[The impact of climate change on health]. / Impacto del cambio climático en la salud.

Climate changes evidenced by an increase in our planet's mean temperature, changes in rainfall, increased sea level and extreme weather conditions, favor air and soil contamination, ocean acidification, droughts, floods, heat waves and forest fires, which affect the health and wellbeing of exposed populations. These changes will exert negative effects on respiratory and cardiovascular systems, nutritional status, burden of infectious diseases, especially vector-borne infections, and human mental health. Moreover, environmental damages, such as loss of biodiversity, ecological collapse and deterioration of socioeconomic factors such as agricultural and fishery production, and the loss of habitable land, will impulse massive migrations. This article summarizes the impact that climate change is expected to have on respiratory, cardiovascular and infectious diseases and its repercussions on people of extreme ages. It is imperative to achieve the immediate commitment of worldwide national governments to control green-house gas emissions. The appropriate technology does exist, but political will is urgently needed to accomplish this goal.

Metastatic small bowel adenocarcinoma: role of metastasectomy and systemic chemotherapy.

BACKGROUND: Metastatic small bowel adenocarcinoma (SBA) has a poor prognosis. Due to its rarity, high-quality data are lacking to guide treatment. This retrospective analysis was conducted to help characterize the treatment options for patients with metastatic SBA while providing clinically meaningful prognostic information. PATIENTS AND METHODS: In total, 437 patients who initially presented with or developed metastatic SBA between September 1977 and September 2019 were identified from the MD Anderson Tumor Registry. Clinical data were collected from review of the medical record. Overall response rates (ORR), time to progression (TTP), and overall survival (OS) were assessed across various treatments and treatment lines. RESULTS: The median OS from diagnosis of metastatic disease was 15.9 months [95% confidence interval (CI): 14.3-17.9]. Seventy-five patients (17.1%) underwent metastasectomy, which was associated with a median OS of 34.5 versus 17.1 months among patients who received chemotherapy alone (P < 0.001). Fluoropyrimidine plus platinum (n = 164) was the most common first-line chemotherapy, associated with an ORR of 59% and TTP of 8.1 months. Irinotecan with 5-FU (n = 101) was the most common second-line therapy associated with an ORR of 31% and TTP of 4.0 months. Twenty-two patients received immunotherapy; 5 of 6 patients with deficient mismatch repair (dMMR) responded, while 0 of 16 with proficient mismatch repair (pMMR) responded. Taxane-based chemotherapy was given to 34 patients with an ORR of 21% and a median TTP of 2.4 months. Among 11 patients who received anti-epidermal-growth-factor-receptor (EGFR) monotherapy, the best response was stable disease (SD) in 1 patient. CONCLUSIONS: In well-selected patients with SBA, metastasectomy appears to be associated with improved OS. This improvement was seen across metastasectomy sites, including liver, lung and peritoneal. Anti-programmed cell death protein 1 (PD-1) based immunotherapy was active for dMMR SBA but not pMMR SBA. While taxane-based chemotherapy demonstrates therapeutic activity, the activity of anti-EGFR therapy was limited.

Impacto del cambio climático en la salud / The impact of climate change on health

Climate changes evidenced by an increase in our planet's mean temperature, changes in rainfall, increased sea level and extreme weather conditions, favor air and soil contamination, ocean acidification, droughts, floods, heat waves and forest fires, which affect the health and wellbeing of exposed populations. These changes will exert negative effects on respiratory and cardiovascular systems, nutritional status, burden of infectious diseases, especially vector-borne infections, and human mental health. Moreover, environmental damages, such as loss of biodiversity, ecological collapse and deterioration of socioeconomic factors such as agricultural and fishery production, and the loss of habitable land, will impulse massive migrations. This article summarizes the impact that climate change is expected to have on respiratory, cardiovascular and infectious diseases and its repercussions on people of extreme ages. It is imperative to achieve the immediate commitment of worldwide national governments to control green-house gas emissions. The appropriate technology does exist, but political will is urgently needed to accomplish this goal.

Indicaciones inhabituales de trasplante hepático. resultados / Unusual indications for liver transplantation. results

Resumen Introducción: El trasplante hepático (TH), es una terapia establecida en el tratamiento de diversas enfermedades del hígado agudas y crónicas terminales y del carcinoma hepatocelular (CHC). Las principales indicaciones en nuestro medio son la cirrosis de diferentes etiologías, el CHC, la atresia de vías biliares en niños y la falla hepática fulminante (FHF). Menos del 10% corresponden a indicaciones inhabituales, que incluyen pacientes con una miscelánea de enfermedades entre las cuales están la enfermedad poliquística hepática (EPH), enfermedades metabólicas (Niemann-Pick, otras), el síndrome hepato/portopulmonar, metástasis de diferentes tumores, etc. Objetivo: Describir y evaluar los resultados obtenidos con el trasplante hepático en estas indicaciones. Materiales y Método: Estudio de cohorte no concurrente que incluyó los TH por indicaciones inhabituales realizados entre marzo de 1997 y diciembre de 2016. De 295 TH realizados, 34 (11,5%) fueron por estas indicaciones. Resultados: Las causas más frecuentes fueron el síndrome porto/hepatopulmonar en 11 (40,7%) pacientes y la EPH en 9 (26,5%). Las enfermedades metabólicas representaron la tercera indicación, con 5 (14,7%) casos. Siete (20,6%) pacientes eran menores de 18 años. Las complicaciones más frecuentes fueron biliares y la trombosis de arteria hepática en 6 (17,6%) y 4 (11,8%) casos respectivamente; estos últimos eran portadores de una EPH masiva. Cuatro (12,5%) pacientes requirieron retrasplante. La mortalidad a 90 días fue de 2 (5,9%) enfermos. Conclusión: El TH es una opción factible en este grupo de pacientes con resultados similares a los obtenidos en las indicaciones clásicas.

Introduction: Liver transplantation (LT) is an established therapy in the treatment of several acute and chronic end-stage liver diseases and hepatocellular carcinoma (HCC). The main indications worldwide are cirrhosis of different etiologies, HCC, biliary atresia in children, and fulminant hepatic failure (FHF). Less than 10% concerns unusual indications which include patients with miscellaneous diseases among which are hepatic polycystic disease (HPD), metabolic diseases (Niemann-Pick, others), portal/hepatopulmonary syndrome, metastasis of different tumors, among others. Aim: The objective of the study is to describe and asses the results obtained with liver transplantation in these indications. Materials and Method: We performed a non-concurrent cohort study that included all LT due to unusual indications between March 1997 and December 2016 in a university medical center. Of 295 TH performed, 34 (11.75%) were due to these indications. Results: The most frequent causes were the portal/hepatopulmonary syndrome in 11 (40.7%) patients and HPD in 9 (26.5%). Metabolic diseases accounted for the third indication in 5 (14.7%) cases. Seven (20.6%) patients were less than 18 years old. The most frequent complications were biliary and hepatic artery thrombosis (HAT) in 6 (17.6%) and 4 (11.8%) cases, respectively. Patients complicated by a HAT suffered a massive EPH. Four (12.5%), required retransplantation. Mortality at 90 days was 2 (5.9%). Conclusión: LT is a feasible option in this group of patients with results similar to those obtained in classic indications of LT.

Evaluación de la infección por VIH en Chile: pronunciamiento del Comité VIH de la Academia Chilena de Medicina / Evaluation of HIV epidemic in Chile: a statement of the Chilean Academy of Medicine

The Chilean Academy of Medicine convened a commission to evaluate the status of HIV epidemic and the national response to it, regarding its achievements, gaps and challenges, aiming to recommend actions to optimize assessment quality and national response. This publication summarizes the agreed upon opinion of its members. The epidemic is overwhelmingly sexually transmitted, predominant in homo/bisexual men. Vertical transmission is very low. An increasing number of new diagnoses is occurring, with relative over representation of foreign people lately. There is a legal guarantee of confidentiality, nondiscrimination and treatment for those affected, both in the private and public sector. All public health services have active HIV care units. Modern antiviral drugs and monitoring tests are also available. Despite these clear achievements, insufficient, occasionally inadequate public policies and certain rigid regulations thwart optimal effectivity and efficiency of the programs, contributing to the slow and incomplete compliance with international commitments. Shortcomings worth highlighting are: suboptimal educational and preventive programs directed to youngsters, vulnerable and general population; persistent underdiagnosis of infected population; cumbersome requirements to request and inform diagnostic tests, thus discouraging testing; excessive centralization and long latency of diagnosis confirmation and monitoring tests; incomplete epidemiologic analysis and public reporting of findings; non flexibility and slow updating of therapeutic guidelines; insufficient adaptation of care and drug delivery modalities to patients' needs; excessive administrative requirements at care centers and restrictive legislation for outcome and interventional clinical research. Recommendations to deal with these issues were proposed.

[Evaluation of HIV epidemic in Chile. A statement of the Chilean Academy of Medicine]. / Evaluación de la infección por VIH en Chile: pronunciamiento del Comité VIH de la Academia Chilena de Medicina.

The Chilean Academy of Medicine convened a commission to evaluate the status of HIV epidemic and the national response to it, regarding its achievements, gaps and challenges, aiming to recommend actions to optimize assessment quality and national response. This publication summarizes the agreed upon opinion of its members. The epidemic is overwhelmingly sexually transmitted, predominant in homo/bisexual men. Vertical transmission is very low. An increasing number of new diagnoses is occurring, with relative over representation of foreign people lately. There is a legal guarantee of confidentiality, nondiscrimination and treatment for those affected, both in the private and public sector. All public health services have active HIV care units. Modern antiviral drugs and monitoring tests are also available. Despite these clear achievements, insufficient, occasionally inadequate public policies and certain rigid regulations thwart optimal effectivity and efficiency of the programs, contributing to the slow and incomplete compliance with international commitments. Shortcomings worth highlighting are: suboptimal educational and preventive programs directed to youngsters, vulnerable and general population; persistent underdiagnosis of infected population; cumbersome requirements to request and inform diagnostic tests, thus discouraging testing; excessive centralization and long latency of diagnosis confirmation and monitoring tests; incomplete epidemiologic analysis and public reporting of findings; non flexibility and slow updating of therapeutic guidelines; insufficient adaptation of care and drug delivery modalities to patients' needs; excessive administrative requirements at care centers and restrictive legislation for outcome and interventional clinical research. Recommendations to deal with these issues were proposed.

[Evolution of mortality, retention and loss to follow up of HIV infected subjects followed in a special clinic]. / Evolución de mortalidad, abandono, traslado y retención a corto, mediano y largo plazo en pacientes con infección por VIH: Fundación Arriarán 1990-2015.

BACKGROUND: The HIV epidemic reached Chile in late 1980s and as an early response, AIDS care centers were organized. Fundación Arriarán (FA) was the first center. Free antiretroviral therapy (ART) was later provided with progressive coverage and complexity over the years. AIM: To quantify evolution of mortality, retention and loss to follow up (LTFU) over 25 years according to different periods of access to ART, from no availability to full coverage with current drugs at FA center. MATERIAL AND METHODS: Retrospective analysis of FA database of 5,080 adults admitted between 1990 and 2014. The sample was distributed in 7 groups: A: no ART (1990-92), B: monotherapy, C: dual therapy, D: dual/triple ART, E: early triple therapy with incomplete coverage, F same as E but with complete coverage and G: contemporary ART (2008-14). Mortality, retention and LTFU were evaluated at 1, 3, 5, 7 and 10 years and at 31/12/2015. RESULTS: Mortality varied from 40% to 2%, and 62% to 7% at 1 and 5 years, for groups A and G respectively; from 71% to 16% at 10 years for groups A and E, respectively. Retention at 5 years were 28%, 23%, 39%, 62%, 75%, 75% and 77% for groups A to G, respectively. LTFU was 10%, 19%, 15%, 17%, 9% 12% and 10% at 5 years for same groups, respectively. At 12/31/2015 22% of patients had died, 11% were LTFU, 60% were retained in care and 6% had been transferred. CONCLUSIONS: There is a marked reduction in mortality and increase in retention of HIV patients' concomitant to expanded access to modern therapy, although LTFU remains a problem.

Evolución de mortalidad, abandono, traslado y retención a corto, mediano y largo plazo en pacientes con infección por VIH: Fundación Arriarán 1990-2015 / Evolution of mortality, retention and loss to follow up of HIV infected subjects followed in a special clinic

Background: The HIV epidemic reached Chile in late 1980s and as an early response, AIDS care centers were organized. Fundación Arriarán (FA) was the first center. Free antiretroviral therapy (ART) was later provided with progressive coverage and complexity over the years. Aim: To quantify evolution of mortality, retention and loss to follow up (LTFU) over 25 years according to different periods of access to ART, from no availability to full coverage with current drugs at FA center. Material and Methods: Retrospective analysis of FA database of 5,080 adults admitted between 1990 and 2014. The sample was distributed in 7 groups: A: no ART (1990-92), B: monotherapy, C: dual therapy, D: dual/triple ART, E: early triple therapy with incomplete coverage, F same as E but with complete coverage and G: contemporary ART (2008-14). Mortality, retention and LTFU were evaluated at 1, 3, 5, 7 and 10 years and at 31/12/2015. Results: Mortality varied from 40% to 2%, and 62% to 7% at 1 and 5 years, for groups A and G respectively; from 71% to 16% at 10 years for groups A and E, respectively. Retention at 5 years were 28%, 23%, 39%, 62%, 75%, 75% and 77% for groups A to G, respectively. LTFU was 10%, 19%, 15%, 17%, 9% 12% and 10% at 5 years for same groups, respectively. At 12/31/2015 22% of patients had died, 11% were LTFU, 60% were retained in care and 6% had been transferred. Conclusions: There is a marked reduction in mortality and increase in retention of HIV patients' concomitant to expanded access to modern therapy, although LTFU remains a problem.

Phase II study of nab-paclitaxel in refractory small bowel adenocarcinoma and CpG island methylator phenotype (CIMP)-high colorectal cancer.

Background: Hypermethylation of promoter CpG islands [CpG island methylator phenotype (CIMP)] represents a unique pathway for the development of colorectal cancer (CRC), characterized by lack of chromosomal instability and a low rate of adenomatous polyposis coli (APC) mutations, which have both been correlated with taxane resistance. Similarly, small bowel adenocarcinoma (SBA), a rare tumor, also has a low rate of APC mutations. This phase II study evaluated taxane sensitivity in SBA and CIMP-high CRC. Patients and methods: The primary objective was Response Evaluation Criteria in Solid Tumors version 1.1 response rate. Eligibility included Eastern Cooperative Oncology Group performance status 0/1, refractory disease, and SBA or CIMP-high metastatic CRC. Nab-paclitaxel was initially administered at a dose of 260 mg/m2 every 3 weeks but was reduced to 220 mg/m2 owing to toxicity. Results: A total of 21 patients with CIMP-high CRC and 13 with SBA were enrolled from November 2012 to October 2014. The efficacy-assessable population (patients who received at least three doses of the treatment) comprised 15 CIMP-high CRC patients and 10 SBA patients. Common grade 3 or 4 toxicities were fatigue (12%), neutropenia (9%), febrile neutropenia (9%), dehydration (6%), and thrombocytopenia (6%). No responses were seen in the CIMP-high CRC cohort and two partial responses were seen in the SBA cohort. Median progression-free survival was significantly greater in the SBA cohort than in the CIMP-high CRC cohort (3.2 months compared with 2.1 months, P = 0.03). Neither APC mutation status nor CHFR methylation status correlated with efficacy in the CIMP-high CRC cohort. In vivo testing of paclitaxel in an SBA patient-derived xenograft validated the activity of taxanes in this disease type. Conclusion: Although preclinical studies suggested taxane sensitivity was associated with chromosomal stability and wild-type APC, we found that nab-paclitaxel was inactive in CIMP-high metastatic CRC. Nab-paclitaxel may represent a novel therapeutic option for SBA.

Surfaceome profiling enables isolation of cancer-specific exosomal cargo in liquid biopsies from pancreatic cancer patients.

Background: Detection of circulating tumor DNA can be limited due to their relative scarcity in circulation, particularly while patients are actively undergoing therapy. Exosomes provide a vehicle through which cancer-specific material can be enriched from the compendium of circulating non-neoplastic tissue-derived nucleic acids. We carried out a comprehensive profiling of the pancreatic ductal adenocarcinoma (PDAC) exosomal 'surfaceome' in order to identify surface proteins that will render liquid biopsies amenable to cancer-derived exosome enrichment for downstream molecular profiling. Patients and methods: Surface exosomal proteins were profiled in 13 human PDAC and 2 non-neoplastic cell lines by liquid chromatography-mass spectrometry. A total of 173 prospectively collected blood samples from 103 PDAC patients underwent exosome isolation. Droplet digital PCR was used on 74 patients (136 total exosome samples) to determine baseline KRAS mutation call rates while patients were on therapy. PDAC-specific exosome capture was then carried out on additional 29 patients (37 samples) using an antibody cocktail directed against selected proteins, followed by droplet digital PCR analysis. Exosomal DNA in a PDAC patient resistant to therapy were profiled using a molecular barcoded, targeted sequencing panel to determine the utility of enriched nucleic acid material for comprehensive molecular analysis. Results: Proteomic analysis of the exosome 'surfaceome' revealed multiple PDAC-specific biomarker candidates: CLDN4, EPCAM, CD151, LGALS3BP, HIST2H2BE, and HIST2H2BF. KRAS mutations in total exosomes were detected in 44.1% of patients undergoing active therapy compared with 73.0% following exosome capture using the selected biomarkers. Enrichment of exosomal cargo was amenable to molecular profiling, elucidating a putative mechanism of resistance to PARP inhibitor therapy in a patient harboring a BRCA2 mutation. Conclusion: Exosomes provide unique opportunities in the context of liquid biopsies for enrichment of tumor-specific material in circulation. We present a comprehensive surfaceome characterization of PDAC exosomes which allows for capture and molecular profiling of tumor-derived DNA.

Estudio pre-trasplante hepático: ¿qué buscar y cómo hacerlo? Si algo es positivo: ¿qué hacemos? / Liver transplant pre-study: what to search for and how to do it? what shall we do in case of positive findings?

The process of evaluation of candidate patients for liver transplantation should include the risk of infectious diseases in order to prevent the drop out of the waiting list due to infections or the occurrence of these in the post-transplant period. Cirrhotic patients in the pre-transplant stage are very ill and usually have severe infections. The most common is spontaneous bacterial peritonitis, but they can also present urinary infections and pneumonias. Mortality due to infectious causes has been reported up to 40% in patients on the transplant waiting list. The transplanted patients may have a poor immune response to vaccination, so the optimal immunization period is pre-transplant. In the post-transplant period, Gram-negative bacterial infections are one of the main complications. Invasive fungal infections and cytomegalovirus can also have a high impact on morbidity and mortality. Transplanted patients may also have mycobacterial infections in relation to a latent tuberculosis infection. In the following article we present the pre-transplant evaluations, vaccination schemes and antimicrobial prophylaxis that are used in liver transplantation.

El proceso de evaluación de pacientes candidatos para trasplante hepático debe incluir el riesgo de enfermedades infecciosas a fin de prevenir la salida de la lista por infecciones o la ocurrencia de éstas en el período post-trasplante. Los pacientes cirróticos en la etapa pre-trasplante están muy enfermos y suelen presentar infecciones graves. La más común es la peritonitis bacteriana espontánea, pero también pueden presentar infecciones urinarias y neumonías. La mortalidad por causa infecciosa se ha reportado hasta en 40% en pacientes en lista de espera de trasplante. Los pacientes trasplantados pueden tener una pobre respuesta inmune a la vacunación, por lo que el momento óptimo de inmunización es en el período pretrasplante. En el período post-trasplante las infecciones bacterianas por Gram negativos son una de las principales complicaciones. Las infecciones por hongos invasores y el citomegalovirus también pueden tener un alto impacto en morbilidad y mortalidad. Los pacientes trasplantados también pueden presentar infecciones por micobacterias en relación a una infección latente por tuberculosis. En el siguiente artículo se presentan las evaluaciones pre-trasplante, esquemas de vacunación y profilaxis antimicrobiana que se utilizan en trasplante hepático.

[A woman with acute bilateral vision loss]. / Een vrouw met acuut bilateraal visusverlies.

A 46-year-old woman presented to the emergency department with progressive bilateral loss of vision followed by headache. She had been taking topiramate 25 mg daily for eight days before presentation. In the end, she was diagnosed with topiramate-induced acute glaucoma for which she received appropriate treatment.

Sublingual tacrolimus administration provides similar drug exposure to per-oral route employing lower doses in liver transplantation: a pilot study.

BACKGROUND: Per-oral tacrolimus administration is not always practicable. Sublingual administration is a potential alternative, but its feasibility and effectiveness compared with oral route has not been established. AIM: To compare tacrolimus drug exposure after sublingual and oral administration in liver transplant recipients. METHODS: Experimental, open-label, non-randomised, cross-over study. Tacrolimus exposure was evaluated in 32 liver transplant recipients receiving oral administration. 12 h tacrolimus area-under-the-curve (AUC0-12 h ) was calculated using tacrolimus blood concentrations at 0-0.5-1-2-4-6-8-12 hrs post-dose. Recipients were switched to sublingual administration, and dose was adjusted to reach similar trough levels, new AUC0-12 h was calculated. Correlation between AUC0-12 h and trough levels was determined for both oral and sublingual phases. RESULTS: Similar trough levels were accomplished with oral and sublingual administration (6.68 ± 2 ng/mL vs. 6.62 ± 1.9 ng/mL (P = 0.8)). Although concentration 2 h post dose was higher in oral phase (15.36 ± 7.14 vs. 13.18 ± 5.64, P = 0.015), AUC0-12 h was similar in both phases (116.6 ± 34.6 vs. 111.5 ± 36.93 ng/mL* h, P = 0.19). Daily dose of tacrolimus required in sublingual phase was 37% lower than that used in oral phase (P < 0.0001), suggesting significantly increased bioavailability of tacrolimus when employing sublingual route. Good correlation between AUC0-12 h and trough levels was observed in sublingual phase (r2 = 0.74). Twenty-two recipients were maintained on sublingual administration after the end of study (mean follow-up: 18.7 ± 5.8 months). No difference in liver function tests or rejection rates was found during follow-up period. CONCLUSIONS: Sublingual administration of tacrolimus is feasible and provides similar drug exposure compared with oral administration. In our study, at long-term follow-up, sublingual administration was not associated with liver transplant rejection.

A predictive model of inflammatory markers and patient-reported symptoms for cachexia in newly diagnosed pancreatic cancer patients.

BACKGROUND: Cachexia is a frequent manifestation of pancreatic cancer, can limit a patient's ability to take chemotherapy, and is associated with shortened survival. We developed a model to predict the early onset of cachexia in advanced pancreatic cancer patients. METHODS: Patients with newly diagnosed, untreated metastatic or locally advanced pancreatic cancer were included. Serum cytokines were drawn prior to therapy. Patient symptoms were recorded using the M.D. Anderson Symptom Inventory (MDASI). Our primary endpoint was either 10% weight loss or death within 60 days of the start of therapy. RESULTS: Twenty-seven of 89 patients met the primary endpoint (either having lost 10% of body weight or having died within 60 days of the start of treatment). In a univariate analysis, smoking, history symptoms of pain and difficulty swallowing, high levels of MK, CXCL-16, IL-6, TNF-a, and low IL-1b all correlated with this endpoint. We used recursive partition to fit a regression tree model, selecting four of 26 variables (CXCL-16, IL-1b, pain, swallowing difficulty) as important in predicting cachexia. From these, a model of two cytokines (CXCL-16 > 5.135 ng/ml and IL-1b < 0.08 ng/ml) demonstrated a better sensitivity and specificity for this outcome (0.70 and 0.86, respectively) than any individual cytokine or tumor marker. CONCLUSIONS: Cachexia is frequent in pancreatic cancer; one in three patients met our endpoint of 10% weight loss or death within 60 days. Inflammatory cytokines are better than conventional tumor markers at predicting this outcome. Recursive partitioning analysis suggests that a model of CXCL-16 and IL-1B may offer a better ability than individual cytokines to predict this outcome.

Neoadjuvant therapy versus upfront surgical strategies in resectable pancreatic cancer: A Markov decision analysis.

BACKGROUND: Neoadjuvant therapy is gaining acceptance as a valid treatment option for borderline resectable pancreatic cancer; however, its value for clearly resectable pancreatic cancer remains controversial. The aim of this study was to use a Markov decision analysis model, in the absence of adequately powered randomized trials, to compare the life expectancy (LE) and quality-adjusted life expectancy (QALE) of neoadjuvant therapy to conventional upfront surgical strategies in resectable pancreatic cancer patients. METHODS: A Markov decision model was created to compare two strategies: attempted pancreatic resection followed by adjuvant chemoradiotherapy and neoadjuvant chemoradiotherapy followed by restaging with, if appropriate, attempted pancreatic resection. Data obtained through a comprehensive systematic search in PUBMED of the literature from 2000 to 2015 were used to estimate the probabilities used in the model. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Of the 786 potentially eligible studies identified, 22 studies met the inclusion criteria and were used to extract the probabilities used in the model. Base case analyses of the model showed a higher LE (32.2 vs. 26.7 months) and QALE (25.5 vs. 20.8 quality-adjusted life months) for patients in the neoadjuvant therapy arm compared to upfront surgery. Probabilistic sensitivity analyses for LE and QALE revealed that neoadjuvant therapy is favorable in 59% and 60% of the cases respectively. CONCLUSION(S): Although conceptual, these data suggest that neoadjuvant therapy offers substantial benefit in LE and QALE for resectable pancreatic cancer patients. These findings highlight the value of further prospective randomized trials comparing neoadjuvant therapy to conventional upfront surgical strategies.

Utility of a molecular prescreening program in advanced colorectal cancer for enrollment on biomarker-selected clinical trials.

BACKGROUND: Incorporation of multiple enrichment biomarkers into prospective clinical trials is an active area of investigation, but the factors that determine clinical trial enrollment following a molecular prescreening program have not been assessed. PATIENTS AND METHODS: Patients with 5-fluorouracil-refractory metastatic colorectal cancer at the MD Anderson Cancer Center were offered screening in the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) program to identify eligibility for companion phase I or II clinical trials with a therapy targeted to an aberration detected in the patient, based on testing by immunohistochemistry, targeted gene sequencing panels, and CpG island methylation phenotype assays. RESULTS: Between August 2010 and December 2013, 484 patients were enrolled, 458 (95%) had a biomarker result, and 157 (32%) were enrolled on a clinical trial (92 on biomarker-selected and 65 on nonbiomarker selected). Of the 458 patients with a biomarker result, enrollment on biomarker-selected clinical trials was ninefold higher for predefined ATTACC-companion clinical trials as opposed to nonpredefined biomarker-selected clinical trials, 17.9% versus 2%, P < 0.001. Factors that correlated positively with trial enrollment in multivariate analysis were higher performance status, older age, lack of standard of care therapy, established patient at MD Anderson, and the presence of an eligible biomarker for an ATTACC-companion study. Early molecular screening did result in a higher rate of patients with remaining standard of care therapy enrolling on ATTACC-companion clinical trials, 45.1%, in contrast to nonpredefined clinical trials, 22.7%; odds ratio 3.1, P = 0.002. CONCLUSIONS: Though early molecular prescreening for predefined clinical trials resulted in an increase rate of trial enrollment of nonrefractory patients, the majority of patients enrolled on clinical trials were refractory to standard of care therapy. Within molecular prescreening programs, tailoring screening for preidentified and open clinical trials, temporally linking screening to treatment and optimizing both patient and physician engagement are efforts likely to improve enrollment on biomarker-selected clinical trials. CLINICAL TRIALS NUMBER: The study NCT number is NCT01196130.

Minimally invasive genomic and transcriptomic profiling of visceral cancers by next-generation sequencing of circulating exosomes.

BACKGROUND: The ability to perform comprehensive profiling of cancers at high resolution is essential for precision medicine. Liquid biopsies using shed exosomes provide high-quality nucleic acids to obtain molecular characterization, which may be especially useful for visceral cancers that are not amenable to routine biopsies. PATIENTS AND METHODS: We isolated shed exosomes in biofluids from three patients with pancreaticobiliary cancers (two pancreatic, one ampullary). We performed comprehensive profiling of exoDNA and exoRNA by whole genome, exome and transcriptome sequencing using the Illumina HiSeq 2500 sequencer. We assessed the feasibility of calling copy number events, detecting mutational signatures and identifying potentially actionable mutations in exoDNA sequencing data, as well as expressed point mutations and gene fusions in exoRNA sequencing data. RESULTS: Whole-exome sequencing resulted in 95%-99% of the target regions covered at a mean depth of 133-490×. Genome-wide copy number profiles, and high estimates of tumor fractions (ranging from 56% to 82%), suggest robust representation of the tumor DNA within the shed exosomal compartment. Multiple actionable mutations, including alterations in NOTCH1 and BRCA2, were found in patient exoDNA samples. Further, RNA sequencing of shed exosomes identified the presence of expressed fusion genes, representing an avenue for elucidation of tumor neoantigens. CONCLUSIONS: We have demonstrated high-resolution profiling of the genomic and transcriptomic landscapes of visceral cancers. A wide range of cancer-derived biomarkers could be detected within the nucleic acid cargo of shed exosomes, including copy number profiles, point mutations, insertions, deletions, gene fusions and mutational signatures. Liquid biopsies using shed exosomes has the potential to be used as a clinical tool for cancer diagnosis, therapeutic stratification and treatment monitoring, precluding the need for direct tumor sampling.

Controversias en el diagnóstico de enfermedad por hígado graso no alcohólico / Controversies in the diagnosis of non-alcoholic fatty liver disease

There has been an increase in the prevalence of nonalcoholic fatty liver disease (NAFLD) throughout the western world and especially in Latin America. This condition is associated with metabolic syndrome, risk of diabetes, cardiovascular risk and extrahepatic cancer. However, in patients with NAFLD, risk of mortality from diseases affecting the liver does not exceed 5 percent in contrast to 60 percent when advanced fibrosis is present. Only 10 to 20 percent of patients with NAFLD have non-alcoholic steatohepatitis (NASH), a condition that can potentially progress to fibrosis and cirrhosis. The non-invasive diagnostic tools for discriminating current patients at risk of progression to advanced fibrosis are sub-optimal. Clinical variables and routine laboratory tests help in detecting NAFLD but do not allow discrimination of NASH patients. New diagnostic tools could allow prediction of NASH such as markers of oxidative stress, inflammatory markers and markers of apoptosis. Regarding liver fibrosis biomarkers, there are indirect markers that are related to the degree of liver function and direct markers that reflect the dynamics of extracellular matrix. Imaging methods such as ultrasound-based elastography, (ARFI) and magnetic resonance elastography have shown a good correlation with the degree of fibrosis. Finally various predictor models that combine clinical and laboratory variables have a very good correlation with the degree of fibrosis. Although there is still some controversy on its clinical utility, liver biopsy still plays a role in NAFLD severity assessment for initiation of drug therapy.

Se ha registrado un aumento en la prevalencia de la enfermedad por hígado graso no alcohólico HGNA (NAFLD, por su sigla en inglés) en todo el mundo occidental y especialmente en Latinoamérica. Esta condición se relaciona con síndrome metabólico, riesgo de diabetes, riesgo cardiovascular y cáncer extrahepático. Sin embargo, en pacientes con HGNA el riesgo de mortalidad por enfermedades que afectan al hígado no supera el 5 por ciento en contraste con 60 por ciento cuando hay fibrosis avanzada. Sólo 10 a 20 por ciento de los pacientes presenta esteatohepatitis no alcohólica EHNA (NASH, por su sigla en inglés), una condición que potencialmente puede progresar a fibrosis y cirrosis. Las herramientas de diagnóstico no invasivo actuales para discriminar pacientes con riesgo de progresión a fibrosis avanzada son subóptimas. Las variables clínicas y exámenes de laboratorio habituales ayudan en la detección de HGNA,pero no permiten discriminar pacientes con EHNA. Nuevas herramientas diagnósticas podrían permitir predecir EHNA como marcadores de estrés oxidativo, marcadores de inflamación y de apoptosis. De los marcadores de fibrosis existen los indirectos que se relacionan con el grado de función hepática, marcadores directos que reflejan la dinámica de la matriz extracelular. Los métodos de imagen como la elastografía por ultrasonido (ARFI), elastografía por resonancia magnética, han demostrado una buena correlación con el grado de fibrosis. Finalmente, diversos índices que combinan variables clínicas y de laboratorio tienen una muy buena correlación con el grado de fibrosis. La biopsia aun cumple un rol a pesar de la controversia en su real necesidad para iniciar tratamiento.