenylselanyl) quinoline (4-PSQ) on OXA-induced peripheral neuropathy was also investigated. Swiss mice received OXA (10 mg kg-1) or vehicle by intraperitoneal route (days 0 and 2). Oral administration of 4-PSQ (1 mg kg-1) or vehicle was performed on days 2 to 14. Behavioural tasks started on day 9, after the first OXA administration. It was observed that 4-PSQ reduced the mechanical and thermal hypersensitivity induced by OXA. 4-PSQ and OXA did not affect locomotor and exploratory activities. The results revealed, for the first time, a high concentration of platinum in the spinal cord of mice exposed to OXA. 4-PSQ reversed the increased levels of RS in the spinal cord, cerebral cortex and hippocampus of mice exposed to OXA. The alterations in the activity and expression of the GPx, SOD, CAT and AChE induced by OXA exposure were normalized by 4-PSQ. Therefore, the 4-PSQ might be a good prototype for the development of a more effective drug for the treatment of OXA-induced peripheral neuropathy. The results obtained by the present study expanded the knowledge about the mechanisms involved in the physiopathology of peripheral neuropathy. Graphical abstract.

Asunto(s)

Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Quinolinas/uso terapéutico , Acetilcolinesterasa/metabolismo , Animales , Antioxidantes/farmacología , Catalasa/metabolismo , Conducta Exploratoria/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Masculino , Ratones , Actividad Motora/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Quinolinas/farmacología , Reproducibilidad de los Resultados , Médula Espinal/efectos de los fármacos , Médula Espinal/enzimología , Médula Espinal/patología , Superóxido Dismutasa/metabolismo , Temperatura

RESUMEN

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a frequent and devastating side effect of cancer therapy. No preventive strategies are currently available. We investigated the use of resveratrol (RESV) in the prevention of CIPNP and evaluated key components of the antioxidant defense system and neuroinflammatory factors as possible mediators contributing to RESV actions. Male rats were injected with oxaliplatin (OXA) and received daily oral RESV. Paw mechanical and thermal allodynia, oxidative stress, antioxidant, pro-inflammatory and neuronal injury/activation markers were evaluated in the sciatic nerve (SN), lumbar dorsal root ganglia (DRG) and spinal cord (SC). OXA-injected animals developed mechanical and thermal allodynia, while those receiving OXA + RESV showed patterns of response similar to control animals. Higher TBARS levels and lower GSH/GSSG ratios were observed in the SN of animals receiving OXA. The mRNA levels of the transcription factor NFκB and the pro-inflammatory cytokine TNFα were found to be upregulated both in lumbar DRG and SC. In addition, the antioxidant enzymes NQO-1 and HO-1 and the neuronal injury marker ATF3 showed increased levels of expression in lumbar DRG. In the dorsal SC the neuronal activation marker c-fos and the transcription factor Nrf2, main regulator of antioxidant defenses, were found to be upregulated. RESV early and sustained administration prevented NFκB, TNFα, ATF3 and c-fos upregulation, while increasing the expression of Nrf2, NQO-1, HO-1 and the redox-sensitive deacetylase SIRT1. RESV treatment was also able to restore TBARS levels and GSH/GSSG ratio. Thus, RESV administration resulted in the upregulation of antioxidant mediators, suppression of pro-inflammatory parameters and prevention of OXA-induced mechanical and thermal allodynia.

Asunto(s)

Antiinflamatorios/uso terapéutico , Antioxidantes/uso terapéutico , Hiperalgesia/prevención & control , Estrés Oxidativo/efectos de los fármacos , Resveratrol/uso terapéutico , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Citocinas/metabolismo , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Masculino , Oxaliplatino/efectos adversos , Dimensión del Dolor , Ratas , Resveratrol/farmacología , Nervio Ciático/efectos de los fármacos , Nervio Ciático/metabolismo , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo

RESUMEN

Over the last 2 decades, the standard fluoropyrimidine-based chemotherapy backbone for metastatic colorectal cancer has been complemented by the addition of novel biological agents, achieving impressive increases in 5-year survival rates. Nonetheless, these new combinations have also entailed increases in toxicity, leading to evaluation of de-escalated chemotherapy regimens and "drug holiday" periods in attempts to reduce side effects and optimise quality of life without impairing efficacy. Here, we review the current and emerging evidence for maintenance schedules with chemotherapy and targeted agents, versus continuous treatment after induction treatment, in metastatic colorectal cancer patients.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Quimioterapia de Mantención/métodos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/administración & dosificación , Camptotecina/administración & dosificación , Camptotecina/análogos & derivados , Capecitabina/administración & dosificación , Cetuximab/administración & dosificación , Ensayos Clínicos como Asunto , Neoplasias Colorrectales/patología , Progresión de la Enfermedad , Clorhidrato de Erlotinib/administración & dosificación , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Humanos , Quimioterapia de Inducción , Irinotecán/administración & dosificación , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Enfermedades del Sistema Nervioso/inducido químicamente , Enfermedades del Sistema Nervioso/prevención & control , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino/administración & dosificación , Oxaliplatino/efectos adversos , Oxaloacetatos/administración & dosificación , Panitumumab/administración & dosificación , Privación de Tratamiento

RESUMEN

BACKGROUND: Chemotherapy-associated liver injury (CALI) is a matter of concern for hepatobiliary surgeons as it can entail postoperative liver failure after an extensive hepatectomy. Recent studies have taken special interest in liver function parameters which can correlate with CALI to decrease this adverse event. Therefore, the current study investigates the usefulness of splenic volume as a biomarker of CALI through a portal hypertension mechanism, in patients with colorectal liver metastases (CRLM). STUDY DESIGN: We carried out a study in patients with CRLM operated on between 2009 and 2014 in our center. All samples of healthy liver were graded for non-alcoholic fatty liver disease (NAFLD) and sinusoidal obstructive syndrome. Computarized tomography scans for spleen volumetry were analyzed for each patient at CRLM diagnosis, after neoadjuvant chemotherapy, 1 and 6 months after resection. RESULTS: A group of 65 consecutive patients with CRLM of large bowel adenocarcinoma submitted to liver resection were included. Patients receiving neoadjuvant chemotherapy had a greater spleen volume increase than those who did not receive treatment (p = 0.053), finding a statistically significant spleen growth in patients with NAFLD (p = 0.036). There was no correlation between spleen enlargement and postoperative complications or average stay. However, survival was decreased in patients with spleen growth and CALI. CONCLUSIONS: Patients who receive neoadjuvant chemotherapy for liver metastasis surgery have a greater splenic volume increase, which correlates with NAFLD and a lower survival.

Asunto(s)

Adenocarcinoma/terapia , Antineoplásicos/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Neoplasias Colorrectales/patología , Hepatectomía , Enfermedad Veno-Oclusiva Hepática/patología , Neoplasias Hepáticas/terapia , Enfermedad del Hígado Graso no Alcohólico/patología , Bazo/diagnóstico por imagen , Adenocarcinoma/secundario , Antineoplásicos/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Hígado Graso/inducido químicamente , Hígado Graso/patología , Enfermedad Veno-Oclusiva Hepática/inducido químicamente , Humanos , Neoplasias Hepáticas/secundario , Metastasectomía , Terapia Neoadyuvante , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Tamaño de los Órganos , Oxaliplatino/efectos adversos , Oxaliplatino/uso terapéutico , Complicaciones Posoperatorias , Bazo/patología , Tasa de Supervivencia , Tomografía Computarizada por Rayos X

RESUMEN

Taste changes caused by the use of platinum drugs have been described. However, few studies qualify the impaired tastes and whether these changes are derived exclusively from chemotherapy (QTx). AIMS: Evaluation of changes in sweet, sour, salty, bitter, and umami tastes in patients receiving QTx with platinum drugs was the aim of this study. METHODS: A total of 43 subjects, 21 from the study group and 22 from the control, were studied in two time periods, one before the start of QTx (T0) and another after two cycles of QTx (T1). The usual dietary intake, body mass index (BMI), handgrip strength and fatigue (through the fatigue pictogram) were evaluated to characterize the group studied. Taste Strips tests were performed for all 4 tastes and umami was studied by comparing Likert's scale using monosodium glutamate (GMS) food. Statistical analysis was performed using repeated measures (ANOVA), mixed model, with significance level p≤0.05. RESULTS: Salty and sour were the most affected tastes in the study group (p = 0.001 and 0.05); as well as the ionotropic receptors (p = 0.02) responsible for identifying these tastes. There was a difference between the times for BMI, dynamometry and impact in daily activities, by the fatigue pictogram (p = 0.008, 0.009 and 0.006 respectively). CONCLUSION: These findings suggest an important role in altering taste recognition, mainly in salty and sour tastes, identified by ionotropic receptors, which seems to be related to dietary changes. QTx has demonstrated a contribution to impairment of functionality and fatigue.

Asunto(s)

Antineoplásicos/efectos adversos , Compuestos de Platino/efectos adversos , Trastornos del Gusto/inducido químicamente , Gusto/efectos de los fármacos , Adulto , Anciano , Carboplatino/efectos adversos , Estudios de Casos y Controles , Cisplatino/efectos adversos , Disgeusia/inducido químicamente , Disgeusia/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Neoplasias/fisiopatología , Oxaliplatino/efectos adversos , Receptores Ionotrópicos de Glutamato/efectos de los fármacos , Receptores Ionotrópicos de Glutamato/fisiología , Receptores de Glutamato Metabotrópico/efectos de los fármacos , Receptores de Glutamato Metabotrópico/fisiología , Gusto/fisiología , Trastornos del Gusto/fisiopatología

RESUMEN

INTRODUCTION: Chemotherapy-induced peripheral neuropathy is a common adverse reaction in a variety of medications frequently used for a great number of cancer treatments. This condition consists of mainly sensory-type symptoms, motor components and autonomic changes. Reported prevalence ranges from 30-68%, after the completion of chemotherapy in non-Latin American people with different populations and socioeconomic levels. AIM: To determine the prevalence of chemotherapy-induced peripheral neuropathy in a Colombian population. PATIENTS AND METHODS: A real-world evidence cross-sectional retrospective study was performed in all patients from oncological clinical centers in Colombia, which received pharmacological therapy for any cancer between January 2015 and December 2016, with taxanes (paclitaxel, docetaxel), alkylators (oxaliplatin), proteasome inhibitors (bortezomib), and epothilone B analogs (ixabepilone). RESULTS: A total of 1,551 patients in four cities were included, and 11,280 doses were applied; predominantly females (n = 1,094; 70.5%), with a mean age of 57 ± 13 years old. Paclitaxel was the most commonly prescribed drug (n = 788; 50.8%). Chemotherapy-induced peripheral neuropathy was developed in 48.9% of paclitaxel, 58.5% of oxaliplatin, 50.5% of docetaxel, 43.7% of bortezomib and 95.2% of ixabepilone patients. Thirty-three patients were treated with two of these medications simultaneously. CONCLUSIONS: Chemotherapy-induced peripheral neuropathy is a frequent adverse reaction to daily cancer therapy in Colombian patients managed with taxanes, alkylators, proteasome inhibitors, and epothilone B analogs. Hence, it is necessary to establish more successful diagnostic methods and incorporate validated scales in the routine evaluation of all patients receiving these medications in our environment.

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TITLE: Prevalencia de neuropatia periferica asociada a quimioterapia en cuatro centros oncologicos de Colombia.Introduccion. La neuropatia periferica inducida por quimioterapia es una reaccion comun a una variedad de medicamentos usados en el tratamiento del cancer, que consiste principalmente en sintomas sensitivos, con componentes motores y cambios autonomicos. La prevalencia es del 30-68% despues de terminar la quimioterapia en paises no latinoamericanos. Objetivo. Determinar la prevalencia de la neuropatia periferica inducida por quimioterapia en la poblacion colombiana. Pacientes y metodos. Estudio retrospectivo con evidencia del mundo real en la totalidad de pacientes atendidos en cuatro centros oncologicos de Colombia, quienes recibieron terapia farmacologica para algun tipo de cancer entre enero de 2015 y diciembre de 2016 con taxanos (paclitaxel, docetaxel), agentes alquilantes (oxaliplatino), inhibidores de proteasoma (bortezomib) y analogos de epotilona B (ixabepilona). Resultados. Se siguio a un total de 1.551 pacientes en cuatro ciudades a quienes se les aplicaron 11.280 dosis, con predominio femenino (n = 1.094; 70,5%) y una edad media de 57 ± 13 años. El paclitaxel fue el farmaco mas prescrito (n = 788; 50,8%). La neuropatia inducida por quimioterapia se presento en el 48,9% de los pacientes con paclitaxel, el 58,5% de los pacientes con oxaliplatino, el 50,5% de los pacientes con docetaxel, el 43,7% de los pacientes con bortezomib y el 95,2% de los pacientes con ixabepilona. Se trato a 33 pacientes con dos de estos medicamentos simultaneamente. Conclusiones. La neuropatia periferica inducida por quimioterapia es una reaccion adversa frecuente en pacientes con cancer en Colombia tratados con taxanos, alquilantes, inhibidores de proteasoma e ixabepilona. Es necesario establecer metodos diagnosticos efectivos e incorporar escalas validadas en la evaluacion rutinaria de los pacientes que reciben estas medicaciones.

Asunto(s)

Antineoplásicos/efectos adversos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Adulto , Anciano , Antineoplásicos/uso terapéutico , Bortezomib/efectos adversos , Instituciones Oncológicas/estadística & datos numéricos , Colombia/epidemiología , Estudios Transversales , Epotilonas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxaliplatino/efectos adversos , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/epidemiología , Prevalencia , Inhibidores de Proteasas/efectos adversos , Estudios Retrospectivos , Taxoides/efectos adversos

RESUMEN

PURPOSE: To develop recommendations for duration of adjuvant chemotherapy with a fluoropyrimidine and oxaliplatin for patients with completely resected stage III colon cancer based on the results of trials of 3 months compared with 6 months of treatment. METHODS: ASCO convened an Expert Panel and conducted a systematic review of relevant studies. The guideline recommendations were based on the review of evidence by the Expert Panel. RESULTS: Pooled data from the six International Duration Evaluation of Adjuvant Chemotherapy (IDEA) Collaboration randomized controlled trials comprise the evidence base for these guideline recommendations. RECOMMENDATIONS: The recommendations for therapy duration apply to patients with completely resected stage III colon cancer who are being offered adjuvant chemotherapy with oxaliplatin and a fluoropyrimidine. Recommendations are informed by the findings of a recent pooled analysis of clinical trials that compared 6 months versus 3 months of oxaliplatin-based chemotherapy. For patients at a high risk of recurrence (T4 and/or N2), adjuvant chemotherapy should be offered for a duration of 6 months. For patients at a low risk of recurrence (T1, T2, or T3 and N1), either 6 months of adjuvant chemotherapy or a shorter duration of 3 months may be offered on the basis of a potential reduction in adverse events and no significant difference in disease-free survival with the 3-month regimen. In determining duration of therapy, the Expert Panel recommends a shared decision-making approach, taking into account patient characteristics, values and preferences, and other factors and including a discussion of the potential for benefit and risks of harm associated with treatment duration. Additional information is available at www.asco.org/gastrointestinal-cancer-guidelines .

Asunto(s)

Antineoplásicos/administración & dosificación , Colectomía , Neoplasias del Colon/terapia , Oxaliplatino/administración & dosificación , Antineoplásicos/efectos adversos , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Colectomía/efectos adversos , Colectomía/mortalidad , Neoplasias del Colon/mortalidad , Neoplasias del Colon/patología , Consenso , Supervivencia sin Enfermedad , Esquema de Medicación , Medicina Basada en la Evidencia , Humanos , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Oxaliplatino/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Factores de Tiempo

RESUMEN

Colorectal cancer (CRC) is one of the tumours with the highest incidence and mortality in the Spanish population. Nevertheless, the advances in prevention and treatment have contributed to an increased number of patients who survive for prolonged periods of time. In addition, despite recurrences, improved survival following metastasis resection is likewise on the rise. This underscores the importance of carrying out follow-up programmes even in low-risk patients for the early detection of recurrence. The main objective of this article is to provide a set of recommendations for optimising the follow-up of CRC survivors as well as for managing the sequelae that result from either pharmacological or surgical treatment.

Asunto(s)

Supervivientes de Cáncer , Neoplasias del Colon/diagnóstico , Continuidad de la Atención al Paciente , Recurrencia Local de Neoplasia/diagnóstico , Vigilancia de la Población , Neoplasias del Recto/diagnóstico , Antineoplásicos/efectos adversos , Antígeno Carcinoembrionario/análisis , Neoplasias del Colon/patología , Neoplasias del Colon/terapia , Colonoscopía , Femenino , Humanos , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/secundario , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/secundario , Masculino , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Oxaliplatino/efectos adversos , Grupo de Atención al Paciente , Complicaciones Posoperatorias , Prevención Primaria , Radioterapia/efectos adversos , Neoplasias del Recto/patología , Neoplasias del Recto/terapia , Prevención Secundaria , Disfunciones Sexuales Fisiológicas/etiología , Factores de Tiempo