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Abundant ribonucleoside-triphosphate (rNTP) incorporation into DNA by DNA polymerases in the form of ribonucleoside monophosphates (rNMPs) is a widespread phenomenon in nature, resulting in DNA-structural change and genome instability. The rNMP distribution, characteristics, hotspots and association with DNA metabolic processes in human mitochondrial DNA (hmtDNA) remain mostly unknown. Here, we utilize the ribose-seq technique to capture embedded rNMPs in hmtDNA of six different cell types. In most cell types, the rNMPs are preferentially embedded on the light strand of hmtDNA with a strong bias towards rCMPs; while in the liver-tissue cells, the rNMPs are predominately found on the heavy strand. We uncover common rNMP hotspots and conserved rNMP-enriched zones across the entire hmtDNA, including in the control region, which links the rNMP presence to the frequent hmtDNA replication-failure events. We show a strong correlation between coding-sequence size and rNMP-embedment frequency per nucleotide on the non-template, light strand in all cell types, supporting the presence of transient RNA-DNA hybrids preceding light-strand replication. Moreover, we detect rNMP-embedment patterns that are only partly conserved across the different cell types and are distinct from those found in yeast mtDNA. The study opens new research directions to understand the biology of hmtDNA and genomic rNMPs.
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Replicación del ADN , Genoma Mitocondrial , Ribonucleósidos , Humanos , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Ribonucleósidos/metabolismo , Ribonucleótidos/genética , Ribonucleótidos/metabolismoRESUMEN
Medical imaging is the mainstay of clinical diagnosis and management. Optical coherence tomography (OCT) is a non-invasive imaging technology that has revolutionized the field of ophthalmology. Since its introduction, OCT has undergone significant improvements in image quality, speed, and resolution, making it an essential diagnostic tool for various ocular pathologies. OCT has not only improved the diagnosis and management of ocular diseases but has also found applications in other fields of medicine. In this manuscript, we provide a brief overview of the history of OCT, its current uses and diagnostic capabilities to assess the posterior segment of the eye, and the evolution of this technology from time-domain (TD) to spectral-domain (SD) and swept-source (SS). This brief review will also discuss the limitations, advantages, disadvantages, and future perspectives of this technology in the field of ophthalmology.
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Oftalmología , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodosRESUMEN
BACKGROUND: Daily experience tells us that breast cancer can be controlled using standard protocols up to the advent of a relapse. Now new frontiers in precision medicine like liquid biopsy of cell free DNA (cfDNA) give us the possibility to understand cancer evolution and pick up the key mutation on specific cancer driver gene. However, tight schedule of standardized protocol may impair the use of personalized experimental drugs in a timely therapeutic window. MAIN BODY: Here, using a combination of deep next generation sequencing and cfDNA liquid biopsy, we demonstrated that it is possible to monitor cancer relapse over time. We showed for the first time the exact correspondence from the increasing clonal expansion and clinical worsening of metastatic breast cancer. CONCLUSION: Thanks to liquid biopsy may be possible to introduce new experimental drugs in the correct therapeutic window which would lead in the near future to an effective treatment which otherwise remains challenging.
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Hyperthermic intraperitoneal chemotherapy (HIPEC), a strategy combining maximal cytoreductive surgery and maximal regional chemotherapy, has been applied to treat ovarian cancer resulting in long-term survival rates in selected patients. However, the status of HIPEC in ovarian cancer remains an experimental procedure, given the many variables among the data and trials reviewed, to enable us to derive strong conclusions about its role from this overview. In this review we discuss treatment with HIPEC in patients with ovarian cancer and future prospective of its use in clinical setting. HIPEC is an effective tool in the treatment of selected patients with peritoneal carcinomatosis from ovarian cancer. Unfortunately, due to the lack of randomised trials, the evidence of HIPEC is very limited. Future randomised studies are awaited to define the role and clinical impact of HIPEC in ovarian cancer.
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Quimioterapia del Cáncer por Perfusión Regional , Procedimientos Quirúrgicos de Citorreducción , Hipertermia Inducida , Neoplasias Ováricas/terapia , Animales , Terapia Combinada , Femenino , Humanos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/cirugía , Pronóstico , Resultado del TratamientoRESUMEN
Differentiated retinal pigmented epithelial (RPE) cells have been obtained from human induced pluripotent stem (hiPS) cells. However, the visual (retinoid) cycle in hiPS-RPE cells has not been adequately examined. Here we determined the expression of functional visual cycle enzymes in hiPS-RPE cells compared with that of isolated wild-type mouse primary RPE (mpRPE) cells in vitro and in vivo. hiPS-RPE cells appeared morphologically similar to mpRPE cells. Notably, expression of certain visual cycle proteins was maintained during cell culture of hiPS-RPE cells, whereas expression of these same molecules rapidly decreased in mpRPE cells. Production of the visual chromophore, 11-cis-retinal, and retinosome formation also were documented in hiPS-RPE cells in vitro. When mpRPE cells with luciferase activity were transplanted into the subretinal space of mice, bioluminance intensity was preserved for >3 months. Additionally, transplantation of mpRPE into blind Lrat(-/-) and Rpe65(-/-) mice resulted in the recovery of visual function, including increased electrographic signaling and endogenous 11-cis-retinal production. Finally, when hiPS-RPE cells were transplanted into the subretinal space of Lrat(-/-) and Rpe65(-/-) mice, their vision improved as well. Moreover, histological analyses of these eyes displayed replacement of dysfunctional RPE cells by hiPS-RPE cells. Together, our results show that hiPS-RPE cells can exhibit a functional visual cycle in vitro and in vivo. These cells could provide potential treatment options for certain blinding retinal degenerative diseases.
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Células Madre Pluripotentes Inducidas/trasplante , Degeneración Retiniana/genética , Degeneración Retiniana/terapia , Epitelio Pigmentado de la Retina/trasplante , cis-trans-Isomerasas/genética , Animales , Diferenciación Celular , Células Cultivadas , Regulación Enzimológica de la Expresión Génica , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/enzimología , Ratones , Degeneración Retiniana/patología , Epitelio Pigmentado de la Retina/enzimología , Retinaldehído/biosíntesis , Retinaldehído/genética , Visión Ocular/genética , Visión Ocular/fisiología , cis-trans-Isomerasas/deficienciaRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic horizons of various cancers. However, immune-related adverse events have been reported, including interstitial lung diseases. Our aim was to describe the clinical and radiological features and survival of a multicentre cohort of patients who developed ICI-related lung toxicity. METHODS: Six Italian centres were involved in the study. Patients who were treated with anti-PD-1/PD-L1 and CTLA-4 mAbs and developed ICI-related lung toxicity were recruited retrospectively to study clinical, radiological, immunological and survival data. RESULTS: A total of 41 patients (25 males, 66.8 ± 9.9 years) were enrolled. Lung toxicity occurred after 204.3 ± 208.3 days of therapy, with ground glass opacities being the most common HRCT pattern (23 cases). Male sex, lung cancer and acute respiratory failure were associated with a shorter latency of toxicity (p = 0.0030, p = 0.0245 and p = 0.0390, respectively). Patients who required high-flow oxygen therapy showed significantly worse survival (p = 0.0028). CONCLUSIONS: Our cohort showed heterogeneous clinical and radiological aspects of ICI-related lung toxicity, with a latency not limited to the first year of treatment. Severity was mainly mild to moderate, although life-threatening events did occur. Our data indicate that strict long-term follow-up is needed to enable early diagnosis and appropriate management.
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Ribonuclease (RNase) H2 is a key enzyme for the removal of RNA found in DNA-RNA hybrids, playing a fundamental role in biological processes such as DNA replication, telomere maintenance, and DNA damage repair. RNase H2 is a trimer composed of three subunits, RNASEH2A being the catalytic subunit. RNASEH2A expression levels have been shown to be upregulated in transformed and cancer cells. In this study, we used a bioinformatics approach to identify RNASEH2A co-expressed genes in different human tissues to underscore biological processes associated with RNASEH2A expression. Our analysis shows functional networks for RNASEH2A involvement such as DNA replication and DNA damage response and a novel putative functional network of cell cycle regulation. Further bioinformatics investigation showed increased gene expression in different types of actively cycling cells and tissues, particularly in several cancers, supporting a biological role for RNASEH2A but not for the other two subunits of RNase H2 in cell proliferation. Mass spectrometry analysis of RNASEH2A-bound proteins identified players functioning in cell cycle regulation. Additional bioinformatic analysis showed that RNASEH2A correlates with cancer progression and cell cycle related genes in Cancer Cell Line Encyclopedia (CCLE) and The Cancer Genome Atlas (TCGA) Pan Cancer datasets and supported our mass spectrometry findings.
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BACKGROUND: Few prospective studies investigated neoadjuvant chemotherapy (NAC), interval cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) in advanced ovarian cancer. We report the results of a phase II study where 6 rather than 3 cycles of NAC, followed by CRS and HIPEC, were adopted (HIPEC_ovaio, EudraCT number 2007-005674-31). MATERIALS AND METHODS: Between 2007 and 2014, 56 patients with stage III primary ovarian cancer and peritoneal carcinomatosis were assigned to 6 cycles of platinum and taxane-based NAC. Of these, two had progression, 8 underwent palliative surgery, and 46 had CRS and HIPEC. RESULTS: A complete pathological response was observed in 9 patients. Of 46 patients who completed the treatment protocol, 29 had no macroscopic residual tumor. Postoperative grade III morbidity rate was 28.2%; no grade IV complications or mortality events were observed. Five-year overall survival (OS) of the entire series was 36 ± 7% (median: 36, 95% CI: 26-45 months). In 46 patients treated by CRS and HIPEC, 5-year OS was 42 ± 8% (median: 53, 95% CI: 29-76 months), and 5-year progression-free survival was 26 ± 7% (median: 23, 95% CI: 19-27 months). Completeness of cytoreduction, peritoneal cancer index and FIGO stage resulted as significant prognostic factors. CONCLUSIONS: A novel protocol consisting of 6 cycles of NAC, followed by CRS and HIPEC, is associated with notable improvement in peritoneal carcinomatosis, limited postoperative morbidity risk and high survival rates in responders, and could deserve further investigations in randomized clinical trials.
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Quimioterapia Adyuvante/métodos , Procedimientos Quirúrgicos de Citorreducción/métodos , Quimioterapia Intraperitoneal Hipertérmica/métodos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/cirugía , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Femenino , Humanos , Quimioterapia Intraperitoneal Hipertérmica/efectos adversos , Italia , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Estadificación de Neoplasias , Neoplasias Ováricas/patología , Neoplasias Peritoneales/patología , Tasa de SupervivenciaRESUMEN
OBJECTIVES: To analyze the outcomes of cytoreductive surgery and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. METHODS: Fifty-three patients with peritoneal carcinomatosis from primary (45 cases) and recurrent (8 cases) ovarian cancer were previously treated by systemic chemotherapy with platinum and taxanes and then submitted to surgical cytoreduction and HIPEC (cisplatin and mitomycin-C) with a closed abdomen technique. The median follow-up period was 27 months (range: 3-107). RESULTS: At the end of operation a complete cytoreduction (CCR-0) was obtained in 37 patients (70%). Major morbidity occurred in 12 patients (23%); reoperation was necessary in 2 patients (4%), and no postoperative mortality was observed. Overall 5-year survival probability was 55%; it was 71% in CCR-0, 44% in CCR-1, and none in patients with CCR-2 or CCR-3 residual tumor (log-rank test: P = 0.017). The cumulative risk of recurrence in 37 CCR-0 cases was 54% at 5 years from operation. CONCLUSIONS: The results of our study indicate the feasibility and the potential benefit of a protocol including systemic chemotherapy, surgical cytoreduction and HIPEC in patients with peritoneal carcinomatosis from ovarian cancer. A phase III trial to compare this approach with conventional treatment is needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carcinoma/tratamiento farmacológico , Carcinoma/secundario , Neoplasias Ováricas/patología , Neoplasias Peritoneales/tratamiento farmacológico , Neoplasias Peritoneales/secundario , Adulto , Anciano , Carcinoma/cirugía , Quimioterapia del Cáncer por Perfusión Regional , Terapia Combinada , Femenino , Humanos , Hipertermia Inducida , Inyecciones Intraperitoneales , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Neoplasias Peritoneales/cirugía , Recurrencia , Resultado del TratamientoRESUMEN
BACKGROUND: Although the efficacy of molecularly target agents in vitro, their use in routine setting is limited mainly to the use of anti-HER2 and antiEGFR agents in vivo. Moreover, core biopsy of a single cancer site may not be representative of the whole expanding clones and cancer molecular profile at relapse may differ with respect to the primary tumor. METHODS: We assessed the status of a large panel of cancer driver genes by cell-free DNA (cfDNA) analysis in a cohort of 68 patients with 13 different solid tumors at disease progression. Whenever possible, a second cfDNA analysis was performed after a mean of 2.5 months, in order to confirm the identified clone(s) and to check the correlation with clinical evolution. RESULTS: The approach was able to identify clones plausibly involved in the disease progression mechanism in about 65% of cases. A mean of 1.4 mutated genes (range 1-3) for each tumor was found. Point mutations in TP53, PIK3CA, and KRAS and copy number variations in FGFR3 were the gene alterations more commonly observed, with a rate of 48%, 20%, 16%, and 20%, respectively. Two-points-Next-Generation Sequencing (NGS) analysis demonstrated statistically significant correlation between allele frequency variation and clinical outcome (P = .026). CONCLUSIONS: Irrespective of the primary tumor mutational burden, few mutated genes are present at disease progression. Clinical outcome is consistent with variation of allele frequency of specific clones indicating that cfDNA two-point-NGS analysis of cancer driver genes could be an efficacy tool for precision oncology.
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Biomarcadores de Tumor/genética , ADN Tumoral Circulante/genética , Análisis Mutacional de ADN , Secuenciación de Nucleótidos de Alto Rendimiento , Neoplasias/diagnóstico , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , Niño , Preescolar , ADN Tumoral Circulante/sangre , Evolución Clonal , Variaciones en el Número de Copia de ADN , Progresión de la Enfermedad , Estudios de Factibilidad , Femenino , Estudios de Seguimiento , Humanos , Lactante , Masculino , Persona de Mediana Edad , Mutación , Neoplasias/sangre , Neoplasias/genética , Neoplasias/terapia , Mutación Puntual , Medicina de Precisión/métodos , Estudios Prospectivos , Adulto JovenRESUMEN
AIMS AND BACKGROUND: No available scientific report deals with high-dose (> or = 70 Gy) radiotherapy plus temozolomide chemotherapy (TMZ CHT) in high-grade gliomas. The survival results of a protocol-driven, postoperative treatment schedule are reported here to contribute to the discussion on this issue. METHODS AND STUDY DESIGN: Uniform criteria were prospectively adopted for case selection during the period 1993-2006 in the management of 123 patients, and we progressively introduced three-dimensional conformal radiotherapy (3D-CRT, 60 Gy), TMZ CHT and a high-dose (70 Gy) stereotactic boost (HDSRT) in the treatment schedule. Palliative radiotherapy was delivered by whole brain irradiation (WBI, 50 Gy) for bulky tumors, whereas radical irradiation was performed with 3D-CRT throughout the study period. Two periods of accrual are considered: 36 patients were treated before 31 December 1999 (29.25%) and 87 (70.75%) after 1 January 2000. This subdivision was due to the implementation of HDSRT hardware and TMZ CHT from January 2000. RESULTS: The median overall survival was 13 months and the 1-, 2- and 3-year survival rates were 53%, 19.5% and 11.6%, respectively. The differences in survival related to the treatment variables were highly significant, both in univariate and multivariate analysis. The median survival and 1-, 2- and 3-year survival rates in the palliative WBI group were 9.75 months and 37%, 2%, and 0%, respectively; in the 3D-CRT group 17.25 months and 64%, 34%, and 15%, respectively; in the TMZ CHT concomitant with radiotherapy group 20 months and 61%, 39%, and 21%, respectively; in the TMZ CHT concomitant with and sequential to radiotherapy group 25.75 months and 84%, 54%, and 26%, respectively, and in the HDSRT group 22 months and 72%, 48%, and 37%, respectively. No symptomatic radiation necrosis occurred in any of the groups. CONCLUSIONS: The results reported here are generally better than those reported in the literature. The selection of patients on the basis of favorable prognostic factors and suitability to the currently available, aggressive postoperative treatment resources can be the mainstay for improving therapeutic results. In particular, the new treatment option reported here (HDSRT in association with TMZ CHT) proved to be safe and effective in obtaining a relatively favorable outcome.
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Antineoplásicos Alquilantes/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/radioterapia , Irradiación Craneana/métodos , Dacarbazina/análogos & derivados , Glioma/tratamiento farmacológico , Glioma/radioterapia , Radioterapia Conformacional , Adulto , Anciano , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/cirugía , Quimioterapia Adyuvante , Protocolos Clínicos , Dacarbazina/uso terapéutico , Femenino , Glioma/patología , Glioma/cirugía , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Periodo Posoperatorio , Pronóstico , Modelos de Riesgos Proporcionales , Radioterapia Adyuvante/métodos , Radioterapia Conformacional/métodos , Técnicas Estereotáxicas , Análisis de Supervivencia , Temozolomida , Resultado del TratamientoRESUMEN
PURPOSE: The dose limiting toxicity of oxaliplatin (l-HOP) is neurotoxicity, which is characterized by an acute neuropathy and a clinically distinct chronic neuropathy. This randomized study evaluated if prolonged l-HOP infusion over the conventional l-HOP schedule was useful in reducing acute and possibly chronic l-HOP induced neurotoxicity in colon and gastric cancer patients receiving l-HOP-based regimen as adjuvant chemotherapy. METHODS: Sixty-four patients were randomly assigned to group A (26 colon and 6 gastric cancer) and to group B (23 colon and 9 gastric cancer). Chemotherapy in both groups consisted of l-HOP 85 mg/m(2) i.v. only on day 1, with leucovorin 100 mg/m(2) i.v. as a 2-h infusion followed by bolus 5-fluorouracil (5-FU) 400 mg/m(2)/day and a 22-h infusion of 5-FU 600 mg/m(2)/day, repeated for two consecutive days every 2 weeks for a maximum of 12 cycles. Patients in group A received l-HOP as a continuous 6-h i.v. infusion, and patients in group B received l-HOP as the conventional 2-h i.v. infusion. RESULTS: The percentage of patients presenting with grade >/=2 neurotoxicity was statistically lower in group A than in group B (28.1% vs. 59.3%: P = 0.02). There was a statistically lower percentage of cycles with grade >/=2 neurotoxicity in group A (6.1%) than in group B (18.5%) (P < 0.001). CONCLUSIONS: This study suggests that l-HOP as a continuous 6-h infusion is useful in preventing and reducing acute l-HOP induced neurotoxicity in patients with colon and gastric cancer receiving FOLFOX-4 regimen as adjuvant treatment.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias del Colon/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Neoplasias Gástricas/tratamiento farmacológico , Enfermedad Aguda , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Estudios de Seguimiento , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversosRESUMEN
Optic neuritis is an acute inflammatory demyelinating disorder of the optic nerve (ON) and is an initial symptom of multiple sclerosis (MS). Optic neuritis is characterized by ON degeneration and retinal ganglion cell (RGC) loss that contributes to permanent visual disability and lacks a reliable treatment. Here, we used the experimental autoimmune encephalomyelitis (EAE) mouse model of MS, a well-established model also for optic neuritis. In this model, C57BL6 mice, intraperitoneally injected with a fragment of the myelin oligodendrocyte glycoprotein (MOG), were found to develop inflammation, Müller cell gliosis, and infiltration of macrophages with increased production of oncomodulin (OCM), a calcium binding protein that acts as an atypical trophic factor for neurons enabling RGC axon regeneration. Immunolabeling of retinal whole mounts with a Brn3a antibody demonstrated drastic RGC loss. Dietary supplementation with Neuro-FAG (nFAG®), a balanced mixture of fatty acids (FAs), counteracted inflammatory and gliotic processes in the retina. In contrast, infiltration of macrophages and their production of OCM remained at elevated levels thus eventually preserving OCM trophic activity. In addition, the diet supplement with nFAG exerted a neuroprotective effect preventing MOG-induced RGC death. In conclusion, these data suggest that the balanced mixture of FAs may represent a useful form of diet supplementation to limit inflammatory events and death of RGCs associated to optic neuritis. This would occur without affecting macrophage infiltration and the release of OCM thus favoring the maintenance of OCM neuroprotective role.
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Encefalomielitis Autoinmune Experimental/complicaciones , Ácidos Grasos/farmacología , Esclerosis Múltiple/complicaciones , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/patología , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Suplementos Dietéticos , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Ácidos Grasos/administración & dosificación , Femenino , Humanos , Ratones , Ratones Endogámicos C57BL , Fármacos NeuroprotectoresRESUMEN
Purpose: The activation of the urokinase-type plasminogen activator and its receptor system is associated with retinal diseases. Among peptide inhibitors of this system, UPARANT acts by preventing the onset of pathologic signs of neovascular ocular diseases. We investigated whether systemic UPARANT may act in a therapeutic regimen by suppressing the retinal damage that characterizes diabetic retinopathy using a rat model of streptozotocin-induced diabetes. Methods: In healthy rats, plasma, eye, and retina concentrations of UPARANT were evaluated by mass spectrometry. In rat models of streptozotocin-induced diabetes, the appearance of diabetic retinopathy was assessed by electroretinogram (ERG). UPARANT was then administered at different dosages and daily regimens. ERG recording, Evans blue perfusion, and real-time PCR were used to evaluate UPARANT efficacy. UPARANT safety was also determined. Results: UPARANT was found in plasma, eye, and retina soon after its administration and remained detectable after 24 hours. Between the 4th and the 5th week after diabetes onset, UPARANT at 8 mg/kg (daily for 5 days) was effective in recovering dysfunctional ERG. Three-day treatments at 8 mg/kg or a half dose for 5 days were ineffective. ERG recovery lasted approximately 2 weeks. ERG recovery was accompanied by restored blood-retinal barrier integrity and inhibition of inflammatory and angiogenic responses. UPARANT showed a safety profile. Conclusions: These data suggest that targeting the urokinase-type plasminogen activator and its receptor system by systemic UPARANT is a potential therapeutic approach for the treatment of early diabetic retinopathy, thus providing a potential alternative approach to delay disease progression in humans.
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Barrera Hematorretinal/efectos de los fármacos , Diabetes Mellitus Experimental , Retinopatía Diabética/tratamiento farmacológico , Electrorretinografía/efectos de los fármacos , Oligopéptidos/farmacocinética , Recuperación de la Función/efectos de los fármacos , Animales , Barrera Hematorretinal/fisiología , Western Blotting , Retinopatía Diabética/metabolismo , Retinopatía Diabética/fisiopatología , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
The spontaneously diabetic Torii (SDT) rat is of increasing preclinical interest because of its similarities to human type 2 diabetic retinopathy (DR). The system formed by urokinase-type plasminogen activator (uPA) and its receptor (uPAR) is a player in blood-retinal barrier (BRB) breakdown in DR. Here, we investigated whether in SDT rats, preventive administration of UPARANT, an inhibitor of the uPAR pathway, counteracts the retinal impairment in response to chronic hyperglycemia. Electroretinogram (ERG) monitoring was followed over time. Fluorescein-dextran microscopy, CD31 immunohistochemistry, quantitative PCR, ELISA, Evans blue perfusion, and Western blot were also used. UPARANT prevented ERG dysfunction, upregulation of vascular endothelial growth factor and fibroblast growth factor-2, BRB leakage, gliosis, and retinal cell death. The mechanisms underlying UPARANT benefits were studied comparing them with the acute streptozotocin (STZ) model in which UPARANT is known to inhibit DR signs. In SDT rats, but not in the STZ model, UPARANT downregulated the expression of uPAR and its membrane partners. In both models, UPARANT reduced the levels of transcription factors coupled to inflammation or inflammatory factors themselves. These findings may help to establish the uPAR system as putative target for the development of novel drugs that may prevent type 2 DR.
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Retinopatía Diabética/prevención & control , Oligopéptidos/uso terapéutico , Receptores del Activador de Plasminógeno Tipo Uroquinasa/antagonistas & inhibidores , Activador de Plasminógeno de Tipo Uroquinasa/metabolismo , Animales , Barrera Hematorretinal/metabolismo , Retinopatía Diabética/tratamiento farmacológico , Retinopatía Diabética/metabolismo , Modelos Animales de Enfermedad , Electrorretinografía , Hiperglucemia/metabolismo , Masculino , RatasRESUMEN
PURPOSE: Tumor cell killing by anticancer drugs may be supported by their immuno- and pharmacologic effects. Chemotherapy is in fact able to (A) upregulate tumor-associated antigen expression, including carcinoembryonic antigen (CEA) or other target molecules such as thymidylate synthase (TS); and (B) downregulate tumor cell resistance to the death signals induced by tumor antigen-specific cytotoxic T lymphocytes. This provides the rationale for combining chemo- and immunotherapy. MATERIALS AND METHODS: We describe the results of a translational phase II trial designed to evaluate the toxicity, antitumor activity and immunologic effects of gemcitabine + FOLFOX-4 (oxaliplatin, fluorouracil, and folinic acid) polychemotherapy followed by the subcutaneous administration of granulocyte macrophage colony-stimulating factor and low-dose interleukin-2 in colorectal carcinoma patients. The study involved 29 patients (16 males and 13 females with a mean age of 69 years), 21 of whom had received a previous line of treatment, and 19 had liver involvement. RESULTS: The treatment was well tolerated and induced very high objective response (68.9%) and disease control rates (96.5%), with an average time to progression of 12.5 months. An immunologic study of peripheral blood mononuclear cells (PBMCs) taken from 20 patients showed an enhanced proliferative response to colon carcinoma antigen and a significant reduction in suppressive regulatory T lymphocytes (CD4+CD25T-reg+). A cytofluorimetric study of the PBMCs of five HLA-A(*)02.01+ patients who achieved an objective response showed an increased frequency of cytolytic T lymphocyte precursors specific for known CEA- and TS-derived epitopes. CONCLUSION: The results show that our regimen has strong immunologic and antitumor activity in colorectal cancer patients and deserves to be investigated in phase III trials.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias del Colon/tratamiento farmacológico , Neoplasias Colorrectales/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Inmunoterapia/métodos , Anciano , Antígenos de Neoplasias/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Antígeno Carcinoembrionario/inmunología , Neoplasias del Colon/inmunología , Neoplasias del Colon/secundario , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Citotoxicidad Inmunológica/efectos de los fármacos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Desoxicitidina/análogos & derivados , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Humanos , Infusiones Intravenosas , Interleucina-2/administración & dosificación , Interleucina-2/efectos adversos , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Masculino , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Oxaliplatino , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/inmunología , Timidilato Sintasa/inmunología , Resultado del Tratamiento , GemcitabinaRESUMEN
BACKGROUND AND AIMS: oxaliplatin in combination with folinic acid (FA) and infusional 5-fluorouracil (5-FU) has shown significant anti-tumor activity in gastric cancer patients (FOLFOX). Previous studies have shown that gemcitabine (GEM), a new fluorinated anti-metabolite, enhances the individual anti-tumor activity of either 5-FU or oxaliplatin. We have therefore designed a multi-center phase II trial in order to test a novel GEM+FOLFOX-4 regimen in patients with metastatic gastric cancer. METHODS: we enrolled 36 patients, 28 males and 8 females, with an average age of 64.4 years (range 37-78), who received bi-weekly treatment with GEM (1,000 mg/m2 on day 1), levo-FA (100 mg/m2 on days 1 and 2), a 5-FU (400 mg/m2) bolus injection followed by 22-h continuous infusion (800 mg/m2) on days 1 and 2, and oxaliplatin 85 mg/m2 in a 4-6 h intravenous (i.v.) infusion before the second FUFA administration on day 2. RESULTS: the most frequent side effect was grade 1-2 hematological toxicity and late sensorial neurotoxicity. Two patients developed hypersensitivity to oxaliplatin while another developed an aseptic eosinophilic pneumonitis. Two patients refused to continue the treatment after two cycles of chemotherapy and were lost at the follow-up. Among the remaining 34 patients four achieved a complete response, 15 a partial response, 12 had a stable disease and three progressed. CONCLUSIONS: these results may grant the rationale to evaluate this multi-drug combination in randomized phase III trials in advanced gastric cancer.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Desoxicitidina/análogos & derivados , Neoplasias Gástricas/tratamiento farmacológico , Adenocarcinoma/mortalidad , Adenocarcinoma/secundario , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Fluorouracilo/administración & dosificación , Enfermedades Gastrointestinales/inducido químicamente , Enfermedades Gastrointestinales/patología , Enfermedades Hematológicas/inducido químicamente , Enfermedades Hematológicas/patología , Humanos , Infusiones Intravenosas , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Síndromes de Neurotoxicidad/etiología , Síndromes de Neurotoxicidad/patología , Compuestos Organoplatinos/administración & dosificación , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Tasa de Supervivencia , GemcitabinaRESUMEN
We have performed a translational phase II trial testing an original immunotherapy schedule based on the monthly subcutaneous (s.c.) administration of hrGM-CSF (days 1 through 5) and very low dose hrIL-2 (days 6 through 15) in 19 patients with metastatic renal cell carcinoma. Bone pain, first dose reaction to GM-CSF, asthenia and fever were the most common side effects. A partial response, and a disease stabilization were respectively observed in 4 and 11 cases, with a rate of objective response and a disease control rate respectively of 21% and 79%. We recorded a time to progression of 9 months and a 2- and 3-year survival respectively of 42% (8/19 patients) and 26% (5/19 patients). Our results suggest that this GM-CSF/hrIL-2 combination is active and well tolerated in patients with renal cell carcinoma and deserves to be investigated in larger comparative trials.
Asunto(s)
Carcinoma de Células Renales/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Inmunoterapia/métodos , Interleucina-2/uso terapéutico , Neoplasias Renales/terapia , Anciano , Anciano de 80 o más Años , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Inmunoterapia/economía , Interleucina-2/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Proteínas Recombinantes/química , Resultado del TratamientoRESUMEN
BACKGROUND/AIMS: The aim of this study was to evaluate the survival benefit of adjuvant chemotherapy with etoposide, leucovorin and 5-fluorouracil (ELF) in gastric cancer patients undergoing previous surgery with a curative intent. METHODOLOGY: The clinical outcome of 49 patients with resected gastric cancer treated with adjuvant chemotherapy was compared with that of 85 surgically treated historical controls who did not receive any adjuvant treatment. The chemotherapy regimen consisted of six cycles of daily 1-hour intravenous infusions of folinic acid 100 mg/m2 and 5-FU 400 mg/ m2, and a 2-hour infusion of etoposide 100 mg/m2, for three days every 28 days. RESULTS: The 5-year relapse-free survival was 32% in the adjuvant arm and 27% in the control arm (p = 0.6). At the last follow-up, there were 32 deaths in the adjuvant arm and 60 in the control arm. The median duration of survival was respectively 23 and 19 months, and the 5-year survival rates were 34% and 29% (p = 0.4). The chemotherapy was well tolerated. CONCLUSIONS: Our data suggest that ELF adjuvant treatment is a safe and well tolerable combination chemotherapy in patients with resected gastric cancer, but it does not seem to improve prognosis in comparison with historical controls.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/cirugía , Quimioterapia Adyuvante , Etopósido/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Gastrectomía , Humanos , Leucovorina/uso terapéutico , Levoleucovorina , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/mortalidadRESUMEN
Gastrointestinal stromal tumor (GIST) metastases are found most commonly in the liver, on average 16 to 38 months after resection of the primary tumor, even if some delayed hepatic metastases from GISTs have been described. We report a case of a man with a giant liver mass at computed tomography scan. In September 1984, the patient had undergone resection of a duodenal tumor, diagnosed as schwannoma. A liver biopsy revealed a neoplasm composed of epithelioid and spindled cells, immunohistochemically positive to c-kit and Dog-1. Reexamining the duodenal tumor resected in 1984, it was reclassified as GIST. Sequencing revealed the same mutation of the c-kit gene in both duodenal and hepatic lesions. To the best of our knowledge, this case represents the longest disease-free interval between a primary GIST and its metastasis. A brief review of the literature and an analysis of the potential prognostic role of particular c-kit mutations are also provided.