Actualización del abordaje de la hipertensión pulmonar tromboembólica crónica / Update in the management of chronic thrombo-embolic pulmonary hypertension

La hipertensión pulmonar tromboembólica crónica (HPTEC) es una forma potencialmente curable de hipertensión pulmonar (HP) que aparece hasta en 3% de los pacientes tras una embolia pulmonar (EP). En estos pacientes, la EP no se resuelve, dando paso a coágulos fibróticos organizados, con el desarrollo de HP precapilar debido a la obstrucción proximal de las arterias pulmonares. También puede desarrollarse una microvasculopatía distal que contribuye al aumento de la resistencia vascular pulmonar (RVP). La ecocardiografía transtorácica (ETT) es la exploración que permite establecer la sospecha de HP. La gammagrafía pulmonar de ventilación-perfusión (V/Q) es la herramienta fundamental en el estudio de los pacientes con sospecha de HPTEC; si es normal, prácticamente la descarta. El cateterismo cardiaco derecho es obligatorio para el diagnóstico. La HPTEC se define como la existencia de síntomas, defectos de perfusión residuales e HP precapilar tras un periodo mínimo de tres meses de anticoagulación. La angiografía pulmonar ayuda a determinar la extensión y la accesibilidad quirúrgica de las lesiones tromboembólicas. Las personas con HPTEC son candidatas a anticoagulación indefinida. La endarterectomía pulmonar es el tratamiento de elección, resultando en una mejoría clínica y hemodinámica significativa. Aproximadamente un 25% de los pacientes presentan HP residual postendarterectomía. La angioplastia pulmonar con balón (APB) es una técnica endovascular dirigida a lesiones más distales, de utilidad para sujetos con HPTEC inoperable o HP persistente/recidivante postendarterectomía. Ambos tipos de pacientes también se pueden beneficiar de tratamiento farmacológico para la HP. Las tres terapias constituyen los pilares de la terapia, que ha evolucionado hacia un enfoque multimodal.(AU)

Chronic thrombo-embolic pulmonary hypertension (CTEPH) is a potentially curable form of pulmonary hypertension (PH) that develops in up to 3% of patients after pulmonary embolism (PE). In these patients, PE does not resolve, leading to organized fibrotic clots, with the development of precapillary PH as a result of the proximal obstruction of the pulmonary arteries. In addition, a distal microvasculopathy may also develop, contributing to the increase of pulmonary vascular resistance. Transthoracic echocardiography is the diagnostic tool that allows to establish the suspicion of PH. Ventilation-perfusion lung scintigraphy is the fundamental tool in the study of patients with suspected CTEPH; if it is normal, virtually rules out the diagnosis. Right heart catheterization is mandatory for the diagnosis of these patients. CTEPH is defined as the existence of symptoms, residual perfusion defects and precapillary PH after a minimum period of three months of anticoagulation. Pulmonary angiography helps determine the extent and surgical accessibility of thromboembolic lesions. CTEPH patients are candidates for long-term anticoagulation. Pulmonary endarterectomy is the treatment of choice, resulting in significant clinical and hemodynamic improvement. About 25% of patients have residual PH post-endarterectomy. Balloon pulmonary angioplasty is an endovascular technique that targets more distal lesions, being potentially useful for patients with inoperable CTEPH or persistent/recurrent PH post-endarterectomy. Both types of patients may also benefit from pharmacological treatment for PH. These three therapies are the cornerstone of CTEPH treatment, which has evolved towards a multimodal approach.(AU)

[Update in the management of chronic thrombo-embolic pulmonary hypertension]. / Actualización del abordaje de la hipertensión pulmonar tromboembólica crónica.

Chronic thrombo-embolic pulmonary hypertension (CTEPH) is a potentially curable form of pulmonary hypertension (PH) that develops in up to 3% of patients after pulmonary embolism (PE). In these patients, PE does not resolve, leading to organized fibrotic clots, with the development of precapillary PH as a result of the proximal obstruction of the pulmonary arteries. In addition, a distal microvasculopathy may also develop, contributing to the increase of pulmonary vascular resistance. Transthoracic echocardiography is the diagnostic tool that allows to establish the suspicion of PH. Ventilation-perfusion lung scintigraphy is the fundamental tool in the study of patients with suspected CTEPH; if it is normal, virtually rules out the diagnosis. Right heart catheterization is mandatory for the diagnosis of these patients. CTEPH is defined as the existence of symptoms, residual perfusion defects and precapillary PH after a minimum period of three months of anticoagulation. Pulmonary angiography helps determine the extent and surgical accessibility of thromboembolic lesions. CTEPH patients are candidates for long-term anticoagulation. Pulmonary endarterectomy is the treatment of choice, resulting in significant clinical and hemodynamic improvement. About 25% of patients have residual PH post-endarterectomy. Balloon pulmonary angioplasty is an endovascular technique that targets more distal lesions, being potentially useful for patients with inoperable CTEPH or persistent/recurrent PH post-endarterectomy. Both types of patients may also benefit from pharmacological treatment for PH. These three therapies are the cornerstone of CTEPH treatment, which has evolved towards a multimodal approach.

IGF1R acts as a cancer-promoting factor in the tumor microenvironment facilitating lung metastasis implantation and progression.

Given the long-term ineffectiveness of current therapies and late-stage diagnoses, lung cancer is a leading cause of malignant diseases. Tumor progression is influenced by cancer cell interactions with the tumor microenvironment (TME). Insulin-like growth factor 1 receptor (IGF1R) was reported to affect the TME; however, the role of IGF1R in lung TME has not been investigated. First, we assessed IGF1R genomic alterations and expression in NSCLC patient tissue samples, as well as IGF1R serum levels. Next, we performed tumor heterotopic transplantation and pulmonary metastases in IGF1R-deficient mice using melanoma and Lewis lung carcinoma (LLC) cells. Herein we report increased amplification and mRNA expression, as well as increased protein expression (IGF1R/p-IGF1R) and IGF1R levels in tumor samples and serum from NSCLC patients, respectively. Moreover, IGF1R deficiency in mice reduced tumor growth, proliferation, inflammation and vascularization, and increased apoptosis after tumor heterotopic transplantation. Following induction of lung metastasis, IGF1R-deficient lungs also demonstrated a reduced tumor burden, and decreased expression of tumor progression markers, p-IGF1R and p-ERK1/2. Additionally, IGF1R-deficient lungs showed increased apoptosis and diminished proliferation, vascularization, EMT and fibrosis, along with attenuated inflammation and immunosuppression. Accordingly, IGF1R deficiency decreased expression of p-IGF1R in blood vessels, fibroblasts, tumor-associated macrophages and FOXP3+ tumor-infiltrating lymphocytes. Our results demonstrate that IGF1R promotes metastatic tumor initiation and progression in lung TME. Furthermore, our research indicates that IGF1R could be a potential biomarker for early prediction of drug response and clinical evolution in NSCLC patients.

Cytogenetic and immunohistochemical study of 42 pigmented microcystic chromophobe renal cell carcinoma (PMChRCC).

Pigmented microcystic chromophobe renal cell carcinoma (PMChRCC) is a recently described morphologic variant of ChRCC. We have identified 42 cases in 40 patients in the last 24 years. We have investigated their clinical, morphologic, immunohistochemical, and cytogenetic features. Chromosomal abnormalities of chromosomes 7 and 17 were evaluated by automated dual-color silver-enhanced in situ hybridization on paraffin-embedded tissue. Chromosomal imbalance was defined on the basis of changes in both chromosomal index and signal distribution. The main age was 60.20 years, being 34 males and 6 women. The mean tumor diameter was 4.84 cm, with 39 intrarenal tumors. Grossly, the tumors were solid with a brown dark colored. Microscopically, tumors consisted of pale and eosinophilic cells arranged in microcysts or microalveolar in a cribriform pattern; there were microcalcifications and a dark brown pigment, mostly extracellular. One case showed sarcomatoid transformation. All tumors were positive for epithelial membrane antigen (EMA), Claudin 7, and E-cadherin. Monosomy of 7 and 17 chromosomes was present in 1/36 cases and 2/37 cases, respectively. Polysomy of chromosome 7 and 17 was found in 26/36 cases and in 4/37, respectively. With a median follow-up of 74.05 months, 37 patients were alive without disease and two were alive with disease progression. PMChRCCs expand the morphologic spectrum of the ChRCC with an unusual immunohistochemical profile. Cytogenetically, they showed monosomy to chromosome (CHR) 17 as other ChRCCs and polysomy of CHR 7 infrequent to ChRCCs. We present the probably largest series of PMCRCC, confirming their low aggressive behavior, with exceptional sarcomatoid transformation and distant metastases.

A novel mutation in the CDH1 gene in a Spanish family with hereditary diffuse gastric cancer.

Hereditary diffuse gastric cancer (HDGC) is an inherited form of diffuse type gastric cancer. Germline CDH1 mutations have been identified in approximately 15-50 % of affected kindred that meet the clinical criteria for HDGC. If any of the criteria is met the individual is referred to genetic counseling and CDH1 testing is offered. In this report we present the case of a Spanish family with HDGC harboring a novel CDH1 mutation. A 47 year-old female with a diagnostic of gastric adenocarcinoma and some of her relatives were tested. Study of the entire CDH1 gene, including intron-exon boundaries, by PCR and sequencing and immunohistochemical determination of the expression of E-cadherin were performed. A novel heterozygous deletion in exon 9 of CDH1 gene (c.1220_1220delC, p.P407Qfs10), was found in the proband, one sister and a nephew. It generates a premature stop codon giving rise to a truncated protein that leads to a pathogenic variant. Expression of E-cadherin was absent or frankly reduced in the proband's tumor but normal in tumor cells of great-uncle. After these results, the sister underwent prophylactic total gastrectomy, and the nephew is under annual endoscopic surveillance. Personal or familial history of diffuse gastric cancer, above all at young age, should encourage CDH1 genetic testing. In this sense, the review of the criteria and the addition in the last guideline of the recommendation: "other families in which genetic testing may also be considered" broadens the number of individuals at risk detected. Since there are not reliable methods for early detection, DGC is usually diagnosed at an advanced stage and consequently associated with a poorer outcome. Thus, CDH1 mutations detection contributes to an improvement in diagnosis and therapeutic intervention.

Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: An analysis of 500 cases.

BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long-term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the analmargin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016).

Resultados oncológicos a largo plazo en el cáncer de recto tratado con quimio-radioterapia preoperatoria y cirugía: análisis de 500 casos / Long-term oncologic results in cancer of the rectum treated by preoperative chemoradiotherapy and surgery: an analysis of 500 cases

ANTECEDENTES: el tratamiento del cáncer de recto localmente avanzado (CRLA) y de casos selectivos de estadio IV es la quimioradioterapia (QRT) preoperatoria seguida de la extirpación completa del meso-recto (ETM). A pesar de la reducción en la recurrencia local, la supervivencia libre de enfermedad (SLE) permanece estable en los últimos años. OBJETIVO: el objetivo de este trabajo es analizar el patrón de recidiva, supervivencia a largo plazo y los factores pronósticos en un programa de QRT neoadyuvante y cirugía en el CRLA. MÉTODOS: entre enero de 1992 y diciembre de 2011, 446 pacientes con CRLA y 54 pacientes (con metástasis únicas) fueron tratados con QRT preoperatoria de curso largo y cirugía. Se realizaron 344 (68,8%) resecciones anteriores de recto y 123 (24,6%) amputaciones abdominoperineales. RESULTADOS: con una mediana de seguimiento de 70,06 meses, la recurrencia local fue del 4,8% y a distancia del 25,5%. No se encontraron diferencias en los factores pronósticos histopatológicos entre los tres grupos estudiados dependiendo de la distancia (cm) al margen anal. La afectación del margen circunferencial (MCR+) fue significativamente mayor en el tercio distal (8,5%; p = 0,04). Sesenta y siete pacientes (13,4%) mostraron una respuesta patológica completa. La supervivencia libre de enfermedad a los 5 y 10 años fue significativamente menor en los tumores del tercio distal del recto que en los del tercio medio (61,9% y 57,7%; p = 0,04). En dicha localización se produjo una incidencia significativamente mayor de metástasis pulmonares (p = 0,016)

BACKGROUND: The standard treatment for locally advanced cancer of the rectum (LACR) and selective cases of stage IV disease is preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME). Despite reductions in local recurrence, disease-free survival (DSF) has remained stable in recent years. OBJECTIVE: The objective of this study is to analyze patterns of recurrence, long-term survival and prognostic factors in a program of neoadjuvant CRT and surgery in LACR. METHODS: Between January 1992 and December 2011, 446 patients with LACR and 54 patients (with single metastases) were treated with pre-operative long course CRT and surgery. Three hundred forty four (66.8%) anterior resections of the rectum and 123 (24.6%) abdomino-perineal resections were performed. RESULTS: With a mean follow-up of 70.06 months, local recurrence was 4.8% and distant recurrence 25.5%. No differences were found in the histopathologic prognostic factors across the three groups studied depending on distance (cm) from the anal margin. Involvement of the circumferential resection margin (CRM+) was significantly greater in tumors in the distal third of the rectum (8.5%; p = 0.04). 67 patients (13.4%) showed a complete pathologic response. DSF at 5 and 10 years was significantly lower in patients with tumors affecting the distal third as compared to the middle third of the rectum (61.9% vs. 57.7%; p = 0.04). Tumors at this distal location resulted in a significantly higher incidence of lung metastases (p = 0.016)

Tumor response assessment in locally advanced colon cancer after neoadjuvant chemotherapy.

BACKGROUND: Preoperative chemotherapy followed by radical surgery is a novel therapeutic approach for locally advanced colon cancer (LACC). Neoadjuvant strategies require highly accurate diagnostic tests for a proper selection of candidate patients, allowing a low risk of overtreatment. This paper assesses the radiological, metabolic and pathological findings induced by preoperative oxaliplatin and fluoropyrimidines-based chemotherapy in LACC. METHODS: Forty-four consecutive patients with a confirmed diagnosis of LACC who received neoadjuvant chemotherapy and colon surgery were included. All patients were staged at baseline and before surgery. Clinical diagnosis consisted of physical examination, endoscopy with biopsy and computed tomography (CT) scan. In selected cases, a positron emission tomography/CT (PET/CT) scan was also performed. Accuracy and correlations between CT scan findings and pathologic report was assayed for T stage, N stage and TN stage. This study is retrospective in design. RESULTS: After chemotherapy, a statistical significant tumor volume reduction of 62.5% was achieved by CT-scan (P<0.001; Wilcoxon test) and a 38.9% decrease of standard uptake value (SUVmax) was observed on PET/CT (P=0.004). No progressive disease was reported during neoadjuvant treatment. Accuracy for T and N classification was 62% and 87%, respectively. Accuracy for TN stage was 77%, with 13.6% and 9.1% of the patients being under or overstaged, respectively. Pathologic stage II and III disease was observed in 29/44 (65.9%) and 15/44 (34.1%) of the patients, respectively. Pathologic complete response was achieved in three patients. CONCLUSIONS: Oxaliplatin/fluorpyrimidine neoadjuvant chemotherapy induces major tumour shrinkage at both the pathological and radiological levels. The CT scan shows a high accuracy and a low overstaged rate in LACC patients treated by means of a neoadjuvant approach.

Trial of complete weaning from immunosuppression for liver transplant recipients: factors predictive of tolerance.

Recipients of liver transplantation (LT) may develop immunological tolerance. Factors predictive of tolerance are not clearly understood. Transplant recipients with normal liver function tests and without active viral hepatitis or autoimmune disease who presented with side effects of immunosuppression or a high risk of de novo malignancies were selected to participate in this prospective study. Twenty-four patients fulfilled the inclusion criteria and, therefore, underwent a gradual reduction of immunosuppression. Tolerance was defined as normal liver function tests after immunosuppression withdrawal. Basal clinical and immunological characteristics, including lymphocyte counts and subpopulations (T, B, natural killer, CD4(+) , CD8(+) , and regulatory T cells) and the phytohemagglutinin stimulation index (SI), were compared for tolerant and nontolerant patients. Fifteen of the 24 patients (62.5%) were tolerant at a median of 14 months (interquartile range = 8.5-22.5 months) after complete immunosuppression withdrawal. Tolerant patients had a longer median interval between transplantation and inclusion in the study (156 for tolerant patients versus 71 months for nontolerant patients, P = 0.003) and a lower median SI (7.49 for tolerant patients versus 41.73 for nontolerant patients, P = 0.01). We identified 3 groups of patients with different probabilities of tolerance: in the first group (n = 7 for an interval > 10 years and an SI < 20), 100% reached tolerance; in the second group (n = 10 for an interval > 10 years and an SI > 20 or an interval < 10 years and an SI < 20), 60% reached tolerance; and in the third group (n = 7 for an interval < 10 years and an SI > 20), 29% reached tolerance. In conclusion, a high proportion of select LT recipients can reach tolerance over the long term. Two simple basal variables-the time from transplantation and the SI-may help to identify these patients.

Long-term follow-up study of gastroduodenal lesions after radioembolization of hepatic tumors.

AIM: To evaluate the long-term natural history of the gastroduodenal lesions secondary to extrahepatic embolization with Ytrium 90 (9°Y) spheres. METHODS: From September 2003 to January 2012, 379 procedures of liver radioembolization (RE) using resin microspheres loaded with 9°Y were performed in our center. We have retrospectively compiled the data from 379 RE procedures performed in our center. We report a comprehensive clinical, analytical, endoscopic and histologic long-term follow-up of a series of patients who developed gastroduodenal lesions after the treatment. RESULTS: Six patients (1.5%) developed gastrointestinal symptoms and had gastrointestinal lesions as shown by upper endoscopy in the next 12 wk after RE. The mean time between RE and the appearance of symptoms was 5 wk. Only one patient required endoscopic and surgical treatment. The incidence of gastrointestinal ulcerations was 3.75% (3/80) when only planar images were used for the pre-treatment evaluation. It was reduced to 1% (3/299) when single-photon emission computed tomography (SPECT) images were also performed. The symptoms that lasted for a longer time were nausea and vomiting, until 25 mo after the treatment. CONCLUSION: All patients were free from severe symptoms at the end of follow-up. The routine use of SPECT has decreased the incidence of gastrointestinal lesions due to unintended deployment of 9°Y particles.

Surgical training on rectal cancer surgery: do supervised senior residents differ from consultants in outcomes?

INTRODUCTION: The present work is a comparative study to investigate the independent effect of tutored senior residents on rectal cancer surgery in an academic university hospital. The variable "surgeon" is held to be a major determinant of outcome following total mesorectal excision (TME) for rectal cancer. OBJECTIVE: We hypothesized that TME can be tutored to senior surgical residents without compromising surgical and oncological outcomes. METHODS: Demographics, preoperative characteristics, and surgical data from consecutive patients undergoing elective TME in an academic center over the last decade were retrospectively reviewed from a prospectively collected database. Outcomes were compared in the two cohorts by a principal surgeon (senior resident or staff) and supervised in all cases by a senior colorectal consultant. Association of outcome variables with the type of surgeon was determined by univariate and multivariate analyses and results were corrected by tumor's height. RESULTS: A total of 230 patients were treated over the study period; 136 (59 %) surgeries were performed by staff surgeons (group S) and 94 (41 %) by residents (group R). Both groups were comparable except for distance to anal verge; staff surgeons operated on lower tumors and performed a high percentage of coloanal anastomosis. There were no statistical differences between groups in terms of surgical and oncological outcomes when tumors were located over 7 cm from the anal verge. CONCLUSIONS: Rectal surgery can be performed by senior residents with equal results to staff surgeons when there is direct supervision by a senior consultant and when the tumor is located in the mid-upper rectum (>7 cm from the anal verge). For lower tumors, a careful selection must be made as the operation may require a higher level of training.

Prognosis factors for recurrence in patients with locally advanced rectal cancer preoperatively treated with chemoradiotherapy and adjuvant chemotherapy.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision has improved the outcome of locally advanced rectal carcinoma. OBJECTIVE: The aim of this study was to identify independent prognosis factors of disease recurrence in a group of patients treated with this approach. DESIGN AND PATIENTS: This study was retrospective in design. Data from patients with locally advanced rectal cancer who had completed treatment from 2000 to 2010 were reviewed. SETTINGS: The analysis was performed in a tertiary referral center. MAIN OUTCOME MEASURES: The primary outcomes measured were the recurrence risk factors. RESULTS: The cohort consisted of 228 patients; 69.3% of them were men, and median age was 59 years. Stage III rectal cancer was found in 64.9% of patients. The most frequently administered therapy was concurrent capecitabine, oxaliplatin, and 7-field radiotherapy, followed by 3-field radiotherapy and fluoropyrimidines. After a median follow-up of 49 months, 23.7% of the patients experienced disease recurrence: 2.6% had local recurrence, 21.1% had distant metastases, and 0.5% had both. Factors significantly correlated with recurrence risk in multivariate logistic regression were y-pathological stage (III vs I/II: OR = 2.51), tumor regression grade (1/2 vs 3+/4: OR = 3.34; 3 vs 3+/4: OR = 1.20), and low rectal location (OR = 2.36). The only independent prognosis factor for liver metastases was tumor regression grade (1/2 vs 3+/4: OR = 4.67; 3 vs 3+/4: OR = 1.41), whereas tumor regression grade (1-2 vs 3+/4: OR = 5.5; 3 vs 3+/4: OR = 1.84), low rectal location (OR = 3.23), and previous liver metastasis (OR = 7.73) predicted lung recurrence. LIMITATIONS: This is a single institutional experience, neoadjuvant combined therapy is not homogeneous, and the analysis has been performed in a retrospective manner. CONCLUSIONS: Patients with low third locally advanced rectal cancer with a poor response to neoadjuvant chemoradiotherapy (high y-pathological stage or low tumor regression grade) are at high risk of recurrence. Intense surveillance and the design of alternative therapeutic approaches aimed to lower the distant failure rate seem warranted.

Hereditary diffuse gastric cancer: strategies to reduce tumoral risk.

The main goal at a High-Risk Gastrointestinal Cancer Clinic is to identify individuals at increased risk of developing tumors for diagnosis them in presymptomatic stages, when they are potentially curable. We report an asymptomatic patient belonging to a family with hereditary diffuse gastric cancer syndrome with a novel pathogenic mutation in the E-cadherin gene. In the absence of any proven diagnostic tool in surveillance tumor of this syndrome, the recommendation accepted today for an asymptomatic individual with known mutation is to perform prophylactic surgery. This patient underwent total laparoscopic gastrectomy. A microscopic focus of tumor was detected in the surgical specimen. Strategies to reduce the tumor risk in the hereditary diffuse gastric cancer syndrome are limited, but it is necessary to recognize them in order to treat these patients accordingly to the available evidence.

Cáncer gástrico hereditario difuso: estrategias para disminuir el riesgo tumoral / Hereditary diffuse gastric cancer: strategies to reduce tumoral risk

La Consulta de Alto Riesgo de Tumores Digestivos tiene como objetivo fundamental identificar individuos con mayor riesgo de desarrollar tumores para hacer un diagnóstico presintomático de los mismos detectándolos en estadios en los que son potencialmente curables. Presentamos el caso de una paciente asintomática perteneciente a una familia con síndrome de cáncer gástrico hereditario difuso en la que se detectó una mutación de significado patológico en el gen de la cadherina-E. Al no disponer de ninguna herramienta diagnóstica de eficacia probada en la vigilancia tumoral de este síndrome, la recomendación aceptada hoy en día para un individuo asintomático con mutación conocida es realizar cirugía profiláctica. A esta paciente se le realizó una gastrectomía total por vía laparoscópica, detectándose en la pieza quirúrgica un foco microscópico de tumor. Las estrategias para disminuir el riesgo tumoral en el síndrome de cáncer gástrico hereditario difuso son limitadas, pero es necesario conocerlas para poder tratar a estos pacientes de la manera más adecuada según las evidencias disponibles(AU)

The main goal at a High-Risk Gastrointestinal Cancer Clinic is to identify individuals at increased risk of developing tumors for diagnosis them in presymptomatic stages, when they are potentially curable. We report an asymptomatic patient belonging to a family with hereditary diffuse gastric cancer syndrome with a novel pathogenic mutation in the E-cadherin gene. In the absence of any proven diagnostic tool in surveillance tumor of this syndrome, the recommendation accepted today for an asymptomatic individual with known mutation is to perform prophylactic surgery. This patient underwent total laparoscopic gastrectomy. A microscopic focus of tumor was detected in the surgical specimen. Strategies to reduce the tumor risk in the hereditary diffuse gastric cancer syndrome are limited, but it is necessary to recognize them in order to treat these patients accordingly to the available evidence(AU)

Fc gamma receptor polymorphisms as predictive markers of Cetuximab efficacy in epidermal growth factor receptor downstream-mutated metastatic colorectal cancer.

BACKGROUND: The immunoglobulin G1 (IgG(1)) monoclonal antibody (MoAb) Cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumours. IgG(1) may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by Fc gamma receptor (FcγR) polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus Cetuximab. PATIENTS AND METHODS: Tumour tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester, United Kingdom). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays. RESULTS: DCR was significantly higher in KRAS wild-type tumours (61% versus 39%, p = 0.049). In epidermal growth factor receptor (EGFR) downstream-mutated mCRC patients, those harbouring an FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% versus 33%, p = 0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p = 0.008). CONCLUSION: FcγR polymorphisms may play a role in the clinical efficacy of Cetuximab in EGFR downstream mutated mCRC patients. Further research into Cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.

Four-week neoadjuvant intensity-modulated radiation therapy with concurrent capecitabine and oxaliplatin in locally advanced rectal cancer patients: a validation phase II trial.

PURPOSE: To validate tolerance and pathological complete response rate (pCR) of a 4-week preoperative course of intensity-modulated radiation therapy (IMRT) with concurrent capecitabine and oxaliplatin (CAPOX) in patients with locally advanced rectal cancer. METHODS AND MATERIALS: Patients with T3 to T4 and/or N+ rectal cancer received preoperative IMRT (47.5 Gy in 19 fractions) with concurrent capecitabine (825 mg/m(2) b.i.d., Monday to Friday) and oxaliplatin (60 mg/m(2) on Days 1, 8, and 15). Surgery was scheduled 4 to 6 weeks after the completion of chemoradiation. Primary end points were toxicity and pathological response rate. Local control (LC), disease-free survival (DFS), and overall survival (OS) were also analyzed. RESULTS: A total of 100 patients were evaluated. Grade 1 to 2 proctitis was observed in 73 patients (73%). Grade 3 diarrhea occurred in 9% of the patients. Grade 3 proctitis in 18% of the first 50 patients led to reduction of the dose per fraction to 47.5 Gy in 20 treatments. The rate of Grade 3 proctitis decreased to 4% thereafter (odds ratio, 0.27). A total of 99 patients underwent surgery. A pCR was observed in 13% of the patients, major response (96-100% of histological response) in 48%, and pN downstaging in 78%. An R0 resection was performed in 97% of the patients. After a median follow-up of 55 months, the LC, DFS, and OS rates were 100%, 84%, and 87%, respectively. CONCLUSIONS: Preoperative CAPOX-IMRT therapy (47.5 Gy in 20 fractions) is feasible and safe, and produces major pathological responses in approximately 50% of patients.

MicroRNA-451 is involved in the self-renewal, tumorigenicity, and chemoresistance of colorectal cancer stem cells.

Many antitumor therapies affect rapidly dividing cells. However, tumor proliferation may be driven by cancer stem cells (CSCs), which divide slowly and are relatively resistant to cytotoxic drugs. Thus, many tumors may progress because CSCs are not sensitive to the treatment. In this work, we searched for target genes whose expression is involved in proliferation and chemoresistance of CSCs. Both of these processes could be controlled simultaneously by cell regulators such as microRNAs (miRNAs). Therefore, colonospheres with properties of CSCs were obtained from different colon carcinoma cells, and miRNA profiling was performed. The results showed that miR-451 was downregulated in colonspheres versus parental cells. Surprisingly, expression of miR-451 caused a decrease in self-renewal, tumorigenicity, and chemoresistance to irinotecan of colonspheres. We identified cyclooxygenase-2 (COX-2) as an indirect miR-451 target gene involved in sphere growth. Our results indicate that miR-451 downregulation allows the expression of the direct target gene macrophage migration inhibitory factor, involved in the expression of COX-2. In turn, COX-2 allows Wnt activation, which is essential for CSC growth. Furthermore, miR-451 restoration decreases expression of the ATP-binding cassette drug transporter ABCB1 and results in irinotecan sensitization. These findings correlate well with the lower expression of miR-451 observed in patients who did not respond to irinotecan-based first-line therapy compared with patients who did. Our data suggest that miR-451 is a novel candidate to circumvent recurrence and drug resistance in colorectal cancer and could be used as a marker to predict response to irinotecan in patients with colon carcinoma.

Accuracy of endoscopic ultrasound to assess tumor response after neoadjuvant treatment in rectal cancer: can we trust the findings?

BACKGROUND: The finding that some rectal cancers respond to neoadjuvant chemoradiation is broadening new surgical options for the treatment of some of these tumors that, until now, required a total mesorectal excision. Nevertheless, a fine match between clinical and pathological response is required when planning conservative surgical approaches. OBJECTIVE: This study aims to prospectively validate the use of endoscopic ultrasound as a predictor of clinical and pathological tumor response in patients with locally advanced rectal cancer. DESIGN: : This is an observational study of a cohort of patients undergoing chemoradiation followed by surgery. SETTINGS: This study was conducted at a tertiary medical center. PATIENTS: A total of 235 consecutive patients who underwent chemoradiation followed by surgery at a single institution during a 7-year period were included. MAIN OUTCOME MEASURES: All tumors were staged and restaged at 4 to 6 weeks after neoadjuvant treatment. Downsizing and downstaging were calculated between the initial and posttreatment measures and correlated to the pathological stage. The accuracy of endoscopic ultrasound to predict response was determined. RESULTS: Findings after chemoradiation showed T-downstaging in 54 patients (23%) and N-downstaging in 110 (47%). Overstaging occurred in 88 (37%) patients and was more commonly observed than understaging (21 patients; 9%). Related to the pathological report, endoscopic ultrasound correctly matched the T stage in 54% and the N stage in 75% of tumors. Sensitivity, specificity, and positive and negative predictive values to predict nodal involvement were 39%, 91%, 67%, and 76%. Accuracy was not influenced by such factors as age, distance of the tumor from the anal verge, or time to surgery. LIMITATIONS: This study was limited by the lack of comparison with other imaging methods. CONCLUSIONS: Endoscopic ultrasound allows prediction of involved lymph nodes in 75% of the cases; however, 1 in 5 patients are missclassified as uN0 after neoadjuvant treatment. In our point of view, this percentage is too high to rely only on this diagnostic modality to support a "wait and see" approach.

Hamartoma gigante de glándulas de Brunner: diagnóstico y tratamiento endoscópico / Giant Brunner's gland hamartoma: diagnosis and endoscopic treatment

El hamartoma de glándulas de Brunner es una lesión polipoidea que histológicamente se caracteriza por una hiperplasia de estas glándulas junto con una proporción variable de músculo liso. Generalmente, cursa de forma silente y se comporta como una tumoración benigna. Ocasionalmente su crecimiento puede generar sintomatología digestiva que junto con la posibilidad de transformación maligna obliga a su resección tras realizar un amplio diagnóstico diferencial de masa duodenal. Tanto la clínica como los estudios radiológicos con frecuencia son inespecíficos y no permiten establecer su diagnóstico. El estudio endoscópico básico (gastroscopia) junto con una adecuada caracterización de la lesión mediante ecoendoscopia alta permiten establecer un diagnóstico de sospecha y determinar la mejor opción terapéutica (endoscópica o quirúrgica).Presentamos un caso de hamartoma de glándulas de Brunner gigante que debutó a modo de anemia ferropénica sin evidencia de sangrado. El estudio mediante ecoendoscopia alta permitió, tras adecuada caracterización de la lesión, su completa y segura resección endoscópica evitando un tratamiento quirúrgico más invasivo

Brunner's gland hamartoma is a polypoid lesion typically composed of an increased quantity of normal-appearing Brunner's glands, accompanied by a variable proportion of smooth muscle. Most of these masses are asymptomatic and behave as benign tumors. Occasionally tumoral growth can provoke gastrointestinal problems which, together with the possibility of malignant transformation, will require resection after a broad differential diagnosis has been made with solitary duodenal mass. Both clinical and radiographic studies are nonspecific and often do not allow diagnosis of these tumors. Basic endoscopic studies (upper endoscopy) with adequate characterization of the lesion by endoscopic ultrasound (EUS) can establish a high diagnostic suspicion and determine the best therapeutic option (endoscopy or surgery).We present a case of giant Brunner's gland hamartoma. The initial manifestation was iron-deficiency anemia with no evidence of bleeding. After adequate characterization of the lesion, EUS allowed complete and safe endoscopic resection, avoiding more invasive surgical treatment

[Giant Brunner's gland hamartoma: diagnosis and endoscopic treatment]. / Hamartoma gigante de glándulas de Brunner: diagnóstico y tratamiento endoscópico.

Brunner's gland hamartoma is a polypoid lesion typically composed of an increased quantity of normal-appearing Brunner's glands, accompanied by a variable proportion of smooth muscle. Most of these masses are asymptomatic and behave as benign tumors. Occasionally tumoral growth can provoke gastrointestinal problems which, together with the possibility of malignant transformation, will require resection after a broad differential diagnosis has been made with solitary duodenal mass. Both clinical and radiographic studies are nonspecific and often do not allow diagnosis of these tumors. Basic endoscopic studies (upper endoscopy) with adequate characterization of the lesion by endoscopic ultrasound (EUS) can establish a high diagnostic suspicion and determine the best therapeutic option (endoscopy or surgery). We present a case of giant Brunner's gland hamartoma. The initial manifestation was iron-deficiency anemia with no evidence of bleeding. After adequate characterization of the lesion, EUS allowed complete and safe endoscopic resection, avoiding more invasive surgical treatment.