Phylogenetic analysis of papillomaviruses in dogs from southern Brazil: molecular epidemiology and investigation of mixed infections and spillover events.

Papillomaviruses (PVs) have been identified in several animal species, including dogs (canine papillomaviruses, CPVs) and cattle (bovine papillomaviruses, BPVs). Although some BPVs may occasionally infect species other than cattle, to the best of our knowledge, BPVs have not been reported in dogs to date. Herein, we carried out a retrospective phylogenetic study of PVs circulating in dogs from southern Brazil between 2017 and 2022, also investigating possible mixed infections and spillover events. For this, we screened 32 canine papilloma samples by PCR using the degenerate primers FAP59/64 and/or MY09/11, which amplify different regions of the L1 gene; the genomic target often used for PV classification/typing. Out these, 23 PV DNA samples were successfully amplified and sequenced. All PVs amplified by FAP59/64 (n = 22) were classified as CPV-1. On the other hand, PVs amplified by MY09/11 (n = 4) were classified as putative BPV-1. Among these, three samples showed mixed infection by CPV-1 and putative BPV-1. One of the putative BPV-1 detected in co-infected samples had the L1 gene full-sequenced, confirming the gene identity. Furthermore, the phylogenetic classifications from the FAP59/64 and/or MY09/11 amplicons were supported by a careful in silico analysis, which demonstrated that the analysis based on them matches to the classification from the complete L1 gene. Overall, we described CPV-1 circulation in southern Brazil over the years and the potencial BPV infection in dogs (potential spillover event), as well as possible CPV/1/BPV-1 co-infections. Finally, we suggest the analysis of the complete genome of the putative BPVs detected in dogs in order to deepen the knowledge about the PV-host interactions.

68Ga-DOTA-D-Alanine-BoroPro Radiotracer for Imaging of the Fibroblast Activation Protein in Malignant and Non-Malignant Diseases.

Recently, we reported a new fibroblast activation protein (FAP) inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-HYNIC-D-Alanine-BoroPro)(99mTc-HYNIC-iFAP) structure for tumor microenvironment SPECT imaging. This research aimed to synthesize 68Ga-[2,2',2″,2‴-(2-(4-(2-(5-(((S)-1-((S)-2-boronopyrrolidin-1-yl)-1-oxopropan-2-yl)carbamoyl)pyridin-2-yl)hydrazine-1-carbothioamido)benzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid] (68Ga-DOTA-D-Alanine-BoroPro)(68Ga-iFAP) as a novel radiotracer for PET imaging and evaluate its usefulness for FAP expression in malignant and non-malignant tissues. The coupling of p-SCN-benzene DOTA with HYNIC-iFAP was used for the chemical synthesis and further labeling with 68Ga. Radiochemical purity was verified by radio-HPLC. The specificity of 68Ga-iFAP was evaluated in HCT116 cells, in which FAP expression was verified by immunofluorescence and Western blot. Biodistribution and biokinetic studies were performed in murine models. 68Ga-iFAP uptake at the myocardial level was assessed in mice with induced infarction. First-in-human images of 68Ga-iFAP in healthy subjects and patients with myocardial infarction, glioblastoma, prostate cancer, and breast cancer were also obtained. DOTA-D-Alanine BoroPro was prepared with a chemical purity of 98% and was characterized by UPLC mass spectroscopy, FT-IR, and UV-vis. The 68Ga-iFAP was obtained with a radiochemical purity of >95%. In vitro and in vivo studies demonstrated 68Ga-iFAP-specific recognition for FAP, rapid renal elimination, and adequate visualization of the glioblastoma, breast tumor, prostate cancer, and myocardial infarction sites. The results of this research justify further dosimetry and clinical trials to establish the specificity and sensitivity of 68Ga-iFAP PET for FAP expression imaging.

Fibroblast Activation Protein Activates Macrophages and Promotes Parenchymal Liver Inflammation and Fibrosis.

BACKGROUND & AIMS: Fibroblast activation protein (FAP) is expressed on activated fibroblast. Its role in fibrosis and desmoplasia is controversial, and data on pharmacological FAP inhibition are lacking. We aimed to better define the role of FAP in liver fibrosis in vivo and in vitro. METHODS: FAP expression was analyzed in mice and patients with fibrotic liver diseases of various etiologies. Fibrotic mice received a specific FAP inhibitor (FAPi) at 2 doses orally for 2 weeks during parenchymal fibrosis progression (6 weeks of carbon tetrachloride) and regression (2 weeks off carbon tetrachloride), and with biliary fibrosis (Mdr2-/-). Recombinant FAP was added to (co-)cultures of hepatic stellate cells (HSC), fibroblasts, and macrophages. Fibrosis- and inflammation-related parameters were determined biochemically, by quantitative immunohistochemistry, polymerase chain reaction, and transcriptomics. RESULTS: FAP+ fibroblasts/HSCs were α-smooth muscle actin (α-SMA)-negative and located at interfaces of fibrotic septa next to macrophages in murine and human livers. In parenchymal fibrosis, FAPi reduced collagen area, liver collagen content, α-SMA+ myofibroblasts, M2-type macrophages, serum alanine transaminase and aspartate aminotransferase, key fibrogenesis-related transcripts, and increased hepatocyte proliferation 10-fold. During regression, FAP was suppressed, and FAPi was ineffective. FAPi less potently inhibited biliary fibrosis. In vitro, FAP small interfering RNA reduced HSC α-SMA expression and collagen production, and FAPi suppressed their activation and proliferation. Compared with untreated macrophages, FAPi regulated macrophage profibrogenic activation and transcriptome, and their conditioned medium attenuated HSC activation, which was increased with addition of recombinant FAP. CONCLUSIONS: Pharmacological FAP inhibition attenuates inflammation-predominant liver fibrosis. FAP is expressed on subsets of activated fibroblasts/HSC and promotes both macrophage and HSC profibrogenic activity in liver fibrosis.

Toxicity Assessment of [177Lu]Lu-iFAP/iPSMA Nanoparticles Prepared under GMP-Compliant Radiopharmaceutical Processes.

The fibroblast activation protein (FAP) is heavily expressed in fibroblasts associated with the tumor microenvironment, while the prostate-specific membrane antigen (PSMA) is expressed in the neovasculature of malignant angiogenic processes. Previously, we reported that [177Lu]lutetium sesquioxide-iFAP/iPSMA nanoparticles ([177Lu]Lu-iFAP/iPSMA) inhibit HCT116 tumor progression in mice. Understanding the toxicity of [177Lu]Lu-iFAP/iPSMA in healthy tissues, as well as at the tissue and cellular level in pathological settings, is essential to demonstrate the nanosystem safety for treating patients. It is equally important to demonstrate that [177Lu]Lu-iFAP/iPSMA can be prepared under good manufacturing practices (GMP) with reproducible pharmaceutical-grade quality characteristics. This research aimed to prepare [177Lu]Lu-iFAP/iPSMA under GMP-compliant radiopharmaceutical processes and evaluate its toxicity in cell cultures and murine biological systems under pathological environments. [177Lu]Lu2O3 nanoparticles were formulated as radiocolloidal solutions with FAP and PSMA inhibitor ligands (iFAP and iPSMA), sodium citrate, and gelatin, followed by heating at 121 °C (103-kPa pressure) for 15 min. Three consecutive batches were manufactured. The final product was analyzed according to conventional pharmacopeial methods. The Lu content in the formulations was determined by X-ray fluorescence. [177Lu]Lu-iFAP/iPSMA performance in cancer cells was evaluated in vitro by immunofluorescence. Histopathological toxicity in healthy and tumor tissues was assessed in HCT116 tumor-bearing mice. Immunohistochemical assays were performed to corroborate FAP and PSMA tumor expression. Acute genotoxicity was evaluated using the micronuclei assay. The results showed that the batches manufactured under GMP conditions were reproducible. Radiocolloidal solutions were sterile and free of bacterial endotoxins, with radionuclidic and radiochemical purity greater than 99%. The lutetium content was 0.10 ± 0.02 mg/mL (0.9 GBq/mg). Significant inhibition of cell proliferation in vitro and in tumors was observed due to the accumulation of nanoparticles in the fibroblasts (FAP+) and neovasculature (PSMA+) of the tumor microenvironment. No histopathological damage was detected in healthy tissues. The data obtained in this research provide new evidence on the selective toxicity to malignant tumors and the absence of histological changes in healthy tissues after intravenous injection of [177Lu]Lu-iFAP/iPSMA in mammalian hosts. The easy preparation under GMP conditions and the toxicity features provide the added value needed for [177Lu]Lu-iFAP/iPSMA clinical translation.

[99mTc]Tc-iFAP/SPECT Tumor Stroma Imaging: Acquisition and Analysis of Clinical Images in Six Different Cancer Entities.

Fibroblast activation protein (FAP) is highly expressed on the cancer-associated fibroblasts (CAF) of the tumor stroma. Recently, we reported the preclinical evaluation and clinical biokinetics of a novel 99mTc-labeled FAP inhibitor radioligand ([99mTc]Tc-iFAP). This research aimed to evaluate [99mTc]Tc-iFAP for the tumor stroma imaging of six different cancerous entities and analyze them from the perspective of stromal heterogeneity. [99mTc]Tc-iFAP was prepared from freeze-dried kits with a radiochemical purity of 98 ± 1%. The study included thirty-two patients diagnosed with glioma (n = 5); adrenal cortex neuroendocrine tumor (n = 1); and breast (n = 21), lung (n = 2), colorectal (n = 1) and cervical (n = 3) cancer. Patients with glioma had been evaluated with a previous cranial MRI scan and the rest of the patients had been involved in a [18F]FDG PET/CT study. All oncological diagnoses were corroborated histopathologically. The patients underwent SPECT/CT brain imaging (glioma) or thoracoabdominal imaging 1 h after [99mTc]Tc-iFAP administration (i.v., 735 ± 63 MBq). The total lesions (n = 111) were divided into three categories: primary tumors (PT), lymph node metastases (LNm), and distant metastases (Dm). [99mTc]Tc-iFAP brain imaging was positive in four high-grade WHO III-IV gliomas and negative in one treatment-naive low-grade glioma. Both [99mTc]Tc-iFAP and [18F]FDG detected 26 (100%) PT, although the number of positive LNm and Dm was significantly higher with [18F]FDG [82 (96%)], in comparison to [99mTc]Tc-iFAP imaging (35 (41%)). Peritoneal carcinomatosis lesions in a patient with recurrent colorectal cancer were only visualized with [99mTc]Tc-iFAP. In patients with breast cancer, a significant positive correlation was demonstrated among [99mTc]Tc-iFAP uptake values (Bq/cm3) of PT and the molecular subtype, being higher for subtypes HER2+ and Luminal B HER2-enriched. Four different CAF subpopulations have previously been described for LNm of breast cancer (from CAF-S1 to CAF-S4). The only subpopulation that expresses FAP is CAF-S1, which is preferentially detected in aggressive subtypes (HER2 and triple-negative), confirming that FAP+ is a marker for poor disease prognosis. The results of this pilot clinical research show that [99mTc]Tc-iFAP SPECT imaging is a promising tool in the prognostic assessment of some solid tumors, particularly breast cancer.

[99mTc]Tc-iFAP Radioligand for SPECT/CT Imaging of the Tumor Microenvironment: Kinetics, Radiation Dosimetry, and Imaging in Patients.

Tumor microenvironment fibroblasts overexpress the fibroblast activation protein (FAP). We recently reported the preclinical evaluation of [99mTc]Tc-iFAP as a new SPECT radioligand capable of detecting FAP. This research aimed to evaluate the kinetic and dosimetric profile of [99mTc]Tc-iFAP in healthy volunteers, and to assess the radioligand uptake by different solid tumors in three cancer patients. [99mTc]Tc-iFAP was obtained from lyophilized formulations prepared under GMP conditions with >98% radiochemical purity. Whole-body scans of six healthy subjects were obtained at 0.5, 2, 4, and 24 h after [99mTc]Tc-iFAP (740 MBq) administration. A 2D-planar/3D-SPECT hybrid activity quantitation method was used to fit the biokinetic models of the source organs (volume of interest: VOI) as exponential functions (A(t)VOI). The total nuclear transformations (N) that occurred in the source organs were calculated from the mathematical integration (0,∞) of A(t)VOI. The OLINDA code was used to estimate the radiation doses. Three treatment-naive patients (breast, lung, and cervical cancer) with a prior [18F]FDG PET/CT scan underwent whole-body, chest, and abdominal SPECT/CT scanning after [99mTc]Tc-iFAP (740 MBq) administration. Both imaging methods were compared visually and quantitatively. Oncological diagnoses were performed histopathologically. The results showed favorable [99mTc]Tc-iFAP biodistribution and kinetics due to rapid blood activity removal (t1/2α = 2.22 min and t1/2ß = 90 min) and mainly renal clearance. The mean radiation equivalent doses were 5.2 ± 0.8 mSv for the kidney and 1.7 ± 0.3 mSv for the liver after administration of 740 MBq. The effective dose was 2.3 ± 0.4 mSv/740 MBq. [99mTc]Tc-iFAP demonstrated high and reliable uptake in the primary tumor lesions and lymph node metastases in patients with breast, cervical, and lung cancer, which correlated with that detected by [18F]FDG PET/CT. The tumor microenvironment molecular imaging from cancer patients obtained in this research validates the performance of additional clinical studies to determine the utility of [99mTc]Tc-iFAP in the diagnosis and prognosis of different types of solid tumors.

Design, Synthesis and Preclinical Assessment of 99mTc-iFAP for In Vivo Fibroblast Activation Protein (FAP) Imaging.

Fibroblast activation protein (FAP) is expressed in the microenvironment of most human epithelial tumors. 68Ga-labeled FAP inhibitors based on the cyanopyrrolidine structure (FAPI) are currently used for the detection of the tumor microenvironment by PET imaging. This research aimed to design, synthesize and preclinically evaluate a new FAP inhibitor radiopharmaceutical based on the 99mTc-((R)-1-((6-hydrazinylnicotinoyl)-D-alanyl) pyrrolidin-2-yl) boronic acid (99mTc-iFAP) structure for SPECT imaging. Molecular docking for affinity calculations was performed using the AutoDock software. The chemical synthesis was based on a series of coupling reactions of 6-hidrazinylnicotinic acid (HYNIC) and D-alanine to a boronic acid derivative. The iFAP was prepared as a lyophilized formulation based on EDDA/SnCl2 for labeling with 99mTc. The radiochemical purity (R.P.) was verified via ITLC-SG and reversed-phase radio-HPLC. The stability in human serum was evaluated by size-exclusion HPLC. In vitro cell uptake was assessed using N30 stromal endometrial cells (FAP positive) and human fibroblasts (FAP negative). Biodistribution and tumor uptake were determined in Hep-G2 tumor-bearing nude mice, from which images were acquired using a micro-SPECT/CT. The iFAP ligand (Ki = 0.536 nm, AutoDock affinity), characterized by UV-Vis, FT-IR, 1H-NMR and UPLC-mass spectroscopies, was synthesized with a chemical purity of 92%. The 99mTc-iFAP was obtained with a R.P. >98%. In vitro and in vivo studies indicated high radiotracer stability in human serum (>95% at 24 h), specific recognition for FAP, high tumor uptake (7.05 ± 1.13% ID/g at 30 min) and fast kidney elimination. The results found in this research justify additional dosimetric and clinical studies to establish the sensitivity and specificity of the 99mTc-iFAP.

Effectiveness of Counseling Based on Functional Analytic Psychotherapy with Enhanced Cognitive Therapy on the Sexual Quality of Life of Married Adolescent Women / Eficácia do aconselhamento baseado em psicoterapia analítica funcional - Com abordagem de terapia cognitiva aprimorada (FECT) na qualidade de vida sexual de mulheres adolescentes casadas

Abstract Objective Early marriage has many deleterious effects on the health of girls, such as sexual dissatisfaction, an inevitable result of the lack of sufficient knowledge about sexual issues at the time of the marriage. The goal of the present study was to determine the effectiveness of counseling based on functional analytic psychotherapy with enhanced cognitive therapy (FECT) on the sexual quality of life of married adolescent women. Methods This clinical trial was conducted between July and October 2019 on 150 married adolescent women who met the inclusion criteria. In the intervention group, FECTwas conducted in sixteen 90-minute sessions twice a week. The Sexual Quality of Life-Female (SQOL-F) questionnaire was used. When the study ended, the control group was given the choice of receiving the same intervention as the intervention group. Results The paired t-test showed a significant difference between the mean score of sexual quality of life before (52.33±23.09) and after (88.08±10.51) counseling in the intervention group (p<0.0001). According to the analysis of covariance, there was a significant difference between the score on sexual quality after counseling between the intervention (88.08±10.51) and control (60.32±23.73) groups (p<0.0001). There was also a significant difference between the mean score on the four dimensions of sexual quality of life in the intervention group (p<0.0001). Conclusion The results showed that counseling based on FECT improved the sexual quality of life in all dimensions in married adolescent women.

Resumo Objetivo O casamento precoce tem muitos efeitos deletérios sobre a saúde das meninas, como a insatisfação sexual, resultado inevitável da falta de conhecimento suficiente sobre questões sexuais no momento do casamento. O objetivo do presente estudo foi determinar a eficácia do aconselhamento baseado em psicoterapia analítica funcional com terapia cognitiva aprimorada (FECT) na qualidade de vida sexual de mulheres adolescentes casadas. Métodos Este ensaio clínico foi realizado entre julho e outubro de 2019 em 150 mulheres adolescentes casadas que preencheram os critérios de inclusão. No grupo de intervenção, FECT foi realizado em dezesseis sessões de 90 minutos duas vezes por semana. Foi utilizado o questionário Sexual Quality of Life-Female (SQOL-F). Quando o estudo terminou o grupo de controle teve a opção de receber a mesma intervenção do grupo de intervenção. Resultados O teste t pareado mostrou diferença significativa entre o escore médio da qualidade de vida sexual antes (52,33±23,09) e após (88,08±10,51) o aconselhamento no grupo intervenção (p<0,0001). De acordo com a análise de covariância houve diferença significativa entre o escore de qualidade sexual após aconselhamento entre os grupos intervenção (88,08±10,51) e controle (60,32±23,73) (p<0,0001). Também houve diferença significativa entre a pontuação média nas quatro dimensões da qualidade de vida sexual no grupo de intervenção (p<0,0001). Conclusão Os resultados mostraram que o aconselhamento baseado no FECT melhorou a qualidade de vida sexual em todas as dimensões em mulheres adolescentes casadas.

Identification of a Novel Pathogenic Rearrangement Variant of the APC Gene Associated with a Variable Spectrum of Familial Cancer.

Familial adenomatous polyposis (FAP) is an autosomal-dominant condition characterized by the presence of multiple colorectal adenomas, caused by germline variants in the adenomatous polyposis coli (APC) gene. More than 300 germline variants have been characterized. The detection of novel variants is important to understand the mechanisms of pathophysiology. We identified a novel pathogenic germline variant using next-generation sequencing (NGS) in a proband patient. The variant is a complex rearrangement (c.422+1123_532-577 del ins 423-1933_423-1687 inv) that generates a complete deletion of exon 5 of the APC gene. To study the variant in other family members, we designed an endpoint PCR method followed by Sanger sequencing. The variant was identified in the proband patient's mother, one daughter, her brother, two cousins, a niece, and a second nephew. In patients where the variant was identified, we found atypical clinical symptoms, including mandibular, ovarian, breast, pancreatic, and gastric cancer. Genetic counseling and cancer prevention strategies were provided for the family. According to the American College of Medical Genetics (ACMG) guidelines, this novel variant is considered a PVS1 variant (very strong evidence of pathogenicity), and it can be useful in association with clinical data for early surveillance and suitable treatment.

Spanish Validation of the "Life Snapshot Inventory".

INTRODUCTION: The Life Snapshot Inventory (LSI) is a self-report instrument to measure the meaningful vital, personal, and social directions. It was created in the Functional Analytic Psychotherapy as a continuous evaluation of vital changes in areas of life (family, work, love, spirituality, sexuality, health, etc.). OBJECTIVE: The aim was to validate its psychometric characteristics for the first time. METHOD: This study involved 530 participants (average age 33 years), in a Spanish sample. The questionnaire has been compared with the Rosenberg Self-Esteem Scale (RSES) to obtain convergent validity. RESULTS: The results showed a high internal consistency (α = .93) and a correlation of .61, both statistically significant. The factorial analysis showed only one factor (43.56% of variance). In addition, it was sensitive to changes due to interventions, and made it possible to differentiate those people with vital problems. CONCLUSION: This questionnaire could be a helpful measure for healthcare and clinical contexts.

INTRODUCCIÓN: El Inventario de Instantánea Vital (Life Snapshot Inventory; LSI) es un instrumento de autoinforme para medir las direcciones sociales, personales y vitales significativas para el individuo. Se ha creado desde la Psicoterapia Analítica Funcional (FAP) como una evaluación continua de los cambios en diversas áreas de la vida de un individuo (familia, trabajo, amor, espiritualidad, sexualidad, salud, etc.). Objetivo: Validar por primera vez las características psicométricas de este instrumento. METODOLOGÍA: Este estudio implicó una muestra española donde participaron 530 personas (edad media 33 años). El cuestionario se ha comparado con la Escala de Autoestima de Rosenberg (RSES) para obtener validez convergente. RESULTADOS: Los resultados mostraron una alta fiabilidad como consistencia interna (α = .93) y una correlación de .61, ambas estadísticamente significativas. El análisis factorial mostró un único factor (43.56% de la varianza). Además, el instrumento fue sensible a los cambios originados por la intervención, y permitió diferenciar aquellas personas con problemas vitales. CONCLUSIÓN: Este cuestionario podría ser una medida de gran ayuda para utilizar en contextos clínicos y sanitarios.

Radiolabeled Protein-inhibitor Peptides with Rapid Clinical Translation towards Imaging and Therapy.

Protein interactions are the basis for the biological functioning of human beings. However, many of these interactions are also responsible for diseases, including cancer. Synthetic inhibitors of protein interactions based on small molecules are widely investigated in medicinal chemistry. The development of radiolabeled protein-inhibitor peptides for molecular imaging and targeted therapy with quickstep towards clinical translation is an interesting and active research field in the radiopharmaceutical sciences. In this article, recent achievements concerning the design, translational research and theranostic applications of structurally-modified small radiopeptides, such as prostate-specific membrane antigen (PSMA) inhibitors, fibroblast activation protein (FAP) inhibitors and antagonists of chemokine-4 receptor ligands (CXCR-4-L), with high affinity for cancer-associated target proteins, are reviewed and discussed.

Upper gastrointestinal neoplasia in familial adenomatous polyposis: prevalence, endoscopic features and management.

BACKGROUND: To evaluate the prevalence of upper gastrointestinal (GI) polyps in familial adenomatous polyposis (FAP), and to discuss current therapeutic recommendations. METHODS: Clinical, endoscopic, histological and treatment data were retrieved from charts of 102 patients [1958-2016]. Duodenal adenomatosis was classified according to Spigelman stages. RESULTS: this series comprised 59 women (57.8%) and 43 men (42.1%) with a median age of 32.3 years. Patients underwent 184 endoscopic procedures, the first at a median age of 35.9 years (range, 13-75 years). Fundic gastric polyps (n=31; 30.4%) prevailed in the stomach. While only 5 adenomas were found in the stomach, 33 patients (32.4%) presented duodenal ones. Advanced lesions (n=13; 12.7%) were detected in the stomach (n=2) and duodenum (n=11). During follow-up, Spigelman stages improved in 6 (12.2%) patients, remained unchanged in 25 (51.0%) and worsened in 18 (36.7%). Carcinomas were diagnosed in the stomach and duodenum (4 lesions each, 3.9%), at median ages of 50.2 and 55.0 years, respectively. Advanced lesions and carcinomas were managed through local or surgical resections. Severe complications occurred in only 2 patients (one death). Enteroscopy in 21 patients revealed jejunal adenomas in 12, 11 of whom also presented duodenal adenomas. CONCLUSIONS: There is a high prevalence of upper GI adenomas and cancer in FAP. There were diagnosed fundic gastric polyps (30.4%), duodenal (32.4%) and jejunal adenomas (11.8%), respectively. One third of duodenal polyps progressed slowly throughout the study. The rates of advanced gastroduodenal lesions (12.7%) and cancer (7.8%) raise the need for continuous surveillance during follow-up.

Laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP).

OBJECTIVE: To discuss and evaluate the safety and value of laparoscopy adjuvant total colorectal resection for the treatment of familial adenomatous polyposis (FAP). METHODS: From March 2010 to June 2015, 38 cases were retrospectively analyzed and divided into 2 groups, of which 17 cases used laparoscopy adjuvant total colorectal resection, and 21 cases used conventional laparotomy. Clinical data were obtained, and the safety and prognosis were observed. RESULTS: Seventeen cases using laparoscopy adjuvant total colorectal resection achieved success with no conversion to laparotomy and intraoperative complications. There was no significant difference in operation time between the two groups. There were significant differences in blood loss, the length of incision, postoperative recovery time of intestinal function and postoperative hospital stay between the two groups (P < 0.05). The trauma in laparoscopy group was less, and could recover faster, and there was no significant difference in complications between the two groups. In addition, there were no recurrence, distant metastasis and death in the follow-up period from 6 to 56 months. CONCLUSION: Laparoscopy adjuvant total colorectal resection is more safe and feasible, which has minimal invasion and can recover fast.

Aggressive mutation in a familial adenomatous polyposis syndrome family: when phenotype guides clinical surveillance.

Familial adenomatous polyposis (FAP) is an autosomal dominant genetic condition, caused by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene. Desmoid tumors (DTs) are seen in 15% to 20% of FAP patients. Specific location of mutation serves as a guide to predict colonic and extra colonic manifestations and their aggressiveness. A severe FAP-phenotypic family was registered in a genetic counselling high-risk Uruguayan hereditary cancer clinic. Proband's DNA was analysed by NGS, detecting a pathogenic mutation in APC gene. All willing family members were counselled and encouraged to be tested. Here we report a kindred formed by 16 individuals with a very severe FAP phenotype. A two-base deletion mutation: c.4393_4394delAG in APC gene and a consequent premature stop codon was detected. DTs were diagnosed in 6 individuals, ranging from 2 to 25 years of age. The causes of death were diverse: gastric cancer, rectal cancer and desmoid tumor. The already described genotype-phenotype correlation has proved its worth in this family, as clinical features reflect the mutation location at 3' end of APC gene. The inheritable and lethal nature of the disease needs a tailored follow up approach in order to reduce mortality, optimize local tumor control, and preserve patients' quality of life.

Reconstrucción facial con colgajo de músculo temporal posexenteración orbitaria / Facial reconstructon with temporalis muscle fap afer orbital exenteraton

La exenteración orbitaria y la maxilectomía son cirugías que conducen a pérdidas funcionales y estéticas. Representan un reto reconstructivo. El colgajo de músculo temporal es un colgajo versátl y seguro en la cirugía plástica. Fue descripto por primera vez por Lentz en 1895. En 1898, Golovine describió este colgajo para la reconstrucción de un defecto posexenteración de órbita y, en 1948, lo hizo Campbell con respecto a una reconstrucción posmaxilectomía6. El objetivo es presentar nuestra experiencia con el uso de colgajo de músculo temporal pediculado, como una alternativa válida en reconstrucciones posmaxilectomía y exenteración orbitaria asociada a carcinoma de células escamosas. Se presentan dos casos de tumores gigantes por carcinomas de células escamosas en órbita y malar con compromiso periorbital, reconstruidos con colgajo de músculo temporal pediculado, asociado a un injerto de piel, en dos instituciones públicas en la ciudad de Mendoza, República Argentina. El estudio incluyó dos pacientes de sexo femenino, de 71 y 58 años de edad. Ambos tumores comprometan tanto la región orbitaria como la periorbitaria y malar. La anatomía patológica arrojó como resultado carcinoma de células escamosas. La reconstrucción se logró con colgajo de músculo temporal pediculado e injerto de piel. Las complicaciones informadas en la literatura, como la necrosis del colgajo o el injerto, fistulas orbitales, o parálisis facial7, no se registraron en nuestros casos. A la primera paciente se le ofreció radioterapia posoperatoria por presentar resección R1. En la segunda paciente la resección fue R0. El uso de colgajo de músculo temporal pediculado más injerto de piel es una opción importante para la reconstrucción facial posmaxilectomía asociada a exenteración orbitaria. Permite cubierta y relleno de la zona, con resultados estéticos y de reparación aceptables, y es una alternativa válida al uso de colgajos libres, con una curva de aprendizaje más baja y una tasa de complicaciones aceptables.

Orbital exenteraton and maxillectomy result in functonal and aesthetic loss, representing a challenge for reconstructive surgeons. The temporalis muscle fap is a versatle and safe opton for plastic surgery. It was frst described by Lentz in 1895. In 1898 Golovine described this fap for the reconstructon of the defect afer exenteraton of the orbit. In 1948 Campbell described itis use for the reconstructon of a defect afer a maxillectomy6. Our objective was to report the use of pedicle temporalis fap for post-maxillectomy reconstructon and associated orbital exenteraton due to squamous cell carcinoma. We report on two cases of giant tumors due to squamous cell carcinomas of the skin with orbital, periorbital and malar involvement. Reconstructon was done with a temporalis fap associated with a skin graf. The study included two female patentis, aged 71 and 58 years, respectively, afected by a tumor involving he orbital, periorbital and malar regions. Histology confirmed squamous cell carcinoma. Reconstructon was done with a temporal pedicle and a skin graf. No morbidity or mortality occurred. The frst patent underwent radiotherapy postoperatively, as the resecton was R1. Resecton for the second patent was R0. Pediculated temporal muscle fap plus a skin graf is a valid opton for post-maxillectomy reconstructon with associated orbital exenteraton. It allows covering and flling of the area, with acceptable aesthetic and repair Results, posing an alternative to the use of free faps with a lower lear-ning curve and a lower complicaton rate.

Advanced duodenal neoplasia and carcinoma in familial adenomatous polyposis: outcomes of surgical management.

BACKGROUND: In addition to the presence of neoplasia in the colon and rectum, patients with familial adenomatous polyposis (FAP) may develop numerous polyps and carcinoma within the upper gastrointestinal tract. METHODS: The aim of the present paper was to review the incidence advanced duodenal polyposis or cancer and their surgical outcomes. A retrospective review of patients' records from our department was performed. Information was retrieved from a prospective collected data, including clinical (gender, age, family history), endoscopic [association with colorectal cancer (CRC), polyposis severity, age at diagnosis] and surgical management (age, time from the index surgery, type of procedure, morbidity). Duodenal adenomatosis at the time of surgery was classified according to Spigelman stages. RESULTS: In a group of 145 FAP patients, 8 (5.5%) had been surgically treated for duodenal advanced neoplasia [3] or cancer [5]. There were included 2 women and 6 men whose first endoscopic examination and diagnosis of advanced neoplasia/cancer was made at median ages of 47.3 [28-63] and 51.8 years, respectively. Duodenal carcinomas occurred later (55.8 years) when compared to advanced adenomatosis (45.3 years). Three patients were diagnosed due to symptoms, while the others were detected under endoscopic surveillance. Age interval between FAP treatment and duodenal neoplasia diagnosis was 15.3 years [0-47]. All but one patient underwent duodenopancreatectomy (DP). Two from the 7 patients undergoing DP died, one from pulmonary embolism 30 days after surgery and the other from recurrent T4N0 duodenal tumor. Thus, major operative morbidity and mortality were 12.5%. CONCLUSIONS: In this single-center Brazilian series of FAP patients: (I) advanced duodenal neoplasia or cancer requiring surgery occurred in 5.5% of patients; (II) when reaching the fifth decade of life, patients should be carefully evaluated to diagnose and treat early lesions; (III) in spite of the technical complexity of DP, operative morbidity is acceptable in experienced hands; and (IV) continuous surveillance is necessary during follow-up.

Risk perception in subjects at-risk for Familial Amyloidotic Polyneuropathy / Percepción del riesgo en sujetos con riesgo de Polineuropatía Amiloide Familiar

Abstract The aims of this study are to know if subjects at-risk were aware of their 50% risk for Familial Amyloidotic Polyneuropathy (FAP); to know the value of the subjective risk; to understand the association between sociodemographic characteristics and risk perception, and between the risk status and the subjective perception of risk. 174 subjects 50% at-risk for FAP were tested. 52.9% subjects at-risk were aware of their 50% risk condition. The mean value of the subjective risk was higher and closer to 50% when the subjects were aware of their 50% risk condition. Education was associated to a higher awareness of being at 50% risk. It seems that information on previous knowledge before performing the genetic counselling increases the subjective risk.

Resumen Los objetivos de este estudio son saber si los sujetos en riesgo eran conscientes de su riesgo del 50% para la polineuropatía amiloide familiar (PAF); conocer el valor del riesgo subjetivo; y comprender la asociación entre las características sociodemográficas y la percepción del riesgo y entre el riesgo real y la percepción subjetiva del riesgo. Se examinaron 174 sujetos con riesgo de PAF del 50%. 52,9% de los sujetos en riesgo eran conscientes de su condición de riesgo del 50%. El valor medio del riesgo subjetivo fue mayor y más cercano al 50% cuando los sujetos eran conscientes de su condición de riesgo del 50%. La educación se asoció a una mayor conciencia de estar al 50% de riesgo. Parece que la información sobre los conocimientos previos antes de realizar el asesoramiento genético aumenta el riesgo subjetivo.

Motivation to perform presymptomatic testing in portuguese subjects at-risk for late-onset genetic diseases

El papel del psicólogo clínico en el contexto del consejo genético incluye brindar apoyo a los sujetos en riesgo en el proceso de toma de decisiones, independientemente de la decisión adoptada por el sujeto (conociendo o no el resultado de las pruebas genéticas). El estudio que se informa aborda la motivación para realizar las pruebas pre-sintomáticas (PPS) de sujetos en situación de riesgo para tres enfermedades: polineuropatía amiloide familiar (PAF), la enfermedad de Huntington (EH) y la enfermedad de Machado-Joseph (EMJ) y comparar con la motivación para realizar las PPS para hemocromatosis (HH). La muestra consistió en 213 sujetos portugueses que tenían riesgo genético para contraer las tres enfermedades y 31 sujetos en situación de riesgo genético para contraer hemocromatosis. Ellos fueron evaluados con una entrevista para obtener datos sociodemográficos y debían responder a una pregunta sobre la motivación para llevar a cabo las pruebas pre-sintomáticas. Se obtuvieron siete categorías principales y las siguientes son las más significativas para PAF, EH y EMJ: razones relacionadas con el futuro, razones relacionadas con los demás y razones relacionadas con la curiosidad y la necesidad de conocer. Para hemocromatosis, las más importantes resultaron ser razones relacionadas con los demás y las relacionadas con las características de la enfermedad. La motivación para realizar el test pre-sintomático (PST) de la PAF, EH y EMJ es externa y sin relación con la enfermedad, mientras que la motivación de los sujetos en situación de riesgo para la HH está relacionada con la enfermedad. Las razones relacionadas con los demás es una motivación común en ambos grupos. A los sujetos también les preocupa la posibilidad de transmitir la enfermedad a sus hijos.

The role of the clinical psychologist in the context of genetic counseling includes support for the process of decision-making for subjects at-risk, regardless of the decision that was made. For this, it is important to know the motivations behind these decisions. What may be considered advant-ageous and justifiable reasons to perform the PST for genetic diseases from the medical and public point of view, i.e., planning for the future, helping in the choice of a profession, family planning, improving quality of life and contributing to health, may not be recognized as such by the individual seeking the PST. This study addresses the motivation to perform the presymptomatic testing (PST) of subjects at-risk for three diseases, Familial Amyloid Polyneuro pathy (FAP), Huntington's disease (HD), and Machado-Joseph disease (MJD), compared with the motivation to perform the PST for Hemochromatosis (HH). FAP, HD and MJD are three genetic (monogenic) autosomal dominant late-onset diseases (LON-Ds) with no cure. FAP is a progressive sensorimotor and autonomic neuropathy of adult hood. HD is characterized by a triad of clinical symptoms of chorea (motor, cognitive and psychiatric symptoms), emotional distress and cognitive decline. MJD is characterized by slowly progressive clumsiness in the arms and legs, a staggering lurching gait, sometimes mistaken for drunkenness, difficulty with speech and swallowing, involuntary eye movements, and may be accompanied by double vision or bulging eyes, and lower limb spasticity. HH is a disease in which too much iron accumulates in parenchymal organs, leading to iron overload and subsequent organ toxicity and failure. The study participants consisted in 213 subjects at genetic risk for FAP, HD, and MJD and 31 subjects at genetic risk for HH, that were assessed through an interview to obtain sociodemographic data and the answer to one question about motivation to perform PST: "Which were the reasons that led you to perform the predictive test? "This study was carried out in Center for Predictive and Preventive Genetics (CGPP), Institute for Molecular and Cell Biology (IBMC), Porto (Portugal). This research used a mixed-method, since qualitative and quantitative techniques of data analysis were used. Before deciding to seek genetic counseling and to know their genetic status, subjects at-risk have naturally considered their motives and it was probably the pro-counseling reasons the ones dictating the motivation to perform the PST. This may suggest that in fact there is a prior self-selection to the test, i.e. only those considering to have emotional skills to go through the process, performing the test. Seven major categories were obtained. The most significant ones for FAP, HD and MJD were reasons related to the future, reasons related to others and reasons related to curiosity and to the need to know. For HH, the most important ones were reasons related to others and reasons related to the characteristics of the disease. The motivation of subjects at-risk to perform the PST for FAP, HD and MJD is external and unrelated to the disease, while the motivation of subjects at-risk to perform the PST for HH is related to the disease. Reasons related to others area common motivation: as subjects at-risk for FAP, HD and MJD, subjects at-risk for HH also chose reasons related to others as one of the most important motivations to carry out the PST. These subjects also care about the fact that they can transmit the disease to their children and care about other family members which are already ill. The category reasons related to others includes sub-categories that identify the person and the situation that led to the decision to perform a PST. Subjects at-risk are also concerned about the fact that they have to decide whether or not to have children and its economic implications.

Food assistance programmes are indirectly associated with anaemia status in children <5 years old in Mexico.

Anaemia in children is a public health concern in Mexico; Federal food assistance programmes are being implemented to prevent it. We undertook this research to investigate the indirect association between food assistance programmes (FAP) and anaemia through dietary and socio-economic conditions of beneficiary children. A structural equation model (SEM) was constructed to assess associations among FAP, dietary and socio-economic conditions, as well as anaemia. A cross-sectional comparative study was conducted based on a sample of 1214 households with children <5 years old, beneficiaries of two FAP: Prospera and rescue from malnutrition with amaranth (RMA) and a comparison group in San Luis Potosí, Mexico. The SEM and a decomposition effect analysis revealed the existence of a significant indirect association of FAP on the prevalence of anaemia via dietary and socio-economic conditions in children under 5 years old. The Prospera assistance programme showed a significant indirect positive association with the prevalence of anaemia (standard coefficient=0·027, P<0·031), and the RMA programme showed a significant indirect negative association with the prevalence of anaemia (standard coefficient=-0·029, P=0·047). There was a direct association between FAP and dietary and socio-economic conditions. FAP could indirectly modify the prevalence of anaemia in young children with a direct improvement on dietary and socio-economic conditions. The unexpected finding of the association between RMA, dietary and socio-economic conditions and the prevalence of anaemia reflects differences in the focus of the programmes.

A especificação do responder contingente do terapeuta na psicoterapia analítica funcional / Specifying the therapist contingent responding in the functional analytic psychotherapy

O responder contingente do terapeuta aos comportamentos clinicamente relevantes (CRB) do cliente consiste no mecanismo de mudança clínica na Psicoterapia Analítica Funcional (FAP). Os procedimentos clínicos são resumidos em cinco regras para o terapeuta, que têm o objetivo de maximizar a frequência de ocorrência de CRBs. A interação lógica da FAP apresenta as cinco regras desdobradas em 12 passos, os quais descrevem as respostas do terapeuta e seus efeitos no comportamento do cliente. Apesar dos avanços no refinamento da descrição da FAP e da validação empírica de seu mecanismo de mudança clínica, a tarefa de especificar o responder contingente do terapeuta permanece inacabada. O objetivo deste artigo é apresentar a interação lógica e discuti-la propondo alternativas de operacionalização do responder contingente do terapeuta aos comportamentos clinicamente relevantes relacionados ao problema clínico. O método consistiu em examinar os passos da interação lógica da FAP para hipotetizar alternativas de ação para o terapeuta em resposta ao comportamento problema que ocorre na sessão. Quatro alternativas de resposta do terapeuta são listadas e exemplificadas com verbalizações extraídas de registros de interações terapeuta/cliente. Discutem-se os possíveis efeitos indesejáveis provocados pela descontinuidade do reforço ao comportamento problema e sugerem-se questões para estudos futuros.(AU)

The therapist contingent responding to clinically relevant behaviors (CRB) corresponds to Functional Analytic Psychotherapy (FAP) mechanism of change. The clinical procedures are summarized in five rules to therapists, which aim to maximize the frequency of CRBs. FAP logical interaction presents the five rules deployed in 12 steps, which describe therapist's behaviors and their effects on client's behaviors. Despite of the advances reached through refinement in FAP description and the empirical validation of FAP' mechanism of change, the task of specifying therapist contingent responding is still unfinished. The purpose of this paper is to present FAP logical framework and discuss proposing an operationalization alternative to the therapist contingent responding to clinically relevant behaviors related to the clinical problem. The methods consisted in examining FAP logical framework steps to elucidate courses of actions for the therapist in response to the clinical problem. Four courses of action for the therapist are listed and illustrated with verbalizations extracted from recordings of client-therapist interactions. Possible undesirable effects caused by the discontinuing of reinforcement are discussed and questions for future studies are suggested.(AU)