Biomedical subjects

E Villafranca

Publications and source records attributed to E Villafranca.

16 recordsLinked to original sources

PubMed2004

[Neutropenia and fever in the patient with cancer].

Infection in the immunocompromised host is a serious clinical situation due to its high morbi-mortality and is one of the most frequent complications in the patient with cancer. In patients treated with chemotherapy, the risk of infection basically depends on the duration and intensity of the neutropenia. It is essential to evaluate, the most probable pathogen involved to initiate, a priori, the most suitable treatment, and also to evaluate the general clinical situation of the patient, because from the very beginning the treatment is quite aggressive. Outpatient care is possible for patients at "low risk" of complications. By evaluating the antecedents and clinical history of the patient, through physical exploration and from the data of laboratory and radiological explorations these points can be acknowledged. The early start of broad spectrum antibiotherapy is crucial, and in this chapter we review the most recent therapeutical recommendations.

Clinical Protocols↗

PubMed2004

[Malign obstruction of the superior vena cava].

The present paper offers a review of the malign syndromes of the superior vena cava, their clinical expressions related to the anatomical characteristics of the compartment where the superior vena cava runs, the diagnostic requirements for realising treatment under the best conditions and the ensemble of measures that must be adopted in dealing with this.

Humans↗

PubMed2004

[Acute dysphagia of oncological origin. Therapeutic management].

Dysphagia is one of the most frequent syndromes in patients with tumours of the head and neck, and the oesophagus. This can be the initial symptom or, more frequently, related to the oncological treatment. We review the most important therapeutic and physio-pathological aspects of acute dysphagia of oncological origin. Deglutition is a complex process in which numerous muscular-skeletal structures intervene under the neurological control of different cranial nerves. The complex neuro-muscular coordination needed for a correct deglutition can be affected by numerous situations, both from the effect of the tumours and from their treatment, basically surgery or radiotherapy. In conclusion, it can be affirmed that for a suitable treatment of oncological dysphagia, a correct initial evaluation and an active treatment are required, since not only the patient's quality of life but, on numerous occasions, the possibility of continuing the treatment and thus maintaining the possibilities of a cure depend on control of the dysphagia.

Acute Disease↗

PubMed2004

[Emergency treatment of urological complications in cancer patients].

Patients affected by neoplastic diseases frequently come for consultation to the emergency services of our hospitals. A large part of these consultations occur due to complications of an urological type, whatever the origin of the tumour that the patient presents. The pathology can be secondary to the neoplasy or to the means used in its treatment, although they are often complications that appear independently of the course of the disease. We offer an outline of the most frequent causes of emergency consultation due to urological problems in the patient affected by neoplastic diseases, whether they are in the urogential apparatus or not. We comment especially on the initial study and treatment by the emergency doctor or by the oncologist.

Emergency Treatment↗

PubMed2004

[Metastatic bone disease. Diagnosis and treatment].

The high incidence of bone metastasis secondary to carcinomas and its serious functional repercussion are motives for constant study and advance in the methods of evaluation, diagnosis and treatment. Pain is the most frequently shown symptom, although at times the start is a pathological fracture. The classic tests of detection and evaluation of the spread of the metastatic disease, simple radiology and gammagraphy, are today complemented by others such as computerised tomography (CT) and magnetic resonance (MR), improving the information on the characteristics of the lesion both inside and outside the bone. On the other hand, positron emission tomography (PET) is showing a far higher sensitivity than gammagraphy and will probably be the test of the future for the early detection of metastasis and of silent primary tumours. The possibilities of treatment of bone metastasis are based on the use of bone regenerators, radiotherapy and surgery. The former two are indicated in lesions already detected in radiography, whether symptomatic or not, if there is no foreseeable risk of fracture. Surgery is indicated in situations of poor or null response to those treatments, when the risk of fracture is high or a pathological fracture has been produced. Before any therapeutic planning, a detailed evaluation of the patient must be carried out, both at a local level (size, site, extension of the metastasis) and general (type of primary tumour, phase of treatment and response, estimated survival).

Bone Neoplasms↗

PubMed2004

[Medullar compression].

Medullar compression is an oncological and neurological emergency, whose diagnosis and early treatment are key factors for avoiding severe and irreversible neurological damage. Paralysis, loss of consciousness and alteration in control of the sphincters are the final consequence of the process, and represent an important source of morbidity of the oncology patient, besides being related to a shorter time of survival. The invasion of the vertebral body by haematogenous dissemination is the most frequent cause of medullar compression. On occasions it can create mechanical vertebral instability which represents a real orthopaedic emergency. Pain is the earliest and most frequent symptom. The signs and symptoms appear to the degree that the process advances, passing through motor weakness, alterations in consciousness until paralysis and incontinence of the sphincters are reached, as a result of complete neurological damage. Clinical history and physical exploration should lead to suspicion about the level at which medullar compression is developing, and the most important complementary exploration is MR of the entire spine, which should be requested immediately in order to decide on starting treatment. Treatment is individualised and must be started early. In general, corticoids in combination with radiotherapeutic oncological treatment and/or surgery are the therapeutic weapons to employ.

Humans↗

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↗

PubMed1998

Two-site interaction of nuclear factor of activated T cells with activated calcineurin.

Transcription factors belonging to the nuclear factor of activated T cells (NFAT) family regulate the expression of cytokine genes and other inducible genes during the immune response. The functions of NFAT proteins are directly controlled by the calcium- and calmodulin-dependent phosphatase calcineurin. Here we show that the binding of calcineurin to NFAT is substantially increased when calcineurin is activated with calmodulin and calcium. FK506.FKBP12 drug-immunophilin complexes inhibited the interaction of NFAT with activated calcineurin much more effectively than they inhibited the interaction with inactive calcineurin, suggesting that part of the interaction with activated calcineurin involved the enzyme active site. We have previously shown that NFAT is targeted to inactive calcineurin at a region distinct from the calcineurin active site (Aramburu, J., Garcia-Cozar, F. J., Raghavan, A., Okamura, H., Rao, A., and Hogan, P. G. (1998) Mol. Cell 1, 627-637); this region is also involved in NFAT binding to activated calcineurin, since binding is inhibited by an NFAT peptide spanning the calcineurin docking site on NFAT. The interacting surfaces are located on the catalytic domain of the calcineurin A chain and on an 86-amino acid fragment of the NFAT regulatory domain. NFAT binding to the calcineurin catalytic domain was inhibited by the calcineurin autoinhibitory domain and the RII substrate peptide, which bind in the calcineurin active site, as well as by the NFAT docking site peptide, which binds to a region of calcineurin distinct from the active site. We propose that, in resting cells, NFAT is targeted to a region of the calcineurin catalytic domain that does not overlap the calcineurin active site. Upon cell activation, displacement of the autoinhibitory domain by calmodulin binding allows NFAT to bind additionally to the calcineurin active site, thus positioning NFAT for immediate dephosphorylation at functional phosphoserine residues.

Amino Acid Sequence↗

PubMed1998

[Conservative treatment of microcytic carcinoma of the bladder; report of a new case].

OBJECTIVE: To report an additional case of small cell carcinoma treated conservatively. METHODS: Herein we describe a case of small cell carcinoma of the bladder that had been treated conservatively because of the age of the patient. The specific characteristics of the case are described and the clinical and pathological aspects of the disease are briefly reviewed. RESULTS/CONCLUSION: Although treatment of this disease is primarily by cystectomy followed by chemo and radiotherapy, organ-sparing neoadjuvant chemo and radiotherapy as an alternative to surgery could be attempted to obtain complete remission in selected patients.

Aged↗

PubMed1997

Radical chemoradiotherapy for elderly patients with bladder carcinoma invading muscle.

BACKGROUND: Chemoradiotherapy is becoming an alternative to radical cystectomy among patients with bladder carcinoma invading muscle. In 1988, the authors began a protocol with methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC regimen) and radiotherapy for these patients. Traditionally, age has been considered a determinant factor thereby excluding the older patients from the oncologic protocols that are considered to be more aggressive. The authors analyzed 20 patients (age > 70 years) who were treated during this period with the same protocol as the authors' other patients. METHODS: The study included 20 patients (age range, 70-78 years; median age, 74 years) including 4 patients with T2 disease, 9 with T3 disease, and 7 with T4 disease. All patients had a Karnofsky performance status of > 60. Treatment protocol included cytoreductive transurethral resection, 2 cycles of M-VAC chemotherapy, and radiotherapy (45 grays [Gy] on pelvic volume) with concurrent cisplatin (20 mg/m2 on Days 1-5. Response was determined by cystoscopic evaluation. If there was a complete response, radiotherapy continued until a total dose of 65 Gy; if there was not a complete response, cystectomy was performed. RESULTS: Tumor response after a dose of 45 Gy included 11 complete responses (55%), 5 partial responses (25%), and 4 nonresponses (20%). Overall survival was 75%, 34%, and 27% in the 2nd, 3rd, and 5th years of follow-up, respectively. Cause specific survival was 79%, 54%, and 38%, respectively. Survival for patients with complete response was 100%, 60%, and 48%, respectively. Severe toxicity was uncommon, with the most frequent toxicities being leukopenia and cystitis. No treatment-related death occurred with either treatment protocol. CONCLUSIONS: The age of the individual must not become a strict exclusion criterion for the radical treatment of old patients with invasive bladder carcinoma.

Aged↗

PubMed1995

Inhibition of Ras/Raf interaction by anti-oncogenic mutants of neurofibromin, the neurofibromatosis type 1 (NF1) gene product, in cell-free systems.

The neurofibromatosis type 1 (NF1) gene encodes a protein, neurofibromin, containing GTPase-activating protein-related domain (GRD) that stimulates intrinsic GTPase activity of Ras protein. By screening a randomly mutagenized NF1-GRD library in Saccharomyces cerevisiae, we isolated two NF1-GRD mutants (NF201 and NF204) with single amino acid substitutions, which suppress the heat shock-sensitive phenotype of the RAS2(G19V) mutant. The NF1-GRD mutants also suppress the oncogenic Ras-induced transformation of NIH 3T3 mouse fibroblasts (Nakafuku, M., Nagamine, M., Ohtoshi, A., Tanaka, K., Toh-e, A., and Kaziro, Y. (1993) Proc. Natl. Acad. Sci. U.S.A. 90, 6706-6710). In this paper, we investigated the molecular mechanism of inhibition of the transforming Ras-specific function by the NF1-GRD mutants in mammalian cells. In human embryonic kidney (HEK) 293 cells, the mutant NF1-GRDs attenuated the stimulation of mitogen-activated protein kinase by Ras(G12V), but not by platelet-derived growth factor. In cell-free systems, purified recombinant NF1-GRD mutants showed an inhibitory effect on the association of Ras.guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) with Raf at several times lower concentrations than the wild type. Furthermore, it was revealed that the binding affinity of the mutant NF1-GRDs toward Ras.GTP gamma S is approximately 5-10 times higher than the wild type. These results suggest that the mutant NF1-GRDs tightly bind to an oncogenic Ras in its GTP-bound active conformation and block the interaction between Ras and its effector, Raf.

3T3 Cells↗

PubMed1995

Split hyperfractionated accelerated radiation therapy and concomitant cisplatin for locally advanced head and neck carcinomas: a preliminary report.

PURPOSE: The feasibility and activity of an intensive chemoradiotherapeutic scheme for patients with locally advanced squamous cell head and neck cancers were tested in a single institution Phase II pilot study. METHODS AND MATERIALS: Between January 1990 and February 1992, 40 patients were entered into this trial. The treatment protocol consisted of split hyperfractionated accelerated radiation therapy (SHART), 1.6 Gy per fraction given twice per day to a total dose of 64-67.2 Gy for a total of 6 weeks with a 2-week gap, and cisplatin (20 mg/sqm/Days 1 to 5, in continuous perfusion) concomitantly. RESULTS: All of the 40 patients are evaluable for response and survival. Toxicity was significant, but tolerable. A complete tumor response to this treatment was achieved by 37 patients (92.5%). With a minimal follow-up of 22 months (median 30 months) there have been 16 local relapses and 19 patients have died, 2 without tumor. The projected 2- and 3-year overall survival rates are 64% (confidence interval (CI) 95%, 49-79%) and 47%, respectively. The 2-year local control probability has been 56% (CI 95%, 39-73%). CONCLUSION: This treatment obtains a high rate of complete responses with increased acute toxicity but tolerable late effects. Preliminary results are encouraging for laryngeal neoplasms. A longer follow-up is needed to evaluate the impact of this treatment on patient survival.

Adult↗

PubMed1995

Different structural requirements within the switch II region of the Ras protein for interactions with specific downstream targets.

Ras proteins function through the formation of specific complexes with Raf-1, B-raf, PI-3 kinase and RalGDS. These interactions all require Ras-GTP with an intact effector binding domain (Switch I region). We have examined the requirements of the Switch II region (amino acids 60-72) for the production of stable interactions between Ras and its downstream effectors. A point mutation at position 65 or 64 combined with additional mutations at either position 65 or 71 rendered nucleotide-free Ras protein unable to stably interact with Ras specific guanine nucleotide exchange factors. Ha-Ras containing point mutations at positions 65 and 71 possessed a twofold higher affinity for B-raf and consequently MEK1. The point mutation at 64, in combination with additional point mutations at either position 65 or 71, resulted in a protein which failed to interact with either PI-3 kinase or neurofibromin, though these Ras mutants effectively bound both Raf-1 and B-raf. An activated form of Ras, Q61L-Ras, associated with all effector proteins independent of the bound guanine nucleotide. Q61L-Ras-GDP was almost as effective as wild type Ras-GMPPNP in the in vitro activation of MEK1 and MAP kinase. Competitive studies with the catalytic domain if neurofibromin, NF1-GRD, demonstrated that its interaction with Ras-GMPPNP is mutually exclusive with both Raf-1 and B-raf. These data suggest that rasGAP and neurofibromin are unable to downregulate Ras-GTP complexed to Raf-1 or B-raf.

Amino Acid Sequence↗

PubMed1994

Mutations that abolish the ability of Ha-Ras to associate with Raf-1.

Recent studies have revealed that Ras can associate physically with Raf. In the present study, we tested 34 mutants of Ha-Ras carrying substitution(s) in the region of residues 23-71 for their ability to associate with Raf-1. Mouse Ba/F3 cell lysates were incubated with each mutant Ras protein, in either the guanosine 5'-[gamma-thio]triphosphate (GTP gamma S)- or the guanosine 5'-[beta-thio]diphosphate (GDP beta S)-bound form, and the anti-Ras antibody Y13-238. The immunoprecipitates were analysed for the presence of Raf-1 by Western blotting with an anti-Raf-1 antibody. Six mutants of Ras, E31K, P34G, T35S, D38N, D57A and A59T, failed to bind Raf-1. Mutations N26G, V29A, S39A, Y40W, R41A, V44A, V45E, L56A and T58A partially reduced the ability to bind Raf-1. All the other mutants could associate with Raf-1 with nearly the same efficiency as that of wild-type Ras. Thus, the Raf-I-binding ability of Ras appears to be affected by mutations in the N-terminal region, and in particular, by those in and neighboring the effector region (residues 32-40) and in the region (residues 56-59) flanking the N-terminal of Switch II. The abilities to bind Raf-1 and to induce neurite outgrowth of pheochromocytoma (PC) 12 cells correlate to each other for 22 Ras mutants. However, mutation A59T, which does not reduce the neurite-inducing or transforming activities, abolishes the ability to bind Raf-1. In contrast, mutations Y32F, K42A and L53A, which impair the neurite-inducing activity of Ras, have no effect on the Ras.Raf-1 association. Partially reduced Raf-1-binding ability was observed for mutants V29A, S39A, Y40W, R41A, V44A, L56A and T58A, which exhibit full neurite-inducing activity, and also for mutant V45E, which has no activity of neurite induction.

Animals↗

PubMedDate not supplied

[Quality of Life of cancer patients: studies by the Oncology Department of the Hospital of Navarra in the Quality of Life Group of the EORTC].

The Quality of Life of cancer patients and its assessment are of great important nowadays. They are useful in offering a treatment that is better adapted to the characteristics of the patient and the development of his/her illness. Patients have to evaluate their Quality of Life through measurement instruments. The European Organisation of Research and Treatment of Cancer-EORTC is an international body devoted to research in cancer treatment. One of its divisions is working on the study of the Quality of Life. They have developed a core questionnaire for Quality of Life measurement and modules for different types of tumour and treatment to complement this. The Oncology Department of the Hospital of Navarra has been collaborating in this group since 1992. The Department has participated in the creation or validation of the core questionnaire and different modules. It is measuring the Quality of Life in different clinical studies. All members of the department are collaborating in these studies.

English Abstract↗

PubMedDate not supplied

[Effect of PSA nadir and the time to nadir in the disease-free period in localized prostatic carcinoma treated with radical radiation].

OBJECTIVE: To evaluate the prognostic significance of PSA nadir (nPSA) and the time to nadir in disease free of recurrence (DFR) in localized carcinoma of prostate treated with radical radiotherapy (RTR). MATERIAL AND METHODS: From October 1984 to December 1998, 86 patients have been treated with prostate carcinoma. It was considered of Low risk those patients with PSA < or = 10 ng/ml, Gleason = 6 or stage T1-T2. Moderate risk: those with one elevated of the three parameters. High risk: two or more parameters. The treatment was carried out in a lineal accelerator using photons of 15 MV, with standard technique and frationation, administering a median dose of 66 Gy (58-75 Gy). It was defined disease free of recurrence (DFR), the time to clinical PSA or biochemical failure. This one was defined as the time starting from the date of nadir PSA to the second consecutive increase of PSA value after three separate serial measurements separated for at least one month. RESULTS: The median of initial PSA value was of 16 ng/ml (1-270), initial clinical stage T1-T2 (70p), stages T3-T4 (14p), and unknown in 2p. The median of Gleason score was 6 (2-10). According to the group of risk they were classified as: low risk in 16 patients (19%), moderated risk in 22 patients (26%), high risk in 21 patients (24%), and unknown in 27 patients (31%). Median nPSA value was 0.8 ng/ml (limits: 0-139) and the median time elapsed between the initial PSA and nPSA has been of 11 months (limits: 0-72 months). The actuarial DFR projected to five years in those patients with nPSA = 1 ng/ml was of 67% vs. 47% in patient with nPSA figures > 1 ng/ml (p = 0.0018). The PFD in patients with time to nadir (t nadir) < 12 months it was of 20% vs. 80% in patients with t nadir > 12 months (p < 0.0001). Multivariate analysis demonstrated that time to nadir (H.R: 0.11 p = 0.001), group of risk (H.R: 28.72 p = 0.020), and grade of differentiation (HR: 28.72 p = 0.010), were determinant to DFR. CONCLUSIONS: nPSA is an important factor to determine the objective response to radiotherapy. nPSA and time to nadir are prognostic factors that influences significantly on the DFR. The indication of adjuvant treatment in those patients with unfavorable prognostic factors such us those who do not reach nadir PSA < or = 1 ng/ml and time to nadir < or = 12 months, deserves the realization of a prospective study.

Aged↗