Clinicopathological Findings on 28 Cases with XP11.2 Renal Cell Carcinoma.

Xp11.2 translocation carcinoma is a distinct subtype of renal cell carcinoma characterized by translocations involving the TFE3 gene. Our study included the morphological, immunohistochemical and clinicopathological examination of 28 Xp11.2 RCCs. The immunophenotype has been assessed by using CA9, CK7, CD10, AMACR, MelanA, HMB45, Cathepsin K and TFE3 immunostainings. The diagnosis was confirmed by TFE3 break-apart FISH in 25 cases. The ages of 13 male and 15 female patients, without underlying renal disease or having undergone chemotherapy ranged from 8 to 72. The mean size of the tumors was 78.5 mm. Forty-three percent of patients were diagnosed in the pT3/pT4 stage with distant metastasis in 6 cases. Histological appearance was branching-papillary composed of clear cells with voluminous cytoplasm in 13 and variable in 15 cases, including one tumor with anaplastic carcinoma and another with rhabdoid morphology. Three tumors were labeled with CA9, while CK7 was negative in all cases. Diffuse CD10 reaction was observed in 17 tumors and diffuse AMACR positivity was described in 14 tumors. The expression of melanocytic markers and Cathepsin K were seen only in 7 and 6 cases, respectively. TFE3 immunohistochemistry displayed a positive reaction in 26/28 samples. TFE3 rearrangement was detected in all the analyzed cases (25/25), including one with the loss of the entire labeled break-point region. The follow-up time ranged from 2 to 300 months, with 7 cancer-related deaths. In summary, Xp11.2 carcinoma is an uncommon form of renal cell carcinoma with a variable histomorphology and rather aggressive clinical course.

Mucosectomy disrupting the enteric nervous system causes contraction and shrinkage of gastrointestinal flaps: potential implications for augmentation cystoplasty.

INTRODUCTION: Augmenting the bladder with a seromuscular gastrointestinal flap is a promising alternative approach aiming for a mucus-free bladder augmentation; however, the contraction (shrinkage) of the flaps remains a major concern. Enteric nervous system (ENS) abnormalities cause a failure of relaxation of the intestinal muscle layers in motility disorders such as Hirschsprung's disease and intestinal neuronal dysplasia. In mammals, the submucosal enteric nervous plexus contains nitrergic inhibitory motor neurons responsible for muscle relaxation. The authors hypothesize that mucosectomy disconnects the submucosal nervous plexus from the myenteric plexus resulting in flap shrinkage. STUDY DESIGN: After ethical approval, mucosectomy was performed on vascularized flaps from the ileum, colon, and stomach in five anesthetized pigs. In Group (I), only the mucosa was scraped off with forceps, creating a sero-musculo-submucosal flap, while in Group (II), the mucosa and submucosa were peeled off as one layer, leaving a seromuscular flap. Isolated and detubularized segments served as control. The width of each flap was measured before and after the mucosectomy. The ENS was assessed by neurofilament immunohistochemistry in conventional sections and by acetylcholinesterase and NADPH-diaphorase enzyme histochemistry in whole-mount preparations. RESULTS: The stomach contracted to a lesser extent of its original width, 92.82 ± 7.86% in Group (I) and 82.24 ± 6.96% in Group (II). The ileum contracted to 81.68 ± 4.25% in Group (I) and to 72.675 ± 5.36% in Group (II). The shrinkage was most noticeable in the colon: 83.89 ± 15.73% in Group (I) and to 57.13 ± 11.51% in Group (II). One-way equal variance test showed significant difference (P < 0,05) between Group (I) and (II), comparing stomach with ileum and ileum with colon. The histochemistry revealed that the submucosal nervous plexus containing nitrergic inhibitory neurons was disconnected from the myenteric plexus in Group (II) of all specimens. CONCLUSION: Mucosectomy resulted in significant immediate shrinkage of the flaps. This was more expressed when also the submucosa was peeled off, thus fully disrupting the ENS. The shrinkage affected the stomach the least and the colon the greatest. This phenomenon should be taken into consideration when planning mucus-free bladder augmentation.

Relation of the IGF/IGF1R system to autophagy in colitis and colorectal cancer.

Metabolic syndrome (MetS), as a chronic inflammatory disorder has a potential role in the development of inflammatory and cancerous complications of the colonic tissue. The interaction of DNA damage and inflammation is affected by the insulin-like growth factor 1 receptor (IGF1R) signaling pathway. The IGF1R pathway has been reported to regulate autophagy, as well, but sometimes through a bidirectional context. Targeting the IGF1R-autophagy crosstalk could represent a promising strategy for the development of new antiinflammatory and anticancer therapies, and may help for subjects suffering from MetS who are at increased risk of colorectal cancer. However, therapeutic responses to targeted therapies are often shortlived, since a signaling crosstalk of IGF1R with other receptor tyrosine kinases or autophagy exists, leading to acquired cellular resistance to therapy. From a pharmacological point of view, it is attractive to speculate that synergistic benefits could be achieved by inhibition of one of the key effectors of the IGF1R pathway, in parallel with the pharmacological stimulation of the autophagy machinery, but cautiousness is also required, because pharmacologic IGF1R modulation can initiate additional, sometimes unfavorable biologic effects.