White adipose tissue distribution and amount are associated with increased white matter connectivity.

Obesity represents a significant public health concern and is linked to various comorbidities and cognitive impairments. Previous research indicates that elevated body mass index (BMI) is associated with structural changes in white matter (WM). However, a deeper characterization of body composition is required, especially considering the links between abdominal obesity and metabolic dysfunction. This study aims to enhance our understanding of the relationship between obesity and WM connectivity by directly assessing the amount and distribution of fat tissue. Whole-body magnetic resonance imaging (MRI) was employed to evaluate total adipose tissue (TAT), visceral adipose tissue (VAT), and subcutaneous adipose tissue (SAT), while MR liver spectroscopy measured liver fat content in 63 normal-weight, overweight, and obese males. WM connectivity was quantified using microstructure-informed tractography. Connectome-based predictive modeling was used to predict body composition metrics based on WM connectomes. Our analysis revealed a positive dependency between BMI, TAT, SAT, and WM connectivity in brain regions involved in reward processing and appetite regulation, such as the insula, nucleus accumbens, and orbitofrontal cortex. Increased connectivity was also observed in cognitive control and inhibition networks, including the middle frontal gyrus and anterior cingulate cortex. No significant associations were found between WM connectivity and VAT or liver fat. Our findings suggest that altered neural communication between these brain regions may affect cognitive processes, emotional regulation, and reward perception in individuals with obesity, potentially contributing to weight gain. While our study did not identify a link between WM connectivity and VAT or liver fat, further investigation of the role of various fat depots and metabolic factors in brain networks is required to advance obesity prevention and treatment approaches.

[Breast reconstruction after mastectomy: necessity, evolution, techniques and research goals]. / Reconstruction mammaire après mastectomie : nécessité, évolution, techniques et objectifs de recherche.

Breast reconstruction is recognized as an integrated part of breast cancer treatment today. Depending on tumor characteristics, different types of partial and total breast resections are indicated: tumorectomy, nipple/skin sparing or complete mastectomy. Patients' desires, general health status and body shape, as well as the necessity of adjuvant therapies, lead to the individual reconstruction plan. Next to implant-based reconstructions, autologous reconstructions play a great role, including local, pedicled and free flaps as well as autologous fat grafting. In cases of tumorectomy, oncoplastic surgery comes into play: it is the combination of a large tumor resection and immediate breast reconstruction with the remaining breast tissue.

À l'heure actuelle, la reconstruction mammaire est reconnue comme partie intégrante du traitement du cancer du sein. En fonction des caractéristiques tumorales, différents types de résections mammaires sont indiqués : tumorectomie, mastectomie avec épargne du mamelon ou de la peau, ou mastectomie totale. L'état de santé général, la nécessité de thérapies adjuvantes, la morphologie et les souhaits des patientes déterminent le plan de reconstruction. En plus de la reconstruction à base d'implants, celle par lambeaux autologues (lambeaux locaux, pédiculés ou libres), ainsi que le transfert de graisse autologue jouent un rôle important. En cas de tumorectomie, la chirurgie oncoplastique entre en jeu, soit la combinaison d'une résection tumorale importante et d'une reconstruction mammaire immédiate par remaniement de la glande persistante.

Influence of prehospital physician presence on survival after severe trauma: Systematic review and meta-analysis.

BACKGROUND: As trauma is one of the leading causes of death worldwide, there is great potential for reducing mortality in trauma patients. However, there is continuing controversy over the benefit of deploying emergency medical systems (EMS) physicians in the prehospital setting. The objective of this systematic review and meta-analysis is to assess how out-of-hospital hospital management of severely injured patients by EMS teams with and without physicians affects mortality. METHODS: PubMed and Google Scholar were searched for relevant articles, and the search was supplemented by a hand search. Injury severity in the group of patients treated by an EMS team including a physician had to be comparable to the group treated without a physician. Primary outcome parameter was mortality. Helicopter transport as a confounder was accounted for by subgroup analyses including only the studies with comparable modes of transport. Quality of all included studies was assessed according to the Cochrane handbook. RESULTS: There were 2,249 publications found, 71 full-text articles assessed, and 22 studies included. Nine of these studies were matched or adjusted for injury severity. The odds ratio (OR) of mortality was significantly lower in the EMS physician-treated group of patients: 0.81; 95% confidence interval (CI): 0.71-0.92. When analysis was limited to the studies that were adjusted or matched for injury severity, the OR was 0.86 (95% CI, 0.73-1.01). Analyzing only studies published after 2005 yielded an OR for mortality of 0.75 (95% CI, 0.64-0.88) in the overall analysis and 0.81 (95% CI, 0.67-0.97) in the analysis of adjusted or matched studies. The OR was 0.80 (95% CI, 0.65-1.00) in the subgroup of studies with comparable modes of transport and 0.74 (95% CI, 0.53-1.03) in the more recent studies. CONCLUSION: Prehospital management of severely injured patients by EMS teams including a physician seems to be associated with lower mortality. After excluding the confounder of helicopter transport we have shown a nonsignificant trend toward lower mortality. LEVEL OF EVIDENCE: Systematic review and meta-analysis, level III.

Escherichia coli heme oxygenase modulates host innate immune responses.

Induction of mammalian heme oxygenase (HO)-1 and exposure of animals to carbon monoxide (CO) ameliorates experimental colitis. When enteric bacteria, including Escherichia coli, are exposed to low iron conditions, they express an HO-like enzyme, chuS, and metabolize heme into iron, biliverdin and CO. Given the abundance of enteric bacteria residing in the intestinal lumen, our postulate was that commensal intestinal bacteria may be a significant source of CO and those that express chuS and other Ho-like molecules suppress inflammatory immune responses through release of CO. According to real-time PCR, exposure of mice to CO results in changes in enteric bacterial composition and increases E. coli 16S and chuS DNA. Moreover, the severity of experimental colitis correlates positively with E. coli chuS expression in IL-10 deficient mice. To explore functional roles, E. coli were genetically modified to overexpress chuS or the chuS gene was deleted. Co-culture of chuS-overexpressing E. coli with bone marrow-derived macrophages resulted in less IL-12p40 and greater IL-10 secretion than in wild-type or chuS-deficient E. coli. Mice infected with chuS-overexpressing E. coli have more hepatic CO and less serum IL-12 p40 than mice infected with chuS-deficient E. coli. Thus, CO alters the composition of the commensal intestinal microbiota and expands populations of E. coli that harbor the chuS gene. These bacteria are capable of attenuating innate immune responses through expression of chuS. Bacterial HO-like molecules and bacteria-derived CO may represent novel targets for therapeutic intervention in inflammatory conditions.

Unique roles of infiltrating myeloid cells in the murine uterus during early to midpregnancy.

Leukocyte infiltration into the uterus is a characteristic feature in early to midpregnancy, but the composition and function of these leukocytes are not well understood. Using a pregnant murine model, we showed that myeloid cells and uterine NK (uNK) cells were the predominant populations in uteri during early to midgestation, whereas T and B cells were constrained. Uterine myeloid populations included cells that infiltrated from the circulation (myeloid-derived suppressor cells [MDSCs], monocyte-derived macrophages [Mφs], and dendritic cells [DCs]) or proliferated from resident precursors (resident Mφs [Re-Mφs] and DCs). CD11b(hi)Ly6-G(hi) cells, representing neutrophils in both blood and uterine MDSCs, significantly increased from embryonic days 8.5 to 9.5. To understand their putative functions, we used anti-Gr-1 Ab to deplete circulating neutrophils and uterine MDSCs. In the absence of MDSC suppression, uterine DCs, T cells, and regulatory T cells expanded. Conversely, uterine MDSCs responded to LPS-induced inflammation and transformed into CD14(+)-activated neutrophils, resulting in an upregulation of tolerogenic DCs. A high dose of LPS (2.5 µg/mouse) significantly increased the influx of neutrophils and production of proinflammatory cytokines, such as IL-1ß and TNF-α, resulting in the reduction of Re-Mφs and uNK cells, and led to placental hemorrhages and fetal deaths. In summary, uterine MDSCs are important in early to midpregnancy by responding to the maternal immunologic milieu and protecting uNK cells and Re-Mφs via MDSC's suppressive and anti-inflammatory functions. Upsetting this delicate immune balance by factors leading to either insufficient MDSCs or excessive neutrophil infiltration in the fetomaternal interface may contribute to pregnancy failure.

Heme oxygenase-1 confers protection and alters T-cell populations in a mouse model of neonatal intestinal inflammation.

BACKGROUND: Necrotizing enterocolitis (NEC), an intestinal inflammatory disease affecting premature infants, is associated with low regulatory T (Treg) to effector T (Teff) cell ratios. We recently demonstrated that heme oxygenase-1 (HO-1) deficiency leads to increased NEC development. Here, we investigated the effects of HO-1 on T-cell proportions in a murine NEC-like injury model. METHODS: Intestinal injury was induced in 7-d-old wild-type (WT) or HO-1 heterozygous (HO-1 Het) pups by formula-feeding every 4 h for 24-78 h by oral gavage and exposures to 5%O2. Controls remained breastfed. HO-1 was induced in WT pups by administering heme preinjury induction. Lamina propria T cells were identified by flow cytometry. For adoptive transfer studies, WT splenic/thymic Tregs were injected intraperitoneally into HO-1 Het pups 12-24 h preinduction. RESULTS: Het mice showed increased intestinal injury and decreased Treg/Teff ratios. Genes for pattern recognition (Toll-like receptor-4, C-reactive protein, MyD88) and neutrophil recruitment increased in Het pups after NEC induction. Inducing intestinal HO-1 decreased NEC scores and incidence, and increased Treg/Teff ratios. Moreover, adoptive transfer of Tregs from WT to HO-1 Het pups decreased NEC scores and incidence and restored Treg/Teff ratios. CONCLUSION: HO-1 can change Treg proportions in the lamina propria of young mice under inflammatory conditions, which might, in part, confer intestinal protection.

Prognostic role of restenosis in 10 004 patients undergoing routine control angiography after coronary stenting.

AIM: Routine control angiography is a valuable tool with high-sensitivity in detecting restenosis after coronary stenting. However, the prognostic role of restenosis is still controversial. We investigated the impact of restenosis on 4-year mortality in patients undergoing routine control angiography after coronary stenting. METHODS AND RESULTS: All the patients undergoing successful implantation of coronary stents for de novo lesions from 1998 to 2009 and routine control angiography after 6-8 months at two centres in Munich, Germany were studied. Restenosis was defined as diameter stenosis ≥50% in the in-segment area at follow-up angiography. The primary outcome was 4-year mortality. The study included 10 004 patients with 15 004 treated lesions. Restenosis was detected in 2643 (26.4%) patients. Overall, there were 702 deaths during the follow-up. Of these, 218 deaths occurred among patients with restenosis and 484 deaths occurred among patients without restenosis [unadjusted hazard ratio: HR: 1.19; (95% confidence interval CI: 1.02-1.40); P = 0.03]. The Cox proportional hazards model adjusting for other variables identified restenosis as an independent correlate of 4-year mortality [HR: 1.23; (95% CI: 1.03-1.46); P = 0.02]. Other independent correlates of 4-year mortality were age [for each 10-year increase, HR: 2.34; (95% CI: 2.12-2.60); P < 0.001], diabetes mellitus [HR: 1.68; (95% CI: 1.41-1.99); P < 0.001], current smoking habit [HR: 1.39; (95% CI: 1.09-1.76); P = 0.01], and left ventricular ejection fraction [for each 5% decrease, HR: 1.39; (95% CI: 1.31-1.48); P < 0.001]. CONCLUSIONS: In this large cohort of patients, the presence of restenosis at follow-up angiography after coronary stenting was predictive of 4-year mortality. Whether routine control angiography after coronary stenting is beneficial and influences outcomes should be evaluated by properly designed randomized trials.

Selective antigen-specific CD4(+) T-cell, but not CD8(+) T- or B-cell, tolerance corrupts cancer immunotherapy.

Self-tolerance, presumably through lineage-unbiased elimination of self-antigen-specific lymphocytes (CD4(+) T, CD8(+) T, and B cells), creates a formidable barrier to cancer immunotherapy. In contrast to this prevailing paradigm, we demonstrate that for some antigens, self-tolerance reflects selective elimination of antigen-specific CD4(+) T cells, but preservation of CD8(+) T- and B-cell populations. In mice, antigen-specific CD4(+) T-cell tolerance restricted CD8(+) T- and B-cell responses targeting the endogenous self-antigen guanylyl cyclase c (GUCY2C) in colorectal cancer. Although selective CD4(+) T-cell tolerance blocked GUCY2C-specific antitumor immunity and memory responses, it offered a unique solution to the inefficacy of GUCY2C vaccines through recruitment of self-antigen-independent CD4(+) T-cell help. Incorporating CD4(+) T-cell epitopes from foreign antigens into vaccines against GUCY2C reconstituted CD4(+) T-cell help, revealing the latent functional capacity of GUCY2C-specific CD8(+) T- and B-cell pools, producing durable antitumor immunity without autoimmunity. Incorporating CD4(+) T-cell epitopes from foreign antigens into vaccines targeting self-antigens in melanoma (Trp2) and breast cancer (Her2) produced similar results, suggesting selective CD4(+) T-cell tolerance underlies ineffective vaccination against many cancer antigens. Thus, identification of self-antigens characterized by selective CD4(+) T-cell tolerance and abrogation of such tolerance through self-antigen-independent T-cell help is essential for future immunotherapeutics.

Effects of light on metalloporphyrin-treated newborn mice.

UNLABELLED: Zinc protoporphyrin (ZnPP) is a promising metalloporphyrin with sufficient potency, but has poor solubility and is not absorbed well orally. Intragastric administration of ZnPP microparticles (30 µmol/kg) to 3-day-old mice resulted in a twofold increase in potency and no signs of phototoxicity. CONCLUSION: The use of polymeric particulate delivery systems can improve the stability and enhance intestinal absorption of ZnPP, while retaining HO inhibitory potency without photosensitising effects, and thus is potentially useful in treating neonatal hyperbilirubinemia.

Intestinal GUCY2C prevents TGF-ß secretion coordinating desmoplasia and hyperproliferation in colorectal cancer.

Tumorigenesis is a multistep process that reflects intimate reciprocal interactions between epithelia and underlying stroma. However, tumor-initiating mechanisms coordinating transformation of both epithelial and stromal components are not defined. In humans and mice, initiation of colorectal cancer is universally associated with loss of guanylin and uroguanylin, the endogenous ligands for the tumor suppressor guanylyl cyclase C (GUCY2C), disrupting a network of homeostatic mechanisms along the crypt-surface axis. Here, we reveal that silencing GUCY2C in human colon cancer cells increases Akt-dependent TGF-ß secretion, activating fibroblasts through TGF-ß type I receptors and Smad3 phosphorylation. In turn, activating TGF-ß signaling induces fibroblasts to secrete hepatocyte growth factor (HGF), reciprocally driving colon cancer cell proliferation through cMET-dependent signaling. Elimination of GUCY2C signaling in mice (Gucy2c(-/-)) produces intestinal desmoplasia, with increased reactive myofibroblasts, which is suppressed by anti-TGF-ß antibodies or genetic silencing of Akt. Thus, GUCY2C coordinates intestinal epithelial-mesenchymal homeostasis through reciprocal paracrine circuits mediated by TGF-ß and HGF. In that context, GUCY2C signaling constitutes a direct link between the initiation of colorectal cancer and the induction of its associated desmoplastic stromal niche. The recent regulatory approval of oral GUCY2C ligands to treat chronic gastrointestinal disorders underscores the potential therapeutic opportunity for oral GUCY2C hormone replacement to prevent remodeling of the microenvironment essential for colorectal tumorigenesis.

Evaluation of window-tinting films for sunlight phototherapy.

We evaluated nine semi-transparent plastic window-tinting films for their ability to block ultraviolet A (UVA) and infrared (IR) radiation and transmit therapeutic blue light (400-520 nm) for treating jaundiced newborns. For indoor testing, three light sources (TL/52 special blue fluorescent, Black Light UVA and IR heat lamps) were positioned above each film and measured successively using a thermocouple thermometer, UVA radiometer and blue light irradiance meter, placed below each film. For outdoor testing, the same setup was used with the sun at zenith and a cloudless sky. Compared with unfiltered radiation, blue light transmission through films ranged from 24 to 83%, UVA transmission was 0.1-7.1% and reductions in IR heat were 6-12°C and 5-10°C for heat lamp and sun, respectively. The data suggest that most of the relatively low-cost window-tinting films tested can effectively reduce sunlight UV and IR and offer a range of significant attenuations of therapeutic blue light.

Heme oxygenase-1 deficiency promotes the development of necrotizing enterocolitis-like intestinal injury in a newborn mouse model.

Necrotizing enterocolitis (NEC) is typified by mucosal destruction, which subsequently can lead to intestinal necrosis. Prematurity, enteral feeding, and bacterial colonization are the main risk factors and, combined with other stressors, can cause increased intestinal permeability, injury, and an exaggerated inflammatory response. Heme oxygenase-1 (HO-1) mediates intestinal protection due to anti-inflammatory, antioxidative, and antiapoptotic effects of its products carbon monoxide, biliverdin, and bilirubin. This study investigates a possible role of HO-1 in the pathogenesis of NEC using a newborn mouse model. We induced NEC-like intestinal injury in 7-day-old HO-1 heterozygous (HO-1 Het, Hmox1(+/-)) and wild-type (Wt, Hmox1(+/+)) mice by gavage feeding and hypoxic exposures. Control (Con) pups of both genotypes were dam-fed. Intestines of HO-1 Het Con pups appeared predisposed to injury, with higher histological damage scores, more TUNEL-positive cells, and a significant reduction in muscularis externa thickness compared with Wt Con pups. The increase in HO activity after HO-1 induction by the substrate heme or by hypoxic stress was significantly impaired in HO-1 Het pups. After induction of intestinal injury, HO-1 Het pups displayed significantly higher NEC incidence (78 vs. 43%), mortality (83 vs. 54%), and median scores (2.5 vs. 1.5) than Wt NEC pups. PCR array analyses revealed increased expressions of IL-1ß, P-selectin, matrix metallopeptidase 2, collagen type XVIII-α1, serpine 1, and others in NEC-induced HO-1 Het ileal and jejunal tissues. We conclude that a partial HO-1 deficiency promotes experimental NEC-like intestinal injury, possibly mediated by exaggerated inflammation and disruption in tissue repair.

GUCY2C molecular staging personalizes colorectal cancer patient management.

While the most significant prognostic and predictive marker in the management of colorectal cancer patients is cancer cells in regional lymph nodes, approximately 30% of patients whose lymph nodes are ostensibly free of tumor cells by histopathology ultimately develop recurrent disease reflecting occult metastases. Molecular techniques utilizing highly specific markers and ultra-sensitive detection technologies have emerged as powerful staging platforms to establish prognosis and predict responsiveness to chemotherapy in colorectal cancer patients. This review describes the evolution of the tumor suppressor GUCY2C as a prognostic and predictive molecular biomarker that quantifies occult tumor burden in regional lymph nodes for staging patients with colorectal cancer.

Effect of light exposure on metalloporphyrin-treated newborn mice.

BACKGROUND: Neonatal hyperbilirubinemia arises from increased bilirubin production and decreased bilirubin elimination. Although phototherapy safely and effectively reduces bilirubin levels, recent evidence shows that it has adverse effects. Therefore, alternative treatments are warranted. Metalloporphyrins, competitive inhibitors of heme oxygenase (HO), the rate-limiting enzyme in bilirubin production, effectively reduce bilirubin formation; however, many are photoreactive. Here, we investigated possible photosensitizing effects of chromium mesoporphyrin (CrMP) and zinc deuteroporphyrin bis-glycol (ZnBG). METHODS AND RESULTS: Administration of CrMP or ZnBG to 3-d-old mouse pups (3.75-30.0 µmol/kg intraperitoneally) and exposure to cool white (F20T12CW) and blue (TL20W/52) fluorescent lights (+L) for 3 h, resulted in a dose-dependent mortality (50% lethal dose (LD50) = 21.5 and 19.5 µmol/kg, respectively). In contrast to ZnBG, there was no significant difference in survival between the CrMP+L and CrMP groups. Following 30 µmol/kg ZnBG+L, we found significant weight loss, decreased liver antioxidant capacities, and increased aspartate aminotransaminase levels. At 6-d post-light exposure, ZnBG+L-treated pups showed gross and histologic skin changes at doses >7.5 µmol/kg. No lethality was observed following treatment with 30 µmol ZnBG/kg plus exposure to blue light-emitting diodes. Phototoxicity of ZnBG was dependent on light source, emission spectrum, and irradiance. CONCLUSION: Low doses of ZnBG (<3.75 µmol/kg) retained maximal HO inhibitory potency without photosensitizing effects, and therefore are potentially useful in treating neonatal hyperbilirubinemia.

Metalloporphyrins - an update.

Metalloporphyrins are structural analogs of heme and their potential use in the management of neonatal hyperbilirubinemia has been the subject of considerable research for more than three decades. The pharmacological basis for using this class of compounds to control bilirubin levels is the targeted blockade of bilirubin production through the competitive inhibition of heme oxygenase (HO), the rate-limiting enzyme in the bilirubin production pathway. Ongoing research continues in the pursuit of identifying ideal metalloporphyrins, which are safe and effective, by defining therapeutic windows and targeted interventions for the treatment of excessive neonatal hyperbilirubinemia.

Molecular staging individualizing cancer management.

Although the most important prognostic and predictive marker in colorectal cancer is tumor cells in lymph nodes, approximately 30% of patients who are node-negative die from occult metastases. Molecular staging employing specific markers and sensitive detection technologies has emerged as a powerful platform to assess prognosis in node-negative colon cancer. Integrating molecular staging into algorithms that individualize patient management will require validation and the definition of relationships between occult tumor cells, prognosis, and responses to chemotherapy.

GUCY2C opposes systemic genotoxic tumorigenesis by regulating AKT-dependent intestinal barrier integrity.

The barrier separating mucosal and systemic compartments comprises epithelial cells, annealed by tight junctions, limiting permeability. GUCY2C recently emerged as an intestinal tumor suppressor coordinating AKT1-dependent crypt-villus homeostasis. Here, the contribution of GUCY2C to barrier integrity opposing colitis and systemic tumorigenesis is defined. Mice deficient in GUCY2C (Gucy2c(-/-)) exhibited barrier hyperpermeability associated with reduced junctional proteins. Conversely, activation of GUCY2C in mice reduced barrier permeability associated with increased junctional proteins. Further, silencing GUCY2C exacerbated, while activation reduced, chemical barrier disruption and colitis. Moreover, eliminating GUCY2C amplified, while activation reduced, systemic oxidative DNA damage. This genotoxicity was associated with increased spontaneous and carcinogen-induced systemic tumorigenesis in Gucy2c(-/-) mice. GUCY2C regulated barrier integrity by repressing AKT1, associated with increased junction proteins occludin and claudin 4 in mice and Caco2 cells in vitro. Thus, GUCY2C defends the intestinal barrier, opposing colitis and systemic genotoxicity and tumorigenesis. The therapeutic potential of this observation is underscored by the emerging clinical development of oral GUCY2C ligands, which can be used for chemoprophylaxis in inflammatory bowel disease and cancer.

Analytic lymph node number establishes staging accuracy by occult tumor burden in colorectal cancer.

BACKGROUND AND OBJECTIVES: Recurrence in lymph node-negative (pN0) colorectal cancer suggests the presence of undetected occult metastases. Occult tumor burden in nodes estimated by GUCY2C RT-qPCR predicts risk of disease recurrence. This study explored the impact of the number of nodes analyzed by RT-qPCR (analytic) on the prognostic utility of occult tumor burden. METHODS: Lymph nodes (range: 2-159) from 282 prospectively enrolled pN0 colorectal cancer patients, followed for a median of 24 months (range: 2-63), were analyzed by GUCY2C RT-qPCR. Prognostic risk categorization defined using occult tumor burden was the primary outcome measure. Association of prognostic variables and risk category were defined by multivariable polytomous and semi-parametric polytomous logistic regression. RESULTS: Occult tumor burden stratified this pN0 cohort into categories of low (60%; recurrence rate (RR) = 2.3% [95% CI 0.1-4.5%]), intermediate (31%; RR = 33.3% [23.7-44.1%]), and high (9%; RR = 68.0% [46.5-85.1%], P < 0.001) risk of recurrence. Beyond race and T stage, the number of analytic nodes was an independent marker of risk category (P < 0.001). When >12 nodes were analyzed, occult tumor burden almost completely resolved prognostic risk classification of pN0 patients. CONCLUSIONS: The prognostic utility of occult tumor burden assessed by GUCY2C RT-qPCR is dependent on the number of analytic lymph nodes.

Epitope-targeted cytotoxic T cells mediate lineage-specific antitumor efficacy induced by the cancer mucosa antigen GUCY2C.

Guanylyl cyclase C (GUCY2C) is the index cancer mucosa antigen, an emerging class of immunotherapeutic targets for the prevention of recurrent metastases originating in visceral epithelia. GUCY2C is an autoantigen principally expressed by intestinal epithelium, and universally by primary and metastatic colorectal tumors. Immunization with adenovirus expressing the structurally unique GUCY2C extracellular domain (GUCY2C(ECD); Ad5-GUCY2C) produces prophylactic and therapeutic protection against GUCY2C-expressing colon cancer metastases in mice, without collateral autoimmunity. GUCY2C antitumor efficacy is mediated by a unique immunological mechanism involving lineage-specific induction of antigen-targeted CD8(+) T cells, without CD4(+) T cells or B cells. Here, the unusual lineage specificity of this response was explored by integrating high-throughput peptide screening and bioinformatics, revealing the role for GUCY2C-directed CD8(+) T cells targeting specific epitopes in antitumor efficacy. In BALB/c mice vaccinated with Ad5-GUCY2C, CD8(+) T cells recognize the dominant GUCY2C(254-262) epitope in the context of H-2K(d), driving critical effector functions including interferon gamma secretion, cytolysis ex vivo and in vivo, and antitumor efficacy. The ability of GUCY2C to induce lineage-specific responses targeted to cytotoxic CD8(+) T cells recognizing a single epitope mediating antitumor efficacy without autoimmunity highlights the immediate translational potential of cancer mucosa antigen-based vaccines for preventing metastases of mucosa-derived cancers.

Occult tumor burden contributes to racial disparities in stage-specific colorectal cancer outcomes.

BACKGROUND: There are differences in outcomes in blacks compared with whites with lymph node-negative (pN0) colorectal cancer. Recurrence in pN0 patients suggests the presence of occult metastases undetected by conventional approaches. This study explores the association of racial differences in outcomes with occult tumor burden in regional lymph nodes. METHODS: Lymph nodes (range, 2-159) from 282 prospectively enrolled pN0 colorectal cancer patients followed for a median of 24 months (range, 2-63 months) were subjected to molecular analysis. Occult tumor burden was estimated by quantifying the expression of GUCY2C, a biomarker for metastatic colorectal cancer cells. Risk categories defined using occult tumor burden was the primary outcome measure. Association of prognostic variables and risk were defined by multivariate polytomous logistic regression. RESULTS: Occult tumor burden stratified this cohort of 259 whites and 23 blacks into categories with low (60%; recurrence rate [RR] = 2.3%; 95% confidence interval [CI], 0.1%-4.5%), intermediate (31%; RR = 33.3%; 95% CI, 23.7%-44.1%), and high (9%; RR = 68.0%; 95% CI, 46.5%-85.1%; P < .001) risk. Blacks compared with whites exhibited 4-fold greater occult metastases in individual lymph nodes (P < .001). Multivariate analysis revealed that race (P = .02), T stage (P = .02), and number of lymph nodes collected (P = .003) were independent prognostic markers of risk category. Blacks compared with whites were more likely to harbor levels of occult tumor burden, associated with the highest recurrence risk (adjusted odds ratio = 5.08; 95% CI, 1.69-21.39; P = .007). CONCLUSIONS: Racial disparities in stage-specific outcomes in colorectal cancer are associated with differences in occult tumor burden in regional lymph nodes.