Functional gastrointestinal disorders frequency by Rome IV criteria.

INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are a very common pediatric disease, with strong implications for children and their families. We aimed to determine their frequency in our environment (per Rome IV criteria) and to establish if there is seasonal variability in diagnosis. METHODS: Descriptive, prospective study. For 12 months, children under 16 years of age with suspected FGIDs who had a first pediatric gastroenterology consultation were included and classified according to Rome IV criteria. Statistical analysis was done with SPSS v22. RESULTS: 574 children received consultations, 67% were >4 years of age. FGIDs were suspected in 44.6% of the patients, 32.4% were diagnosed according to Rome IV criteria (16.4% <4 years, 40.3% >4 years). 51.1% were female, average age of 8.4 ±â€¯4.2 years and mean of 7 months of symptoms until diagnosis (range 3-150). In patients <4 years, the most common disorders were functional constipation (48.4%), regurgitation (22.5%) and functional diarrhea (16.1%); in patients >4 years of age, functional abdominal pain (29%), functional dyspepsia (28.4%) and functional constipation (16.8%) were most frequent. We didn't discern seasonal variations in diagnosis in the global study population (p = 0.96) or by age group (<4 p = 0.51; >4 p = 0.57). CONCLUSIONS: FGIDs account for one third of our patients' consultations. While the Rome IV criteria are more inclusive than before, almost 30% of patients with suspected FGIDs don't meet said criteria. Although a seasonal difference regarding diagnosis was observed, it wasn't statistically significant either in the sample group as a whole or by age group.

[Functional gastrointestinal disorders frequency by Rome IV criteria]. / Frecuencia de trastornos gastrointestinales funcionales según criterios Roma IV.

INTRODUCTION: Functional gastrointestinal disorders (FGIDs) are a very common pediatric disease, with strong implications for children and their families. We aimed to determine their frequency in our environment (per Rome IV criteria) and to establish if there is seasonal variability in diagnosis. MATERIAL AND METHODS: Descriptive, prospective study. For 12 months, children under 16 years of age with suspected FGIDs who had a first pediatric gastroenterology consultation were included and classified according to Rome IV criteria. Statistical analysis was done with SPSS v22. RESULTS: 574 children received consultations, 67% were >4 years of age. FGIDs were suspected in 44.6% of the patients, 32.4% were diagnosed according to Rome IV criteria (16.4%, <4 years; 40.3%, >4 years). 51.1% were female, average age of 8.4±4.2 years and mean of 7 months of symptoms until diagnosis (range 3-150). In patients <4 years, the most common disorders were functional constipation (48.4%), regurgitation (22.5%) and functional diarrhea (16.1%); in patients >4 years of age, functional abdominal pain (29%), functional dyspepsia (28.4%) and functional constipation (16.8%) were most frequent. We did not discern seasonal variations in diagnosis in the global study population (p=.96) or by age group (< 4, P=.51; > 4, P=.57). CONCLUSIONS: FGIDs account for one third of our patients' consultations. While the Rome IV criteria are more inclusive than before, almost 30% of patients with suspected FGIDs do not meet said criteria. Although a seasonal difference regarding diagnosis was observed, it was not statistically significant either in the sample group as a whole or by age group.

Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma.

Mounting an effective immune response against cancer requires the activation of innate and adaptive immune cells. Metastatic melanoma is the most aggressive form of skin cancer. While immunotherapies have shown a remarkable success in melanoma treatment, patients develop resistance by mechanisms that include the establishment of an immune suppressive tumor microenvironment. Thus, understanding how metastatic melanoma cells suppress the immune system is vital to develop effective immunotherapies against this disease. In this study, we find that macrophages (MOs) and dendritic cells (DCs) are suppressed in metastatic melanoma and that the Ig-CDR-based peptide C36L1 is able to restore MOs and DCs' antitumorigenic and immunogenic functions and to inhibit metastatic growth in lungs. Specifically, C36L1 treatment is able to repolarize M2-like immunosuppressive MOs into M1-like antitumorigenic MOs, and increase the number of immunogenic DCs, and activated cytotoxic T cells, while reducing the number of regulatory T cells and monocytic myeloid-derived suppressor cells in metastatic lungs. Mechanistically, we find that C36L1 directly binds to the MIF receptor CD74 which is expressed on MOs and DCs, disturbing CD74 structural dynamics and inhibiting MIF signaling on these cells. Interfering with MIF-CD74 signaling on MOs and DCs leads to a decrease in the expression of immunosuppressive factors from MOs and an increase in the capacity of DCs to activate cytotoxic T cells. Our findings suggest that interfering with MIF-CD74 immunosuppressive signaling in MOs and DCs, using peptide-based immunotherapy can restore the antitumor immune response in metastatic melanoma. Our study provides the rationale for further development of peptide-based therapies to restore the antitumor immune response in metastatic melanoma.

Blockade of insulin-like growth factors increases efficacy of paclitaxel in metastatic breast cancer.

Breast cancer remains the leading cause of cancer death in women owing to metastasis and the development of resistance to established therapies. Macrophages are the most abundant immune cells in the breast tumor microenvironment and can both inhibit and support cancer progression. Thus, gaining a better understanding of how macrophages support cancer could lead to the development of more effective therapies. In this study, we find that breast cancer-associated macrophages express high levels of insulin-like growth factors 1 and 2 (IGFs) and are the main source of IGFs within both primary and metastatic tumors. In total, 75% of breast cancer patients show activation of insulin/IGF-1 receptor signaling and this correlates with increased macrophage infiltration and advanced tumor stage. In patients with invasive breast cancer, activation of Insulin/IGF-1 receptors increased to 87%. Blocking IGF in combination with paclitaxel, a chemotherapeutic agent commonly used to treat breast cancer, showed a significant reduction in tumor cell proliferation and lung metastasis in pre-clinical breast cancer models compared to paclitaxel monotherapy. Our findings provide the rationale for further developing the combination of paclitaxel with IGF blockers for the treatment of invasive breast cancer, and Insulin/IGF1R activation and IGF+ stroma cells as potential biomarker candidates for further evaluation.

Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors.

Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163+ TAM infiltration. In vivo, we found that TAM and myofibroblasts were the main sources of IGF production, and pharmacologic blockade of IGF sensitized pancreatic tumors to gemcitabine. These findings suggest that inhibition of IGF in combination with chemotherapy could benefit patients with PDAC, and that insulin/IGF1R activation may be used as a biomarker to identify patients for such therapeutic intervention. Cancer Res; 76(23); 6851-63. ©2016 AACR.

Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis.

Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

A humanized mouse model of HPV-associated pathology driven by E7 expression.

Human papillomavirus (HPV) is the causative agent of human cervical cancer and has been associated with oropharyngeal squamous cell carcinoma development. Although prophylactic vaccines have been developed, there is a need to develop new targeted therapies for individuals affected with malignant infected lesions in these locations, which must be tested in appropriate models. Cutaneous beta HPV types appear to be involved in skin carcinogenesis. Virus oncogenicity is partly achieved by inactivation of retinoblastoma protein family members by the viral E7 gene. Here we show that the E7 protein of cutaneous beta HPV5 binds pRb and promotes its degradation. In addition, we described an in vivo model of HPV-associated disease in which artificial human skin prepared using primary keratinocytes engineered to express the E7 protein is engrafted onto nude mice. Expression of E7 in the transplants was stably maintained for up to 6 months, inducing the appearance of lesions that, in the case of HPV16 E7, histologically resembled human anogenital lesions caused by oncogenic HPVs. Moreover, it was confirmed through biomarker expression analysis via immunodetection and/or quantitative PCR from mRNA and miRNA that the 16E7-modified engrafted skin shares molecular features with human HPV-associated pretumoral and tumoral lesions. Finally, our findings indicate a decrease of the in vitro capacity of HPV5 E7 to reduce pRb levels in vivo, possibly explaining the phenotypical differences when compared with 16E7-grafts. Our model seems to be a valuable platform for basic research into HPV oncogenesis and preclinical testing of HPV-associated antitumor therapies.