Successful gene therapy in the RPGRIP1-deficient dog: a large model of cone-rod dystrophy.

For the development of new therapies, proof-of-concept studies in large animal models that share clinical features with their human counterparts represent a pivotal step. For inherited retinal dystrophies primarily involving photoreceptor cells, the efficacy of gene therapy has been demonstrated in canine models of stationary cone dystrophies and progressive rod-cone dystrophies but not in large models of progressive cone-rod dystrophies, another important cause of blindness. To address the last issue, we evaluated gene therapy in the retinitis pigmentosa GTPase regulator interacting protein 1 (RPGRIP1)-deficient dog, a model exhibiting a severe cone-rod dystrophy similar to that seen in humans. Subretinal injection of AAV5 (n = 5) or AAV8 (n = 2) encoding the canine Rpgrip1 improved photoreceptor survival in transduced areas of treated retinas. Cone function was significantly and stably rescued in all treated eyes (18-72% of those recorded in normal eyes) up to 24 months postinjection. Rod function was also preserved (22-29% of baseline function) in four of the five treated dogs up to 24 months postinjection. No detectable rod function remained in untreated contralateral eyes. More importantly, treatment preserved bright- and dim-light vision. Efficacy of gene therapy in this large animal model of cone-rod dystrophy provides great promise for human treatment.

Imaging of a primitive clitoral epidermoid cyst.

An 11-year-old Caucasian girl was investigated for a clitoromegaly that had increased in size over 5 weeks. Clitoromegaly is a rare condition in childhood. Among nonhormonal causes are tumours, both benign and malignant. Evaluation of the adrenal glands and ovaries was performed by US. An epidermoid cyst was suggested by MRI including diffusion-weighted imaging, and this was confirmed histopathologically.

[PEComas: report of five abdominopelvic cases]. / PEComes abdomino-pelviens: à propos d'une série de cinq cas.

We report five cases of abdomino-pelvic PEComas diagnosed in the last 10 years in the Rouen University Hospital. Four are hepatic and one is in a pelvic location which is unusual due to its strongly pigmented aspect. The tumors derived from "perivascular epithelioid cells" are rare. They are characterized by spindle or epithelioid cells in an immediate perivascular location. The immunochemistry is positive for HMB45, MelanA and smooth muscle Actin. The criteria for malignancy are infiltrative growth pattern, necrosis, high cellularity, high nuclear grade and mitotic activity. There are 8% of recurrence and 20% of metastasis (lung, bones, liver). This study presents the clinical, pathologic, immunohistochemical and molecular aspects of these PEComas and discusses the main differential diagnosis of the pigmented one.

The RPGRIP1-deficient dog, a promising canine model for gene therapy.

PURPOSE: To evaluate the RPGRIP1-deficient miniature longhaired dachshund (MLHD) dog as a potential candidate for gene therapy. METHODS: Six RPGRIP1-deficient MLHD dogs from our dog colony have been observed for two years using a variety of noninvasive procedures. These included bilateral full-field electroretinograms (ERG) to evaluate retinal function, fundus photographs to evaluate retinal vascularization, and optical coherence tomographs (OCT) to evaluate retinal thickness. We also performed histological examination of hematoxylin- and eosin-stained retinal sections as well as sections labeled in situ by the terminal dUTP nick end labeling (TUNEL) method. RESULTS: ERG findings showed that as early as 2 months of age, cone function was lost while rod function was preserved. However, by 9 months of age, both cone and rod functions could not be detected. Functional visual assessment based on the ability to avoid obstacles showed that vision was retained up to the age of 11 months. Both OCT and histopathology studies revealed a progressive thinning of the outer nuclear layer (ONL) over the first 2 years of age. TUNEL labeling identified apoptotic photoreceptor cell death as the cause of this thinning of the ONL. CONCLUSIONS: A treatment strategy should consist in initiating gene therapy as early as possible after birth to prevent or delay the loss of rod function. In the MLHD, successful subretinal delivery of a therapeutic vector is feasible at 2 months of age and may prevent or delay the loss of rod function.

Endoplasmic reticulum stress, unfolded protein response and development of colon adenocarcinoma.

When misfolded proteins accumulate in the endoplasmic reticulum (ER), the cell is said to experience ER stress. This triggers an unfolded protein response (UPR) to restore the balance between misfolded proteins and ER chaperones such as BiP. UPR signalling is required for the growth of many solid cancers. In chronic ER stress, factors including CHOP have been shown to mediate cell death. Colorectal adenocarcinoma arises due to progressive changes within pre-malignant lesions. Our aim was to test the hypothesis that the expression of BiP and CHOP correlates with the progression of those pre-malignant lesions.Eighty-one patients with colon neoplasms treated at Rouen University Hospital between January 1, 2003 and January 1, 2013 were randomly selected. The expression of BiP and CHOP was estimated by immunohistochemical staining of a tissue microarray generated from colon cores: normal tissue, low-grade and high-grade adenoma, invasive colon adenocarcinoma and lymph node metastasis of colon adenocarcinoma. In parallel, nine cases comprising areas from normal epithelium to dyplasia to invasive carcinoma and included in the TMA were analysed on whole sections.As colon epithelium shows increasing evidence of pre-malignant and then malignant changes, BiP expression significantly increases (p for trend < 0.001), whereas CHOP expression is attenuated (p for trend < 0.001).We identified a positive relationship between BiP expression and colon carcinogenesis, and a negative correlation for CHOP expression. These findings are consistent with a model in which ER stress accompanies oncogenesis and in which loss of proteins that mediate the toxicity of ER stress, such as CHOP, may facilitate tumorigenesis. This raises the exciting possibility that restoration of the negative feedback loop of UPR, if achievable, might antagonise the malignant process.

Complete germline deletion of the STK11 gene in a family with Peutz-Jeghers syndrome.

Peutz-Jeghers syndrome (PJS, MIM175200) is an autosomal-dominant inherited disorder characterised by multiple gastrointestinal hamartomatous polyps, melanin spots of the oral mucosa and digits, and an increased risk for various neoplasms. The PJS results from germline alterations of the STK11/LKB1 tumour suppressor gene, located on 19p13.3, and encoding a serine/threonine kinase. The detection of STK11 germline mutations, in only 50-70% of PJS families, has suggested a genetic heterogeneity of the disease. We report the case of a family with typical features of PJS, including gastrointestinal hamartomatous, breast cancers and melanin spots of the oral mucosa. Quantitative multiplex PCR of short fluorescent fragments (QMPSF) of the 19p13 region allowed us to identify an approximately 250 kb heterozygous deletion removing entirely the STK11 locus. This report, which constitutes the first description of a complete germline deletion of STK11, shows that the presence of such large genomic deletions should be considered in PJS families without detectable point mutations of STK11.

[Retrorectal cystic hamartomas. Report of one case]. / Hamartome kystique rétrorectal. A propos d'une observation.

Retrorectal cystic hamartomas (RCH) are rare congenital lesions of the presacral space, of which 68 cases are reported under different terms. Clinicopathologic features are usually constant and similar to the present case. A 23-year-old woman complained of abdominal and perineal pains for several months. Physical examination revealed a nodular mass in the posterior part of the rectum. A pelvic MRI showed a 5.5 cm cystic retrorectal mass compressing the rectum. The patient underwent surgical resection. Pathologic examination found an ill-defined nodular mass, composed by numerous cysts surrounded by fibroadipose tissue. Cysts were lined by different epithelia: keratinized and non keratinized squamous, transitional, ciliated and mucus-producing columnar epithelia. Few mucinous glands were noted, connected to some cysts. These epithelial structures were surrounded by connective tissue in which well-differentiated bundles of smooth muscle fibers were present without well-formed muscularis. The RCH differential diagnosis includes principally congenital cysts: epidermal cysts, cystic teratomas, dermoid cysts, anal gland cysts and rectal duplications. An embryologic origin of RCH from remnants of the postanal gut is currently accepted. Loco-regional inflammatory process frequently complicates this lesion and can cause perirectal fistulae. RCH also possesses a malignancy potential, with development of adenocarcinomas. To avoid these complications, complete excision is recommended.

[Cytokeratins 7 and 20 immunohistochemistry in ampullary carcinomas]. / Expression immunohistochimique des cytokératines 7 et 20 dans les carcinomes ampullaires.

UNLABELLED: Ampullary carcinomas (AC) account for 33% of all surgically operable pancreatoduodenal tumors. The 5-year relative survival rate is 50% and tumoral stage is the main prognostic factor. However, among the three AC histological subtypes (intestinal, pancreatobiliary and mixed), a favorable prognostic has been reported for the intestinal subtype. BACKGROUND: The aims of this study were to determine the prognostic impact of AC histologic subtype and of cytokeratins (CK) 7 and 20 immunostaining profile in these tumors. PATIENTS AND METHODS: Clinical data of 54 AC were obtained retrospectively. Macroscopic and histologic documents were reviewed and immunostainings for CK7 and CK20 were performed. RESULTS: The classification of tumors, according to histological subtype, was: intestinal 26%, pancreatobiliary 65% and mixed 9%. No correlation was found between histological subtype and tumor stage. The 5-year survival rate varied from 100% for intestinal subtype to 35% for pancreatobiliary subtype. A strong correlation (p < 0.0001) was found between histological subtype and CK7/CK20 immunostaining profile. The 5-year survival rate varied from 100% for CK7-/CK20 + AC to 40% for CK7 + /CK20- AC. CONCLUSION: In our study, the intestinal histological subtype had a favorable prognostic value. CK7/CK20 immunostaining profile was helpful for the identification of histological subtype and appears to provide additional prognostic information.

Phlegmonous gastritis in a 32-week pregnant woman managed by conservative surgical treatment and antibiotics.

Phlegmonous gastritis is an extremely rare and life-threatening condition. We report the case of a 32-week pregnant women presenting a peritonitis owing to phlegmonous gastritis caused by a group A streptococcus and successfully managed by conservative surgical treatment and antibiotics. Multiple endoscopies with biopsies illustrate progressive and complete gastric recovery.