Genotype in BRCA‐associated Breast Cancers

Women with BRCA1 or 2 mutations are at high risk for breast cancer. For BRCA1, a trend of increasing risk has been associated with increasing downstream (3′) location for mutations compared to the upstream (5′) mutations in the gene. For BRCA2, an increased risk of breast cancer has been associated with mutations outside of the ovarian cancer cluster region (OCCR). We sought to determine the mutation position in BRCA‐associated breast cancers and whether or not there was a genotype‐phenotype correlation. Breast cancer patients with BRCA1/2 mutations were identified by a search of a prospectively maintained data base. Mutation site, patient, and tumor characteristics were determined through retrospective review. One hundred and sixty‐four patients with BRCA1‐associated breast cancer and 109 patients with BRCA2‐associated breast cancer were identified. Among patients with BRCA1‐associated cancers, 86 (52%) had mutations in the 5′ half of the gene. Among patients with BRCA2‐associated breast cancers, 40 (37%) had OCCR mutations. Although BRCA1‐associated tumors were more likely to be ER/PR‐ than BRCA2‐associated cancers (p < 0.0001), there was no difference in the tumor characteristics among BRCA1 or BRCA2‐associated cancers based on mutation location. In this single‐institution study, over half of BRCA1‐associated and over a third of BRCA2‐associated breast cancers were associated with putative lower risk mutations. Although we cannot exclude the possibility that mutations in these regions confer a lower relative risk for breast cancer, vigilance in cancer screening and prevention remains necessary. Further studies in genotype/phenotype correlation are needed to individualize prevention strategies.     

B cell lymphoma and myeloma in murine Gaucher's disease

Multiple myeloma and B cell lymphoma are leading causes of death in Gaucher's disease but the nature of the stimulus driving the often noted clonal expansion of immunoglobulin‐secreting B cells and cognate lymphoid malignancy is unknown. We investigated the long‐term development of B cell malignancies in an authentic model of non‐neuronopathic Gaucher's disease in mice: selective deficiency of β‐glucocerebrosidase in haematopoietic cells [Gba^{tm1Karl/tm1Karl}Tg(Mx1‐cre)1Cgn/0, with excision of exons 9–11 of the murine GBA1 gene, is induced by poly[I:C]. Mice with Gaucher's disease showed visceral storage of β‐glucosylceramide and greatly elevated plasma β‐glucosylsphingosine [median 57.9 (range 19.8–159) nm; n = 39] compared with control mice from the same strain [median 0.56 (range 0.04–1.38) nm; n = 29] (p < 0.0001). Sporadic fatal B cell lymphomas developed in 11 of 21 GD mice (6–24 months) but only two of eight control animals developed tumours by age 24 months. Unexpectedly, most mice with overt lymphoma had absent or few Gaucher cells but local inflammatory macrophages were present. Eleven of 39 of Gaucher mice developed monoclonal gammopathy, but in the control group only one animal of 25 had clonal immunoglobulin abnormalities. Seven of 10 of the B cell lymphomas were found to secrete a monoclonal paraprotein and the lymphomas stained intensely for pan‐B cell markers; reactive T lymphocytes were also present in tumour tissue. In the Gaucher mouse strain, it was notable that, as in patients with this disease, CD138⁺ plasma cells frequently surrounded splenic macrophages engorged with glycosphingolipid. Our strain of mice, with inducible deficiency of β‐glucocerebrosidase in haematopoietic cells and a high frequency of sporadic lethal B cell malignancies, faithfully recapitulates human Gaucher's disease: it serves as a tractable model to investigate the putative role of bioactive sphingolipids in the control of B cell proliferation and the pathogenesis of myelomatosis—the most prevalent human cancer associated with this disorder. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

A benchmark comparison of deterministic and probabilistic methods for defining manual review datasets in duplicate records reconciliation

Introduction

Clinical databases require accurate entity resolution (ER). One approach is to use algorithms that assign questionable cases to manual review. Few studies have compared the performance of common algorithms for such a task. Furthermore, previous work has been limited by a lack of objective methods for setting algorithm parameters. We compared the performance of common ER algorithms: using algorithmic optimization, rather than manual parameter tuning, and on two-threshold classification (match/manual review/non-match) as well as single-threshold (match/non-match).

Methods

We manually reviewed 20 000 randomly selected, potential duplicate record-pairs to identify matches (10 000 training set, 10 000 test set). We evaluated the probabilistic expectation maximization, simple deterministic and fuzzy inference engine (FIE) algorithms. We used particle swarm to optimize algorithm parameters for a single and for two thresholds. We ran 10 iterations of optimization using the training set and report averaged performance against the test set.

Results

The overall estimated duplicate rate was 6%. FIE and simple deterministic algorithms allowed a lower manual review set compared to the probabilistic method (FIE 1.9%, simple deterministic 2.5%, probabilistic 3.6%; p<0.001). For a single threshold, the simple deterministic algorithm performed better than the probabilistic method (positive predictive value 0.956 vs 0.887, sensitivity 0.985 vs 0.887, p<0.001). ER with FIE classifies 98.1% of record-pairs correctly (1/10 000 error rate), assigning the remainder to manual review.

Conclusions

Optimized deterministic algorithms outperform the probabilistic method. There is a strong case for considering optimized deterministic methods for ER.     

Career track of Society of University Surgeons Resident Research Award recipients

Background

The Society of University Surgeons (SUS) has an ongoing competitive funding program to support research training for residents. We sought to determine the career track of award recipients.

Methods

We included in the study SUS resident awardees who completed awards from 1989–2007. Characteristics of awardees and their academic productivity were extracted from curriculum vitae provided by awardees (n = 24), or from online sources (n = 7).

Results

Awardees spent an average of 2.7 y (range, 1–4 y) of dedicated research time during residency. Awardees averaged 9.8 publications (range, 1–32), with 5.4 as first author (range, 1–17), with their mentor within 3 y of award completion, with an average maximum impact factor of 5.7. A total of 25 residents (81%) pursued fellowships. At an average follow-up of 11.4 y (range, 4–22 y) from the end of the award and 7.2 y (range, 0–18 y) from end of clinical training, awardees had a Hirsch index of 14.5 (range, 2–48). At the time of the study, 26 awardees (84%) were in academic surgery. Of the 23 awardees who had completed surgical training ≥ 3 y earlier, 11 (48%) received independent research funding, seven of whom (30%) received R01 or equivalent funding.

Conclusions

The SUS resident research awardees had a productive research experience. Although our retrospective study cannot determine causation, the SUS award mechanism delivers on its promise of supporting junior surgeon-scientists who pursue academic careers and establish independent research programs. Further studies are needed to determine how rates of subsequent independent research funding can be improved.     

Intraductal papillary-mucinous tumors of the pancreas: Clinicopathologic features, outcome, and nomenclature. Members of the Pancreas Clinic, and Pancreatic Surgeons of Mayo Clinic

BACKGROUND & AIMS: Intraductal papillary-mucinous tumor (IPMT) of the pancreatic ducts is increasingly recognized. This study investigated if clinical, imaging, or, histological features predicated outcome, formulated a treatment algorithm, and clarified relationships among IPMT, mucinous cystic neoplasms of the pancreas (MCN), and chronic pancreatitis. METHODS: The medical records, radiographs, and pathological specimens of 15 patients with IPMT (dilated main pancreatic duct or branch ducts with mucin overproduction) who were evaluated between October 1983 and January 1994 were reviewed. RESULTS: One patient had hepatic metastases. Fourteen underwent an operation (6 distal pancreatectomy, 4 total pancreatectomy, and 4 pancreaticoduodenectomy); all had dysplastic intraductal epithelium and chronic pancreatitis, whereas 3 had invasive adenocarcinoma. After a median of 25 months, 10 patients were alive; 3 of 4 with malignant and 2 of 11 with benign IPMT died (P < 0.05). Patients with or without carcinoma had similar clinical and radiographic features. A clinical diagnosis of chronic pancreatitis had been made in 9 patients with benign IMPT and in none with malignant IPMT (P < 0.05). CONCLUSIONS: IPMT is a dysplastic and likely precancerous lesion that is frequently diagnosed as chronic pancreatitis and is separate from MCN. Because it is not possible to distinguish noninvasive from invasive IPMT preoperatively, complete surgical excision of the dysplastic process is our treatment of choice whenever appropriate. (Gastroenterology 1996 Jun;110(6):1909-18)     

Antithrombin-III-Hamilton: a gene with a point mutation (guanine to adenine) in codon 382 causing impaired serine protease reactivity

Antithrombin-III-Hamilton is a structural mutant of antithrombin III with defective serine protease reactivity, demonstrable in three members of a French Canadian family. The propositus, a 54-year-old man with a history of recurrent thromboembolic events, and his two asymptomatic grown children are heterozygous for the mutant antithrombin III gene. In all three individuals, the immunoreactive antithrombin III level is normal, while the antithrombin and antifactor Xa activity is approximately 50% of the control value. Two dimensional immunoelectrophoresis of antithrombin-III-Hamilton in the presence of heparin is normal. Purified antithrombin-III-Hamilton did not form thrombin-antithrombin III complex when incubated with thrombin for up to 30 minutes. The normal and mutant antithrombin III alleles of the propositus could be distinguished by linkage to Pstl restriction fragment length polymorphisms (RFLP). Genomic DNA from the propositus was cloned into EMBL 3 phage vectors and two clones containing nearly complete copies of the antithrombin-III-Hamilton allele were identified. Exon 6 of both clones was subcloned into M13 phage vector and sequenced, revealing a G----A point mutation in the first base of codon 382. Codon 382 codes for alanine in the normal allele and for threonine in the antithrombin-III-Hamilton allele. Alanine-382, 12 residues from the reactive center, is a highly conserved amino acid in the family of serine protease inhibitors known as the serpins. We postulate that, as a result of the substitution of threonine for alanine in antithrombin-III-Hamilton, either the tertiary structure or the hydrophobicity of the thrombin-binding region is altered, causing aberrant conformation of the Arg-393-Ser-394 bond at the reactive center impairing the interaction between antithrombin-III-Hamilton and the activated serine proteases.     

Quality of weight loss advice on internet forums

Background

Adults use the Internet for weight loss information, sometimes by participating in discussion forums. Our purpose was to analyze the quality of advice exchanged on these forums.

Methods

This was a retrospective analysis of messages posted to 18 Internet weight loss forums during 1 month in 2006. Advice was evaluated for congruence with clinical guidelines; potential for causing harm; and subsequent correction when it was contradictory to guidelines (erroneous) or potentially harmful. Message- and forum-specific characteristics were evaluated as predictors of advice quality and self-correction.

Results

Of 3368 initial messages, 266 (7.9%) were requests for advice. Of 654 provisions of advice, 56 (8.6%) were erroneous and 19 of these 56 (34%) were subsequently corrected. Forty-three (6.6%) provisions of advice were harmful, and 12 of these 43 (28%) were subsequently corrected. Messages from low-activity forums (fewer messages) were more likely than those from high-activity forums to be erroneous (10.6% vs 2.4%, P < .001) or harmful (8.4% vs 1.2%, P < .001). In high-activity forums, 2 of 4 (50%) erroneous provisions of advice and 2 of 2 (100%) potentially harmful provisions of advice were corrected by subsequent postings. Compared with general weight loss advice, medication-related advice was more likely to be erroneous (P = .02) or harmful (P = .01).

Conclusions

Most advice posted on highly active Internet weight loss forums is not erroneous or harmful. However, clinical and research strategies are needed to address the quality of medication-related advice.     

Correlations among improvements in urgency urinary incontinence, health-related quality of life, and perception of bladder-related problems in incontinent subjects with overactive bladder treated with tolterodine or placebo

Background  

Previous studies demonstrate that tolterodine extended release (ER) significantly improves urgency urinary incontinence (UUI) episodes. Instruments that measure patient-reported outcomes (PROs) provide additional information that is valuable for assessing whether clinical improvements are meaningful to the patient. This study determined the correlation of changes in bladder diary variables and other PROs in subjects with overactive bladder (OAB).