Extracellular Vesicle and Particle Biomarkers Define Multiple Human Cancers.

There is an unmet clinical need for improved tissue and liquid biopsy tools for cancer detection. We investigated the proteomic profile of extracellular vesicles and particles (EVPs) in 426 human samples from tissue explants (TEs), plasma, and other bodily fluids. Among traditional exosome markers, CD9, HSPA8, ALIX, and HSP90AB1 represent pan-EVP markers, while ACTB, MSN, and RAP1B are novel pan-EVP markers. To confirm that EVPs are ideal diagnostic tools, we analyzed proteomes of TE- (n = 151) and plasma-derived (n = 120) EVPs. Comparison of TE EVPs identified proteins (e.g., VCAN, TNC, and THBS2) that distinguish tumors from normal tissues with 90% sensitivity/94% specificity. Machine-learning classification of plasma-derived EVP cargo, including immunoglobulins, revealed 95% sensitivity/90% specificity in detecting cancer. Finally, we defined a panel of tumor-type-specific EVP proteins in TEs and plasma, which can classify tumors of unknown primary origin. Thus, EVP proteins can serve as reliable biomarkers for cancer detection and determining cancer type.

Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Author Correction: Commensal-driven immune zonation of the liver promotes host defence.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03346-0.

Commensal-driven immune zonation of the liver promotes host defence.

The liver connects the intestinal portal vasculature with the general circulation, using a diverse array of immune cells to protect from pathogens that translocate from the gut1. In liver lobules, blood flows from portal triads that are situated in periportal lobular regions to the central vein via a polarized sinusoidal network. Despite this asymmetry, resident immune cells in the liver are considered to be broadly dispersed across the lobule. This differs from lymphoid organs, in which immune cells adopt spatially biased positions to promote effective host defence2,3. Here we used quantitative multiplex imaging, genetic perturbations, transcriptomics, infection-based assays and mathematical modelling to reassess the relationship between the localization of immune cells in the liver and host protection. We found that myeloid and lymphoid resident immune cells concentrate around periportal regions. This asymmetric localization was not developmentally controlled, but resulted from sustained MYD88-dependent signalling induced by commensal bacteria in liver sinusoidal endothelial cells, which in turn regulated the composition of the pericellular matrix involved in the formation of chemokine gradients. In vivo experiments and modelling showed that this immune spatial polarization was more efficient than a uniform distribution in protecting against systemic bacterial dissemination. Together, these data reveal that liver sinusoidal endothelial cells sense the microbiome, actively orchestrating the localization of immune cells, to optimize host defence.

Predicting Survival in Mucinous Adenocarcinoma of the Appendix: Demographics, Disease Presentation, and Treatment Methodology.

BACKGROUND: Mucinous adenocarcinoma of the appendix (MACA) follows a complex disease course with variable survival. Large-scale predictive modeling may determine subtle yet important prognostic factors otherwise unseen in smaller cohort analyses. METHODS: Patients with MACA were identified from the Surveillance, Epidemiology, and End Results (SEER) Research Plus database (2005-2019). Primary, secondary, and tertiary outcomes were disease-specific survival (DSS), overall survival (OS), and average annual percent change (AAPC) in incidence. RESULTS: Among 4,258 included patients, MACA was most frequently diagnosed at 50 to 69 years (52.0%), with female preponderance (55.9%). MACA incidence AAPC was 3.8 (95% confidence interval [CI] 1.9-5.9). For patients with exclusive, first-diagnosis MACA included in survival analysis (3,222 patients), median DSS and OS were 118 and 88 months, respectively. In DSS-based multivariable analysis, worse prognosis was associated with non-Hispanic Black background (HR 1.36, 95% CI 1.02-1.82; p = 0.036), high grade (grade 3 HR 3.10, 95% CI 2.44-3.92; p < 0.001), lymphatic spread (HR 2.73, 95% CI 2.26-3.30; p < 0.001), and distant metastasis (HR 5.84, 95% CI 3.86-8.83; p < 0.001). In subcohort analysis of patients with rationale for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC, 2,387 patients), CRS-HIPEC was associated with survival benefit compared with surgery alone but only for moderate-grade tumors (median DSS/OS 138/138 vs. 116/87 months; p < 0.001). CONCLUSIONS: Mucinous adenocarcinoma of the appendix incidence is increasing in the United States. Survival rates are affected by both demographics and classical risk factors, and CRS-HIPEC-associated survival benefit predominantly occurs in moderate-grade tumors. Further exploration of biologic and clinicopathologic features may enhance risk stratification for this disease.

Increased prevalence of Kidney cysts in individuals carrying heterozygous COL4A3 or COL4A4 pathogenic variants.

BACKGROUND: Clinical variability among individuals with heterozygous pathogenic/likely pathogenic (P/LP) variants in the COL4A3/COL4A4 genes (also called autosomal dominant Alport syndrome or COL4A3/COL4A4 related disorder) is huge; many individuals are asymptomatic or show microhematuria, while others may develop proteinuria and chronic kidney disease (CKD). The prevalence of simple kidney cysts (KC) in the general population varies according to age, and patients with advanced CKD are prone to have them. A possible association between heterozygous COL4A3, COL4A4, and COL4A5 P/LP variants and KC has been described in small cohorts. The presence of KC in a multicenter cohort of individuals with heterozygous P/LP variants in the COL4A3/COL4A4 genes is assessed in this study. METHODS: We evaluated the presence of KC by ultrasound in 157 individuals with P/LP variants in COL4A3 (40.7%) or COL4A4 (53.5%) without kidney replacement therapy. The association between presence of KC and age, proteinuria, eGFR, and causative gene was analyzed. Prevalence of KC was compared with historical case series in the general population. RESULTS: Half of the individuals with P/LP variants in COL4A3/COL4A4 showed KC, which is a significantly higher percentage than in the general population. Only 3.8% (6/157) had cystic nephromegaly. Age and eGFR showed an association with the presence of KC (p<0.001). No association was found between KC and proteinuria, sex, or causative gene. CONCLUSIONS: Individuals with COL4A3/COL4A4 P/LP variants are prone to develop KC more frequently than the general population, and their presence is related to age and to eGFR. Neither proteinuria, sex nor the causative gene influences the presence of KC in these individuals.

Defining the role of multiparametric MRI in predicting prostate cancer extracapsular extension.

OBJECTIVES: To identify the predictive factors of prostate cancer extracapsular extension (ECE) in an institutional cohort of patients who underwent multiparametric MRI of the prostate prior to radical prostatectomy (RP). PATIENTS AND METHODS: Overall, 126 patients met the selection criteria, and their medical records were retrospectively collected and analysed; 2 experienced radiologists reviewed the imaging studies. Logistic regression analysis was conducted to identify the variables associated to ECE at whole-mount histology of RP specimens; according to the statistically significant variables associated, a predictive model was developed and calibrated with the Hosmer-Lomeshow test. RESULTS: The predictive ability to detect ECE with the generated model was 81.4% by including the length of capsular involvement (LCI) and intraprostatic perineural invasion (IPNI). The predictive accuracy of the model at the ROC curve analysis showed an area under the curve (AUC) of 0.83 [95% CI (0.76-0.90)], p < 0.001. Concordance between radiologists was substantial in all parameters examined (p < 0.001). Limitations include the retrospective design, limited number of cases, and MRI images reassessment according to PI-RADS v2.0. CONCLUSION: The LCI is the most robust MRI factor associated to ECE; in our series, we found a strong predictive accuracy when combined in a model with the IPNI presence. This outcome may prompt a change in the definition of PI-RADS score 5.

Decision-making and regret in patients with germline CDH1 variants undergoing prophylactic total gastrectomy.

INTRODUCTION: Prophylactic total gastrectomy (PTG) can eliminate gastric cancer risk and is recommended in carriers of a germline CDH1 pathogenic variant. PTG has established risks and potential life-long morbidity. Decision-making regarding PTG is complex and not well-understood. METHODS: Individuals with germline CDH1 pathogenic or likely pathogenic variants who underwent surveillance endoscopy and recommended for PTG were evaluated. Factors associated with decision to pursue PTG (PTGpos) or not (PTGneg) were queried. A decision-regret survey was administered to patients who elected PTG. RESULTS: Decision-making was assessed in 120 patients. PTGpos patients (63%, 76/120) were younger than PTGneg (median 45 vs 58 years) and more often had a strong family history of gastric cancer (80.3% vs 34.1%). PTGpos patients reported decision-making based on family history more often and decided soon after diagnosis (8 vs 27 months) compared with PTGneg. Negative endoscopic surveillance results were more common among PTGneg patients. Age >60 years, male sex and longer time to decision were associated with deferring PTG. Strong family history, a family member who died of gastric cancer and carcinoma on endoscopic biopsies were associated with decision to pursue PTG. In the PTGpos group, 30 patients (43%) reported regret which was associated with occurrence of a postoperative complication and no carcinoma detected on final pathology. CONCLUSION: The decision to undergo PTG is influenced by family cancer history and surveillance endoscopy results. Regret is associated with surgical complications and pathological absence of cancer. Individual cancer-risk assessment is necessary to improve pre-operative counselling and inform the decision-making process. TRIAL REGISTRATION NUMBER: NCT03030404.

Metabolic and transcriptomic study of pennycress natural variation identifies targets for oil improvement.

Pennycress (Thlaspi arvense L.), a member of the Brassicaceae family, produces seed oil high in erucic acid, suitable for biodiesel and aviation fuel. Although pennycress, a winter annual, could be grown as a dedicated bioenergy crop, an increase in its seed oil content is required to improve its economic competitiveness. The success of crop improvement relies upon finding the right combination of biomarkers and targets, and the best genetic engineering and/or breeding strategies. In this work, we combined biomass composition with metabolomic and transcriptomic studies of developing embryos from 22 pennycress natural variants to identify targets for oil improvement. The selected accession collection presented diverse levels of fatty acids at maturity ranging from 29% to 41%. Pearson correlation analyses, weighted gene co-expression network analysis and biomarker identifications were used as complementary approaches to detect associations between metabolite level or gene expression and oil content at maturity. The results indicated that improving seed oil content can lead to a concomitant increase in the proportion of erucic acid without affecting the weight of embryos. Processes, such as carbon partitioning towards the chloroplast, lipid metabolism, photosynthesis, and a tight control of nitrogen availability, were found to be key for oil improvement in pennycress. Besides identifying specific targets, our results also provide guidance regarding the best timing for their modification, early or middle maturation. Thus, this work lays out promising strategies, specific for pennycress, to accelerate the successful development of lines with increased seed oil content for biofuel applications.

Cytoreduction and HIPEC for Gastric Carcinomatosis: Multi-institutional Analysis of Two Phase II Clinical Trials.

INTRODUCTION: There are no approved locoregional therapies for peritoneal carcinomatosis from gastric adenocarcinoma (GA). Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) represents a potential treatment for advanced GA with isolated peritoneal metastasis. PATIENTS AND METHODS: Two separate single-institution phase II, single-arm studies evaluating CRS-HIPEC using cisplatin with mitomycin C (NIH: NCT03092518, MDACC: NCT02891447) in patients with GA and confirmed peritoneal metastasis were analyzed. The primary endpoint of each trial was overall survival (OS). Clinical, pathologic, and treatment variables were analyzed for association with outcomes. RESULTS: Over 4 years, 41 patients with peritoneal carcinomatosis from GA underwent CRS-HIPEC. All patients had synchronous peritoneal metastasis and received systemic chemotherapy as front-line therapy. A total of 23 patients also received laparoscopic HIPEC prior to open CRS-HIPEC. The majority (63%, n = 26) were male, and median PCI score at CRS-HIPEC was 2. Median OS was 24.9 months from diagnosis and 14.4 months from CRS-HIPEC. Three-year OS was 25% from diagnosis and 22% from CRS-HIPEC. Median RFS was 7.4 months. The rate of 30-day Clavien-Dindo grade ≥ 3 complications was 32%; specifically, the rate of anastomotic leak was 22%. Multivariable analysis identified the number of pathologically positive lymph nodes as an independent predictor of postoperative OS. CONCLUSIONS: In patients with gastric adenocarcinoma and isolated peritoneal metastasis treated with CRS-HIPEC, 3-year OS was 22% from CRS-HIPEC, and complications were common. The number of pathologic lymph node metastases was inversely correlated with overall survival. Further investigation of CRS-HIPEC for GA should include patient selection based on response to systemic chemotherapy or incorporate novel intraperitoneal treatment strategies.

Breast Surgical Oncology Fellowship applicant selection and ranking: A survey of Society of Surgical Oncology programs.

BACKGROUND AND OBJECTIVES: In 2003, the Society of Surgical Oncology (SSO) initiated a breast surgical oncology fellowship, which has now grown to 60 SSO accredited programs as of 2021. Limited knowledge exists on the traits of successful applicants and the factors influencing the rank list. METHODS: A web-based, anonymous survey was sent to all SSO Breast Surgical Oncology Fellowship program directors. The survey consisted of 26 questions. Descriptive statistics were used to analyze survey responses and evaluate impact on applicant interview and rank list. RESULTS: Thirty-four programs (57% response rate) completed the survey. Programs received an average of 70 applications and granted 24 interviews. Most programs reported a minimum ABSITE cut-off score (n = 28, 82%) and a defined publication requirement (n = 22, 65%), including a first-author requirement (n = 18, 53%) to extend an invitation to interview. For postinterview rank, applicant interpersonal skills were highly valued. The interview was the most important aspect for the rank list. CONCLUSIONS: Many programs have ABSITE and publication thresholds before offering an interview. Upon receiving interview invitation, the applicant's interview performance, interpersonal skills, and letters of recommendation were the most important aspect in rank list decision making.

IBEX: A versatile multiplex optical imaging approach for deep phenotyping and spatial analysis of cells in complex tissues.

The diverse composition of mammalian tissues poses challenges for understanding the cell-cell interactions required for organ homeostasis and how spatial relationships are perturbed during disease. Existing methods such as single-cell genomics, lacking a spatial context, and traditional immunofluorescence, capturing only two to six molecular features, cannot resolve these issues. Imaging technologies have been developed to address these problems, but each possesses limitations that constrain widespread use. Here we report a method that overcomes major impediments to highly multiplex tissue imaging. "Iterative bleaching extends multiplexity" (IBEX) uses an iterative staining and chemical bleaching method to enable high-resolution imaging of >65 parameters in the same tissue section without physical degradation. IBEX can be employed with various types of conventional microscopes and permits use of both commercially available and user-generated antibodies in an "open" system to allow easy adjustment of staining panels based on ongoing marker discovery efforts. We show how IBEX can also be used with amplified staining methods for imaging strongly fixed tissues with limited epitope retention and with oligonucleotide-based staining, allowing potential cross-referencing between flow cytometry, cellular indexing of transcriptomes and epitopes by sequencing, and IBEX analysis of the same tissue. To facilitate data processing, we provide an open-source platform for automated registration of iterative images. IBEX thus represents a technology that can be rapidly integrated into most current laboratory workflows to achieve high-content imaging to reveal the complex cellular landscape of diverse organs and tissues.

Preserved cardiac performance and adrenergic response in a rabbit model with decreased ryanodine receptor 2 expression.

Ryanodine receptor 2 (RyR2) is an ion channel in the heart responsible for releasing into the cytosol most of the Ca2+ required for contraction. Proper regulation of RyR2 is critical, as highlighted by the association between channel dysfunction and cardiac arrhythmia. Lower RyR2 expression is also observed in some forms of heart disease; however, there is limited information on the impact of this change on excitation-contraction (e-c) coupling, Ca2+-dependent arrhythmias, and cardiac performance. We used a constitutive knock-out of RyR2 in rabbits (RyR2-KO) to assess the extent to which a stable decrease in RyR2 expression modulates Ca2+ handling in the heart. We found that homozygous knock-out of RyR2 in rabbits is embryonic lethal. Remarkably, heterozygotes (KO+/-) show ~50% loss of RyR2 protein without developing an overt phenotype at the intact animal and whole heart levels. Instead, we found that KO+/- myocytes show (1) remodeling of RyR2 clusters, favoring smaller groups in which channels are more densely arranged; (2) lower Ca2+ spark frequency and amplitude; (3) slower rate of Ca2+ release and mild but significant desynchronization of the Ca2+ transient; and (4) a significant decrease in the basal phosphorylation of S2031, likely due to increased association between RyR2 and PP2A. Our data show that RyR2 deficiency, although remarkable at the molecular and subcellular level, has only a modest impact on global Ca2+ release and is fully compensated at the whole-heart level. This highlights the redundancy of RyR2 protein expression and the plasticity of the e-c coupling apparatus.

Passive quadrature demodulation of multiplexed interferometric sensors using a CW correlation reflectometer with a single DFB diode laser.

In this Letter, we report a novel, to the best of our knowledge, and simple approach for passive quadrature-phase demodulation of relatively long multiplexed interferometers based on two-channel coherence correlation reflectometry. Two-wavelength channels are generated using a single unmodulated CW-DFB diode laser and an acousto-optic frequency shifter. The introduced frequency shift determines the optical lengths of the interferometers. In our experiments, all interferometers have the same optical length of 32 cm corresponding to the π/2 phase difference between channel signals. An additional fiber delay line was introduced between channels to destroy coherence between initial and frequency-shifted channels. Demultiplexing of channels and sensors was performed using correlation-based signal processing. Amplitudes of cross correlation peaks obtained for both channels were used to extract the interferometric phase for each interferometer. Phase demodulation of relatively long multiplexed interferometers is experimentally demonstrated. Experimental results prove that the proposed technique is suitable for interrogating a serial array of relatively long interferometers dynamically modulated with phase excursions exceeding 2π. Simultaneous interrogation and phase demodulation were experimentally demonstrated using an in-line array of low-finesse Fabry-Perot interferometric sensors.

A quantitative method for proteome reallocation using minimal regulatory interventions.

Engineering resource allocation in biological systems is an ongoing challenge. Organisms allocate resources for ensuring survival, reducing the productivity of synthetic biology functions. Here we present a new approach for engineering the resource allocation of Escherichia coli by rationally modifying its transcriptional regulatory network. Our method (ReProMin) identifies the minimal set of genetic interventions that maximizes the savings in cell resources. To this end, we categorized transcription factors according to the essentiality of its targets and we used proteomic data to rank them. We designed the combinatorial removal of transcription factors that maximize the release of resources. Our resulting strain containing only three mutations, theoretically releasing 0.5% of its proteome, had higher proteome budget, increased production of an engineered metabolic pathway and showed that the regulatory interventions are highly specific. This approach shows that combining proteomic and regulatory data is an effective way of optimizing strains using conventional molecular methods.

Author Correction: A quantitative method for proteome reallocation using minimal regulatory interventions.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Surgical Correction of Adult Congenital Penile Curvature: A Systematic Review.

BACKGROUND: Congenital penile curvature (CPC) is corrected surgically by various corporoplasty or tunica albuginea plication techniques, but the optimal surgical approach is not well-defined. AIM: To provide a comprehensive evaluation of the published literature pertaining to outcomes with penile plication and corporoplasty techniques for surgical management of CPC. To determine if plication or corporoplasty offers superior outcomes in surgical correction of CPC. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Checklist. The following databases were queried from inception to March 18, 2020 to search for studies describing surgical treatment of CPC: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus. OUTCOMES: Objective and subjective postoperative outcomes including penile straightening, shortening, penile sensory changes, and reoperation rates for both corporoplasty and tunica albuginea plication were summarized. RESULTS: Fifty-five articles comprising 2,956 patients with CPC who underwent a plication procedure (n = 1,375) or corporoplasty (n = 1,580) were included. The definition of "treatment success" varied widely and most often involved subjective patient reporting (22 studies; 40%) or objective assessment (15 studies; 27%). We considered curvature correction to be satisfactory if there was self-reported patient satisfaction or residual curvature after correction of <20˚. Reported rates of successful straightening ranged from 75 to 100% and 73 to 100% for plication and corporoplasty, respectively. A comprehensive and accurate assessment of surgical outcomes for CPC correction, such as satisfactory penile straightening, reoperation rates, glans sensory changes, and other complications was limited by significant inter-study heterogeneity with respect to the reporting of treatment outcomes. CLINICAL IMPLICATIONS: While both plication and corporoplasty appear to be safe and effective options in the treatment of CPC, definitive conclusions cannot be drawn with respect to treatment superiority due to low-quality study design, methodology flaws, and significant heterogeneity in reporting. STRENGTH & LIMITATIONS: This report represents the most comprehensive review of CPC surgical management. However, there is a significant lack of standardization in the reporting of treatment outcomes for CPC, thereby limiting the reliability of the published data summarization encompassed by our review. CONCLUSION: Both plication and corporoplasty demonstrate high success rates and relatively low complication rates in the treatment of CPC, albeit with low-level evidence available in most research publications. Robust comparison of the surgical techniques used to correct CPC is limited by significant variation in reporting methods used in the literature. C. J. Britton, F. A. Jefferson, B. L. Findlay, et al. Surgical Correction of Adult Congenital Penile Curvature: A Systematic Review. J Sex Med 2022;19:364-376.

Age Determines Adjuvant Chemotherapy Use in Resected Stage II Colon Cancer.

BACKGROUND: The role of adjuvant chemotherapy in resected stage II colon cancer remains controversial. Treatment recommendations rely largely on the presence of certain high-risk features for recurrence. OBJECTIVE: We sought to define patient and clinicopathologic differences between early-onset and late-onset colorectal cancer and determine whether these differences impact treatment. We hypothesized that high-risk features in stage II colorectal cancer differed between age groups and would most strongly influence administration of adjuvant chemotherapy. DESIGN: This was a retrospective cohort study. SETTING: The study was conducted at a Commission on Cancer designated hospital as well as the National Cancer Institute Intramural Research Program. PATIENTS: Patients with resected stage II colon cancer were identified in the National Cancer Database, and clinicopathologic characteristics were recorded. Patients were stratified into young (≤45), middle-aged (50-75), and older (>75) age groups. MAIN OUTCOME MEASURES: Incidence of high-risk clinicopathologic features and receipt of adjuvant chemotherapy were measured. RESULTS: A total of 14,966 patients met inclusion criteria. Young patients were found to have had at least one high-risk feature ( n = 489, 44%) slightly more often than both middle-aged ( n = 3734, 40%) and older patients ( n = 1890, 42%). A total of 332 (7%) older patients received adjuvant chemotherapy compared to 627 (56%) young patients and 2854 (30%) middle-aged patients. Age group was independently associated with receipt of adjuvant chemotherapy when controlling for relevant clinicopathologic factors. LIMITATIONS: This was a retrospective study without granular detail on treatment decisions. CONCLUSIONS: Young patients are frequently prescribed adjuvant chemotherapy for both high- and low-risk tumors despite questionable benefit in the latter. Older patients rarely receive adjuvant therapy. Both medical and surgical oncologists should be aware of disparities in cancer treatment and remain conscientious about making treatment decisions solely based on age. See Video Abstract at http://links.lww.com/DCR/B846 . LA EDAD DETERMINA EL USO DE QUIMIOTERAPIA ADYUVANTE EN EL CNCER DE COLON RESECADO EN ESTADIO II: ANTECEDENTES:El papel de la quimioterapia adyuvante en el cáncer de colon resecado en estadio II sigue siendo controversial . Las recobmendaciones para el tratamiento dependen en gran medida de la presencia de ciertas características de alto riesgo de recurrencia.OBJETIVO:Buscamos definir las diferencias clínico-patológicas del paciente entre el CCR de inicio temprano y tardío; y determinar si estas diferencias afectan el tratamiento. Hipotetizamos que las características de alto riesgo del cáncer colorrectal en estadio II difieren entre los grupos de edad y que influyen fuertemente en la administración de quimioterapia adyuvante.DISEÑO:Este fue un estudio de cohorte retrospectivo.ENTORNO CLINICO:El estudio se llevó a cabo en un hospital designado por la Comisión sobre el Cáncer, así como el Programa de Investigación Intramural del Instituto Nacional del Cáncer.PACIENTES:Se identificaron los pacientes con cáncer de colon resecado en estadio II en la Base de datos nacional del cáncer y se registraron las características clínico-patológicas. Los pacientes se estratificaron en grupos de edad jóvenes (≤45), de mediana edad (50-75) y mayores (> 75).PRINCIPALES MEDIDAS DE RESULTADO:Se estudiaron la incidencia de las características clínico-patológicas de alto riesgo y la recepción de quimioterapia adyuvante.RESULTADOS:Un total de 14.966 pacientes cumplieron con los criterios de inclusión. Se encontró que los pacientes jóvenes tenían al menos una característica de alto riesgo (n = 489, 44%) un poco más frecuente que los pacientes de mediana edad (n = 3734, 40%) y los pacientes mayores (n = 1890, 42%). Un total de 332 (7%) de los pacientes mayores recibieron quimioterapia adyuvante en comparación con 627 (56%) de los pacientes jóvenes y 2854 (30%) de los pacientes de mediana edad. El grupo de edad se asoció de forma independiente con la recepción de quimioterapia adyuvante al controlar los factores clínico-patológicos relevantes.LIMITACIONES:Este fue un estudio retrospectivo sin detalles granulares sobre las decisiones de tratamiento.CONCLUSIONES:A los pacientes jóvenes se les prescribe con frecuencia quimioterapia adyuvante para tumores de alto y bajo riesgo, a pesar de los cuestionables beneficios en estos últimos. Los pacientes de edad avanzada rara vez reciben terapia adyuvante. Tanto los oncólogos clínicos como los quirúrgicos deben ser conscientes de las disparidades en el tratamiento del cáncer y ser conscientes de tomar decisiones de tratamiento basadas únicamente en la edad. Consulte Video Resumen en http://links.lww.com/DCR/B846 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Adjuvant chemotherapy is associated with improved overall survival in select patients with Stage II colon cancer: A National Cancer Database analysis.

BACKGROUND AND OBJECTIVES: Guidelines for Stage II colon cancer recommend adjuvant chemotherapy (AC) only for tumors with high-risk features, but long-term outcomes data are mixed. We aimed to determine if AC was associated with a survival benefit in this population. METHODS: Patients were identified from the National Cancer Database and included if they met the following criteria: diagnosis of Stage II colon cancer, surgery, survival data, and complete data on six high-risk features. The cohort of 57 335 patients was stratified by receipt of AC. Subgroup analysis was performed on patients under the age of 65 years with no comorbidities. Overall survival (OS) was the primary endpoint. RESULTS: An increasing number of high-risk features was associated with significantly decreased median OS. AC was associated with significantly increased OS for patients with 0, 1, 2, and ≥3 high-risk features. On subgroup analysis, receipt of AC was associated with a reduced risk of death (hazard ratio: 0.66; confidence interval: 0.59-0.74). For patients in the subgroup who had a T4 tumor, AC was associated with increased OS (92.7 vs. 83.6 months). CONCLUSIONS: AC should be considered for all younger, healthy patients with Stage II colon cancer and may be associated with a survival benefit for patients with T4 disease.