Constitutive Hedgehog/GLI2 signaling drives extracutaneous basaloid squamous cell carcinoma development and bone remodeling.

Uncontrolled activation of the Hedgehog (Hh) signaling pathway, operating through GLI transcription factors, plays a central role in the pathogenesis of cutaneous basal cell carcinoma and contributes to the development of several malignancies arising in extracutaneous sites. We now report that K5-tTA;tetO-Gli2 bitransgenic mice develop distinctive epithelial tumors within their jaws. These tumors consist of large masses of highly proliferative, monomorphous, basaloid cells with scattered foci of keratinization and central necrosis, mimicking human basaloid squamous cell carcinoma (BSCC), an aggressive upper aerodigestive tract tumor. Like human BSCC, these tumors express epidermal basal keratins and differentiation-specific keratins within squamous foci. Mouse BSCCs express high levels of Gli2 and Hh target genes, including Gli1 and Ptch1, which we show are also upregulated in a subset of human BSCCs. Mouse BSCCs appear to arise from distinct epithelial sites, including the gingival junctional epithelium and epithelial rests of Malassez, a proposed stem cell compartment. Although Gli2 transgene expression is restricted to epithelial cells, we also detect striking alterations in bone adjacent to BSCCs, with activated osteoblasts, osteoclasts and osteal macrophages, indicative of active bone remodeling. Gli2 transgene inactivation resulted in rapid BSCC regression and reversal of the bone remodeling phenotype. This first-reported mouse model of BSCC supports the concept that uncontrolled Hh signaling plays a central role in the pathogenesis of a subset of human BSCCs, points to Hh/GLI2 signaling as a potential therapeutic target and provides a powerful new tool for probing the mechanistic underpinnings of tumor-associated bone remodeling.

An Endoscopic View of Multiple Hemangiomas of the Small Intestine.

Small intestinal hemangiomas may present as a severe gastrointestinal hemorrhage associated with a hematologic emergency. In the emergent setting, this may result in more extensive intestinal resection than would otherwise be necessary with elective intervention. The widespread application of capsule endoscopy and double-balloon enteroscopy presents an opportunity to diagnose small bowel hemangiomas prior to symptomatic onset. In one of the first published cases of multiple small intestinal hemangiomas, we highlight the importance of maintaining a broad differential and pursuing a thorough workup, including small bowel imaging, in patients with complaints of chronic abdominal pain and anemia.

Young-Onset Colon Cancer: A Case Report.

Colorectal cancer (CRC) which is diagnosed in patients under the age of 50 years is defined as young-onset CRC. There has been a substantial increase in the incidence and mortality of young-onset CRC in the past four decades and the patients have delayed diagnoses leading to the advanced stages of CRC at the time of diagnosis. Here we present a case of a 34-year-old male patient with colon cancer and a literature review on young-onset colon cancer to highlight the age-related disparities in CRC incidence and try to explore the possible causative factors for the rise in incidence and mortality in young patients due to CRC.

Epidemiology, Diagnosis, Staging and Multimodal Therapy of Esophageal and Gastric Tumors.

Gastric and esophageal tumors are diverse neoplasms that involve mucosal and submucosal tissue layers and include squamous cell carcinomas, adenocarcinomas, spindle cell neoplasms, neuroendocrine tumors, marginal B cell lymphomas, along with less common tumors. The worldwide burden of esophageal and gastric malignancies is significant, with esophageal and gastric cancer representing the ninth and fifth most common cancers, respectively. The approach to diagnosis and staging of these lesions is multimodal and includes a combination of gastrointestinal endoscopy, endoscopic ultrasound, and cross-sectional imaging. Likewise, therapy is multidisciplinary and combines therapeutic endoscopy, surgery, radiotherapy, and systemic chemotherapeutic tools. Future directions for diagnosis of esophageal and gastric malignancies are evolving rapidly and will involve advances in endoscopic and endosonographic techniques including tethered capsules, optical coherence tomography, along with targeted cytologic and serological analyses.

Loss of tolerance to glycoprotein 2 isoforms 1 and 4 is associated with Crohn's disease of the pouch.

BACKGROUND: Zymogen granule glycoprotein 2 (GP2) is a major autoantigen of Crohn's disease-specific pancreatic autoantibodies. AIM: To test a link between loss of tolerance to isoforms of GP2 and pouch disorders in a cross-sectional study in ulcerative colitis patients with ileal pouch-anal anastomosis (IPAA). METHODS: Serum samples of 117 consecutive ulcerative colitis patients after IPAA were tested for presence of Anti-GP2 isoforms 1 (GP21 ) & 4 (GP24 ) IgG and IgA as well as anti-Saccaromyces cervisiae (ASCA) IgG and IgA antibodies in a blinded fashion via enzyme-linked immunosorbent assay. Pouch disorders were diagnosed based on clinical, endoscopic, histological and radiographic criteria. Crohn's disease of the pouch was defined as involvement of the small bowel mucosa proximal to the ileal pouch with Crohn's disease, development of perianal complications or pouch fistula more than 3 months after ileostomy closure. RESULTS: Positivity and level of Anti-GP21 IgG (AUC 0.77; P < 0.001 & P = 0.02, respectively), Anti-GP24 IgG (AUC 0.74; P < 0.001 & P = 0.025, respectively) and Anti-GP24 IgA (AUC 0.77; P < 0.001 to P = 0.018, respectively) were specifically associated with Crohn's disease of the pouch. Anti-GP2 was not associated with endoscopic or histological pouch disease activity index. Neither positivity nor levels of ASCA IgG (AUC 0.63; P = 0.12 & P = 0.35, respectively) or ASCA IgA (AUC 0.67; P = 0.38 & P = 0.53) were associated with pouch phenotypes. CONCLUSIONS: The novel anti-GP21 and GP24 antibodies are associated with Crohn's disease of the pouch in ulcerative colitis patients after IPAA. Serological anti-GP2 antibodies could aid in diagnosis of Crohn's disease of the pouch.

Reação granulomatosa tardia por ácido hialurônico associada à artrite reumatoide em uso de leflunomide / Late granulomatous reaction to hyaluronic acid associated with rheumatoid arthritis treated with leflunomide

O ácido hialurônico é o preenchedor atualmente mais utilizado na dermatologia devido ao baixo risco de efeitos colaterais. O objetivo deste trabalho é relatar um caso de reação granulomatosa após preenchimento com dois tipos de ácido hialurônico, na região perioral e no sulco nasogeniano. A paciente, portadora de artrite reumatoide em tratamento com leflunomide, apresentou início dos sintomas 30 meses após o preenchimento. Doenças autoimunes podem facilitar a ocorrência de complicações e devem ser observadas com cuidado antes do preenchimento com ácido hialurônico. Como já relatado com uso de interferon e omalizumab, a reação granulomatosa por preenchedores pode ocorrer após o uso de leflunomide.

Hyaluronic acid is the currently most used filler in dermatology due to its low risk of adverse events. The objective of this study is to report a case of granulomatous reaction after filling with two types of hyaluronic acid, in the perioral region and in the nasolabial folds. A female patient with rheumatoid arthritis treated with leflunomide presented onset of symptoms 30 months after filling. Autoimmune diseases may facilitate the occurrence of complications and should be followed carefully before filling with hyaluronic acid. As already reported with the use of interferon and omalizumab, granulomatous reaction to fillers may occur after use of leflunomide.

Sustained Hedgehog signaling is required for basal cell carcinoma proliferation and survival: conditional skin tumorigenesis recapitulates the hair growth cycle.

Temporally and spatially constrained Hedgehog (Hh) signaling regulates cyclic growth of hair follicle epithelium while constitutive Hh signaling drives the development of basal cell carcinomas (BCCs), the most common cancers in humans. Using mice engineered to conditionally express the Hh effector Gli2, we show that continued Hh signaling is required for growth of established BCCs. Transgene inactivation led to BCC regression accompanied by reduced tumor cell proliferation and increased apoptosis, leaving behind a small subset of nonproliferative cells that could form tumors upon transgene reactivation. Nearly all BCCs arose from hair follicles, which harbor cutaneous epithelial stem cells, and reconstitution of regressing tumor cells with an inductive mesenchyme led to multilineage differentiation and hair follicle formation. Our data reveal that continued Hh signaling is required for proliferation and survival of established BCCs, provide compelling support for the concept that these tumors represent an aberrant form of follicle organogenesis, and uncover potential limitations to treating BCCs using Hh pathway inhibitors.