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Biomedical subjects

J García-Foncillas

Publications and source records attributed to J García-Foncillas.

At least 19 recordsLinked to original sources
PubMed2006

Xeroderma pigmentosum group D 751 polymorphism as a predictive factor in resected gastric cancer treated with chemo-radiotherapy.

AIM: To evaluate the potential association of xeroderma pigmentosum group D (XPD) codon 751 variant with outcome after chemo-radiotherapy in patients with resected gastric cancer. METHODS: We used PCR-RFLP to evaluate the genetic XPD Lys751Gln polymorphisms in 44 patients with stage III (48%) and IV (20%) gastric cancer treated with surgery following radiation therapy plus 5-fluorouracil/leucovorin based chemotherapy. RESULTS: Statistical analysis showed that 75% (12 of 16) of relapse patients showed Lys/Lys genotype more frequently (P = 0.042). The Lys polymorphism was an independent predictor of high-risk relapse-free survival from Cox analysis (HR: 3.07, 95% CI: 1.07-8.78, P = 0.036) and Kaplan-Meir test (P = 0.027, log-rank test). CONCLUSION: XPD Lys751Gln polymorphism may be an important marker in the prediction of clinical outcome to chemo-radiotherapy in resected gastric cancer patients.

Adult↗
PubMed2006

Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues.

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes. In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent non-neoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor. Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia.

Cluster Analysis↗
PubMed2006

Ileal carcinoid tumor with liver metastases and cardiac involvement treated with intraarterial liposomal doxorubicin and valve replacement.

Unless carcinoid are in general slow-growing tumors, some cases could be frankly malignant. The commonest cause of death in patients suffering a carcinoid tumor is liver failure due to tumor progression. When tumors have a fast evolution a multidisciplinary approach must be perform. This case report is an example of this specific situation.

Antibiotics, Antineoplastic↗
PubMed2006

Potential application of GSTT1-null genotype in predicting toxicity associated to 5-fluouracil irinotecan and leucovorin regimen in advanced stage colorectal cancer patients.

Our aim was to evaluate the role of C-69T in GSTA1, Ile105Val in GSTP1, null allele in GSTT1 and GSTM1 in the prediction of toxicity in patients treated with 5-Fu/CPT-11/Lv regimens in metastatic CRC patients. Fifty-one patients with CRC metastatic disease were analysed. All patients had bidimensionally measurable disease according to WHO criteria. The gender distribution was 37 (74%) males and 13 (26%) females; age ranged from 41 to 71 years; performance status was in all patients > or = 80 (Karnofsky index). The analysis of gene polymorphism was performed in lymphocytes by using PCR-RFLP (GSTA1, GSTP1), PCR (GSTT1, GSTM1) and sequencing analysis (UGT1A1 *28). An appreciable significant association was observed between the GSTT1-null and toxicity: 57% developed gastrointestinal toxicity grade III versus 23% of patients with GSTT1-present genotype (p = 0.053). The other polymorphisms analysed did not show any significant relation with toxicity. Our data suggest that GSTT1-null is associated with a greater probability of developing toxicity to 5-Fu/CPT-11/Lv treatments, indicating a potential application of this genetic analysis in predicting adverse effects of this regimen.

Adult↗
PubMed2005

Association between bone mineral density and polymorphisms of the VDR, ERalpha, COL1A1 and CTR genes in Spanish postmenopausal women.

Bone mineral density (BMD), the major determinant of osteoporotic fracture risk, has a strong genetic component, and several candidate gene polymorphisms have been implicated in the regulation of this process. In view of the reported associations between the BMD and polymorphisms in the collagen type I alpha 1 gene (COL1A1), vitamin D receptor (VDR), estrogen receptor (ER)alpha and calcitonin receptor (CTR) genes, an association study was performed between VDR, COL1A1, CTR and ER genotypes and lumbar spine, femoral neck and Ward's triangle BMD in postmenopausal Spanish women. We statistically controlled for many confounding factors, such as height, weight, age, years since menopause, use of hormone replacement therapy (HRT), tobacco consumption, use of oral contraceptives, calcium dietary intake or exercise practice. No association between COL1A1 or ER genotypes and BMD was detected. However, we described a statistically significant association between a personal history of fractures and COL1A1 genotype. The ss genotype was found to be over-represented between those women who had a personal history of fractures. The analyses of the VDR polymorphisms showed that FF subjects reached the highest values of BMD at the three measured sites, whereas Ff individuals had an intermediate BMD and ff women had the lowest values. However, the VDR-BsmI gene polymorphism was not found to be associated with adjusted BMD. For the CTR polymorphisms, our study showed that women with the aa genotype had a lower adjusted BMD at the femoral neck. In conclusion, in our postmenopausal Spanish women cohort we found a statistically significant association beteween the VDR and CTR gene polymorphisms and the BMD. However, we did not find any association between the ER and COL1A1 gene and the BMD. The COL1A1 gene was found to be associated with the prevalence of osteoporotic fractures. Of all the studied gene polymorphisms, the FokI VDR gene polymorphism seems to be the strongest BMD genetic determinant of postmenopausal Spanish women.

Adult↗
PubMed2005

Structure-based assessment of BRCA1 and BRCA2 mutations in a small Spanish population.

Breast cancer is the most frequent cancer type among women in the world. There is abundant evidence, that alterations in the breast cancer susceptibility genes, BRCA1 and BRCA2, are present in a large proportion of families with multiple cases of breast and ovarian cancer. Our aim was to better understand the molecular and structural insights associated with the most frequent alterations, found in the BRCA1 and BRCA2 genes, within our patients. We analyzed 50 breast cancer cases. Of those, 24% were found to carry deleterious mutations, and up to 10 rare variants of unknown significance were detected. The frequency of polymorphic changes was considerably different between genes, BRCA1 (55%) and BRCA2 (19.4%). By looking at the protein level, the changes observed within the BRCA1 and BRCA2 genes could affect not only the nucleic location of the protein but also disrupt the folding and, therefore, the tumor suppressor function.

BRCA1 Protein↗
PubMed2001

Polymorphisms of the repeated sequences in the enhancer region of the thymidylate synthase gene promoter may predict downstaging after preoperative chemoradiation in rectal cancer.

PURPOSE: Thymidylate synthase (TS) is an important target enzyme for the fluoropyrimidines. TS gene promoter possesses regulatory tandemly repeated (TR) sequences that are polymorphic in humans, depending on ethnic factors. These polymorphisms have been reported to influence TS expression. TS expression levels affect tumor downstaging after preoperative fluoruracil (5-FU)-based chemoradiation. Tumor downstaging correlates with improved local control and disease-free survival. The aim of this study is to correlate TR polymorphisms with downstaging and disease-free survival. PATIENTS AND METHODS: Sixty-five patients with rectal cancer underwent tumor resection after preoperative 5-FU-based chemoradiation. Tumor downstaging was evaluated by comparing the pretreatment T stage with the pathologic stage observed in the surgical specimen. TS polymorphism genotype was determined by polymerase chain reaction amplification of the corresponding TS promoter region, and products of amplification were electrophoresed, obtaining products of 220 bp (2/2), 248 bp (3/3), or both (2/3). The TS polymorphism genotype results were subsequently compared with the downstaging observed and with disease-free survival. RESULTS: Patients who were homozygous for triple TR (3/3) had a lower probability of downstaging than patients who were homozygous with double TR or heterozygous patients (2/2 and 2/3): 22% versus 60% (P =.036; logistic regression). Furthermore, a trend toward improved 3-year disease-free survival was detected in the 2/2 and 2/3 groups, compared with that in the 3/3 group (81% v 41%; P =.17). CONCLUSION: This preliminary study suggests that TS repetitive-sequence polymorphisms are predictive for tumor downstaging. TR sequences in TS promoter may be useful as a novel means of predicting response to preoperative 5-FU-based chemoradiation.

Adult↗
PubMed2000

Vascular endothelial growth factor (VEGF) and melanoma. N-acetylcysteine downregulates VEGF production in vitro.

Vascular endothelial growth factor (VEGF), the most potent angiogenic factor identified to date, is associated with growth and metastasis of solid tumours, including melanoma. It has been shown in vitro that melanoma cells produce raised concentrations of VEGF. We examined the VEGF concentrations in plasma of 20 patients with primary melanoma, local recurrence and metastatic melanoma. We also studied the inhibiting effect of one antioxidant, N-acetylcysteine, on VEGF production in three human melanoma cell lines. We found elevated levels of VEGF (median 205 pg ml; 95 percent confidence interval, 80-414) in metastatic melanoma, with respect to primary and locally recurrent melanoma (75 pg/ml; 95 percent confidence interval, 35-130). The health control patients had levels of 25 pg/ml (95 percent confidence interval, 10-35). Human melanoma cell lines secreted VEGF in basal conditions (550-963 +/- 125 pg/ml) and N-acetylcysteine (0.5-20 mM) significantly decreased the VEGF production in a dose-dependent manner. VEGF concentrations were found to be raised in patients with primary melanoma, local recurrence, and above all, metastatic melanoma (P=0.008). N-acetylcysteine inhibits VEGF production in three human melanoma cell lines. This antioxidant might have therapeutic applications in metastatic melanoma in combination with other cytotoxic drugs.

Acetylcysteine↗
PubMed2000

N-acetylcysteine downregulates vascular endothelial growth factor production by human keratinocytes in vitro.

The present study was designed to evaluate the action of various antioxidants including N-acetylcysteine (NAC) and the flavonoids resveratrol and quercetin on the production of VEGF by human keratinocytes (HKC). NAC, resveratrol, and quercetin dose-dependently suppressed the incorporation of 3H-thymidine into HKC. Values of median inhibitory concentration for NAC, resveratrol, and quercetin were 10 mM, 55 microM, and 15 microM, respectively (P < 0.01). RT-PCR demonstrated VEGF 121 and VEGF 206 expression in all HKC samples. HKC showed baseline expression and a progressive gradual time-dependent increase in VEGF secretion (510+/-75 pg/ml at 24 h), and EGF (2.5-100 ng/ml) enhanced the secretion of VEGF in a dose-dependent fashion. HKC were incubated with NAC (2.5-20 mM) for 2 h prior to the addition of EGF (5 ng/ml) or PMA (10 ng/ml), and a significant decrease (P < 0.01) was found after 24 h of incubation with 2.5 mM NAC. However, neither resveratrol nor quercetin reduced the synthesis of this cytokine. In summary we conclude that NAC and the flavonoid antioxidants resveratrol and quercetin inhibit HKC proliferation regardless of the stage of differentiation and that NAC significantly inhibits VEGF secretion in basal and EGF- or PMA-treated HKC.

Acetylcysteine↗
PubMed1999

Pilot study of concurrent cisplatin, 5-fluorouracil, and external beam radiotherapy prior to radical surgery +/- intraoperative electron beam radiotherapy in locally advanced cervical cancer.

PURPOSE: The purpose of this study was to describe the feasibility of a combined preoperative chemoradiation program followed by radical surgery in advanced cervical cancer. MATERIALS AND METHODS: From February 1988 to April 1997, 40 patients with carcinoma of the cervix were treated with preoperative external beam radiotherapy to 45 Gy in 5 weeks. Patients received concurrent continuous infusion cisplatin (20 mg/m2) and 5-fluorouracil (1500 mg) chemotherapy during the first (days 1-4) and fifth (days 22-25) weeks of the radiation course. Radical surgery was performed 4-6 weeks after the completion of the preoperative treatment. Intraoperative radiotherapy was given to 20 patients, based on intraoperative assessment. RESULTS: Toxicity associated with chemoradiation was usually mild except in two patients who presented WHO grade 4 bone marrow aplasia. Three patients developed postoperative ureterovaginal fistula, and five patients developed long-term hydronephrosis that needed ureteral stenting. Clinical response was observed in 95% of the patients (55% complete response). The analysis of the surgical specimens revealed complete pathological response in 67.5% of the cases and partial pathological response in 32.5%. As expected, the degree of pathological response was predicted by the degree of clinical response (P = 0.001). Nine-year local control, distant metastases-free survival, disease-free survival, and overall survival were 86, 84, 81, and 85%, respectively. Patients displaying a complete pathological response had statistically significant improved local control (P = 0.004), distant metastases-free survival (P = 0.009), disease-free survival (P = 0.002), and overall survival (P = 0.038). CONCLUSIONS: Cisplatin plus 5-fluorouracil preoperative chemoradiation is active and usually well tolerated in locally advanced carcinoma of cervix, inducing a high rate of clinical and pathological complete responses. When this therapy is followed by radical surgery, the local control rates are excellent, even in patients with advanced stages or poor response. These improved local control rates may be achievable only through extensive surgical resection, with a parallel increase in the complication rates.

Actuarial Analysis↗
PubMed1998

Microsatellite instability and p53 mutations in sporadic right and left colon carcinoma: different clinical and molecular implications.

BACKGROUND: Left and right colon carcinomas can display different clinical, pathologic, and genetic characteristics. The purpose of this study was to characterize multiple molecular genetic alterations in sporadic colon carcinoma and to correlate them with the location of the tumors and with lymph node metastasis. METHODS: One hundred and twenty-five cases of sporadic colon carcinoma (50 in the right colon and 75 in the left colon in patients with no family history of colon carcinoma) were studied. Status of the p53 gene was assessed by polymerase chain reaction (PCR), single strand conformation polymorphism, and sequencing at exons 5-8. Microsatellite instability was analyzed with five microsatellite markers at chromosome 18. The mismatch repair genes hMLH1 and hMSH2 were studied in tumors found to have microsatellite instability by PCR and sequencing. RESULTS: In the 125 cases studied, there were 53 tumors with mutations of the p53 gene. p53 mutations correlated with lymph node metastases from right colon carcinoma cases (61%), and all cases with p53 mutations and microsatellite instability were AJCC/UICC Stage III (Dukes Stage C). In the right colon carcinoma cases the rate of microsatellite instability was related to the tumor size (19% in tumors measuring < 4 cm, and 34% in tumors measuring > 4 cm). No correlation between microsatellite instability and p53 mutations was detected. In the left colon carcinoma cases, p53 mutations were detected in 41% of tumors and microsatellite instability in 14%; neither finding was related to the tumor size. Mutations of the hMLH1 and hMSH2 mismatch repair genes were detected in 7 of 24 cases with marked microsatellite instability. CONCLUSIONS: Microsatellite instability is prone to occur in sporadic right colon carcinoma during tumor growth and is not associated significantly with mutations in the hMLH1 and hMSH2 mismatch repair genes or in the p53 gene. Concomitant detection of microsatellite instability and p53 mutations in right colon carcinoma is associated with the presence of lymph node metastases.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Alpha-MSH regulates interleukin-10 expression by human keratinocytes.

Normal human keratinocytes (HKC) are able to synthesize alpha-MSH. Because the production of alpha-MSH by HKC is induced significantly by ultraviolet B radiation, the involvement of keratinocyte-derived alpha-MSH in UV-induced immunosuppression has been suggested. The induction of the antiinflammatory cytokine IL-10 in monocytes is a major mechanism in the antiinflammatory actions of alpha-MSH. In the present study, HKC were investigated for their ability to produce IL-10 after alpha-MSH stimulation. HKC were obtained from the skin of human female breast sections and either left untreated or treated with 0.01 or 0.1 microg/ml alpha-MSH for different times. Using RT-PCR, HKC were shown to express IL-10 mRNA even under basal conditions, and treatment with alpha-MSH increased expression. Only minimal concentrations of IL-10 protein were detected in supernatants from the alpha-MSH-stimulated cultures. To the best of our knowledge this is the first report of IL-10 expression by cultured HKC after alpha-MSH stimulation. Further studies are needed to determine the biological and therapeutic relevance of these findings.

Female↗
PubMed1998

CD24 expression on human keratinocytes.

CD24 or Nectadrin is a cell surface glycoprotein expressed in pre-B lymphocytes, T lymphocytes, neurons, muscle cells and carcinoma cells. Its function is not completely known, but it has been suggested that it is involved in cell adhesion and signalling. CD24 has recently been identified as the human molecule homologous to the murine heat-stable antigen (HSA). HSA is expressed by murine keratinocytes and delivers costimulatory signals in T-cell activation. Long-term cultures of normal human keratinocytes (HKC) were obtained from skin of human female breast sections and either left untreated or were treated with phorbol-12-myristate-13-acetate (PMA) at 10-100 ng/ml, calcium 0.5-2 mM or IFN-gamma 100-1000 U/ml, for 24-48 h. Using RT-PCR and flow cytometry we showed that HKC express low levels of CD24 even under basal conditions, and the treatment with calcium, PMA or IFN-gamma increased levels of CD24 mRNA and protein. To the best of our knowledge, this is the first report to measure CD24 expression and production by cultured HKC in basal conditions and after stimulation. Further studies are needed to determine biological and therapeutical relevance of these findings.

Antigens, CD↗
PubMed1997

Patterns of failure and long-term results in high-risk resected gastric cancer treated with postoperative radiotherapy with or without intraoperative electron boost.

BACKGROUND: To evaluate the possible role of adjuvant radiotherapy in the management of high-risk resected gastric carcinoma. METHODS: From 1982 to 1993, 62 patients surgically resected of a primary gastric cancer with adverse pathological features (serosal and/or regional lymph node involvement) were treated with postoperative radiotherapy with (Group I) or without (Group II) intraoperative electron boost to the surgical bed and coeliac axis (IORT). RESULTS: After a median follow-up of 75.6 months (range 4-120+) for IORT patients and 91.2 months (range 6-149+) for non-IORT patients, overall relapse rates for Group I and Group II patients were 44.5% and 48.6% and local-regional relapse rates were 11.1% and 20%, respectively. Actuarial survival rates projected at the maximum follow-up were 41% and 38% in Groups I and II, respectively. CONCLUSIONS: This retrospective analysis suggests a beneficial effect of adjuvant external radiotherapy in promoting local-regional control in high-risk resected gastric cancer.

Adult↗