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.

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.

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.

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.

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.

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.

Sliding esophageal hiatal hernia and reflux peptic esophagitis.

The past two decades have seen outstanding contributions to our knowledge of the physiology of the esophagus, particularly of the lower esophageal sphincter. The clinical syndrome of reflux peptic esophagitis has been clearly delineated and is now well recognized. Although the relationship of the lower esophageal sphincter failure, which causes sliding esophageal hiatal hernia, remains obscure, successful hiatal herniorrhaphy by a variety of methods produces satisfactory clinical results in a majority of patients. There is a significant failure rate in all methods and a morbidity clearly related to operative intervention. Additive surgery such as vagotomy and pyloroplasty is not useful in preventing recurrence and is associated with increased morbidity. Peptic strictures with firm, fibrous stenosis can be satisfactorily treated in most cases with the Thal fundic patch to widen the lumen and Nissen fundoplication to prevent further gastroesophageal reflux.

The effect of vagal stimulation on gastrin release and acid secretion.

Canines with vagally innervated fundic pouches and chronic esophageal fistulas were subjected to sham feeding experiments during which pouch acid output and peripheral serum gastrin levels were measured. These dogs then underwent construction of vagally innervated antral pouches. The sham feeding experiments were repeated after recovery. Preoperatively sham feeding provoked a substantial increase in acid output accompanied by a small serum gastrin increase which did not achieve statistical significance. After creation of the innervated antral pouches, sham feeding evoked an acid secretory response similar to control values. Serum gastrins, however, increased nearly 500 percent in response to sham feeding. Our data support the concept that direct vagal stimulation of the parietal cell mass is the major mechanism by which sham feeding increased acid secretion.

Serum gastrin and secretin levels after the Exalto-Mann-Williamson procedure.

The Exalto-Mann-Williamson procedure produces peptic ulceration in nearly 100% of experimental animals but the mechanism is unknown. To investigate the possible hormonal role of the gastric acid hypersecretion seen after this procedure, we investigated preoperative and postoperative serum gastrin and secretin concentrations. There was no significant change in serum gastrin; however, serum secretin concentrations increased to 2 1/2 times the preoperatve value, most likely secondary to the enhanced secretion of gastric acid. These data do not suppport the theory that alterations in circulating secretin or gastrin levels are responsible for the gastric acid hypersecretion following the Exalto-Mann-Williamson operation.

The history of vagotomy.

The anatomic characteristics of the vagus nerve were described by Galen in the second century AD, and its physiology was studied by Pavlov almost a century ago. Therapeutic possibilities of vagal denervation of the stomach was explored by several surgeons in the first quarter of this century. The most auspicious effort was that of Latarjet. The rebirth of vagotomy in 1943 by Dragstedt was based on cumulative new data supporting the concept that vagal denervation should favorably influence the clinical course of duodenal ulcer. This now proved concept renders vagotomy in some form a basic part of all operations for duodenal ulcer. The Dragstedt operation, vagotomy and pyloroplasty, is particularly useful in cases of acute bleeding and obstruction. Vagotomy and antrectomy has the lowest ulcer recurrence rate. Parietal cell vagotomy has the lowest mortality and morbidity rates and is the procedure of choice in patients with uncomplicated, intractable duodenal ulcer.

Surgical management of the failed jejunoileal bypass.

The jejunoileal bypass is an efficient surgical treatment for morbid obesity, but it has a high complication rate that necessitates reversal in about 25 percent of patients. Conversion to Roux-Y gastric bypass was associated with acceptable morbidity and provided excellent control of weight. On the other hand, conversion to gastric partition resulted in weight gain almost equal to that seen with simple reversal alone. Conversion to Roux-Y gastric bypass is an acceptable procedure in the surgical treatment of the unsuccessful jejunoileal bypass.

Supradiaphragmatic fundoplication. Long-term follow-up and analysis of complications.

Supradiaphragmatic fundoplication has been useful in patients with an acquired short esophagus since the inception of the Nissen technique. Recent reports documenting a large number of life-threatening complications in relatively small groups of patients prompted us to review the records of all patients with supradiaphragmatic fundoplication. Forty-four supradiaphragmatic Nissen fundoplications were performed, with an average follow-up of 42 months. Operative mortality was 7 percent. Acceptable results were obtained in 82 percent (88 percent of patients not lost to follow-up). Poor results were obtained in 5 percent (one patient with scleroderma and one with diaphragmatic hernia). In another 5 percent, postoperative diaphragmatic hernia developed. In two patients, ulceration of the antrum developed that appeared unrelated to the operation. Sixteen patients have been followed for longer than 5 years, with no long-term complications. The wide variation in the incidence of these complications between our patients and those of others is probably related to varying details of operative technique. Supradiaphragmatic fundoplication provides uniformly effective protection against gastroesophageal reflux with an acceptable morbidity and low mortality.

Clinical and radionuclide evaluation of Roux-Y diversion for postgastrectomy dumping.

From 1973 to 1986, 22 patients underwent Roux-Y gastrojejunostomy for the early postgastrectomy dumping syndrome. In the early years, five patients underwent Roux-Y conversion with the addition of a 10 cm antiperistaltic jejunal segment interposed between the Roux-Y limb and the stomach. Within 4 years, all five patients had the jejunal segment removed due to severe symptoms of gastric retention. These patients underwent reconstruction to create Roux-Y limb only and joined the pool of 17 patients who underwent Roux-Y diversion only for the dumping syndrome. Overall, 19 of 22 patients (86 percent) had almost complete resolution of their dumping symptoms on long-term follow-up. Three patients showed no improvement, two with severe gastric retention and one with recurrent dumping symptoms. Overall, 5 of 22 patients (23 percent) had moderate to severe early and late postoperative gastric retention necessitating medical treatment in three and subsequent near-total gastrectomy in two. Although other procedures such as pyloric reconstruction or the addition of isoperistaltic or antiperistaltic jejunal interpositions have been reported to be equally successful in delaying gastric emptying and resolving dumping symptoms, we have preferred Roux-Y diversion for the treatment of combined alkaline reflux gastritis and dumping or the pure early vasomotor postgastrectomy dumping syndrome. As reported, we have abandoned the use of an antiperistaltic jejunal segment interposed between the stomach and the Roux-Y limb due to the high rate of postoperative gastric retention.

Effect of bowel preparation on small bowel microflora and postoperative wound infection.

A method of wound closure utilizing continuous wound compression and suction decompression of the subcutaneous space is described. This method has reduced the incidence of wound complication in the diverse population of patients in whom it has been utilized.

Surgical treatment of the postgastrectomy dumping syndrome.

Fifteen patients were treated surgically for dumping syndrome at the University of Florida between 1972 and 1977. Five of them had a reversed jejunal segment interposed between the stomach and the Roux limb and 10 had simple 45 cm Roux-en-Y gastrojejunostomy. The reversed segment has been, in our experience, a uniform disappointment. Straight Roux-en-Y duodenal diversion, with the exception of temporary delay in gastric emptying in a few cases, has proved successful in treating the postgastrectomy dumping syndrome.

Immediate oophorectomy and adrenalectomy in the treatment of stage III breast carcinoma. A ten year follow-up study.

One hundred twenty-two patients with state III breast carcinoma had radical mastectomy with or without adjunctive radiation therapy, chemotherapy, or steroids. Thirteen randomly selected persons in the group had immediate bilateral oophoroadrenalectomy. Survival ranged from 10 to 147 months (median, 68.0) with seven of thirteen patients (53.8 per cent) alive five years and three of thirteen (23.0 per cent) alive ten year or longer. No statistical difference in survival or disease-free intervals with respect to menopausal status was observed in the nine patients of this group who died. One hundred and nine patients treated by conventional therapy without endocrine ablation had shorter five year (37.6 per cent) and ten year (15.6 per cent) survival intervals. The difference in survival intervals was statistically significant at p smaller than 0.01. This study suggests that immediate endocrine ablation may prolong survival in patients with stage III breast carcinoma.

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.

Late hepatic histopathology after jejunoileal bypass for morbid obesity. Relation of abnormalities on biopsy and clinical course.

Late biopsy results in 53 patients after jejunoileal bypass were reviewed and compared with 1 year postoperative biopsies. Patients were divided into groups based on clinical course and liver function tests. Of 24 patients with normal liver function tests and no clinical symptoms of liver failure, 8 (33 percent) had new or progressive lesions on late biopsy, while 1 of these 8 patients had cirrhosis. Thirty percent (6 of 20) of patients with liver function abnormalities but no evidence of liver failure showed evidence of progression on biopsy; 4 of these 6 patients had cirrhosis. Of those with clinical evidence of liver failure in the first year after operation, 44 percent had evidence of progression, but none had cirrhosis. Clinical parameters and liver function tests did not correlate with liver biopsies. In this series of patients, new and progressive lesions were found in the late postoperative period. Long-term serial biopsies are advisable in all patients after jejunoileal bypass to determine whether progressive deterioration in liver histology had occurred.

Effect of antrectomy on the nervous phase of gastric secretion in the dog.

A method is described for complete isolation of the stomach in the dog with vagal innervation intact. This involves esophagostomy, double mucosal closure of the pylorus and a Maydl gastric fistula combined with gastrojejunostomy. The latter is occluded during periods of study. In this preparation the responses to sham feeding and to insulin-induced hypoglycemia were reduced approximately 10-fold, reiterating the significant synergistic effect of gastrin on vagal stimulation of the parietal cell mass. However, significant acid secretion could still be induced in this preparation by both sham feeding and insulin-induced hypoglycemia.