Foxl-2 in gonad development and pathology.

The Foxl-2 gene is involved in eyelid and ovary development. Mutations can lead to a shortened protein and malformations such as BPES associated or not to POF. Forkhead point mutation C134W is a marker of adult type granulosa cell tumors only. Foxl-2 dysregulation is also present in DSD and DSD associated tumors such as Gonadoblastoma and gonadoblastoma like intratubular undetermined germ cell neoplasia. A similar spectrum of pathology involvement is also found for WT1 and RET and gives a new insight into the relationship between development, malformations and oncogenesis.

Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy.

The specificity of chronic histological lesions induced by calcineurin inhibitors (CNI) is often questioned, but few studies have directly compared long-term lesions in renal-transplant patients who received this treatment and those who did not. We therefore conducted a retrospective study of 141 kidney-transplant recipients treated with (n = 48) or without (n = 93) cyclosporine (CsA) to compare the histological lesions observed at 3-month, 24-month and 10-year protocol biopsies. All of the chronic elementary lesions (glomerulosclerosis, interstitial fibrosis, tubular atrophy, arteriolar hyalinosis, fibrointimal thickening) progressed in frequency and severity in both groups, although significantly more in the CsA group. Ten-year biopsy results showed that 92% of patients in the CsA-treated group and 65% in the control group had arteriolar hyalinosis lesions. When we focused on muscular arteriolar hyaline deposits more specific to CsA arteriolopathy, we observed these lesions in 68% of CsA patients and 28% of patients who had never received CsA. CsA was not the sole factor involved in the development of arteriolar hyalinosis and was independently associated with an increased risk of graft loss. In summary, we observed that histological lesions commonly attributed to CsA nephrotoxicity were not sufficiently specific to definitively diagnose CNI nephrotoxicity.

ABCC8 and KCNJ11 molecular spectrum of 109 patients with diazoxide-unresponsive congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is characterised by an over secretion of insulin by the pancreatic ß-cells. This condition is mostly caused by mutations in ABCC8 or KCNJ11 genes encoding the SUR1 and KIR6.2 subunits of the ATP-sensitive potassium (K(ATP)) channel. CHI patients are classified according to their responsiveness to diazoxide and to their histopathological diagnosis (either focal, diffuse or atypical forms). Here, we raise the benefits/limits of the genetic diagnosis in the clinical management of CHI patients. METHODS: ABCC8/KCNJ11 mutational spectrum was established in 109 diazoxide-unresponsive CHI patients for whom an appropriate clinical management is essential to prevent brain damage. Relationships between genotype and radiopathological diagnosis were analysed. RESULTS: ABCC8 or KCNJ11 defects were found in 82% of the CHI cases. All patients with a focal form were associated with a single K(ATP) channel molecular event. In contrast, patients with diffuse forms were genetically more heterogeneous: 47% were associated with recessively inherited mutations, 34% carried a single heterozygous mutation and 19% had no mutation. There appeared to be a predominance of paternally inherited mutations in patients diagnosed with a diffuse form and carrying a sole K(ATP) channel mutation. CONCLUSIONS: The identification of recessively inherited mutations related to severe and diffuse forms of CHI provides an informative genetic diagnosis and allows prenatal diagnosis. In contrast, in patients carrying a single K(ATP) channel mutation, genetic analysis should be confronted with the PET imaging to categorise patients as focal or diffuse forms in order to get the appropriate therapeutic management.

Fetal urinoma: two new cases and a review of the literature.

OBJECTIVE: To evaluate the functional prognosis of kidneys affected prenatally by urinomas. METHODS: This was a retrospective review of cases of fetal urinoma reported in the literature, as well as two of our own cases. RESULTS: Twenty-three patients with a prenatal diagnosis of urinoma (five bilateral) were included in the analysis. Postnatal ipsilateral renal function was observed in only six of the 28 renal units (i.e. around 20%). CONCLUSIONS: Although the precise causes of urinomas are still unknown, this review shows that in the event of a fetal urinoma, the probability of a non-functional dysplastic ipsilateral kidney lies at around 80%. In-utero puncture only appears to be justified in cases where fluid accumulation has mass effects on adjacent major structures.

Randomised trial comparing three different schedules of infusional 5FU and raltitrexed alone as first-line therapy in metastatic colorectal cancer. Final results of the Fédération Francophone de Cancérologie Digestive (FFCD) 9601 trial.

LV5FU2 with high-dose leucovorin (LV), weekly infusional 5-fluorouracil (5FU) (AIO schedule) and raltitrexed have been demonstrated to be active agents in first-line treatment of colorectal cancer. We performed a 4-arm randomised trial to compare (1) a low-dose intravenous bolus of LV (20 mg/m2), followed by an intravenous bolus of 5FU (400 mg/m2), followed by a 22-hour continuous infusion of 5FU (600 mg/m2) on day 1 and day 2/2 weeks (ldLV5FU2 arm), (2) a weekly continuous infusion of high-dose 5FU (2.6 g/m2/week) for 6 weeks followed by a rest week (HD-FU arm) and (3) raltitrexed (Tomudex arm; 3 mg/m2/3 weeks) to standard LV5FU2. From 1997 to 2001, 294 patients were included. The 4 arms were well balanced for sex ratio, age, WHO performance status, the primary tumour site and prior adjuvant chemotherapy. Treatment was stopped due to low accrual. Two toxicity-related deaths were observed in the Tomudex arm. The treatments gave rise to different rates of grade 3-4 neutropenia (3, 4, 11 and 14% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively, p = 0.028), leucopenia and vomiting. At least one episode of grade 3-4 toxicity was observed in 27, 25, 38 and 47% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.016). An objective response was observed in 28, 21, 22 and 10% of the patients in the LV5FU2, ldLV5FU2, HD-FU and Tomudex arms, respectively (p = 0.04). Progression-free survival (PFS) of the patients in the Tomudex arm was statistically lower compared to that of patients treated with LV5FU2 or ldLV5FU2 (combined group; p = 0.013, log rank test). In conclusion, Tomudex is more toxic and yields shorter PFS than infusional 5FU. Despite the early closure of the study and the lack of power of the comparison, it seems that ldLV5FU2 could be considered as an active, easier and less expensive option for the treatment of metastatic colorectal cancer compared to classic LV5FU2 or weekly HD-FU.

Congenital hyperinsulinism and mosaic abnormalities of the ploidy.

BACKGROUND: Congenital hyperinsulinism and Beckwith-Wiedemann syndrome both lead to beta islet hyperplasia and neonatal hypoglycaemia. They may be related to complex genetic/epigenetic abnormalities of the imprinted 11p15 region. The possibility of common pathophysiological determinants has not been thoroughly investigated. OBJECTIVE: To report abnormalities of the ploidy in two unrelated patients with congenital hyperinsulinism. METHODS: Two patients with severe congenital hyperinsulinism, one overlapping with Beckwith-Wiedemann syndrome, had pancreatic histology, ex vivo potassium channel electrophysiological studies, and mutation detection of the encoding genes. The parental genetic contribution was explored using genome-wide polymorphism, fluorescent in situ hybridisation (FISH), and blood group typing studies. RESULTS: Histological findings diverged from those described in focal congenital hyperinsulinism or Beckwith-Wiedemann syndrome. No potassium channel dysfunction and no mutation of its encoding genes (SUR1, KIR6.2) were detected. In patient 1 with congenital hyperinsulinism and Beckwith-Wiedemann syndrome, paternal isodisomy for the whole haploid set was homogeneous in the pancreatic lesion, and mosaic in the leucocytes and skin fibroblasts (hemihypertrophic segment). Blood group typing confirmed the presence of two erythroid populations (bi-parental v paternal only contribution). Patient 2 had two pancreatic lesions, both revealing triploidy with paternal heterodisomy. Karyotype and FISH analyses done on the fibroblasts and leucocytes of both patients were unremarkable (diploidy). CONCLUSIONS: Diploid (biparental/paternal-only) mosaicism and diploid/triploid mosaicism were present in two distinct patients with congenital hyperinsulinism. These chromosomal abnormalities led to paternal disomy for the whole haploid set in pancreatic lesions (with isodisomy or heterodisomy), thereby extending the range and complexity of the mechanisms underlying congenital hyperinsulinism, associated or not with Beckwith-Wiedemann syndrome.

Eosinophilic esophagitis in children: symptoms, histology and pH probe results.

AIM: To review the authors' experience with eosinophilic esophagitis. METHODS: Between 1993 and 2001, the authors identified 12 patients with eosinophilic esophagitis defined on histologic criteria (> or = 20 eosinophils per high-power field in the distal esophageal epithelium). The authors reviewed medical records for details of clinical presentation; laboratory data; radiologic, endoscopic, and histologic findings; and the results of continuous esophageal pH probe monitoring. RESULTS: Seventy-five percent of the patients were male. The median age at presentation was 10.8 years (range, 1-17 years). Commonly reported symptoms were dysphagia with solid food (66%), epigastric pain (42%), food impaction (50%), and vomiting (8%). Food allergy was reported in 50% and asthma in 33%. Peripheral eosinophilia (> 700/mm3) was found in 42%. Upper gastrointestinal series performed in eight patients, showed esophageal luminal narrowing in three. Computed tomography, performed in two patients, revealed thickening of the esophageal wall. Esophageal pH probe monitoring, performed in nine patients, revealed no abnormal acid reflux. All of the monitored patients had episodic alkalinization of the esophagus. Upper endoscopic analysis revealed white specks on the esophageal mucosa in 42%, esophageal narrowing in 33%, esophageal rings in 25%, and esophageal furrowing in 8%. The mean eosinophils per high-power field was 65 (range, 20-200). Histologic characteristics included juxtaluminar (33%) and peripapillary clusters of eosinophils (33%), increased papillary height (50%), and basal cell hyperplasia (34%). CONCLUSION: Solid food dysphagia was the most common feature of eosinophilic esophagitis in our patients. Alkalinization of the esophagus was found in all nine pH probe recordings of eosinophilic esophagitis patients and may represent a previously unreported characteristic of the condition.

Central processing of rectal pain in patients with irritable bowel syndrome: an fMRI study.

OBJECTIVES: In healthy subjects, the neural correlates of visceral pain bear much similarity with the correlates of somatic pain. In patients with irritable bowel syndrome, the central nervous system is believed to play a strong modulatory or etiological role in the pathophysiology of the disease. We hypothesize that this role must be reflected in aberrations of central functional responses to noxious visceral stimulation in these patients. To verify this hypothesis, we have induced transient rectal pain in patients and assessed the functional responses of the brain by means of functional magnetic resonance imaging. METHODS: Twelve right-handed patients (11 female) were examined. Functional imaging (1.5 T) was performed following a block paradigm, alternating epochs with and without noxious stimulation of the rectum. Rectal pain was induced by inflating a latex balloon. Whole-brain coverage was achieved by means of echo-planar magnetic resonance acquisition. RESULTS: A strong variability of the individual responses to rectal pain was found in patients with irritable bowel syndrome. Significant activations were found in only two patients, and group analysis did not reveal significant activations. In contrast, all patients exhibited significant deactivations. Group analysis revealed significant deactivations within the right insula, the right amygdala, and the right striatum. CONCLUSIONS: This study reveals aberrant functional responses to noxious rectal stimulation in patients with irritable bowel syndrome. Those results add grounds to the hypothesis that the central nervous system plays a significant role in the pathophysiology of this syndrome.

Relationship between acid reflux episodes and gastroesophageal reflux symptoms is very inconstant.

In this prospective study 244 consecutive patients presenting with typical and chronic signs of gastroesophageal reflux were included. Conventional 24-hr esophageal pH monitoring was carried out to establish the symptom association probability, the concordance index, and the symptom sensitivity index. The symptom association probability could be calculated in 110 patients (45%). Two groups were identified: group 1 had normal duration of esophageal acid exposure; subgroup la (nonsignificant symptom association probability) included 39 patients (35.5%) and subgroup lb (significant symptom association probability) included 24 patients (21.8%); group 2 had abnormal duration of esophageal acid exposure; subgroup 2a (nonsignificant symptom association probability) included 21 patients (19.1%) and subgroup 2b (significant symptom association probability) included 26 patients (23.6%). In all, 56.6% of the patients presented typical symptoms of reflux not directly determined by one or repeated acid reflux episodes. The correlation between symptom association probability and the symptom sensitivity index allows for more accurate determination of esophageal acid sensitivity (subgroups lb and 2b).

Effective use of argon plasma coagulation in the treatment of severe radiation proctitis.

PURPOSE: Chronic radiation proctitis, a well described complication of pelvic radiation therapy, can result in severe bleeding that is refractory to conventional treatment. Argon plasma coagulation is an effective treatment for hemorrhagic lesions of the gastrointestinal tract. The aim of this study was to assess the efficacy and safety of argon plasma coagulation in the management of severe radiation proctitis resistant to medical treatment. METHODS: Eleven patients (10 males) aged between 54 and 86 years (mean +/- standard error of the mean, 73 +/- 3 years), with chronic radiation proctitis after radiotherapy for prostate (n = 9), uterine (n = 1) or rectal (n = 1) cancer were enrolled in this prospective study. Traditional therapies had failed including mainly topical steroids, 5-aminosalicylic acid and sometimes sucralfate. All patients had active bleeding from diffuse telangiectasias responsible for chronic anemia and seven of them required blood transfusions. The mean duration of the sessions was 20 minutes and one to five sessions (mean, 3.2 +/- 0.4), usually without anesthesia, were required to stop bleeding. Mean follow-up time was 19 +/- 2 (range, 7-30) months. RESULTS: Rectal bleeding disappeared in nine patients and was greatly reduced in two. All the patients were free of transfusions during the mean follow-up of 19 months. The mean hemoglobin level was 7.7 +/- 2.8 g/dl at the first session and increased significantly (P = 0.003) to 11.5 +/- 2.6 g/dl after treatment. In two patients, a rectal stenosis appeared 7 and 11 months after the first session. CONCLUSION: Argon plasma coagulation is a simple, inexpensive and effective treatment for severe refractory radiation proctitis with telangiectasias. Follow-up supervision is in progress to evaluate long term benefits and the risk of rectal stenosis.

Decreasing oesophageal acid exposure in patients with GERD: a comparison of rabeprazole and omeprazole.

BACKGROUND: Rabeprazole has been shown to be more potent and faster than other proton pump inhibitors in in vitro studies and highly effective in decreasing oesophageal acid exposure in patients with gastro-oesophageal reflux disease (GERD). AIM: This study was a multicentre, double-blind, placebo-controlled, randomized, parallel-group comparison of three active treatment regimens utilizing two different proton pump inhibitors, or placebo, administered over 7 days in patients with GERD. METHODS: Eighty-two patients with symptomatic GERD were given placebo, rabeprazole 10 mg b.d., rabeprazole 20 mg o.m., or omeprazole 20 mg o.m. for 7 days. Twenty-four hour oesophageal pH monitoring was performed at baseline and repeated at the conclusion of the treatment period. RESULTS: At the end of study, the percentage time (mean +/- s.d.) with pH < 4 over a 24-h period was significantly decreased by the three active regimens but without significant difference between them (9.27 +/- 4.77; 2.53 +/- 4.27; 2.02 +/- 1.71 and 2.91 +/- 4.06 for placebo, rabeprazole 10 mg b.d., rabeprazole 20 mg o.m. and omeprazole 20 mg o.m., respectively). Acid exposure was normalized in 90% of patients treated with rabeprazole 10 mg b.d., 95% treated with rabeprazole 20 mg o.m., 78% treated with omeprazole 20 mg o.m., and only 9.5% of patients treated with placebo. Both rabeprazole and omeprazole were well-tolerated. CONCLUSIONS: Although rabeprazole 20 mg o.m. showed greater activity numerically, this study demonstrates that rabeprazole 10 mg b.d. and 20 mg o.m. are equivalent to omeprazole 20 mg o.m. in decreasing oesophageal acid exposure.

Pancreatic arterial calcium stimulation in the diagnosis and localisation of persistent hyperinsulinemic hypoglycaemia of infancy.

BACKGROUND: Persistent hyperinsulinemic hypoglycaemia of infancy (PHHI) is often resistant to medical therapy. Surgery is therefore necessary. It is due to focal adenomatous islet-cell hyperplasia treatable by partial pancreatectomy, or diffuse beta-cell hyperfunction, which requires near-total pancreatectomy. Pancreatic venous sampling (PVS) is the reference technique for the preoperative diagnosis and localization of focal forms of PHHI in the pancreas. However, hypoglycaemia is necessary to analyse the results and PVS is technically challenging. Pancreatic arterial calcium stimulation (PACS) is technically easier and does not require hypoglycaemia. AIM: To study the accuracy in the diagnosis and localization of PHHI. MATERIALS AND METHODS: PACS was performed in 12 patients and correlated with histology. RESULTS: The accuracy of PACS is poor in diffuse lesions since only two of six cases were correctly identified by this test. Five of six focal lesions were correctly recognized and located. CONCLUSIONS: PACS is less accurate than PVS in PHHI. Currently, it should be performed only when PVS fails.

Fetal lung volume measurement by magnetic resonance imaging in congenital diaphragmatic hernia.

OBJECTIVE: To study the potential for prenatal magnetic resonance imaging to predict pulmonary hypoplasia in congenital diaphragmatic hernia. DESIGN: Prospective observational study. SETTING: Tertiary care centre. PARTICIPANTS: Thirteen cases of congenital diaphragmatic hernia (11 left, 2 right) without associated anomalies and 74 controls. METHODS: Measurements by magnetic resonance imaging of fetal lung volume were achieved. In the control fetuses, a regression analysis was performed to associate fetal lung volume with gestational age. This yielded a formula allowing calculation of the expected fetal lung volume as a function of gestational age. In the cases with congenital diaphragmatic hernia, the observed/expected fetal lung volume ratio was compared with perinatal outcome. MAIN OUTCOME MEASURES: Neonatal mortality and pulmonary hypoplasia, which was defined as lung/body weight ratios less than 0.012. RESULTS: The expected fetal lung volume was derived from the following formula: Fetal lung volume (mL) = exp (1.24722 + 0.08939 x gestational age in weeks). The observed/expected fetal lung volume ratio was significantly lower in congenital diaphragmatic hernia (median: 0.31, range: 0.06-0.63), than in controls (median: 0.99, range: 0.42-1.94). This ratio was significantly less in the infants with congenital diaphragmatic hernia who died (median: 0.26, range: 0.06-0.63) compared with those who survived (median: 0.46, range: 0.35-0.56). The observed: expected fetal lung volume ratio was significantly correlated with the post mortem lung: body weight ratio. CONCLUSION: In isolated congenital diaphragmatic hernia, fetal lung volume measurement by magnetic resonance imaging is a potential predictor of pulmonary hypoplasia and postnatal outcome. Further studies are required to establish the clinical value of magnetic resonance imaging for the prenatal assessment of fetal lungs.

Unbalanced expression of 11p15 imprinted genes in focal forms of congenital hyperinsulinism: association with a reduction to homozygosity of a mutation in ABCC8 or KCNJ11.

Congenital hyperinsulinism (CHI), previously named persistent hyperinsulinemic hypoglycemia of infancy, is characterized by profound hypoglycemia because of excessive insulin secretion. CHI presents as two different morphological forms: a diffuse form with functional abnormality of islets throughout the pancreas and a focal form with focal islet cell adenomatous hyperplasia, which can be cured by partial pancreatectomy. Recently, we have shown that focal adenomatous hyperplasia involves the specific loss of the maternal 11p15 region and a constitutional mutation of a paternally inherited allele of the gene encoding the regulating subunit of the K(+)(ATP) channel, the sulfonylurea receptor (ABCC8 or SUR1). In the present study on a large series of 31 patients, describing both morphological features and molecular data, we report that 61% of cases (19 out of 31) carried a paternally inherited mutation not only in the ABCC8 gene as previously described but also in the second gene encoding the K(+)(ATP) channel, the inward rectifying potassium channel (KCNJ11 or KIR6.2), in 15 cases and 4 cases, respectively. Moreover our results are consistent with the presence of a duplicated paternal 11p15 allele probably because of mitotic recombination or reduplication of the paternal chromosome after somatic loss of the maternal chromosome. In agreement with the loss of the maternal chromosome, the level of expression of a maternally expressed tumor suppressor gene, H19, was greatly reduced compared to the level of expression of the paternally expressed growth promoter gene, IGF2. The expression of IGF2 was on average only moderately increased. Thus, focal forms of CHI can be considered to be a recessive somatic disease, associating an imbalance in the expression of imprinted genes in the 11p15.5 region to a somatic reduction to homozygosity of an ABCC8- or KCNJ11-recessive mutation. The former is responsible for the abnormal growth rate, as in embryonic tumors, whereas the latter leads to unregulated secretion of insulin.