Targeting high-risk multiple myeloma genotypes with optimized anti-CD70 CAR-T cells.

Despite the success of BCMA-targeting CAR-Ts in multiple myeloma, patients with high-risk cytogenetic features still relapse most quickly and are in urgent need of additional therapeutic options. Here, we identify CD70, widely recognized as a favorable immunotherapy target in other cancers, as a specifically upregulated cell surface antigen in high risk myeloma tumors. We use a structure-guided design to define a CD27-based anti-CD70 CAR-T design that outperforms all tested scFv-based CARs, leading to >80-fold improved CAR-T expansion in vivo. Epigenetic analysis via machine learning predicts key transcription factors and transcriptional networks driving CD70 upregulation in high risk myeloma. Dual-targeting CAR-Ts against either CD70 or BCMA demonstrate a potential strategy to avoid antigen escape-mediated resistance. Together, these findings support the promise of targeting CD70 with optimized CAR-Ts in myeloma as well as future clinical translation of this approach.

Have we improved postoperative and long-term outcomes of liver surgery for colorectal cancer metastasis? Analysis of 1736 hepatectomies performed over 3 decades in a single center.

INTRODUCTION: Surgery is the only potentially curative treatment for colorectal cancer liver metastases (CRLM) and its indication and results have varied in the last 30 years. METHODS: All patients operated on for CRLM in our centre from 1990 to 2021 were prospectively collected, establishing 3 subgroups based on the year of the first surgery: group A 1990-1999, group B 2000-2010, group C 2011-2021. Clinical characteristics and the results of survival, recurrence and prognostic factors were compared. RESULTS: 1736 hepatectomies were included (Group A n = 208; Group B n = 770; Group C n = 758). Patients in group C had better survival at 5 and 10 years (A 40.5%/28.2%; B 45.9%/32.2%; C 51.6%/33.1%, p = 0.013), although there were no differences between groups in overall recurrence at 5 and 10 years (A 73%/75.7%; B 67.6%/69.2%, and C 63.9%/66%, p = 0.524), nor in liver recurrence (A 46.4%/48.2%; B 45.8%/48.2%; and C 44.4%/48.4%, p = 0.899). An improvement was observed in median survival after recurrence, being 19 months, 23 months, and 31 months (groups A, B and C respectively). Prognostic factors of long-term survival changed over the 3 study periods. The only ones that remained relevant in the last decade were the presence of >4 liver metastasis, extrahepatic disease at the time of hepatectomy, and intraoperative blood transfusion. CONCLUSIONS: Survival after surgery for CRLM has improved significantly, although this cannot be explained by a reduction in overall and hepatic recurrence, but rather by an improvement in post-recurrence survival. Involvement of the resection margin has lost prognostic value in the last decade.

Diagnóstico y tratamiento de los quistes hepáticos. Utilidad de los marcadores tumorales intraquísticos (CEA y CA 19.9.) / Diagnosis and treatment of hepatic cysts: Usefulness of intracystic tumor markers (CEA and CA 19.9)

Introducción: El tratamiento de los quistes hepáticos requiere del diagnóstico diferencial de quiste simple hepático (QSH) de la neoplasia mucinosa quística (NMQ) hepática. Las características radiológicas no son patognomónicas. Algunos estudios han sugerido la utilidad de los marcadores tumorales (MKT) intraquísticos. Métodos: Análisis retrospectivo de base de datos prospectiva incluyendo pacientes diagnosticados de QSH sintomático desde el 2003 hasta el 2021. El objetivo del estudio es evaluar los resultados del tratamiento de los QSH sintomáticos y analizar la utilidad de la determinación de «carcinoembryonic antigen» (CEA) y «carbohydrate antigen» CA 19.9 intraquísticos. Resultados: Se incluyeron 50 pacientes tratados por quiste sintomático. En 15 pacientes el primer tratamiento fue el drenaje percutáneo. En 35 pacientes se realizó fenestración laparoscópica. Cuatro pacientes se diagnosticaron de lesiones premalignas/malignas (NMQ, NPIB, linfoma B); tres de ellos requirieron una segunda cirugía tras la fenestración y el diagnóstico anatomopatológico. La mediana de los valores de CEA y CA- 19.9 fue de 196μg/L y 227.321U/mL respectivamente. Los pacientes con lesiones premalignas no tuvieron valores elevados de MKT. El valor predictivo positivo fue del 0% en ambos MKT, y el valor predictivo negativo fue de 89% y 91% respectivamente. Conclusiones: Los valores de CEA y CA 19.9 intraquísticos no permiten distinguir los QSH de las NMH. El tratamiento más resolutivo de los QSH sintomáticos es la fenestración quirúrgica. El análisis anatomopatológico de la pared del quiste posibilita su correcto diagnóstico, permitiendo indicar una reintervención quirúrgica en los casos de NMQ.(AU)

Introduction: To decide treatment of hepatic cysts diagnosis between simple hepatic cyst (SHC) and cystic mucinous neoplasm (CMN). Radiological features are not pathognomonic. Some studies have suggested the utility of intracystic tumor markers. Methods: Retrospective analysis of our prospective database including patients treated due to symptomatic SHC from 2003 to 2021. The aim of the study was to evaluate the results of treatment of symptomatic SHC and the usefulness of the determination of intracystic “carcinoembryonic antigen” (CEA) and “carbohydrate antigen” CA 19.9. Results: Fifty patients diagnosed and treated for symptomatic SHC were included. In 15 patients the first treatment was percutaneous drainage. In 35 patients the first treatment was laparoscopic fenestration. Four patients were diagnosed of premalignant or malignant liver cystic lesions (MCN, IPMN, and lymphoma B); three of them required surgery after initial fenestration and pathological diagnosis. Median CEA and CA 19.9 were 196μg/L and 227.321U/mL, respectively. Patients with malignant or premalignant pathology did not have higher levels of intracystic tumor markers. Positive predictive value was 0% for both markers, and negative predictive value was 89% and 91%, respectively. Conclusion: Values of intracystic tumor markers CEA and CA 19.9 do not allow distinguishing simple cysts from cystic liver neoplasms. The most effective treatment for symptomatic simple liver cysts is surgical fenestration. The pathological analysis of the wall of the cysts enables the correct diagnosis, allowing to indicate a surgical reintervention in cases of hepatic cyst neoplasia.(AU)

Diagnosis and treatment of hepatic cysts. Usefulness of intracystic tumor markers (CEA and CA 19.9.).

INTRODUCTION: To decide treatment of hepatic cysts diagnosis between simple hepatic cyst (SHC) and cystic mucinous neoplasm (CMN). Radiological features are not patognomonic. Some studies have suggested the utility of intracystic tumor markers. METHODS: Retrospective analysis of our prospective database including patients treated due to symptomatic SHC from 2003 to 2021. The aim of the study was to evaluate the results of treatment of symptomatic SHC and the usefulness of the determination of intracystic "carcinoembryonic antigen" (CEA) and "carbohydrate antigen" CA 19.9. RESULTS: 50 patients diagnosed and treated for symptomatic SHC were included. In 15 patients the first treatment was percutaneous drainage. In 35 patients the first treatment was laparoscopic fenestration. Four patients were diagnosed of premalignant or malignant liver cystic lesions (MCN, IPMN, lymphoma B); three of them required surgery after initial fenestration and pathological diagnosis. Median CEA and CA 19-9 were 196 µg/L and 227.321 U/mL respectively. Patients with malignant or premalignant pathology did not have higher levels of intracystic tumor markers. Positive predictive value was 0% for both markers, and negative predictive value was 89% and 91% respectively. CONCLUSION: Values of intracystic tumor markers CEA and CA 19-9 do not allow distinguishing simple cysts from cystic liver neoplasms. The most effective treatment for symptomatic simple liver cysts is surgical fenestration. The pathological analysis of the wall of the cysts enables the correct diagnosis, allowing to indicate a surgical reintervention in cases of hepatic cyst neoplasia.

Paraneoplastic acquired hemophilia A associated with hilar cholangiocarcinoma arising in an intraductal papillary neoplasm of the bile duct / Paraneoplásico adquirido hemofilia A asociada con colangiocarcinoma hiliar que surge en un papilar intraductal neoplasia del conducto biliar

A 74-year-old female was admitted for painless jaundice. Laboratory tests showed hyperbilirubinemia, cholestasis, normal coagulation, and Ca19-9:163U/L. The CT-scan reported dilation of the intrahepatic and extrahepatic bile ducts secondary to a 24mm tumor in the intrapancreatic common bile duct. The magnetic cholangioresonance showed multiple endoluminal polypoid lesions, suggestive of intraductal papillary neoplasm of the bile duct (IPNB). The endoscopic bile duct brushing was non-conclusive.(AU)

Framework humanization optimizes potency of anti-CD72 nanobody CAR-T cells for B-cell malignancies.

BACKGROUND: Approximately 50% of patients who receive anti-CD19 CAR-T cells relapse, and new immunotherapeutic targets are urgently needed. We recently described CD72 as a promising target in B-cell malignancies and developed nanobody-based CAR-T cells (nanoCARs) against it. This cellular therapy design is understudied compared with scFv-based CAR-T cells, but has recently become of significant interest given the first regulatory approval of a nanoCAR in multiple myeloma. METHODS: We humanized our previous nanobody framework regions, derived from llama, to generate a series of humanized anti-CD72 nanobodies. These nanobody binders were inserted into second-generation CD72 CAR-T cells and were evaluated against preclinical models of B cell acute lymphoblastic leukemia and B cell non-Hodgkin's lymphoma in vitro and in vivo. Humanized CD72 nanoCARs were compared with parental ("NbD4") CD72 nanoCARs and the clinically approved CD19-directed CAR-T construct tisangenlecleucel. RNA-sequencing, flow cytometry, and cytokine secretion profiling were used to determine differences between the different CAR constructs. We then used affinity maturation on the parental NbD4 construct to generate high affinity binders against CD72 to test if higher affinity to CD72 improved antitumor potency. RESULTS: Toward clinical translation, here we humanize our previous nanobody framework regions, derived from llama, and surprisingly discover a clone ("H24") with enhanced potency against B-cell tumors, including patient-derived samples after CD19 CAR-T relapse. Potentially underpinning improved potency, H24 has moderately higher binding affinity to CD72 compared with a fully llama framework. However, further affinity maturation (KD<1 nM) did not lead to improvement in cytotoxicity. After treatment with H24 nanoCARs, in vivo relapse was accompanied by CD72 antigen downregulation which was partially reversible. The H24 nanobody clone was found to have no off-target binding and is therefore designated as a true clinical candidate. CONCLUSION: This work supports translation of H24 CD72 nanoCARs for refractory B-cell malignancies, reveals potential mechanisms of resistance, and unexpectedly demonstrates that nanoCAR potency can be improved by framework alterations alone. These findings may have implications for future engineering of nanobody-based cellular therapies.

Tumor-wide RNA splicing aberrations generate immunogenic public neoantigens.

T-cell-mediated immunotherapies are limited by the extent to which cancer-specific antigens are homogenously expressed throughout a tumor. We reasoned that recurrent splicing aberrations in cancer represent a potential source of tumor-wide and public neoantigens, and to test this possibility, we developed a novel pipeline for identifying neojunctions expressed uniformly within a tumor across diverse cancer types. Our analyses revealed multiple neojunctions that recur across patients and either exhibited intratumor heterogeneity or, in some cases, were tumor-wide. We identified CD8+ T-cell clones specific for neoantigens derived from tumor-wide and conserved neojunctions in GNAS and RPL22 , respectively. TCR-engineered CD8 + T-cells targeting these mutations conferred neoantigen-specific tumor cell eradication. Furthermore, we revealed that cancer-specific dysregulation in splicing factor expression leads to recurrent neojunction expression. Together, these data reveal that a subset of neojunctions are both intratumorally conserved and public, providing the molecular basis for novel T-cell-based immunotherapies that address intratumoral heterogeneity.

Structural surfaceomics reveals an AML-specific conformation of integrin ß2 as a CAR T cellular therapy target.

Safely expanding indications for cellular therapies has been challenging given a lack of highly cancer-specific surface markers. Here we explore the hypothesis that tumor cells express cancer-specific surface protein conformations that are invisible to standard target discovery pipelines evaluating gene or protein expression, and these conformations can be identified and immunotherapeutically targeted. We term this strategy integrating cross-linking mass spectrometry with glycoprotein surface capture 'structural surfaceomics'. As a proof of principle, we apply this technology to acute myeloid leukemia (AML), a hematologic malignancy with dismal outcomes and no known optimal immunotherapy target. We identify the activated conformation of integrin ß2 as a structurally defined, widely expressed AML-specific target. We develop and characterize recombinant antibodies to this protein conformation and show that chimeric antigen receptor T cells eliminate AML cells and patient-derived xenografts without notable toxicity toward normal hematopoietic cells. Our findings validate an AML conformation-specific target antigen and demonstrate a tool kit for applying these strategies more broadly.

Results from the european survey on preoperative management and optimization protocols for PeriHilar cholangiocarcinoma.

BACKGROUND: Major surgery, along with preoperative cholestasis-related complications, are responsible for the increased risk of morbidity and mortality in perihilar cholangiocarcinoma (pCCA). The aim of the present survey is to provide a snapshot of current preoperative management and optimization strategies in Europe. METHODS: 61 European centers, experienced in hepato-biliary surgery completed a 59-questions survey regarding pCCA preoperative management. Centers were stratified according to surgical caseload (<5 and ≥ 5 cases/year) and preoperative management protocols' application. RESULTS: The overall case volume consisted of 6333 patients. Multidisciplinary discussion was routinely performed in 91.8% of centers. Most respondents (96.7%) recognized the importance of a well-structured preoperative protocol. The preferred method for biliary drainage was percutaneous transhepatic biliary drainage (60.7%) while portal vein embolization was the preferred technique for liver hypertrophy (90.2%). Differences in preoperative pathologic confirmation of malignancy (35.8% vs 28.7%; p < 0.001), number of mismanaged referred patients (88.2% vs 50.8%; p < 0.001), biliary drainage (65.1% vs 55.6%; p = 0.015) and liver function evaluation (37.2% vs 5.6%; p = 0.001) were found between centers according to groups' stratification. CONCLUSION: The importance of a correct preoperative management is recognized. Nevertheless, the current lack of guidelines leads to wide heterogeneity of behaviors among centers. This survey can provide recommendations to improve pCCA perioperative outcomes.

Experiencia en la resección del proceso uncinado del páncreas: indicaciones y resultados. Revisión de la literatura / Experience in the resection of the uncinate process of the pancreas: Indications and results. Literature review

Introducción: El objetivo de nuestro trabajo es evaluar la experiencia acumulada en el empleo de la uncinectomía (UC) como técnica de pancreatectomía conservadora de parénquima. Método: Estudio observacional y descriptivo que incluye retrospectivamente todos los pacientes intervenidos mediante la técnica de UC en Hospital Universitari de Bellvitge (HUB), y revisión exhaustiva de los casos descritos en la literatura inglesa hasta la actualidad. Resultados: Desde el 2003 hasta el 2019 han sido intervenidos siete pacientes mediante UC en el HUB con orientación diagnóstica de lesión pancreática considerada premaligna. Todos los pacientes han presentado morbilidad, fundamentalmente en forma de fístula pancreática postoperatoria y ninguno de ellos ha presentado insuficiencia pancreática endocrina ni exocrina. Actualmente todos los pacientes se encuentran vivos y sin recidiva de enfermedad neoplásica. Otros 29 casos han sido descritos en la literatura. Del total de los casos (36 pacientes), el abordaje ha sido mínimamente invasivo (laparoscópico o robotizado) en seis pacientes (16,7%), conllevando una estancia hospitalaria inferior. La incidencia global de fístula pancreática es del 50% comportando una tasa de reingreso inferior al 10%, pero sin necesitar reintervención. Conclusión: La UC es una técnica infrecuente y poco estandarizada para la resección de lesiones benignas o de bajo potencial de malignidad localizadas en el proceso uncinado del páncreas. Aunque se asocia a una morbilidad igual o superior a las técnicas de resección estandarizadas, ofrece una preservación excelente de la función endocrina y exocrina pancreática, con el consiguiente beneficio en la calidad de vida de los pacientes a largo plazo. (AU)

Introduction: The aim of our study is to assess the accumulated experience in the use of uncinatectomy (UC) as a parenchymal-sparing pancreatectomy technique. Method: We have carried out a observational and descriptive study including restrospectively all the patients undergoing UC at Hospital Universitary de Bellvitge (HUB) and an exhaustive review of the cases described in the english literature. Results: From 2003 to 2019, seven patients have been operated by UC in the HUB with a diagnostic orientation of pancreatic lesion considered premalignant. All patients have presented morbidity, mainly in the form of postoperative pancreatic fistula, and none of them have presented endocrine or exocrine pancreatic insufficiency. Currently, all patients are alive and without recurrence of neoplastic disease. Another 29 cases have been described in the literature. Of all the cases (36 patients), the approach was minimally invasive (laparoscopic or robotic) in 6 patients (16.7%), leading to a shorter hospital stay. The global incidence of pancreatic fistula is 50%, with a re-admission rate of less than 10%, but without requiring re-intervention. Conclusion: UC is an infrequent and poorly standardized technique for the resection of benign lesions or those with low potential for malignancy located in the uncinate process of the pancreas. Although it is associated with equal or greater morbidity than standardized resection techniques, it offers excellent preservation of endocrine and exocrine pancreatic function, with the consequent long-term benefit in the patients life quality. (AU)

Dissecting the role of the NADPH oxidase NOX4 in TGF-beta signaling in hepatocellular carcinoma.

The NADPH oxidase NOX4 has been proposed as necessary for the apoptosis induced by the Transforming Growth Factor-beta (TGF-ß) in hepatocytes and hepatocellular carcinoma (HCC) cells. However, whether NOX4 is required for TGF-ß-induced canonical (SMADs) or non-canonical signals is not fully understood yet, neither its potential involvement in other parallel actions induced by TGF-ß. In this work we have used CRISPR Cas9 technology to stable attenuate NOX4 expression in HCC cells. Results have indicated that NOX4 is required for an efficient SMAD2/3 phosphorylation in response to TGF-ß, whereas non-canonical signals, such as the phosphorylation of the Epidermal Growth Receptor or AKT, are higher in NOX4 silenced cells. TGF-ß-mediated inhibition of cell proliferation and viability is attenuated in NOX4 silenced cells, correlating with decreased response in terms of apoptosis, and maintenance of high expression of MYC and CYCLIN D1. These results would indicate that NOX4 is required for all the tumor suppressor actions of TGF-ß in HCC. However, analysis in human HCC tumors has revealed a worse prognosis for patients showing high expression of TGF-ß1-related genes concomitant with high expression of NOX4. Deepening into other tumorigenic actions of TGF-ß that may contribute to tumor progression, we found that NOX4 is also required for TGF-ß-induced migratory effects. The Epithelial-Mesenchymal transition (EMT) program does not appear to be affected by attenuation of NOX4 levels. However, TGF-ß-mediated regulation of cytoskeleton dynamics and focal adhesions require NOX4, which is necessary for TGF-ß-induced increase in the chaperone Hsp27 and correct subcellular localization of Hic-5 within focal adhesions, as well for upregulation of the metalloprotease MMP9. All these results together point to NOX4 as a key element in the whole TGF-ß signaling in HCC cells, revealing an unknown role for NOX4 as tumor promoter in HCC patients presenting activation of the TGF-ß pathway.

Imaging Gallbladder Lesions: What Can Positron Emission Tomography/Computed Tomography Add to the Conventional Imaging Approach?

OBJECTIVE: Incidental gallbladder lesions are common in imaging studies, although it is not always easy to discriminate benign lesions from gallbladder cancer with conventional imaging procedures. The present study aims to assess the capacity of positron emission tomography/computed tomography (PET/CT) with 2-[ 18 F]FDG to distinguish between benign and malignant pathology of the gallbladder, compared with conventional imaging techniques (contrast-enhanced CT or magnetic resonance imaging). METHODS: Positron emission tomography/CT and conventional imaging studies of 53 patients with gallbladder lesions were evaluated and visually classified as benign, malignant, or inconclusive. Agreement between PET/CT and conventional imaging was determined, and imaging findings were correlated with histology or follow-up. Positron emission tomography/CT images were also analyzed semiquantitatively (SUV max and maximum tumor-to-liver ratio [TLR max ]). The presence of adenopathies and distant metastases was assessed and compared between both imaging procedures. RESULTS: According to histology or follow-up, 33 patients (62%) had a malignant process and 20 (38%) had benign lesions. Positron emission tomography/CT and conventional imaging showed a moderate agreement ( κ = 0.59). Conventional imaging classified more studies as inconclusive compared with PET/CT (17.0% and 7.5%, respectively), although both procedures showed a similar accuracy. Malignant lesions had significantly higher SUV max and, especially, TLR max (0.89 and 2.38 [ P = 0.00028] for benign and malignant lesions, respectively). Positron emission tomography/CT identified more pathologic adenopathies and distant metastases, and patients with regional or distant spread had higher SUV max and TLR max in the gallbladder. CONCLUSIONS: Positron emission tomography/CT is accurate to distinguish between benign and malignant pathology of the gallbladder, with a similar performance to conventional imaging procedures but with less inconclusive results. Malignant lesions present higher SUV max and TLR max values.

Differences in glucose metabolic activity in liver metastasis separates two groups of metastatic uveal melanoma patients with different prognosis.

BACKGROUND: Uveal melanoma metastasizes to the liver. We aimed to explore the metabolic activity of liver metastases (LM) as a biomarker for survival. METHODS: We analyzed newly diagnosed patients with metastatic UM (MUM) with LM detected by liver-directed imaging and had undergone a PET/CT at diagnosis. FINDINGS: 51 patients were identified between 2004 and 2019. Median age was 62 years, 41% male and 22% ECOG ≥1. LDH, ALP, and GGT were elevated in 49%, 37%, and 57% of patients. Median LM SUVmax was 8.5 (3-42.2). Same size lesions presented a wide range of metabolic activity. Median OS was 17.3 m (95% CI:10.6-23.9). Patients with SUVmax ≥8.5 had an OS of 9.4 m (95% CI:6.4-12.3), whereas patients with SUVmax <8.5 had an OS of 38.4 m (95% CI:21.4-55.5; p < 0.0001, HR = 2.9). We observed similar results when studying M1a disease separately. Multivariate analysis showed SUVmax as an independent prognostic factor for the whole population and those with M1a disease. INTERPRETATION: Increased metabolic activity of LM seems to be an independent predictor of survival. MUM is a heterogeneous disease and metabolic activity probably reflects a different intrinsic behavior.

Neck masses in aged patients: etiology and semiological features associated with malignancy / Masas cervicales en adultos mayores: Etiología y características semiológicas asociadas a malignidad

Abstract Introduction: The purposes of our study were to describe the distribution of diagnoses in a series of 273 patients over 65 years of age who presented for neck masses and to identify semiological fea tures associated with malignancy. Methods: Neck masses were categorized as congenital lesions (n = 7, 3%, 95% CI: 1%- 5%), inflammatory masses (n = 67, 25%, 95% CI: 19%- 30%), benign neoplasms (n = 77, 28%, 95% CI: 23%- 34%), and malignant neoplasms (n = 87, 32%, 95% CI: 26%- 38%). Results: A group of patients had discontinued care and, consequently, a definitive diagnosis could not be reached (n = 35, 12%). Age (OR 1.06, 95% CI 1.00-1.12), male sex (OR 2.35, 95% CI 1.11-4.96), prior history of cancer (OR 2.66, 95% CI 1.02-6.92), mass fixation to skin or deep tissues (OR 4.87, 95% CI 2.20-10.76), and the involvement of multiple cervical lymph node levels (OR 4.15, 95% CI 1.64-10.51) were identified as semiological features associated with malignancy. Conclusion: In the case of a neck mass in an elderly patient, its neoplastic origin should be strongly suspected.

Resumen Introducción: El objetivo de nuestro estudio fue describir la distribución de diagnósticos en una serie de 273 pacientes mayores de 65 años que consultaron por masas cervicales e identificar características semiológicas asociadas a malignidad. Métodos: Las masas cervicales fueron categorizadas como lesiones congénitas (n = 7, 3%, 95% CI: 1%- 5%), masas de origen inflamatorio (n = 67, 25%, 95% CI: 19%-30%), neoplasias benignas (n = 77, 28%, 95% CI: 23%- 34%) y neoplasias malignas (n = 87, 32%, 95% CI: 26%-38%). Resultados: Un grupo de pacientes discontinuó el tratamiento y en consecuencia no fue posible alcanzar un diagnóstico defini tivo (n = 35, 12%). La edad (OR 1.06, 95% CI 1.00-1.12), el sexo masculino (OR 2.35, 95% CI 1.11-4.96), los antecedentes de cáncer (OR 2.66, 95% CI 1.02-6.92), la fijación de la masa a los planos profundos o a piel (OR 4.87, 95% CI 2.20-10.76) y la afectación de más de un nivel ganglionar del cuello (OR 4.15, 95% CI 1.64-10.51) fueron identificados como características semiológicas asociadas a malignidad. Conclusión: En presencia de una masa cervical en un paciente adulto mayor debe existir una fuerte sospecha de origen neoplásico.

Paraneoplastic acquired hemophilia A associated with hilar cholangiocarcinoma arising in an intraductal papillary neoplasm of the bile duct.

A 74-year-old female was admitted for painless jaundice. Laboratory tests showed hyperbilirubinemia, cholestasis, normal coagulation, and Ca19-9:163U/L. The CT-scan reported dilation of the intrahepatic and extrahepatic bile ducts secondary to a 24mm tumor in the intrapancreatic common bile duct. The magnetic cholangioresonance showed multiple endoluminal polypoid lesions, suggestive of intraductal papillary neoplasm of the bile duct (IPNB). The endoscopic bile duct brushing was non-conclusive.

Neck masses in aged patients: etiology and semiological features associated with malignancy.

INTRODUCTION: The purposes of our study were to describe the distribution of diagnoses in a series of 273 patients over 65 years of age who presented for neck masses and to identify semiological features associated with malignancy. METHODS: Neck masses were categorized as congenital lesions (n = 7, 3%, 95% CI: 1%- 5%), inflammatory masses (n = 67, 25%, 95% CI: 19%- 30%), benign neoplasms (n = 77, 28%, 95% CI: 23%- 34%), and malignant neoplasms (n = 87, 32%, 95% CI: 26%- 38%). RESULTS: A group of patients had discontinued care and, consequently, a definitive diagnosis could not be reached (n = 35, 12%). Age (OR 1.06, 95% CI 1.00-1.12), male sex (OR 2.35, 95% CI 1.11-4.96), prior history of cancer (OR 2.66, 95% CI 1.02-6.92), mass fixation to skin or deep tissues (OR 4.87, 95% CI 2.20-10.76), and the involvement of multiple cervical lymph node levels (OR 4.15, 95% CI 1.64-10.51) were identified as semiological features associated with malignancy. CONCLUSION: In the case of a neck mass in an elderly patient, its neoplastic origin should be strongly suspected.

Introducción: El objetivo de nuestro estudio fue describir la distribución de diagnósticos en una serie de 273 pacientes mayores de 65 años que consultaron por masas cervicales e identificar características semiológicas asociadas a malignidad. Métodos: Las masas cervicales fueron categorizadas como lesiones congénitas (n = 7, 3%, 95% CI: 1%- 5%), masas de origen inflamatorio (n = 67, 25%, 95% CI: 19%-30%), neoplasias benignas (n = 77, 28%, 95% CI: 23%- 34%) y neoplasias malignas (n = 87, 32%, 95% CI: 26%-38%). Resultados: Un grupo de pacientes discontinuó el tratamiento y en consecuencia no fue posible alcanzar un diagnóstico definitivo (n = 35, 12%). La edad (OR 1.06, 95% CI 1.00-1.12), el sexo masculino (OR 2.35, 95% CI 1.11-4.96), los antecedentes de cáncer (OR 2.66, 95% CI 1.02-6.92), la fijación de la masa a los planos profundos o a piel (OR 4.87, 95% CI 2.20-10.76) y la afectación de más de un nivel ganglionar del cuello (OR 4.15, 95% CI 1.64-10.51) fueron identificados como características semiológicas asociadas a malignidad. Conclusión: En presencia de una masa cervical en un paciente adulto mayor debe existir una fuerte sospecha de origen neoplásico.

The NADPH oxidase NOX4 regulates redox and metabolic homeostasis preventing HCC progression.

BACKGROUND AND AIMS: The NADPH oxidase NOX4 plays a tumor-suppressor function in HCC. Silencing NOX4 confers higher proliferative and migratory capacity to HCC cells and increases their in vivo tumorigenic potential in xenografts in mice. NOX4 gene deletions are frequent in HCC, correlating with higher tumor grade and worse recurrence-free and overall survival rates. However, despite the accumulating evidence of a protective regulatory role in HCC, the cellular processes governed by NOX4 are not yet understood. Accordingly, the aim of this work was to better understand the molecular mechanisms regulated by NOX4 in HCC in order to explain its tumor-suppressor action. APPROACH AND RESULTS: Experimental models: cell-based loss or gain of NOX4 function experiments, in vivo hepatocarcinogenesis induced by diethylnitrosamine in Nox4 -deficient mice, and analyses in human HCC samples. Methods include cellular and molecular biology analyses, proteomics, transcriptomics, and metabolomics, as well as histological and immunohistochemical analyses in tissues. Results identified MYC as being negatively regulated by NOX4. MYC mediated mitochondrial dynamics and a transcriptional program leading to increased oxidative metabolism, enhanced use of both glucose and fatty acids, and an overall higher energetic capacity and ATP level. NOX4 deletion induced a redox imbalance that augmented nuclear factor erythroid 2-related factor 2 (Nrf2) activity and was responsible for MYC up-regulation. CONCLUSIONS: Loss of NOX4 in HCC tumor cells induces metabolic reprogramming in a Nrf2/MYC-dependent manner to promote HCC progression.

Defining Surgical Difficulty of Liver Transplantation.

OBJECTIVE: To define technically Diff-LT. SUMMARY OF BACKGROUND DATA: Currently, there is no acknowledged definition of Diff-LT. METHODS: This retrospective study included all first consecutive liver-only transplantations performed in 2 centers from 2011 to 2015. Diff-LT was defined as the combination of the number of blood units transfused, cold ischemia time, and duration of operation, all at or above the median value of the entire population. The correlation of Diff-LT with short- (including the comprehensive complication index) and long-term outcomes was assessed. Outcomes were also compared to the 90-day benchmark cutoffs of LT. Predictors of Diff-LT were identified by multivariable analysis, first using only recipient data and then using all recipient, donor, graft, and surgical data. RESULTS: The study population included 467 patients. The incidence of Diff- LT was 18.8%. Diff-LT was associated with short-term outcomes, including the comprehensive complication index and mortality, but not with patient or graft long-term survival. Previous abdominal surgery, intensive care unitbound at the time of LT, split graft use, nonstandard arterial reconstruction, and porto-systemic shunt ligation were independent predictors of Diff-LT. The proportion of variables below the corresponding LT 90-day benchmark cutoffs was 8/13 (61.5%) for non-Diff-LT, and 4/13 (30.8%) for Diff-LT. CONCLUSIONS: Diff-LT, as defined, occurred frequently. Adjusting modifiable variables might decrease the risk of Diff-LT and improve the postoperative course. This definition of Diff-LT might be useful for patient information, comparison between centers and surgeons, and as a metric in future trials.

Agitation in the Trauma Bay Is an Early Indicator of Hemorrhagic Shock.

INTRODUCTION: Agitation on arrival in trauma patients is known as a sign of impending demise. The aim of this study is to determine outcomes for trauma patients who present in an agitated state. We hypothesized that agitation in the trauma bay is an early indicator for hemorrhage in trauma patients. METHODS: We performed a single-institution prospective observational study from September 2018 to December 2020 that included any trauma patient who arrived agitated, defined as a Richmond Agitation-Sedation Scale of +1 to +4. Variables collected included demographics, mechanism of injury, admission physiology, blood alcohol level, toxicity screen, and injury severity. The primary outcomes were need for massive transfusion (≥ 10 units) and need for emergent therapeutic intervention for hemorrhage control (laparotomy, preperitoneal pelvic packing, sternotomy, thoracotomy, or angioembolization). RESULTS: Of 4657 trauma admissions, 77 (2%) patients arrived agitated. Agitated patients were younger (40 versus 46, P = 0.03), predominantly male (94% versus 66%, P < 0.0001) sustained more penetrating trauma (31% versus 12%, P < 0.0001), had a lower systolic blood pressure (127 versus 137, P < 0.0001), and a higher Injury Severity Score (17 versus 9, P < 0.0001). On multivariable logistic regression, agitation was independently associated with massive transfusion (odds ratio: 2.63 [1.20-5.77], P = 0.02) and emergent therapeutic intervention for hemorrhage control (odds ratio: 2.60 [1.35-5.03], P = 0.005). CONCLUSIONS: Agitation in trauma patients may serve as an early indicator of hemorrhagic shock, as agitation is independently associated with a two-fold increase in the need for massive transfusion and emergent therapeutic intervention for hemorrhage control.

If at First You Do Not Succeed: Consideration of Attempts in Patients With Trauma.

INTRODUCTION: Failed extubation in critically ill patients is associated with poor outcomes. In critically ill trauma patients who have failed extubation, providers must decide whether to proceed with tracheostomy or attempt extubation again. The aim of this study was to describe the natural history of failed extubation in trauma patients and determine whether tracheostomy or a second attempt at extubation is more appropriate. METHODS: Trauma patients admitted to our level I trauma center from 2013 to 2019 were identified. Patients who failed extubation, defined as an unplanned reintubation within 48 h of extubation, were included. Patients who immediately underwent tracheostomy were compared with those who had subsequent attempts at extubation. The primary outcome was mortality, and the secondary outcomes were intensive care unit (ICU) length of stay (LOS), ventilator days, and hospital LOS. RESULTS: The population included 93 patients who failed extubation and met inclusion criteria. A total of 53 patients were ultimately successfully extubated, whereas 40 patients underwent a tracheostomy. There was no statistically significant difference in demographics or injury patterns. Patients who underwent tracheostomy had a longer ICU LOS and more ventilator days. There was no difference in mortality or hospital LOS between the two groups. CONCLUSIONS: In trauma patients, those who underwent subsequent attempts at extubation did not experience higher rates of mortality than those who received a tracheostomy. Tracheostomy was associated with longer ICU LOS and ventilator days. In certain situations, it is appropriate to consider subsequent attempts at extubation in trauma patients who fail extubation rather than proceeding directly to tracheostomy.