Young age at first pregnancy does protect against early onset breast cancer in BRCA1 and BRCA2 mutation carriers.

PURPOSE: Previous research assessing the impact of pregnancy and age at first pregnancy on breast cancer risk in BRCA1 and BRCA2 mutation carriers has produced conflicting results, with some studies showing an increased risk following early first pregnancy in contrast to the reduced risk in the general population of women. The present study addresses these inconsistencies. METHODS: Female BRCA1 and BRCA2 carriers from North West England were assessed for breast cancer incidence prior to 50 years of age comparing those with an early first full-term pregnancy (< 21 years) to those without a full-term pregnancy. Breast cancer incidence per decade from 20 years and Kaplan-Meier analyses were performed. RESULTS: 2424 female mutation carriers (1278 BRCA1; 1146 BRCA2) developed 990 breast cancers under the age of 50 years. Women who had their first term pregnancy prior to age 21 (n = 441) had a lower cancer incidence especially between age 30-39 years. Kaplan-Meier analysis showed an odds ratio of 0.78 for BRCA1 (p = 0.005) and 0.73 for BRCA2 (p = 0.002). CONCLUSIONS: The present study demonstrates a clear protective effect of early first pregnancy on breast cancer risk in both BRCA1 and BRCA2 mutation carriers.

Risk algorithms that include pathology adjustment for HER2 amplification need to make further downward adjustments in likelihood scores.

To assess the need for adjustment in the likelihood of germline BRCA1/2 mutations in women with HER2+ breast cancers. We analysed primary mutation screens on women with breast cancer with unequivocal HER2 overexpression and assessed the likelihood of BRCA1/BRCA2 mutations by age, oestrogen receptor status and Manchester score. Of 1111 primary BRCA screens with confirmed HER2 status only 4/161 (2.5%) of women with HER2 amplification had a BRCA1 mutation identified and 5/161 (3.1%) a BRCA2 mutation. The pathology adjusted Manchester score between 10 and 19% and 20%+ thresholds resulted in a detection rate of only 6.5 and 15% respectively. BOADICEA examples appeared to make even less downward adjustment. There is a very low detection rate of BRCA1 and BRCA2 mutations in women with HER2 amplified breast cancers. The Manchester score and BOADICEA do not make sufficient downward adjustment for HER2 amplification. For unaffected women, assessment of breast cancer risk and BRCA1/2 probability should take into account the pathology of the most relevant close relative. Unaffected women undergoing mutation testing for BRCA1/2 should be advised that there is limited reassurance from a negative test result if their close relative had a HER2+ breast cancer.

Low prevalence of HER2 positivity amongst BRCA1 and BRCA2 mutation carriers and in primary BRCA screens.

The aim of this study is to delineate more clearly the prevalence of HER2+ breast cancer in women with germline BRCA1/2 mutations. For this purpose, we analysed primary mutation screens on women with breast cancer with unequivocal HER2 amplification and assessed the proportion of BRCA1 and BRCA2 breast cancers that were HER2+ comparing this with the existing literature. The results are that 1063 primary BRCA screens had confirmed tumour HER2 status. If HER2+ only 2.5 % (4/156) and 3.2 % (5/156) of women had a BRCA1 or BRCA2 mutation identified respectively; compared to 27.7 % (115/415) and 8.2 % (34/415) with triple negative tumours. Only 2.1 % (4/195) women with BRCA1-related breast cancer had HER2 amplified breast cancers rising to 6.8 % (n = 12, p = 0.04) in BRCA2. These rates are in keeping with most of the existing literature except a recent large multicenter report which documented higher rates but with no control group. The study concluded that true HER2-amplified breast cancers are rare amongst BRCA1 mutation carriers and are less common in BRCA2 than background rates.

Annual surveillance by CA125 and transvaginal ultrasound for ovarian cancer in both high-risk and population risk women is ineffective.

OBJECTIVE: To assess the efficacy of annual CA125 and transvaginal ultrasound (TVU) scan as surveillance for ovarian cancer. DESIGN: Retrospective audit. SETTING: NHS Trust. POPULATION: Three hundred and forty-one asymptomatic women enrolled for ovarian cancer screening: 179 were in a high-risk group (>10% lifetime risk of developing ovarian cancer), 77 in a moderate risk group (4-10% lifetime risk of developing ovarian cancer) and 71 in a near population risk group (<4% lifetime risk). METHODS: Retrospective audit of case records, laboratory CA125 results, radiology reports, histology records and local cancer registry data. MAIN OUTCOME MEASURES: Ovarian cancers occurring in study population. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of TVU, and CA125 as a screening tool for ovarian cancer. RESULTS: Four ovarian cancers and one endometrial cancer occurred. One ovarian cancer was detected at surveillance, three occurred in women who presented symptomatically between screenings. Thirty women underwent exploratory surgery because of abnormal findings at surveillance. Two women had cancer (PPV = 6.7%); one had ovarian cancer and the other endometrial cancer. Twenty-eight women (93.3%) had no malignancy. Sensitivity, specificity, PPV and NPV for TVU in the whole cohort were 33.3, 85.8, 0.6 and 99.8%, respectively. For high-risk individuals, the figures for TVU were 33.3, 84.5, 1.1 and 99.6, respectively. Combining both modalities for the whole cohort, the sensitivity, specificity, PPV and NPV were 66.7, 82.9, 1.5 and 99.8% and 50.0, 82.8, 1.3 and 99.7%, respectively, for the high-risk group alone. CONCLUSIONS: Ovarian screening by annual TVU and CA125 is inefficient at detecting early-stage ovarian cancers.

An epidemiological study of holoprosencephaly from a regional congenital anomaly register: 1995-2004.

BACKGROUND: Adequate contemporary information to counsel patients with a prenatal diagnosis of holoprosencephaly is lacking. We addressed this using data from the West Midlands Congenital Anomaly Register (WMCAR), a population-based malformation register, during a time where technological improvements have been stable and anomaly screening is well established. METHODS: Cases were defined using the ICD 10 code for holoprosencephaly. Cases of livebirths, stillbirths and termination at all gestations were included in the study. The diagnosis was verified by a pathology or definitive radiological report with cross validation from the regional pathology, clinical genetics, cytogenetics and fetal medicine databases. RESULTS: There were 113 cases reported of holoprosencephaly for the years 1995-2004. This represents a prevalence of 1.7 per 10,000 births and terminations, with no change in prevalence over time. There was a decreased risk of holoprosencephaly in the white population [white vs. nonwhite; RR 0.53(0.36-0.79)]. Karyotypical abnormality was noted in 46% of cases where the karyotype was known. Trisomy 13 was the most common chromosomal abnormality. Correct allocation of a diagnosis of holoprosencephaly by ultrasound occurred in 77% of cases, with another 12% having a severe intracranial abnormality but was not reported as holoprosencephaly. In 4%, a prenatal diagnosis of holoprosencephaly was not made. Termination of pregnancy was performed in 80% of all cases. CONCLUSION: Holoprosencephaly is a morbid condition associated with significant secondary etiologies.

Phenocopies in BRCA1 and BRCA2 families: evidence for modifier genes and implications for screening.

BACKGROUND: The identification of BRCA1 and BRCA2 mutations in familial breast cancer kindreds allows genetic testing of at-risk relatives. Those who test negative are usually reassured and additional breast cancer surveillance is discontinued. However, we postulated that in high-risk families, such as those seen in clinical genetics centres, the risk of breast cancer might be influenced not only by the BRCA1/BRCA2 mutation but also by modifier genes. One manifestation of this would be the presence of phenocopies in BRCA1/BRCA2 kindreds. METHODS: 277 families with pathogenic BRCA1/BRCA2 mutations were reviewed and 28 breast cancer phenocopies identified. The relative risk of breast cancer in those testing negative was assessed using incidence rates from our cancer registry based on local population. RESULTS: Phenocopies constituted up to 24% of tests on women with breast cancer after the identification of the mutation in the proband. The standardised incidence ratio for women who tested negative for the BRCA1/BRCA2 family mutation was 5.3 for all relatives, 5.0 for all first-degree relatives (FDRs) and 3.2 (95% confidence interval 2.0 to 4.9) for FDRs in whose family all other cases of breast and ovarian cancer could be explained by the identified mutation. 13 of 107 (12.1%) FDRs with breast cancer and no unexplained family history tested negative. CONCLUSION: In high-risk families, women who test negative for the familial BRCA1/BRCA2 mutation have an increased risk of breast cancer consistent with genetic modifiers. In light of this, such women should still be considered for continued surveillance.

Contrasting effects on HIF-1alpha regulation by disease-causing pVHL mutations correlate with patterns of tumourigenesis in von Hippel-Lindau disease.

The von Hippel-Lindau tumour suppressor gene product (pVHL) associates with the elongin B and C and Cul2 proteins to form a ubiquitin-ligase complex (VCBC). To date, the only VCBC substrates identified are the hypoxia-inducible factor alpha subunits (HIF-1alpha and HIF-2alpha). However, pVHL is thought to have multiple functions and the significance of HIF-1alpha and HIF-2alpha regulation for tumour suppressor activity has not been defined. VHL disease is characterized by distinct clinical subtypes. Thus haemangioblastomas (HABs) and renal cell carcinoma (RCC) but not phaeochromocytoma (PHE) occur in type 1 VHL disease. Type 2 subtypes are characterized by PHE susceptibility but differ with respect to additional tumours (type 2A, PHE+HAB but not RCC; type 2B, PHE+ HAB+RCC; type 2C, PHE only). We investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Consistent effects on pVHL function were observed for all mutations within each subclass. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wild-type binding patterns with pVHL interacting proteins, suggesting that loss of other pVHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of p220 (fibronectin) binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of p220 (fibronectin) binding. Our findings are consistent with impaired ability to degrade HIF-alpha subunit being required for HAB development and RCC susceptibility.

Germline SDHD mutation in familial phaeochromocytoma.

The genetic basis for familial phaeochromocytoma is unknown in many cases. Since the disorder has been reported in some cases of familial head and neck paraganglioma, which is caused by a mutation in the gene encoding succinate dehydrogenase complex subunit D (SDHD), we investigated this gene in kindreds with familial phaeochromocytoma. A germline SDHD frameshift mutation was identified in a two-generation family consisting of four children with phaeochromocytoma, but somatic mutations were not detected in 24 sporadic phaeochromocytoma tumours. Germline SDHD mutation analysis should be done in individuals with familial, multiple, or early-onset phaeochromocytomas even if a personal or family history of head and neck paraganglioma is absent.

Comparative sequence analysis of the VHL tumor suppressor gene.

Comparative genome analysis may provide novel insights into gene evolution and function. To investigate the von Hippel-Lindau (VHL) disease tumor suppressor gene, we sequenced the VHL gene in seven primate species. Comparative analysis was performed for human, primate, and rodent VHL genes and for a putative Caenorhabditis elegans VHL homologue identified by database analysis. The VHL gene has two translation initiation sites (at codons 1 and 54); however, the relative importance of the full-length translation product (pVHL30) and that translated from the second internal translation initiation site (pVHL19) is unclear. The N-terminal sequence of pVHL30 contains eight copies of a GXEEX acidic repeat motif in human and higher primates, but only three copies were present in the marmoset, and only one copy was present in rodent VHL genes. Evolutionary analysis suggested that the N-terminal repetitive sequence in pVHL30 was of less functional importance than those regions present in both pVHL30 and pVHL19. The VHL gene product is reported to form complexes with various proteins including elongin B, elongin C, VBP-1, fibronectin, Spl, CUL2, and HIF-1. Although most of the regions in pVHL that had been implicated in binding specific proteins demonstrated evolutionary conservation, the carboxy-terminal putative VBP-1 binding site was less well conserved, suggesting that VBP-1 binding may have less functional significance. Although an amino acid substitution (K171T) close to the pVHL elongin binding region was found in baboon, analysis of the structure of human pVHL suggested that this substitution would not interfere with pVHL/elongin C interaction. In general, there was a good correlation between the pVHL domains that demonstrated most evolutionary conservation and those that were most frequently mutated in tumors. Analysis of human/C. elegans conservation and human germline and somatic mutation patterns identified a highly conserved mutation cluster region between codons 74 and 90. However, this region is likely to be important for the structural integrity of pVHL rather than representing an additional protein binding domain.

Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes.

Familial renal cell carcinoma (RCC) is genetically heterogeneous. Genetic predisposition to clear cell RCC (CCRCC) is a major feature of von Hippel-Lindau (VHL) disease (MIM 193300) and has rarely been associated with chromosome 3 translocations. In addition, familial papillary (non-clear cell) RCC may result from germline mutations in the MET proto-oncogene (MIM 164860). However, rare kindreds with familial CCRCC (FCRC) not linked to the VHL tumour suppressor gene have been described suggesting that further familial RCC susceptibility genes exist. To investigate the genetic epidemiology of FCRC, we undertook a clinical and molecular study of FCRC in nine kindreds with two or more cases of CCRCC in first degree relatives. FCRC was characterised by an earlier age at onset (mean 47.1 years, 52% of cases <50 years of age) than sporadic cases. These findings differ from the only previous report of two FCRC kindreds and have important implications for renal surveillance in FCRC. The molecular basis of CCRCC susceptibility was investigated in nine FCRC kindreds and seven isolated cases with features of possible genetic susceptibility to CCRCC (four bilateral CCRCC aged <50 years and three with unilateral CCRCC aged <30 years). No germline mutations were detected in the VHL or MET genes, suggesting that FCRC is not allelic with VHL disease or HPRC. As binding of the VHL gene product to the CUL2 protein is important for pVHL function, we then searched for germline CUL2 mutations. Although CUL2 polymorphisms were identified, no pathogenic mutations were detected. These findings further define the clinical features of FCRC and exclude a major role for mutations in VHL, MET, or CUL2 in this disorder.

Long-term consequences after jejunoileal bypass for morbid obesity.

This study assesses the long-term results of jejunoileal bypass (JIB) in 43 prospectively followed patients whose surgical bypass remained intact. Follow-up was 12.6+/-0.25 years from JIB. Weight loss and improved lipid levels, glucose tolerance, cardiac function, and pulmonary function were maintained. Adverse effects such as hypokalemia, cholelithiasis, and B12 or folate deficiency decreased over time. The incidence of diarrhea remained constant (63% vs 64% at five years), while the occurrence of hypomagnesemia increased (67% vs 43% at five years, P < 0.05). Nephrolithiasis occurred in 33% of patients. Hepatic fibrosis developed in 38% of patients and was progressive. Overall, after more than 10 years, 35% of patients appeared to benefit from JIB as defined by alleviation of preoperative symptoms and the development of only mild complications (vs 47% at five years). On the other hand, irreversible complications appeared to outweigh any benefit derived from the JIB in 19% (vs no patients at five years; P < 0.01). In summary, patients with JIB remain at risk for complications, particularly hepatic fibrosis, even into the late postoperative period.

Molecular genetic analysis of von Hippel-Lindau disease.

Von Hippel-Lindau (VHL) disease is a dominantly inherited multisystem family cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal carcinoma, phaeochromocytoma, pancreatic islet cell tumours and endolymphatic sac tumours. In addition, renal, pancreatic and epididymal cysts occur. Morbidity and mortality from VHL disease can be reduced by the identification and surveillance of affected individuals and at-risk relatives so that complications are diagnosed at an early presymptomatic stage. The detailed mapping and subsequent isolation of the VHL tumour suppressor gene has enabled molecular genetic analysis in families and patients with definite or possible VHL disease. Initially, linked DNA markers were used in informative families to modify individual risks and then to make appropriate alterations in surveillance programs. However, currently most DNA analysis involves the characterisation of germline mutations. World-wide, mutations have been identified in almost 500 families (including 132 in our laboratory). These studies have revealed considerable heterogeneity both in the type and in the location of mutations within the VHL gene. In our experience, most recurrent mutations result from de novo mutations at hypermutable sequences, although a founder effect for the Tyr98His ('Black Forest') mutation has been reported in German and American families. Although many mutations are predicted to impair the ability of pVHL to combine with the elongin regulatory subunits, analysis of genotype-phenotype relationships suggests that the VHL protein has multiple and tissue specific functions. Calculation of tumour risks for different classes of VHL mutations has provided important prognostic information especially with respect to the likelihood of phaeochromocytoma. However, there is evidence that retinal involvement does not correlate with allelic heterogeneity, but that the variability in retinal angiomatosis is influenced by modifier gene effects. VHL gene mutation analysis also provides a basis for investigating the genetic basis of familial phaeochromocytoma and renal cell carcinoma, and apparently isolated retinal angiomas. Results to date suggest that a substantial proportion of patients with familial pheochromocytoma have VHL gene mutations but in contrast, most familial clusters of clear cell renal cell carcinoma (RCC) without evidence of VHL do not have germline VHL mutations.

A family with hereditary extra-adrenal paragangliomas without evidence for mutations in the von Hippel-Lindau disease or ret genes.

OBJECTIVES: To characterize a family with hereditary paraganglioma, and to search for germline mutations in the von Hippel-Lindau disease (VHL) tumour suppressor gene and the ret proto-oncogene. DESIGN: Patient records and histopathological reports were reviewed. Available tumour samples were reinvestigated using immunohistochemical techniques. The VHL gene was investigated by single strand conformational polymorphism analysis of PCR products amplified from exons 1, 2 and 3 and the 3' untranslated region. The ret gene was analysed by amplifying and sequencing exons 10, 11 and 16. PATIENTS: A family with paragangliomas in three consecutive generations was investigated. RESULTS: The affected individuals were found to have multiple extra-adrenal paragangliomas. All three affected individuals had retroperitoneal tumours, and two also had paraganglioma in the neck. No mutations of the VHL or ret genes were detected. CONCLUSIONS: The described family may represent a novel dominantly inherited neuroendocrine tumour syndrome.

Genetic predisposition to phaeochromocytoma: analysis of candidate genes GDNF, RET and VHL.

Inherited predisposition to phaeochromocytoma (MIM No 171300) occurs in multiple endocrine neoplasia type 2 (MEN 2) (MIM No 171400), von Hippel-Lindau (VHL) disease (MIM No 199300), and neurofibromatosis type 1 (NF1) (MIM No 162200). In addition, familial phaeochromocytoma alone has also been reported and we and others have identified germline VHL mutations in five of six kindreds analysed previously. Germline mutations in the RET proto-oncogene, which encodes a receptor tyrosine kinase, and in the VHL tumour suppressor gene cause MEN 2 and VHL disease, respectively. To further investigate the genetics of phaeochromocytoma predisposition, we analysed three groups of patients with no evidence of VHL disease, MEN 2 or NF1: Group A, eight kindreds with familial phaeochromocytoma; Group B, two patients with isolated bilateral phaeochromocytoma; and Group C, six cases of multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. Germline missense VHL mutations were identified in three of eight kindreds with familial phaeochromocytoma. A germline VHL mutation was also characterised in one of the two patients with bilateral phaeochromocytoma. No VHL or RET mutations were detected in the final group of patients with multiple extra-adrenal phaeochromocytoma or adrenal phaeochromocytoma with a family history of neuroectodermal tumours. The absence of germline VHL and RET gene mutations in many of these families suggested that other phaeochromoeytoma susceptibility loci may exist. Glial cell line-derived neurotrophic factor (GDNF) has been recently identified as a natural ligand for RET. Thus, it seems plausible that GDNF is a good candidate gene to play a role in phaeochromocytoma susceptibility. We searched for germline mutations in GDNF in 16 cases of familial phaeochromocytoma (groups A, B and C) and looked for evidence of somatic change in GDNF in 28 sporadic phaeochromocytomas, 12 MEN 2 phaeochromocytomas and five VHL phaeochromocytomas. No GDNF mutations were identified in patients with familial phaeochromocytoma disease, but a c277C-->T (R93W) sequence variant was identified in one of 28 sporadic tumours. This candidate mutation was identified in the germline and tumour tissue but was not present in 104 control GDNF alleles. GDNF sequence variants including R93W have been suggested previously to represent low penetrance susceptibility mutations for Hirschsprung disease and the R93W was not identified in 376 control alleles studied by others. These findings suggest that although GDNF mutations do not appear to have a major role in the pathogenesis of familial or sporadic phaeochromocytomas, allelic variation at the GDNF locus may modify phaeochromocytoma susceptibility.

Downstaging of esophageal cancer after preoperative radiation and chemotherapy.

OBJECTIVE: This retrospective, nonrandomized review evaluates 125 patients with esophageal carcinoma (adenocarcinoma and squamous cell) who underwent either surgery only or preoperative chemotherapy and/or radiation therapy followed by surgery. Major end points were survival and postchemoradiation downstaging. METHODS: Forty-four patients underwent radiation therapy of 4500 cGy over 5 weeks. Fluorouracil and cisplatin were administered on the first and fifth week of radiotherapy. Ninety-eight patients underwent "potentially curative" resections-transhiatal esophagectomy (70), Lewis esophagogastrectomy (25), and left esophagogastrectomy (3). All patients with preoperative adjuvant therapy underwent endoscopy and biopsy before surgery. RESULTS: There were no differences in overall mortality (5%) or surgical complications in either group. Fourteen of 44 patients (32%) downstaged to complete pathologic response, with 5-year survival of 57%. Fifteen of 44 patients (34%) downstaged to microscopic residual tumor, with 1- and 3-year survival of 77% and 31%, respectively. Twenty-eight of 29 patients in the two downstaged groups were lymph node negative. Overall, 5-year survival in the adjuvant therapy plus surgery group versus surgery only was 36% and 11% (p = 0.04). Five-year survival in lymph node-negative adjuvant therapy and surgery patients was 49% (p = 0.005). Positive nodes in the surgery only group was 48% versus 23% in the adjuvant therapy and surgery group (p = 0.02). CONCLUSION: Although retrospective and nonrandomized, these results suggest that preoperative chemoradiation results in significant clinical and pathologic downstaging, increases survival, and may sterilize local and regional lymph nodes, accounting for both downstaging and survival statistics.

Clinical and radionuclide evaluation of bile diversion by Braun enteroenterostomy: prevention and treatment of alkaline reflux gastritis. An alternative to Roux-en-Y diversion.

UNLABELLED: OBJECTIVE AND SUMMARY BACKGROUND: Symptomatic, medically resistant postgastrectomy patients with alkaline reflux gastritis (ARG) have increased enterogastric reflux (EGR) documented by quantitative radionuclide biliary scanning. Even asymptomatic patients after gastrectomy have increased EGR compared with nonoperated control patients. Roux-en-Y biliary diversion, although successfully treats the clinical syndrome of ARG, has a high incidence of early and late postoperative severe gastroparesis, Roux limb retention (the Roux syndrome), or both, which often requires further remedial surgery. As an alternative to Roux-en-Y diversion, this review evaluates the efficacy of the Braun enteroenterostomy (BEE) in diverting bile away from the stomach in patients having gastric operations. Based on previous pilot studies, the BEE is positioned 30 cm from the gastroenterostomy. METHODS: Thirty patients had the following operations and were evaluated: standard pancreatoduodenectomy (8), vagotomy and Billroth II (BII) gastrectomy (6), BII gastrectomy only (10), and palliative gastroenterostomy to an intact stomach (6). All anastomoses were antecolic BII with a long afferent limb and a 30-cm BEE. Four symptomatic patients with medically intractable ARG and chronic gastroparesis had subtotal BII gastric resection with BEE rather than Roux-en-Y diversion. Eight control symptomatic patients and six asymptomatic patients with previous BII gastrectomy and no BEE were evaluated. Radionuclide biliary scanning was performed within 30 days in all patients and at 4 to 6 months in 14 patients. Bile reflux was expressed as an EGR index (%). RESULTS: After operation, 18 of 34 patients (53%) had no demonstrable EGR while in the fasting state for as long as 90 minutes. The range of demonstrable bile reflux (EGR) in the remaining 16 patients was from 2% to 17% (mean, 4.5%). Enterogastric reflux in the 14 control patients (with no BEE) ranged from 5% to 82% (mean, 42%). The four patients with ARG and chronic gastroparesis treated by subtotal gastrectomy and BEE had postoperative EGR of 0%, 2%, 2%, and 4%, respectively. They are asymptomatic with no evidence of bile reflux gastritis. In the 14 patients who had late evaluation, EGR ranged from 0% to 16% (mean, 5.5%). No patient had signs or symptoms of ARG after operation. CONCLUSIONS: Braun enteroenterostomy successfully diverts a substantial amount of bile from the stomach. The ARG syndrome might be prevented by performing BEE during gastric resection or bypass in a variety of operations. Conversion to a BII with BEE may be an alternative to Roux-en-Y diversion in treating medically resistant ARG and subsequent may avoid the Roux syndrome.

Marginal ulcer following gastric bypass for morbid obesity.

Four hundred twelve patients underwent gastric bypass for treatment of morbid obesity between 1981 and 1985 at the University of Florida Affiliated Hospitals. Thirty-four patients (8.2%) developed marginal ulcers, considerably higher than the 0-3 per cent ulcer occurrence commonly reported in the literature. Factors predisposing to ulcer formation include: (1) a large gastric pouch; (2) a vertically oriented pouch; and (3) staple-line dehiscence. Twenty-two of 34 patients (65%) with symptomatic marginal ulcers were noted to have staple-line disruption. Twenty-one of these patients (95%) eventually required operative therapy for their ulcers compared with four of 12 patients (33%) with an intact gastric staple line. Surgical therapy consisted of takedown of the Roux-en-Y limb with resection of the ulcer and gastrogastrostomy. Staple-line dehiscence is a significant etiologic factor in the development of marginal ulcer following gastric bypass and when present constitutes an indication for reoperation.

Pouch outlet obstruction following vertical ring gastroplasty for morbid obesity.

We have experienced a 14% (38 of 264 patients) incidence of pouch outlet obstruction following vertical ring gastroplasty. Initial management consisted of dilatation in 34 of 38 patients (94%). Ten of 34 patients (29%) were spared reoperation by 1 to 3 dilatations. Non-passage of an endoscope through the stoma immediately following dilatation predicted the need for surgery; 4 of 11 patients (36%) with passage underwent reoperation compared with 17 of 20 patients (85%) without passage (p less than 0.02). Surgical findings included "tipped bands" in 9 of 28 patients (32%); fibrous reaction to the band in 10 of 28 patients (36%); adhesions with angulation of the pouch in 2 of 28 patients (7%); and no identifiable cause of obstruction in 7 of 28 patients (25%). Surgical therapy consisted of removal of the band (2 patients), removal of the band and replacement with a similar length or larger band (20 patients), "tacking" the band in the horizontal position (4 patients), or conversion to a Roux-Y bypass (2 patients). The first three options were associated with an unacceptably high rate of weight regain and/or continued symptoms, whereas the last-named procedure met with good success.