Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas

'Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations (AU)

Multidisciplinary practice guidelines for the diagnosis, genetic counseling and treatment of pheochromocytomas and paragangliomas.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and the sympathetic/parasympathetic neural ganglia, respectively. The heterogeneity in its etiology makes PPGL diagnosis and treatment very complex. The aim of this article was to provide practical clinical guidelines for the diagnosis and treatment of PPGLs from a multidisciplinary perspective, with the involvement of the Spanish Societies of Endocrinology and Nutrition (SEEN), Medical Oncology (SEOM), Medical Radiology (SERAM), Nuclear Medicine and Molecular Imaging (SEMNIM), Otorhinolaryngology (SEORL), Pathology (SEAP), Radiation Oncology (SEOR), Surgery (AEC) and the Spanish National Cancer Research Center (CNIO). We will review the following topics: epidemiology; anatomy, pathology and molecular pathways; clinical presentation; hereditary predisposition syndromes and genetic counseling and testing; diagnostic procedures, including biochemical testing and imaging studies; treatment including catecholamine blockade, surgery, radiotherapy and radiometabolic therapy, systemic therapy, local ablative therapy and supportive care. Finally, we will provide follow-up recommendations.

Clinical Factors Associated with High Glycemic Variability Defined by Coefficient of Variation in Patients with Type 2 Diabetes.

BACKGROUND: High glycemic Variability (HGV) has become a stronger predictor of hypoglycemia. However, clinical factors associate with HGV still are unknown. OBJECTIVE: To determine clinical variables that were associated with a coefficient of variation (CV) above 36% evaluated by continuous glucose monitoring (CGM) in a group of patients with diabetes mellitus. METHODS: A cohort of patients with type 2 diabetes (T2D) was evaluated. Demographic variables, HbA1c, glomerular filtration rate (GFR) and treatment regimen were assessed. A bivariate analysis was performed, to evaluate the association between the outcome variable (CV> 36%) and each of the independent variables. A multivariate model was constructed to evaluate associations after controlling for confounding variables. RESULTS: CGM data from 274 patients were analyzed. CV> 36% was present in 56 patients (20.4%). In the bivariate analysis, demographic and clinical variables were included, such as time since diagnosis, hypoglycemia history, A1c, GFR and treatment established. In the multivariate analysis, GFR <45 mL/min (OR 2.81; CI 1.27,6.23; p:0.01), A1c > 9% (OR 2.81; CI 1.05,7.51; p:0.04) and hypoglycemia history (OR 2.09; CI 1.02,4.32; p:0.04) were associated with HGV. Treatment with iDPP4 (OR 0.39; CI 0.19,0.82; p:0.01) and AGLP1 (OR 0.08; CI 0.01,0.68; p:0.02) was inversely associated with GV. CONCLUSION: Clinical variables such as GFR <45 mL/min, HbA1C>9% and a history of hypoglycemia are associated with a high GV. Our data suggest that the use of technology and treatments able to reduce glycemic variability could be useful in this population to reduce the risk of hypoglycemia and to improve glycemic control.

Legumes display common and host-specific responses to the rhizobial cellulase CelC2 during primary symbiotic infection.

Primary infection of legumes by rhizobia involves the controlled localized enzymatic breakdown of cell walls at root hair tips. Previous studies determined the role of rhizobial CelC2 cellulase in different steps of the symbiotic interaction Rhizobium leguminosarum-Trifolium repens. Recent findings also showed that CelC2 influences early signalling events in the Ensifer meliloti-Medicago truncatula interaction. Here, we have monitored the root hair phenotypes of two legume plants, T. repens and M. sativa, upon inoculation with strains of their cognate and non-cognate rhizobial species, R. leguminosarum bv trifolii and E. meliloti, (over)expressing the CelC2 coding gene, celC. Regardless of the host, CelC2 specifically elicited 'hole-on-the-tip' events (Hot phenotype) in the root hair apex, consistent with the role of this endoglucanase in eroding the noncrystalline cellulose found in polarly growing cell walls. Overproduction of CelC2 also increased root hair tip redirections (RaT phenotype) events in both cognate and non-cognate hosts. Interestingly, heterologous celC expression also induced non-canonical alterations in ROS (Reactive Oxygen Species) homeostasis at root hair tips of Trifolium and Medicago. These results suggest the concurrence of shared unspecific and host-related plant responses to CelC2 during early steps of symbiotic rhizobial infection. Our data thus identify CelC2 cellulase as an important determinant of events underlying early infection of the legume host by rhizobia.

Usefulness of TSH receptor antibodies as biomarkers for Graves' ophthalmopathy: a systematic review.

PURPOSE: Over the past several decades, many papers have been published about the usefulness of thyrotropin receptor antibodies (TRAbs) as biomarkers of Graves' ophthalmopathy (GO). However, results have been inconsistent. The purpose of this analysis is to determine a possible cause of these discrepancies and to examine the usefulness of TRAbs as biomarkers for GO, especially 'thyrotropin-binding inhibiting immunoglobulin (TBII)' and 'thyroid-stimulating antibody (TSAb)'. METHOD: 26 articles discussing the association between TRAbs and GO were selected which were then divided into three groups based on the study method and whether or not the patients had been treated for hyperthyroidism. From the results of the papers reviewed, a provisional conclusion was made and a theoretical model on the TBII-TSAb coordinate plane was developed to confirm that conclusion. RESULTS: TSAb is reported to be significantly or strongly associated with GO in the studies of pre- and post-treated patients for hyperthyroidism. TBII is positively correlated, negatively correlated or uncorrelated with GO in studies of pre-treated patients. However, it is generally agreed upon that TBII and GO are closely correlated in studies of post-treated patients. CONCLUSION: We conclude that the level of TBII may not be a reliable indicator of the current state of GO in pre-treated patients. Whereas, in post-treated patients, due to changes in the correlation between TBII and TSAb due to the effect of hyperthyroidism treatment, the level of TBII can be a more reliable indicator of GO. Furthermore, the current level of TBII is closely associated with the onset and severity of GO in the future and it can be a valid predictor of GO. However, the TSAb level appears to be more reliable.

Cellulose-Silica Nanocomposites of High Reinforcing Content with Fungi Decay Resistance by One-Pot Synthesis.

Hybrid bionanocomposites based on cellulose matrix, with silica nanoparticles as reinforcers, were prepared by one-pot synthesis of cellulose surface modified by solvent exchange method to keep the biopolymer net void for hosting inorganic nanoparticles. Neither expensive inorganic-particle precursors nor crosslinker agents or catalysts were used for effective dispersion of reinforcer concentration up to 50 wt %. Scanning electron microscopy of the nanocomposites shows homogeneous dispersion of reinforcers in the surface modified cellulose matrix. The FTIR spectra demonstrated the cellulose features even at 50 weight percent content of silica nanoparticles. Such a high content of silica provides high thermal stability to composites, as seen by TGA-DSC. The fungi decay resistance to Trametes versicolor was measured by standard test showing good resistance even with no addition of antifungal agents. This one-pot synthesis of biobased hybrid materials represents an excellent way for industrial production of high performance materials, with a high content of inorganic nanoparticles, for a wide variety of applications.

Homozygous TMEM127 mutations in 2 patients with bilateral pheochromocytomas.

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors that are hereditary in up to 50% of patients. The gene encoding transmembrane-protein-127 (TMEM127) is one of the PCC/PGL-susceptibility genes with an autosomal dominant inheritance pattern. Here, we report 2 patients with bilateral PCC who both harbored a homozygous TMEM127-mutation. In a 31-year-old mentally retarded patient, the homozygous c.410-2A > G mutation was discovered during an update of DNA analysis. A 26-year-old mentally retarded patient was found to have a homozygous c.3G > A mutation. The parents of both patients were consanguineous. We reviewed previously reported clinical features of TMEM127 mutation carriers and compared our findings with case descriptions of homozygous mutations in other PGL/PCC-susceptibility genes. Homozygosity for an autosomal dominant inherited disorder is an extremely rare phenomenon and has, to our knowledge, not been reported before for the gene encoding TMEM127. In the present cases, the clinical picture does not seem to be very different from heterozygous TMEM127 mutation carriers, except for a relatively large tumor size and more pronounced plasma metanephrine concentration. It is unclear whether the mental retardation is causally related to homozygosity of the TMEM127 mutations. Updating genetic screening in patients in whom PCC/PGL has been diagnosed in the past should be considered as it might provide clinically relevant information.

Electroporación percutánea irreversible de un tumor renal: manejo anestésico / Percutaneous irreversible electroporation of a renal tumor: anesthetic management

La electroporación percutánea irreversible (EPI) es un novedoso método de ablación tumoral. Mediante la aplicación al tumor y tejidos adyacentes de breves pulsos eléctricos de alto voltaje se generan alteraciones en la permeabilidad de la membrana de sus células, lo cual termina provocando su muerte. Este alto voltaje aplicado precisa la actuación del anestesiólogo, ya que existe riesgo de desarrollar importantes complicaciones, como arritmias cardíacas o convulsiones. Presentamos el caso de un varón de 66 años diagnosticado de adenocarcinoma renal y sometido a EPI para su ablación con intención curativa bajo anestesia general. Se trata del primer caso en el que se realiza esta técnica en España (AU)

Percutaneous irreversible electroporation (IRE) is a novel tumour ablation method. The application of short and high-voltage electrical pulses to the target lesion induces alterations in cell membrane permeability, finally causing tumour cell death. The extremely high-voltage that is needed in this technique requires the surveillance and management of an experienced anaesthesiologist, as it involves a significant risk of complications, such as cardiac arrhythmias or seizures. The case is presented of a 66 year-old patient diagnosed with a renal adenocarcinoma, and who received without intention-to-cure IRE under general anaesthesia. This case represents the first time this type of technique is used in Spain (AU)

Percutaneous irreversible electroporation of a renal tumor: Anesthetic management. / Electroporación percutánea irreversible de un tumor renal: manejo anestésico.

Percutaneous irreversible electroporation (IRE) is a novel tumour ablation method. The application of short and high-voltage electrical pulses to the target lesion induces alterations in cell membrane permeability, finally causing tumour cell death. The extremely high-voltage that is needed in this technique requires the surveillance and management of an experienced anaesthesiologist, as it involves a significant risk of complications, such as cardiac arrhythmias or seizures. The case is presented of a 66 year-old patient diagnosed with a renal adenocarcinoma, and who received without intention-to-cure IRE under general anaesthesia. This case represents the first time this type of technique is used in Spain.

Mortality among methicillin-resistant Staphylococcus aureus carriers in long-term care facilities.

INTRODUCTION: Little is known about the natural course of patients with chronic stable illnesses colonized with methicillin-resistant Staphylococcus aureus (MRSA). The aim is to determine the impact of MRSA colonization in mortality among long-term health care facility (LTHCF) residents. METHOD: A multicenter, prospective, observational study was designed. Residents in 4 LTHCFs were classified according to MRSA carriage status and followed for 12 months. Treatment consisted of 5 days of nasal mupirocin in MRSA carriers. RESULTS: Ninety-three MRSA-carriers among 413 residents were identified. Thirty-one MRSA-colonized patients died during the study period, 11 of whom from an infectious disease. Independent predictors of their higher mortality rates included heart failure, current neoplasm, MRSA carriage and COPD at 3 months and these same factors plus stroke, Bar-thel index <40, pressure ulcers, and older age at 12 months. MRSA-persistence was 35% and 62.5% at 3 and 12 months, respectively. CONCLUSIONS: MRSA colonization among frail LTHCFs residents is highly prevalent, and is associated with higher mortality. Despite treatment of MRSA carriers, many remained colonized. Factors that promote persistence of MRSA colonization, and the impact of their modification on mortality rates in these patients, need further investigation.

Immunohistochemical expression of stem cell markers in pheochromocytomas/paragangliomas is associated with SDHx mutations.

OBJECTIVE: Pheochromocytomas (PCCs) are neuroendocrine tumors that occur in the adrenal medulla, whereas paragangliomas (PGLs) arise from paraganglia in the head, neck, thorax, or abdomen. In a variety of tumors, cancer cells with stem cell-like properties seem to form the basis of tumor initiation because of their ability to self-renew and proliferate. Specifically targeting this small cell population may lay the foundation for more effective therapeutic approaches. In the present study, we intended to identify stem cells in PCCs/PGLs. DESIGN: We examined the immunohistochemical expression of 11 stem cell markers (SOX2, LIN28, NGFR, THY1, PREF1, SOX17, NESTIN, CD117, OCT3/4, NANOG, and CD133) on tissue microarrays containing 208 PCCs/PGLs with different genetic backgrounds from five European centers. RESULTS: SOX2, LIN28, NGFR, and THY1 were expressed in more than 10% of tumors, and PREF1, SOX17, NESTIN, and CD117 were expressed in <10% of the samples. OCT3/4, NANOG, and CD133 were not detectable at all. Double staining for chromogranin A/SOX2 and S100/SOX2 demonstrated SOX2 immunopositivity in both tumor and adjacent sustentacular cells. The expression of SOX2, SOX17, NGFR, LIN28, PREF1, and THY1 was significantly associated with mutations in one of the succinate dehydrogenase (SDH) genes. In addition, NGFR expression was significantly correlated with metastatic disease. CONCLUSION: Immunohistochemical expression of stem cell markers was found in a subset of PCCs/PGLs. Further studies are required to validate whether some stem cell-associated markers, such as SOX2, could serve as targets for therapeutic approaches and whether NGFR expression could be utilized as a predictor of malignancy.

High frequency and founder effect of the CYP3A4*20 loss-of-function allele in the Spanish population classifies CYP3A4 as a polymorphic enzyme.

Cytochrome P450 3A4 (CYP3A4) is a key drug-metabolizing enzyme. Loss-of-function variants have been reported as rare events, and the first demonstration of a CYP3A4 protein lacking functional activity is caused by CYP3A4*20 allele. Here we characterized the world distribution and origin of CYP3A4*20 mutation. CYP3A4*20 was determined in more than 4000 individuals representing different populations, and haplotype analysis was performed using CYP3A polymorphisms and microsatellite markers. CYP3A4*20 allele was present in 1.2% of the Spanish population (up to 3.8% in specific regions), and all CYP3A4*20 carriers had a common haplotype. This is compatible with a Spanish founder effect and classifies CYP3A4 as a polymorphic enzyme. This constitutes the first description of a CYP3A4 loss-of-function variant with high frequency in a population. CYP3A4*20 results together with the key role of CYP3A4 in drug metabolism support screening for rare CYP3A4 functional alleles among subjects with adverse drug events in certain populations.

Lesión pulmonar aguda como consecuencia de la transfusión de plasma fresco congelado en un paciente con déficit de factor XII / Acute lung injury as a consequence of fresh frozen plasma administration in a patient with factor XII deficiency

Los test de coagulación son, junto con el hemograma, las pruebas de laboratorio más solicitadas a los pacientes antes de una intervención quirúrgica. El tiempo de tromboplastina parcial activado (TTPA) cuantifica la vía intrínseca y común de la coagulación, incluyendo los factores XII, XI, IX, VIII, X, V y II. El déficit de factor XII se asocia a un alargamiento del TTPA y a un aumento de los fenómenos tromboembólicos sin incrementar el riesgo de hemorragia intraoperatoria. A un varón de 20 años con déficit de factor XII se le administraron dos unidades de plasma fresco congelado ante un valor de TTPA de 100 segundos con intención de corregir una posible alteración de la coagulación ante una cirugía de urgencias y el temor de un sangrado intraoperatorio. A la hora del inicio de la trasfusión el paciente desarrolló un cuadro de lesión pulmonar aguda compatible con el diagnóstico de TRALI (transfusión related acute lung injury). La cirugía trascurrió con normalidad y el paciente permaneció ingresado en la unidad de reanimación 72 horas durante las que precisó soporte respiratorio. Ante una prolongación del TTPA en ausencia de sangrado se debe descartar la presencia de un anticoagulante circulante inespecífico, un déficit de factor XI, un déficit de factor XII y un déficit de factor VIII asociado a la enfermedad de von Willebrand. Por lo tanto, en el caso que presentamos fue innecesaria la administración de hemoderivados al paciente pudiendo tener consecuencias tan graves como la que presentó, la aparición de una lesión pulmonar aguda asociada a la trasfusión (AU)

Along with the complete blood count, the coagulation tests are those most demanded before a surgical procedure. The activated partial thromboplastin time (APPT) quantifies the intrinsic and common coagulation pathways, including factors XII, XI, IX, VIII, X, V and II. Factor XII deficiency is associated with a prolonged APPT and an increase in thromboembolic phenomena, without increasing the intraoperative bleeding risk. A 20 year old man with factor XII deficiency was receiving two units of fresh frozen plasma because of an APPT of 100 seconds, with the intention of normalizing it before an urgent surgery procedure, and the fear of intraoperative bleeding. An hour after starting the transfusion the patient developed an acute lung injury (ALI) compatible with the diagnosis of a transfusion related acute lung injury (TRALI). The surgery continued without complications, and the patient was admitted to the resuscitation unit for 72h, needing respiratory support. If the APTT is prolonged in the absence of bleeding, the presence of a non-specific circulating anticoagulant, a deficiency of factor XI, XII and VIII (associated to Von Willebrand disease) must be ruled out. Therefore, in the case presented here, the administration of hemoderivatives was unnecessary and can have consequences as serious as the one that the patient presented, a transfusion related acute lung injury (AU)

Prevalence and risk factors for meticillin-resistant Staphylococcus aureus in an acute care hospital and long-term care facilities located in the same geographic area.

UNLABELLED: To determine the prevalence and risk factors (RF) for methicillin-resistant Staphylococcus aureus (MRSA) during stay in 1 acute care hospital (ACH) and 4 long-term care facilities (LTCF). After obtaining the informed consent, nasal and skin ulcer swabs were taken and a survey was conducted to determine RF for MRSA. Six hundred and ninety nine patients were included, 413 LTCF and 286 ACH patients and MRSA prevalence were 22.5% and 7.3% respectively. MRSA was located in the nares, skin ulcers, and in both in 61.4%, 21.1%, and 17.5%. Among MRSA carriers, 81% of the ACH and 66.7% of the LTCF patients were only colonized. The multivariate analysis for the ACH revealed the following factors to be associated with MRSA: referral from an LTCF (OR 4.84), pressure ulcers (OR 4.32), a Barthel score < 60 (OR 2.60), and being male (OR 5.21). For the LTCF: urinary catheterisation (OR 3.53), pressure ulcers (OR 2.44), other skin lesions (OR 2.64), antibiotic treatment in ≤ 6 months, (OR 2.23), previous MRSA colonization (OR 2.15), and a Barthel score <20 (OR 1.28). Molecular typing identified 2 predominant clones Q, P, present in all centres. No relationship was found between clones and antibiotic susceptibility. IN CONCLUSION: MRSA prevalence is high in all centres but is 3 times greater in LTCF. The risk factors most strongly associated with MRSA were pressure ulcers and a stay in an LTCF. We propose preventive isolation in these cases.

Prevalence and risk factors for meticillin-resistant Staphylococcus aureus in an acute care hospital and long-term care facilities located in the same geographic area / Prevalencia y factores de riesgo de Staphylococcus aureus resistente a meticilina en un hospital de agudos y cuatro centros sociosanitarios de una misma área geográfica

To determine the prevalence and risk factors (RF) for methicillin-resistant Staphylococcus aureus (MRSA) during stay in 1 acute care hospital (ACH) and 4 long-term care facilities (LTCF). After obtaining the informed consent, nasal and skin ulcer swabs were taken and a survey was conducted to determine RF for MRSA. Six hundred and ninety nine patients were included, 413 LTCF and 286 ACH patients and MRSA prevalence were 22.5% and 7.3% respectively. MRSA was located in the nares, skin ulcers, and in both in 61.4%, 21.1%, and 17.5%. Among MRSA carriers, 81% of the ACH and 66.7% of the LTCF patients were only colonized. The multivariate analysis for the ACH revealed the following factors to be associated with MRSA: referral from an LTCF (OR 4.84), pressure ulcers (OR 4.32), a Barthel score < 60 (OR 2.60), and being male (OR 5.21). For the LTCF: urinary catheterisation (OR 3.53), pressure ulcers (OR 2.44), other skin lesions (OR 2.64), antibiotic treatment in ≤ 6 months, (OR 2.23), previous MRSA colonization (OR 2.15), and a Barthel score <20 (OR 1.28). Molecular typing identified 2 predominant clones Q, P, present in all centres. No relationship was found between clones and antibiotic susceptibility. In conclusion: MRSA prevalence is high in all centres but is 3 times greater in LTCF. The risk factors most strongly associated with MRSA were pressure ulcers and a stay in an LTCF. We propose preventive isolation in these cases (AU)

El objetivo de este estudio es determinar la prevalencia y factores de riesgo de Staphylococcus aureus resistente a meticilina (SARM) en 1 hospital de agudos y 4 centros socio sanitarios (CSS) de la misma área geográfica. Después de obtener el consentimiento informado de los pacientes se efectuó un frotis nasal y de úlceras cutáneas a los pacientes ingresados en las 5 instituciones. Al mismo tiempo se pasó un cuestionario para establecer los factores de riesgo de SARM. Se estudiaron 699 enfermos, 413 en los CSS y 286 en el hospital. La prevalencia de SARM en los CSS fue del 22,5% y del 7,3% en el hospital. Las localizaciones fueron nasal 61,4%, úlceras de decúbito 21,1% y ambas localizaciones 17,5%. El 81% de los portadores de SARM en el hospital y el 66,7% en los CSS estaban exclusivamente colonizados. El análisis multivariado en el hospital mostró que eran factores independientemente asociados a SARM: proceder de un CSS o residencia (OR 4,84), tener úlceras de decúbito (OR 4,32), un índice de Barthel <60 (OR 2,60) y ser varón (OR 5,21). En los CSS los factores independientemente asociados a SARM eran el sondaje urinario (OR 3,53), las úlceras de decúbito (OR 2,44) y otras lesiones cutáneas (OR 2,64), haber tomado antibióticos en los últimos 6 meses (OR 2,23), la colonización previa por SARM (OR 2,15) y un índice de Barthel < 20 (OR 1,28). Mediante tipificación molecular se han identificado 2 clones epidémicos predominantes Q y P distribuidos en todos los centros. No se ha observado relación entre los genotipos y la sensibilidad antibiótica. Conclusión: La prevalencia de SARM es alta en los 5 centros, siendo en los CSS tres veces superior a la del hospital. Las úlceras de decúbito y proceder de un CSS son los factores más fuertemente asociados a SARM por lo que proponemos que un aislamiento preventivo en estos pacientes (AU)

[Acute lung injury as a consequence of fresh frozen plasma administration in a patient with factor XII deficiency]. / Lesión pulmonar aguda como consecuencia de la transfusión de plasma fresco congelado en un paciente con déficit de factor xii.

Along with the complete blood count, the coagulation tests are those most demanded before a surgical procedure. The activated partial thromboplastin time (APPT) quantifies the intrinsic and common coagulation pathways, including factors XII, XI, IX, VIII, X, V and II. Factor XII deficiency is associated with a prolonged APPT and an increase in thromboembolic phenomena, without increasing the intraoperative bleeding risk. A 20 year old man with factor XII deficiency was receiving two units of fresh frozen plasma because of an APPT of 100 seconds, with the intention of normalizing it before an urgent surgery procedure, and the fear of intraoperative bleeding. An hour after starting the transfusion the patient developed an acute lung injury (ALI) compatible with the diagnosis of a transfusion related acute lung injury (TRALI). The surgery continued without complications, and the patient was admitted to the resuscitation unit for 72 h, needing respiratory support. If the APTT is prolonged in the absence of bleeding, the presence of a non-specific circulating anticoagulant, a deficiency of factor XI, XII and VIII (associated to Von Willebrand disease) must be ruled out. Therefore, in the case presented here, the administration of hemoderivatives was unnecessary and can have consequences as serious as the one that the patient presented, a transfusion related acute lung injury.

A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia.

Truncating mutations in the AXIN2 gene, a key regulator of ß-catenin degradation in the Wnt pathway, have been reported in three families with gastrointestinal adenomatous polyposis and features of ectodermal dysplasia. However, the role of AXIN2 in familial adenomatous polyposis (FAP) syndrome is not completely understood. We performed an in-depth study of APC and MUTYH, and ruled out their implication in 23 FAP families. We then investigated the role of other genes involved in the Wnt pathway, including AXIN2, and identified a novel missense variant in AXIN2 in one family with attenuated FAP. Carriers of the variant exhibited a variable number of polyps but none showed any sign of ectodermal dysplasia. We have demonstrated the pathogenicity of this novel variant by establishing its low frequency in controls as well as by LOH analysis, a segregation study, and immunofluorescent staining of AXIN2 and ß-catenin proteins. This report expands the phenotype known to be related to AXIN2 alterations and raises the question of whether to screen AXIN2 in FAP cases negative for alterations in APC and MUTYH.

Prospective study assessing hypoxia-related proteins as markers for the outcome of treatment with sunitinib in advanced clear-cell renal cell carcinoma.

BACKGROUND: Previous studies suggest that expression of hypoxia markers may be associated with response to antiangiogenic drugs. Thus, we aimed to identify predictors of sunitinib outcome in clear-cell renal cell carcinoma (ccRCC). PATIENTS AND METHODS: The expression of eight key proteins related to hypoxia (CAIX, HIF1A, HIF2A, VEGFA, VEGFR1, VEGFR2, VEGFR3 and PDGFRB) and P-glycoprotein were assessed by immunohistochemistry in 67 primary ccRCC samples from prospectively recruited patients treated with first-line sunitinib. The proteins expression, VHL inactivation and EGLN3 mRNA content were compared with the patients' response to sunitinib. RESULTS: High expression of HIF2A and PDGFRB was associated with better sunitinib RECIST objective response (P = 0.024 and P = 0.026; respectively) and increased VEGFR3 expression was associated with longer progression-free survival (P = 0.012). VEGFR3 overexpression showed a negative correlation with VEGFR3 polymorphism rs307826 (P = 0.002), a sunitinib resistance predictor. With respect to overall survival (OS), high VEGFA was associated with short (P = 0.009) and HIF2A with long (P = 0.048) survival times. High EGLN3 mRNA content was associated with shorter OS (P = 0.023). CONCLUSIONS: We found an association between several proteins involved in hypoxia and sunitinib efficacy. In addition, low VEGFR3 expression was associated with worse outcome and with VEGFR3 rs307826 variant allele, reinforcing VEGFR3 as a marker of sunitinib resistance.

[Public policy-making on breast cancer in Latin America]. / Formulación de políticas públicas sobre el cáncer de mama en América Latina.

OBJECTIVE: To understand the public policy-making process as it relates to breast cancer care in five Latin American countries. METHODS: An exploratory-evaluative study was conducted in Argentina, Brazil, Colombia, Mexico, and Venezuela in 2010, with the selection of countries based on convenience sampling. Sixty-five semi-structured interviews were conducted with government officials, academics, and representatives of trade associations and civil society organizations. A content analysis of secondary sources was performed. Information sources, data, and informants were mixed using the triangulation method for purposes of analysis. RESULTS: The countries that have made the most progress in public policy-making related to breast cancer are Brazil and Mexico. Although Argentina, Colombia, and Venezuela do not have policies, they do have breast cancer care programs and activities. Two perspectives on the development of public policies became evident: the first includes the broad participation of both governmental and nongovernmental sectors, whereas the second, more narrow approach involves government authorities alone. CONCLUSIONS: The results point to significant differences in public policy-making related to breast cancer in the Region. They also show that greater progress has been made in countries where policies have been developed through inclusive participation processes.

Formulación de políticas públicas sobre el cáncer de mama en América Latina / Public policy-making on breast cancer in Latin America

OBJETIVO: Conocer el proceso de formulación de política pública sobre la atención del cáncer de mama en cinco países de América Latina. MÉTODOS: Estudio evaluativo exploratorio realizado en Argentina, Brasil, Colombia, México y Venezuela en 2010. La muestra de países seleccionados fue de conveniencia. Se realizaron 65 entrevistas semiestructuradas a funcionarios gubernamentales, académicos y representantes de gremios profesionales y de organizaciones de la sociedad civil. Se realizó un análisis de contenido para fuentes secundarias. Se integraron fuentes de información, datos e informantes para el análisis mediante el método de triangulación. RESULTADOS: Los países con mayor avance en la formulación de políticas públicas sobre el cáncer de mama son Brasil y México. Argentina, Colombia y Venezuela, pese a no tener una política definida, disponen de programas y acciones para su atención. Se distinguen dos perspectivas de desarrollo para estas políticas públicas: una con amplia participación de los sectores gubernamental y no gubernamental, y otra más restringida a la participación exclusiva de autoridades gubernamentales. CONCLUSIONES: Los resultados traducen importantes diferencias entre países en la formulación de políticas públicas sobre el cáncer de mama en la Región y destacan el mayor avance en aquellos países donde se han desarrollado a través de procesos de participación incluyente.

OBJECTIVE: To understand the public policy-making process as it relates to breast cancer care in five Latin American countries. METHODS: An exploratory-evaluative study was conducted in Argentina, Brazil, Colombia, Mexico, and Venezuela in 2010, with the selection of countries based on convenience sampling. Sixty-five semi-structured interviews were conducted with government officials, academics, and representatives of trade associations and civil society organizations. A content analysis of secondary sources was performed. Information sources, data, and informants were mixed using the triangulation method for purposes of analysis. RESULTS: The countries that have made the most progress in public policy-making related to breast cancer are Brazil and Mexico. Although Argentina, Colombia, and Venezuela do not have policies, they do have breast cancer care programs and activities. Two perspectives on the development of public policies became evident: the first includes the broad participation of both governmental and nongovernmental sectors, whereas the second, more narrow approach involves government authorities alone. CONCLUSIONS: The results point to significant differences in public policy-making related to breast cancer in the Region. They also show that greater progress has been made in countries where policies have been developed through inclusive participation processes.