[show abstract][hide abstract] ABSTRACT: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance.
We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance.
TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up-regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance.
We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies.
PLoS ONE 01/2014; 9(1):e86263. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Palonosetron is a potent second generation 5- hydroxytryptamine-3 selective antagonist which can be administered by either intravenous (IV) or oral routes, but subcutaneous (SC) administration of palonosetron has never been studied, even though it could have useful clinical applications. In this study, we evaluate the bioavailability of SC palonosetron.
Patients treated with platinum-based chemotherapy were randomized to receive SC or IV palonosetron, followed by the alternative route in a crossover manner, during the first two cycles of chemotherapy. Blood samples were collected at baseline and 10, 15, 30, 45, 60, 90 minutes and 2, 3, 4, 6, 8, 12 and 24 h after palonosetron administration. Urine was collected during 12 hours following palonosetron. We compared pharmacokinetic parameters including AUC0-24h, t1/2, and Cmax observed with each route of administration by analysis of variance (ANOVA).
From October 2009 to July 2010, 25 evaluable patients were included. AUC0-24h for IV and SC palonosetron were respectively 14.1 and 12.7 ng × h/ml (p = 0.160). Bioavalability of SC palonosetron was 118% (95% IC: 69-168). Cmax was lower with SC than with IV route and was reached 15 minutes following SC administration.
Palonosetron bioavailability was similar when administered by either SC or IV route. This new route of administration might be specially useful for outpatient management of emesis and for administration of oral chemotherapy.
PLoS ONE 01/2014; 9(2):e89747. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Inhibitor of DNA binding 1 (Id1) and 3 (Id3) genes have been related with the inhibition of cell differentiation, cell growth promotion and tumor metastasis. Recently, Id1 has been identified as an independent prognostic factor in patients with lung adenocarcinoma, regardless of the stage. Furthermore, Id1 may confer resistance to treatment (both, radiotherapy and chemotherapy). METHODS: We have studied, using monoclonal antibodies for immunohistochemistry, the Id1 and Id3 tumor epithelial expression in 17 patients with stage III-N2 non-small cell lung cancer (NSCLC) treated with definitive chemoradiotherapy. RESULTS: Id1 expression is observed in 82.4% of the tumors, whereas Id3 expression is present in 41.2% of the samples. Interestingly, Id1 and Id3 expression are mutually correlated (R = 0.579, p = 0.015). In a subgroup analysis of patients with the most locally advanced disease (T4N2 stage), co-expression of Id1 and Id3 showed to be related with a worse overall survival (45 vs 6 months, p = 0.002). A trend towards significance for a worse progression free survival (30 vs 1 months, p = 0.219) and a lower response rate to the treatment (RR = 50% vs 87.5%, p = 0.07) was also observed. CONCLUSIONS: A correlation between Id1 and Id3 protein expression is observed. Id1 and Id3 co-expression seems associated with a poor clinical outcome in patients with locally advanced NSCLC treated with definitive chemoradiotherapy.
Journal of Translational Medicine 01/2013; 11(1):13. · 3.46 Impact Factor
[show abstract][hide abstract] ABSTRACT: Objective
To contribute ideas to answer advanced cancer patients asking about the use of medicinal cannabis as a symptomatic treatment.
Based on a real example, we present a summary of the pharmacology of natural and synthetic cannabinoids, the evidence on its effectiveness as a symptomatic treatment in advanced cancer, and the patient's attitude and expectations raised by the medicinal use of cannabis.
There are more than 60 different cannabinoids (the most relevant: delta-9-tetrahydrocannabinol) and other substances in cannabis. In our setting, patients who ask about the use of cannabis as a symptomatic treatment do not look for synthetic cannabinoids approved in other countries, but rather prefer herbal cannabis or its derivatives. They usually consume smoked cannabis (favoring the earlier onset of plasma levels) or, rarely, in infusion. Use of medicinal cannabis causes a wide variation in plasma concentrations of delta-9-tetrahydrocannabinol. There is evidence supporting a certain effect of synthetic cannabinoids in pain relief (also as an adjuvant), and as antiemetic for chemotherapy-induced nausea and vomiting in cancer patients. This evidence is based primarily on results of studies with limited methodological quality. There is insufficient evidence to assert its effectiveness in the treatment of anorexia. Side effects of moderate doses of synthetic cannabinoids or medicinal cannabis are mostly mild, as well as their psycho-neurological profile. The attitude and expectations of the patient, and the way to consume of medical cannabis may favor that part of its benefit may be due to a placebo effect.
Medicinal cannabis does not seem as active as patients expect, or as toxic as many professionals suspect. To respond to the advanced cancer patient asking about their use as symptomatic treatment is advisable to avoid prejudice, to respect and to act with caution seeking the patient's symptomatic benefit.
[show abstract][hide abstract] ABSTRACT: Within an oncology setting, certain chemotherapy drugs, such as cisplatin, may lead to magnesium loss causing nephropathy. Neurological and cardiovascular symptoms caused by hypomagnesaemia are well known. The relationship between serious hypomagnesemia and severe pain is not well documented but nevertheless, when faced with unexplained episodes of pain which do not respond to powerful analgesics, it is important to review blood magnesium levels. We present two cases of opioid-refractory pain attacks. Patients received drugs which have been linked to hypomagnesemia. In both cases, endovenous magnesium replacement led to a drastic improvement in pain management.
Supportive Care in Cancer 12/2012; · 2.09 Impact Factor
[show abstract][hide abstract] ABSTRACT: Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α-primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15(-/-) and IL-7(-/-) recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2(+) CD8 T cells with autologous dendritic cells loaded with MART1(26-35) peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.
The Journal of Immunology 08/2012; 189(7):3299-310. · 5.52 Impact Factor
[show abstract][hide abstract] ABSTRACT: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone.
From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test.
Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group.
The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.
Clinical and Translational Oncology 07/2012; 14(11):835-41. · 1.28 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background: The role of trimodality treatment remains controversial in the management of locally advanced N2 non-small cell lung cancer (NSCLC). We present our institution’s experience in this setting, analyzing whether surgery improves survival when compared to definitive CT-RT.
European Multidisciplinary Conference in Thoracic Oncology (EMCTO) 2011 Meeting, Lugano; 02/2011
[show abstract][hide abstract] ABSTRACT: Dysphagia is a common symptom in neuromuscular junction disorders, but it rarely occurs in isolation or is the presenting feature. We describe a patient presenting with isolated dysphagia to liquids. Electrophysiological studies, such as repetitive nerve stimulation and single-fiber electromyography, were normal. Serum anti-P/Q-type voltage-gated calcium-channel (anti-P/Q-type VGCC) and anti-acetylcholine receptor (AChR ab) antibodies were above the normal range. A computed tomography scan showed a mediastinal mass corresponding to a thymic carcinoma. After chemotherapy, surgical removal of the thymic carcinoma and radiotherapy, the patient no longer complained of dysphagia, AChR ab titers were reduced and anti-P/Q-type VGCC antibodies became negative. To the best of our knowledge, no previous reports of a paraneoplastic myasthenic syndrome related to thymic carcinoma with both anti-P/Q-type VGCC and AChR antibodies have been described.
[show abstract][hide abstract] ABSTRACT: SF2/ASF is a splicing factor recently described as an oncoprotein. In the present work, we examined the role of SF2/ASF in human non-small cell lung cancer (NSCLC) and analyzed the molecular mechanisms involved in SF2/ASF-related carcinogenesis.
SF2/ASF protein levels were analyzed in 81 NSCLC patients by immunohistochemistry. SF2/ASF downregulation cellular models were generated using small interfering RNAs, and the effects on proliferation and apoptosis were evaluated. Survivin and SF2/ASF expression in lung tumors was analyzed by Western blot and immunohistochemistry. Survival curves and log-rank test were used to identify the association between the expression of the proteins and time to progression.
Overexpression of SF2/ASF was found in most human primary NSCLC tumors. In vitro downregulation of SF2/ASF induced apoptosis in NSCLC cell lines. This effect was associated with a reduction in the expression of survivin, an antiapoptotic protein widely upregulated in cancer. In fact, SF2/ASF specifically bound survivin mRNA and enhanced its translation, via a mammalian target of rapamycin complex 1 (mTORC1) pathway-dependent mechanism, through the phosphorylation and inactivation of the translational repressor 4E-BP1. Moreover, SF2/ASF promoted the stability of survivin mRNA. A strong correlation was observed between the expression of SF2/ASF and survivin in tumor biopsies from NSCLC patients, supporting the concept that survivin expression levels are controlled by SF2/ASF. Furthermore, combined expression of these proteins was associated with prognosis.
This study provides novel data on the mTORC1- and survivin-dependent mechanisms of SF2/ASF-related carcinogenic potential, and shows that SF2/ASF and survivin expression is involved in NSCLC progression.
Clinical Cancer Research 08/2010; 16(16):4113-25. · 7.84 Impact Factor
[show abstract][hide abstract] ABSTRACT: Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug.
EGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated.
We demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.
Molecular Cancer 01/2010; 9:139. · 5.13 Impact Factor
[show abstract][hide abstract] ABSTRACT: Microarrays strategies, which allow for the characterization of thousands of alternative splice forms in a single test, can be applied to identify differential alternative splicing events. In this study, a novel splice array approach was developed, including the design of a high-density oligonucleotide array, a labeling procedure, and an algorithm to identify splice events.
The array consisted of exon probes and thermodynamically balanced junction probes. Suboptimal probes were tagged and considered in the final analysis. An unbiased labeling protocol was developed using random primers. The algorithm used to distinguish changes in expression from changes in splicing was calibrated using internal non-spliced control sequences. The performance of this splice array was validated with artificial constructs for CDC6, VEGF, and PCBP4 isoforms. The platform was then applied to the analysis of differential splice forms in lung cancer samples compared to matched normal lung tissue. Overexpression of splice isoforms was identified for genes encoding CEACAM1, FHL-1, MLPH, and SUSD2. None of these splicing isoforms had been previously associated with lung cancer.
This methodology enables the detection of alternative splicing events in complex biological samples, providing a powerful tool to identify novel diagnostic and prognostic biomarkers for cancer and other pathologies.
[show abstract][hide abstract] ABSTRACT: Optimal management of SST is still controversial several years after the proposal of a multidisciplinary approach including neoadjuvant chemotherapy and external radiation. Our objective is to report our experience of this multidisciplinary approach from the surgical point of view.
From January 1997 to January 2008, 24 patients were treated surgically (18 with induction chemotherapy and 15 with radiotherapy). The surgical approach was thoracic (14 cases, 1 with a spinal approach) or cervical (10 patients, 2 thoracotomies). Pulmonary surgery performed consisted of 11 wedge resections, 10 lobectomies, 1 pneumonectomy and 2 cases without lung resection (1 exploratory thoracotomy and 1 local progression after a previously resected tumor). Intraoperative radiotherapy (IORT) was given in 7 cases. Partial vertebral body resection was performed in 5 cases. A pathologically complete response (pT0) was found in 7 cases (29 %).
Surgery-related morbidity was mainly due to respiratory distress (5 patients). Two patients died in the first month after surgery (mortality: 8 %). The surgical approach (cervical vs. thoracic) did not influence postoperative morbidity ( p = NS). Overall 5-year survival was 56.6 % according to the Kaplan-Meier method. No influence on survival was observed with regard to the approach (cervical vs. thoracic), the use of IORT, or the performance of spinal surgery. Patients with a complete pathological response had a better 5-year survival, but this did not reach statistical significance.
Surgery has a role in the multidisciplinary approach, especially when we consider long-term survival. A multidisciplinary approach using neoadjuvant chemo and radiotherapy has a high rate of complete pathological response. It is also associated with a high incidence of postoperative distress syndrome. The 5-year survival is acceptable.
The Thoracic and Cardiovascular Surgeon 10/2009; 57(6):353-7. · 0.93 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pemetrexed is a multitargeted antifolate initially approved as a single agent for the second-line treatment of locally advanced or metastatic non-small cell lung cancer and more recently in the first-line setting combined with cisplatin. The combination of pemetrexed with carboplatin has been tested in several phase II clinical trials showing interesting antitumour activity with mild toxicity. Supplementation with folic acid and vitamin B12 during treatment with pemetrexed is recommended to reduce potential haematological and gastrointestinal adverse events.
A patient experienced cutaneous lesions including widespread erythema, epidermal detachment, and skin denudation, associated with deterioration of his general condition after the second cycle of this chemotherapy combination, which was clinically and histologically compatible with toxic epidermal necrolysis (Lyell's syndrome). Treatment with systemic steroids, antihistamines, and antibiotics led to resolution of the skin lesions and improvement of his general condition.
To our knowledge, this is the second case reported in the literature of this type of suspected adverse drug reaction associated with a pemetrexed-based chemotherapy combination.
[show abstract][hide abstract] ABSTRACT: To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC).
Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m) and cisplatin (100 mg/m) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m) and cisplatin (30 mg/m).
Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12-97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50-91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival.
HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies.1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity).
American journal of clinical oncology 09/2009; 33(2):137-43. · 2.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by the presence of IgG autoantibodies against Dsg3. Our aim was to investigate the molecular events implicated in the development and localization of apoptosis and acantholysis in PV. We used a passive transfer mouse model together with immunohistochemical (IHC) techniques and the TUNEL assay, with quantification analysis in the basal layer of the epidermis. The activated signalling molecules analysed and apoptotic cells detected showed an identical localization. Herein, we found for the first time in vivo an increased expression of activated HER receptor isoforms in the basal layer in PV lesions. Besides, we observed the almost total lack of activated Akt compared with a higher level of activated mTOR within the basal cells of the epidermis. Our observations strongly support that the restriction of acantholysis to the basal layer may be due, at least in part, to the selective and increased presence of activated HER receptor isoforms in these cells. After phosphorylation of HER receptor isoforms, intracellular signalling pathways are activated in the basal layer. In addition, the imbalance in Akt/mTOR that takes place in the basal cells may provide intracellular signals necessary for the development of apoptosis and acantholysis.
[show abstract][hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF) inhibits differentiation and maturation of dendritic cells (DC), suggesting a potential immunosuppressive role for this proangiogenic factor. Bevacizumab, sorafenib and sunitinib target VEGF-mediated angiogenesis and are active against several types of cancer, but their effects on the immune system are poorly understood. In this study, VEGF and supernatants of renal carcinoma cell lines cultured under hypoxia were found to alter the differentiation of human monocytes to DC. Resulting DC showed impaired activity, as assessed by the alloreactive mixed T-lymphocyte reaction. Bevacizumab and sorafenib, but not sunitinib, reversed the inhibitory effects of VEGF, but not of those mediated by tumour supernatants. Dendritic cells matured under the influence of VEGF expressed less human leukocyte antigen-DR (HLA-DR) and CD86, and this effect was restored by bevacizumab and sorafenib. Finally, tumour-cell supernatants decreased interleukin-12 (IL-12) production by mature DC, and such inhibition was not restored by any of the tested drugs, delivered either as single agents or in combination. The deleterious effects of tumour-cell supernatants were mainly mediated by thermostable molecules distinct from VEGF. These results indicate that inhibition of the differentiation of monocytes to DC is a multifactorial effect, and that they support the development of combinations of angiogenesis inhibitors with immunological modulators.
British Journal of Cancer 05/2009; 100(7):1111-9. · 5.08 Impact Factor
[show abstract][hide abstract] ABSTRACT: Pemetrexed is a multitargeted antifolate approved for the second-line treatment of locally advanced or metastatic non-small cell lung cancer. The combination of pemetrexed with gemcitabine has been studied in several clinical trials showing a promising antitumor activity with a mild toxicity profile. We present the case of a patient who experienced fever, arthralgia, skin rash and high serum ferritin levels after first cycle of this chemotherapy combination, compatible with an adult onset Still's disease. This adverse event has not been previously reported.
Lung Cancer 12/2008; 64(1):124-6. · 3.39 Impact Factor