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Study Type: Therapy (case series) Level of Evidence 4., Objective: To report our analysis of the oncological outcome, side-effects and complications after (125)I-brachytherapy, based on 10 years of experience, as low dose-rate (LDR) prostate brachytherapy is an accepted, effective and safe therapy for localized prostate cancer., Patients and Methods: Between April 1999 and December 2006, 734 consecutive patients were treated with clinically localized prostate cancer with a follow-up of >or=30 months. No patients received external beam radiotherapy and 43% received hormonal therapy before brachytherapy; this therapy was given for 3-4 months. All patients had LDR prostate brachytherapy administered by one radiation oncologist. Biochemical failure was defined according to the 'Phoenix consensus'., Results: The median follow-up for the 734 patients was 55 months; 26 had a clinical relapse and 11 died from prostate cancer; 20 patients died from other illnesses. The 10-year actuarial biochemical control was 92%, 84% and 65%, respectively (P < 0.001) for the low-, intermediate- and high-risk groups. Multivariate Cox regression analyses identified Gleason score and prostate-specific antigen (PSA) level as independent prognostic factors for biochemical failure. The actuarial biochemical control with Gleason score was 88%, 76% and 67% for patients with a Gleason score of 7, respectively (P < 0.001). The biochemical control was 90%, 80% and 42% for patients with a PSA level of 20 ng/mL, respectively (P < 0.001). No patients reported incontinence after treatment. There was acute urinary retention in 22 (2.9%) patients. Logistic regression showed that the most significant factors correlating with the probability of catheterization were the pretreatment prostate volume and hormonal therapy., Conclusions: The excellent long-term results and low morbidity, and the many advantages of prostate brachytherapy over other treatments, show that brachytherapy is an effective treatment for clinically organ-confined prostate cancer.

In the familial form of papillary thyroid cancer (PTC), two or more members of the same family have to be affected with PTC. Prevalence is around 5% of all PTC. We performed a clinical analysis in 79 relatives of 16 patients of 7 unrelated kindred with the diagnosis of familial papillary thyroid carcinoma (FPTC). The results were compared with a control group. Thyroid palpation and TSH and TPO-Ab assessment was carried out in the relatives without a diagnosed PTC. Additionally, molecular analysis was performed in the sixteen affected patients. Clinical screening of the 79 family members showed the presence of goiter in 22/79 (29 %). This frequency was much higher than that observed in the control group (8.7%), p < 0.001. Hypothyroidism was found in 4 of the relatives (5%) vs. 2.5% observed in the control group, p < 0.01, and anti-thyroid antibodies (TPO-Ab) were positive in 14% of the relative's group vs. 10 % in the control group, (p = NS). In the molecular analysis, only a protooncogene TRK rearrangement was observed in family # 6. In conclusion, we found a higher incidence of goiter and hypothyroidism in the relatives of patients with FPTC. Nevertheless, TPO-Ab frequency was not different. No molecular abnormalities were indicative of a specific pattern in this subset of patients with FPTC.

Objective: Low dose rate (LDR) prostate brachytherapy (permanent 125I or 103Pd seeds) is an accepted treatment option for low risk prostate cancer patients. However, differences in prostate spatial location, volume and gland deformation between the images obtained during pre-planning and later on during the implant procedure prevent the pre-planned intended dose to be accurately delivered. We are reporting on a new technique based on interactive real-time dynamic intra-operative dose calculation with avoidance of postimplant CT for final dosimetry. The reasons leading us to implementing this new technique are discussed and preliminary results reported. 47-78 years). For the real time intra-operative dosimetric analysis the following values were obtained: a median of 98% (90%-100%) for V90, of 60% (22%-76%) for V150 and 24% (9%-34%) for V200. The median intro-operative D90 obtained was 16,817 cGy with a range of 13,743 to 19,553 cGy. The median dose point calculation to the rectum maximum was 12,936 cGy and for the maximum in urethra was 21,880 cGy. For the real-time dynamic planning, the acute GU grade 1&2 toxicity was reduced from 28% and 2 1% to 16% and 6% respectively. Acute urinary retention was seen in 2/63 or 3% requiring a temporary post-implant bladder catheter. In addition, a decrease in chronic GU grade 1-2 toxicity was also seen from 16% and 17% to 1 1% and 2% respectively. No change in GI toxicity pattern was noted. No severe grade 3-4 intra-operative complications were noted., Conclusion: Real-time intra-operative planning was successfully implemented in our center. It avoids the possible implant quality and dose delivery disadvantages of the standard post-implant CT-based dosimetry by improving the accuracy of seed placement on real time, which was translated in lower rates of acute and chronic GU morbidity. In addition, avoids the unnecessary time, effort and cost of post-implant CT-based dosimetry.

Two types of vulvar squamous cell carcinomas (VSCCs) are recognized according to their relationship to human papillomavirus (HPV). Basaloid or warty carcinomas are considered HPV-associated tumors, whereas differentiated keratinizing neoplasms are considered non-HPV-associated. Recently, immunohistochemical detection of p16 and p53 has been proposed to differentiate these 2 types of VSCCs. We conducted a histologic study with immunohistochemical evaluation of p16 and p53 and HPV detection and typing by polymerase chain reaction using 2 different sets of primers in 92 cases of VSCCs to evaluate the usefulness of immunohistochemistry in the classification of VSCCs and to describe the clinico-pathologic characteristics of both types of VSCCs. HPV was detected in 16/92 (17.4%) specimens, HPV16 being identified in 75% of positive cases. A significant number of discrepancies between histology and HPV detection were observed, with 37.5% of HPV-positive tumors being keratinizing and 9.2% of HPV-negative carcinomas showing basaloid or warty features. Diffuse positivity for p16 and p53 was observed in 100% and 6.2% of HPV-positive tumors and in 2.3% and 64.5% of HPV-negative neoplasms, respectively. The sensitivity and specificity of p16 immunostaining to detect HPV-associated carcinomas (100% and 98.7%, respectively) were better than those of histologic criteria (93.8% and 35.5%) and of p53 negative stain (62.5% and 93.4%). Vulvar intraepithelial neoplasia grade 3 of basaloid/warty type was identified in 53.8% HPV-positive tumors, including 3 keratinizing tumors. All these cases were p16 positive and p53 negative. Vulvar intraepithelial neoplasia grade 3 of differentiated type was observed in 45.6% of HPV-negative cases; 90.8% of them were positive for p53 but all were negative for p16. No differences in age, stage, or development of recurrence were observed between HPV-positive and negative tumors. In summary, the current morphologic criteria to discriminate HPV-positive and negative VSCCs have a significant overlap. Immunostaining for p16 is a reliable marker for HPV-positive VSSCs, which improves the results of histologic classification.

Most autonomous functioning thyroid nodules (AFTN) are benign thyroid follicular neoplasms. There are rare reports of malignant hot nodules, in which activating mutations of the TSH receptor (TSHR) were found. We report a case of follicular carcinoma presenting as an AFTN causing subclinical hyperthyroidism in a 64-year-old woman who had a 6-cm hot nodule in the left thyroid lobe. Genomic DNA was extracted from paraffin-embedded tissues from the tumor and extratumoral thyroid tissue. Sequence analyses revealed point mutations in two different genes: the normal ACC sequence at codon 620 of the TSHR gene was replaced by ATC, changing the threonine by isoleucine (T620I); and the wild-type GGT at codon 12 of Ki-RAS mutated to TGT, replacing glycine by cysteine (G12C). In transfection experiments the T620I mutant showed constitutive activity in terms of cyclic adenosine monophosphate (cAMP) production when permanently transfected in 3T3 cells. Here, we describe for the first time an activating mutation in 3codon 620 of the TSHR. In addition, the cancerous AFTN also contained a G12C Ki-RAS mutation. We hypothesize that the combination of these two mutations might have played an important role in both the hyperfunction of the tumor and the carcinogenetic process.

Our aim in this study was to assess postural control adaptation quantitatively in unsteady elderly patients at risk of falls in open spaces and given balance training with a virtual-reality system reproducing environmental stimulation. Using a balance rehabilitation unit based on a virtual-reality system that changes sensory information (visual, vestibular, and somatosensory), we treated 26 elderly, unsteady patients who were prone to falling (age range, 73-82 years) and who were enrolled in a customized vestibular rehabilitation program. We assessed postural responses by posturography before and after 6 weeks in the vestibular rehabilitation program under two conditions: (1) standing, eyes open, static visual field, and (2) standing, eyes open, dynamic visual field through virtual-reality goggles, generating horizontal optokinetic stimulation (70 degrees per second angular velocity). We recorded postural responses with a platform measuring the confidential ellipse of the center-of-pressure distribution area and sway velocity with a scalogram analyzing postural behavior by wavelets. After 6 weeks of treatment, postural response confidential ellipse and sway velocity values were lower, evincing decreased amplitudes and sway frequency contents in the scalogram by wavelet under both stimulation paradigm conditions. These findings suggest postural adaptation under the two perceptual conditions when patients had static and dynamic visual fields. The possibility of treating elderly fallers with balance disorders using a virtual-reality environmental stimulation reproduction system is discussed.

Introduction: Although the nervous system is highly resistant to radiations, some cases have been reported about adverse effects of radiotherapy on patients with brain tumors. The following delayed effects have been observed: coagulation necrosis of all the cellular elements, fibrinoid and hyaline changes on the walls of the neoformed blood vessels, together with endothelial proliferation and perivascular fibrosis, reactive astrocytes, some of them with bizarre nuclei, as well as telangiectasia, hemorrhage and hemorrhagic infarcts. Telangiectasia and associated hemorrhage may occur in any of the irradiated zones of the brain., Clinical Case: The present case is an example in which the indication of radiotherapy was due to an anatomopathological overdiagnosis. The first biopsy was diagnosed as a grade II cerebellar astrocytoma, after which 20 radiotherapy sessions were indicated. Nine years after that, a second operation was performed. This second biopsy revealed areas of fibrosis, hemorrhages, calcifications, necrosis, and thick hyaline-walled blood vessels. No tumor infiltration was observed. After an unfavorable evolution, the patient died. The microscopical study of the autopsy material revealed an area of neoplastic infiltration which was well defined as a pylocitic astrocytoma of the cerebellum. The rest of the cerebellum sections evidenced damage corresponding to an adverse effect of radiotherapy, particularly large zones of telangiectasia., Conclusions: It is stated that the patient s death was not because of the tumor. The adverse effects of radiotherapy, interpreted as tumor remains, motivated the second operation that generated complications causing the patient s death.

Introduction: Gliomas make up approximately 50% of the primary brain tumors of the central nervous system in adults. Astrocytes from between 70 and 75% of these tumors. Historically grading these has been very controversial, in spite of its importance for prognosis and planning treatment., Development: We have reviewed existing proposals for the classification of astroglial neoplasias, from the initial studies to the latest classification by the World Health Organization. All have pursued the objective of finding the histopathological grade of the neoplasm to relate it to survival and predict prognosis., Conclusion: Further knowledge of these tumors is the aim of professionals and others interested in the subject, in the difficult course of finding better and more efficient treatment for these patients.

Human epithelial thyroid radiation-induced tumorigenesis is the most frequent radiation-induced tumorigenic process in man. Results of different studies, concerning the molecular mecanism(s) of epithelial thyroid radiation-associated tumorigenesis show : 1) that there is not a significant difference in the frequency of activation of ras, gsp and trk proto-oncogenes between radiation-associated and <> thyroid tumors; 2) the relevant role played by RET/PTC ret proto-oncogene activating rearrangements, in the development of radiation-associated thyroid tumors originated after therapeutic radiation (mainly PTC 1) or the atomic accident of Chernobyl (mainly PTC 3) and 3) suggest that the patients who develop thyroid tumors after a history of irradiation, show a genomic instability consisting in a DNA repair defect.

A high frequency (approximately 60%) of ret rearrangements in Chernobyl papillary thyroid carcinomas (PTC) has been reported recently. The data suggested that the radiation exposure may be a direct inducer of activating rearrangements in the ret gene. In our study, we have analyzed for the presence of RET/PTC oncogenes using the RT-PCR, XL-PCR, Southern blot and direct sequencing techniques, 39 human thyroid tumors from patients who had received external radiation for benign or malignant conditions. As controls, we studied 39 'spontaneous' tumors. Our results indicate that: 1) the overall frequency of ret rearrangements was 84% in papillary carcinomas (16/19) and 45% (9/20) in follicular adenomas; 2) in contrast with the results obtained in the Chernobyl tumors, the most frequently observed chimeric gene was RET/PTC1; and 3) all the tumors were negative for RET/PTC2. In the 'spontaneous' tumors, only the papillary carcinomas presented a ret rearrangement (15%: 3/20). Our data confirm the crucial role played by the ret proto-oncogene activating rearrangements in the development of radiation-associated thyroid tumors, and show, for the first time, the presence of RET/PTC genes in follicular adenomas appeared after external irradiation.

A rearranged tpr-met oncogene was identified in a MNNG-transformed human Xeroderma pigmentosum (XP) cell line (ASKMN). A 2016 bp cDNA was cloned and sequenced, disclosing an ORF with a coding capacity for a 523 aa protein. The sequence of this tpr-met cDNA was very similar to that previously reported in another human MNNG-transformed cell line (MNNG-HOS).

A series of 14 thyroid carcinomas, characterized for their basal adenyl cyclase activity (ACA), was examined for the presence of activating point mutations in the TSH receptor (TSHR) gene. Sequencing of the carboxyl-part of this gene revealed the presence of a somatic and heterozygotic point mutation in codon 623 in three out of six tumors showing a constitutively enhanced ACA and a poor response to TSH stimulation. The mutation determines the substitution of a serine for an alanine in the third intracellular loop of the receptor, in a region critical for signal transduction. One tumor bearing a TSHR mutation presented also a N-ras point mutation. Both mutations were detected also in a lung metastasis of this tumor. Our data represent the first report of alterations in the TSHR gene in thyroid malign neoplasia. TSHR mutations may indeed participate, as well as the G alpha s protein (gsp oncogene), in the oncogenesis of some differentiated thyroid carcinomas presenting increased basal levels of cAMP and a poor response to TSH.

The preferential activation of the Ki-ras oncogene in follicular radiation-associated human thyroid carcinomas, has been suggested by Wright et al. (1991). However, only 12 thyroid tumors were analysed in this study. In order to confirm if radiation favours, in human thyroid tumorigenesis, the appearance of a particular molecular lesion, we studied 33 benign and malignant human radiation-associated thyroid tumors. We used polymerase chain reaction (PCR) amplification and allele-specific hybridization with mutant-specific probes for the three ras genes and the gsp oncogene. Compared to 85 'spontaneous' human thyroid tumors, the radiation-associated cases: (1) show a similar overall frequency of ras and gsp mutations (about 30% and 6% respectively); (2) present a similar frequency of mutation of the three ras genes without any predominance in adenomas and papillary carcinomas and (3) all Ki-ras mutations were found in papillary carcinomas (4/15). ras and gsp genes were never found mutated simultaneously, suggesting an alternative role for both oncogenes in the thyroid tumorigenic radiation-associated process.

Human xeroderma pigmentosum (XP) fibroblasts were transformed with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). The transformed cells, called ASKMN, were immortalized, grew in agar and were tumorigenic in nude mice. A trp-met oncogene was identified in ASKMN cells, after transfection of high molecular weight DNA on 3T3 mouse cells. The ASKMN cells and the 3T3 transformants expressed the 5-kb mRNA transcribed by the tpr-met oncogene and its p65tpr-met phosphorylated protein. Using the polymerase chain reaction (PCR) technique followed by hybridization with synthetic probes or direct sequencing, we showed that the sequence encompassing the 'rearranged breakpoint' was the same as that previously described in the tpr-met oncogene present in the MNNG-HOS cells. However, G to A transitions found in the tpr or met sequences of the ASKMN oncogene, probably the result of the specific mutagenic activity of MNNG, were absent in the MNNG-HOS gene. Apparently normal chromosomes 1 and 7 were identified in the ASKMN cell metaphases using several cytogenetic techniques.

The prevalences of Entamoeba histolytica and other intestinal parasites were assessed in a suburban community of Maracaibo, Venezuela, by examination of a stool specimen from each of 342 individuals, using iron-haematoxylin stained faecal smears and formalin-ether concentration. The overall parasitic infection rate was 80.4%, and 65.8% of the population had multiple infections. The overall amoebic infection rate, which was highest in female adults, averaged 39.7%. The E. histolytica infection rate was 8.7% and most of those infected were passing cysts. Entamoeba polecki was observed in two samples. Amongst the protozoa, Entamoeba coli was observed most frequently (24.8%) and Giardia lamblia was the predominant pathogen (13.0%). Trichuris trichiura (71.9%) and Ascaris lumbricoides (54%) were the most common parasites, particularly in school-children. The high rates of parasitic and multiple infections reflect the low socio-economic status of the community studied.

Disorders in vestibulo-ocular functions were studied in 4 patients with olivo-ponto-cerebellar atrophy (OPCA). The phenomenon of habituation, considered as a plastic property of the vestibulo-ocular reflex (VOR), was explored with a behavioural paradigm in these patients. When subjected to the habituation paradigm all patients presented a modified response opposite to that observed in normal subjects. The role played by the cerebellum in relation to VOR plasticity--well known in different experimental models--is analyzed. The hypothesis of a modification of the cerebellum's inhibitory action on vestibular nuclei neurons is put forward to explain the inversion of the VOR habituation phenomenon in these patients.

Human Xeroderma pigmentosum "normal" fibroblasts AS16 (XP4 VI) were transformed after transfection with a recombinant v-myb clone. In this clone (pKXA 3457) derived from avian myeloblastosis virus (AMV), the expression of the oncogene sequences is driven by the AMV U-5 LTR promoter. The transformed cells (ASKXA), which have integrated a rearranged v-myb oncogene, grow in agar, are not tumorigenic in nude mice, and express a 45-kDa v-myb protein. The HMW DNA of these cells transform chicken embryo fibroblasts. The c-Ha-ras oncogene is overexpressed in the ASKXA cells but not in the parental "normal" AS16 cells and a revertant clone (ASKXA Cl 1.1 G). Our results lead to the conclusion that the XP fibroblasts are phenotypically transformed by the presence of the transfected v-myb oncogene, which is able to induce an overexpression of the c-Ha-ras gene.

A study of cases of patients with diagnosis of traumatic arthritis of the temporomandibular joint, assisted at the Department of Maxillo-facial Surgery, was carried out in order to value benefits obtained with a multidisciplinary attention in such cases.

The production of virions by Chinese hamster kidney cells infected with SV 40 DNA is increased 10 to 100 fold by mitomycin C treatment. This observation has been confirmed for different cell clones. The optimum concentration of mitomycin C has been determined.

The search for the genetic targets responsible for tumorigenesis has led to the identification of a number of cancer genes or cellular oncogenes (c-oncogenes). The oncogenes are activated forms of the proto-oncogenes, which are normal cellular genes and are scattered throughout the cellular genome. The number of known cellular proto-oncogenes and associated oncogenes now exceeds 30. There are different proto-oncogene families and their products have different functions and cellular localisation. They may function in normal cells in the process of proliferation, regulation of cellular metabolism through signal transfer, or cell differentiation. Activation of proto-oncogenes in man is now assumed to be due to: 1) point mutation; 2) overexpression or 3) gene rearrangement. The observation that in some tumors multiple oncogenes are altered could be interpreted in terms of a multigene hypothesis. However, in some cases, a single properly-activated oncogene may be able to trigger the whole process of malignant conversion. It is difficult to correlate, without ambiguity, tumor induction to specific types of DNA lesions in human tumors. Xeroderma pigmentosum (XP), a rare recessive autosomal skin disorder characterized biochemically as a DNA repair-deficient disease, is the first example in which unrepaired UV-induced DNA lesions are directly responsible for tumorigenesis. In two independent XP skin tumors, isolated from the same patient, we have detected several (N-ras, c-myc, Ha-ras) altered oncogenes in the same tumor. We postulate that the modifications we have found in these tumors are primarily due to the presence of unrepaired UV-adducts. Long term treatment of human tumoral cell lines bearing an activated ras oncogene, with Interferon-alpha (IFN), showed that IFN can affect the phenotype of the tumor cells without altering the expression of the activated ras gene. IFN may have the capacity to affect diverse cellular pathways. Consequently, the nature of the biological response of a given type of tumor cell to IFN may depend on its inherent properties.

The transfer of high molecular weight (HMW) DNA isolated from Syrian hamster actinomycin D-resistant cells (C12TSV5/R) to sensitive A9 mouse cells, resulted in the growth in selective medium of transferent clones A9 ActR C11, C12 and C13). The resistant mouse cells have presumably acquired a gene(s) conferring actinomycin D resistance and express a 140-150 K surface glycoprotein, apparently involved in the drug resistance.

Treatment of mouse embryo (ME) cells with 5-iodo-2'-deoxyuridine (IdUrd) before infection with SV40 virus, enhances T-antigen (T-Ag) production as detected by immunofluorescence and complement fixation. Cellular DNA and RNA synthesis are inhibited in both SV40 and mock-infected cells after IdUrd treatment. The analogue pretreatment significantly increases the amount of radiolabelled nuclear and cytoplasmic SV40-specific RNA and the RNA polymerase activity of the viral transcriptional complexes of the Sarkosyl supernatants, suggesting that the enhancement of SV40 T-Ag production in infected pretreated ME cells results from an increased synthesis of early virus RNA.

Focus formation following DNA transfection of mouse 3T3-Vill cells was used to search for the presence of activated oncogenes in human thyroid tumors. Oncogenes belonging to the ras family were detected in four out of six thyroid carcinomas (Ki-ras in one anaplastic tumor and one follicular moderately differentiated tumor and Ha-ras and N-ras in two papillary tumors). Normal thyroid tissue samples obtained from two patients, one with an anaplastic tumor and one with a benign adenoma, and samples from 4 benign adenomas and from one toxic goiter of a patient with Graves' disease gave negative results. In one case, restriction enzyme analysis demonstrated the presence of a mutation in codon 12 of the activated Ha-ras oncogene. Our data show that all three ras proto-oncogenes can become activated in malignant thyroid tumors.

The induction by mitomycin C (MC) of SV40 production in three lines of semi- or nonpermissive SV40-transformed cells is described. The production of virions by a line of semipermissive, virus-shedding Chinese hamster kidney cells is increased 1,000-fold by MC treatment; the proportion of infectious centers and V-antigen-containing cells is increased to a lesser degree, suggesting that both the burst per cell and the number of virus-producing cells are increased. MC treatment induces the production of small amounts of infectious DNA and virions in one line of nonpermissive mouse kidney cells, and infectious DNA apparently alone in another.