Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study

BRCA1 and BRCA2 screening in women at high‐risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population‐based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA‐binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC. © 2010 Wiley‐Liss, Inc.     

Vascular surgical training of general and vascular surgery residents

Objective: The opinions of general surgery program directors (SPDs) and vascular surgery program directors (VPDs) regarding vascular surgery training of general surgery residents and the construct of the vascular surgery residency were compared.Methods: Questionnaires were mailed to 55 VPDs and 290 SPDs in 1987 and 1988, and to 80 VPDs and 277 SPDs in 1995. Both questionnaires included questions regarding attitudes about vascular surgical competence, operative experience, future vascular practice opportunities of general surgery residents, and the impact of a vascular surgery residency on general surgery resident education. In addition, the 1995 survey included questions regarding the duration, content, and prerequisite versus requisite experience for the vascular surgery residency.Results: Significant differences in opinions between SPDs and VPDs persisted regarding vascular surgery training of general surgery residents. SPDs were more likely to feel that general surgery graduates are fully competent in vascular surgery, should be exposed to more complex vascular surgery during training, and should be granted unlimited vascular surgical privileges on entering practice. Most VPDs felt that general surgery graduates lack competence in vascular surgery, should be exposed to less complex vascular surgery during training, and should have limited vascular surgery privileges in practice. Both groups of program directors agreed about the construct of vascular surgery residencies and that such residencies have had a favorable impact on general surgery resident education. Both SPDs and VPDs were willing to consider creative restructuring of vascular surgery residencies to accommodate governmental restrictions on funding of graduate medical education.Conclusions: External pressures forcing residency reform may provide an opportunity for SPDs and VPDs to creatively work with regulatory bodies to resolve differences in expectations of vascular surgery education and practice. (J Vasc Surg 1996;24;1057-63.)     

Perioperative bladder management after primary total hip arthroplasty

A retrospective review of 95 consecutive primary total hip arthroplasty patients was performed to assess the clinical outcome of two postoperative bladder management protocols. The first 49 patients (group 1) were treated with a pro re nata straight catheterization protocol. The next 46 patients (group 2) were treated with an indwelling catheterization protocol. There were no differences between the groups with respect to sex or age. The patients in group 2 had significantly lower incidences of urinary retention (P < .0005) and bladder distention (P < .0005) than those in group 1. Preoperative systemic diseases and urologic symptoms did not correlate with the occurrence of postoperative urinary retention or bladder distention. There were no infections in group 1. In group 2, one patient (2%) had bacteriuria and one patient (2%) had a urinary tract infection (P > .1). This trend of increased contamination in the catheterization group may be related to a mean catheterization duration of 72 hours.     

A Meta-Analysis to Determine the Effect of Primary Tumor Resection for Stage IV Colorectal Cancer with Unresectable Metastases on Patient Survival

Background

Approximately 20 % of patients diagnosed with colorectal cancer will have distant metastases at first presentation (stage IV disease). The effect of removing the primary tumor on survival for patients with stage IV disease with unresectable metastases remains unclear. To address this a meta-analysis of all studies comparing primary tumor resection with chemotherapy alone in cases of stage IV colorectal cancer with unresectable metastases was performed.

Methods

A comprehensive search for published studies examining the effect of primary tumor resection in the setting of colorectal cancer with unresectable metastases was performed. Each study was reviewed and data extracted. Random-effects methods were used to combine data.

Results

There were 21 studies including a total of 44,226 patients that met the inclusion criteria. Resection of the primary tumor in patients with unresectable metastases compared with chemotherapy alone was associated with a lower mortality risk (OR 0.28; 95 % CI 0.165–0.474; P < 0.001), translating into a difference in mean survival of 6.4 months in favor of resection (95 % CI 5.025–7.858, P < 0.001). Patients who underwent resection of the primary tumor were more likely to have liver metastasis only (OR 1.551; 95 % CI 1.247–1.929; P < 0.001), were less likely to have ≥2 metastasis (OR 0.653; 95 % CI 0.508–0.839; P = 0.001), and were less likely to have rectal cancer (OR 0.495; 95 % CI 0.390–0.629; P < 0.001). There was significant cross-study heterogeneity.

Conclusions

Resection of the primary tumor may confer a survival advantage in stage IV colorectal cancer with unresectable metastases but significant selection bias exists in current studies. Randomized controlled trials are essential to validate these findings.     

Psychosocial stress and pregnancy outcome

This article is intended to help clinicians better understand the ever-expanding body of research on whether psychosocial stress (both acute and chronic) is linked to 2 major adverse pregnancy outcomes: preterm birth and low birth weight. We summarize the existing literature and then review assessment tools commonly used to diagnose various types of psychosocial stress, with attention to how and when assessments should be made. After discussing the physiologic mechanisms hypothesized to underlie these relationships, we examine the range of existing interventions aimed at reducing psychosocial stress and review their efficacy at improving birth outcomes. Future directions for prevention of adverse pregnancy outcomes are discussed and suggest that an entirely new approach may be necessary.     

Freeze-dried primate sperm retains early reproductive potential after intracytoplasmic sperm injection

Oocytes inseminated by intracytoplasmic sperm injection using fresh ejaculated or freeze-dried rhesus macaque sperm showed similar activation, sperm aster assembly, and male-female pronuclear apposition rates.     

Rheumatoid factor in acute bacterial endocarditis

Sera from 55 parenteral drug abusers with endocarditis due to Staphylococcus aureus were assayed for the presence and titer of rheumatoid factor. Thirteen (24%) of the 55 patients with endocarditis had sera positive for rheumatoid factor at one point or another in their courses; only 2 (7%) of 30 noninfected drug users were found to be positive. It appeared that more severe cases, as evidenced by duration of fever after initiation of antibiotic therapy, were more likely to develop rheumatoid factor.     

Variations in Surgical Treatment and Outcomes of Patients With Pancreatic Cancer: A Population-Based Study

Background There is ongoing debate on how variations in surgical technique affect outcomes in pancreatic cancer. This population-based study examines current surgical practice and outcomes for cancer of the pancreatic head. Methods All patients 18 to 85 years old diagnosed with nonmetastatic adenocarcinoma of the pancreatic head from 1998 through 2003 were identified from the Surveillance, Epidemiology and End Results (SEER) Program registry. Multivariable regression was used to elucidate factors associated with the type of pancreaticoduodenectomy performed, extent of lymph node (LN) assessment, early mortality, and late survival. Results Overall, 2111 patients were included in the study, with 83.7% treated with a standard Whipple pancreaticoduodenectomy (PD). However, there was marked regional variation in the use of pylorus-preserving pancreaticoduodenectomy (PPPD; range, .03%–32.0%; P < .0001) and total pancreatectomy (TP; range, .04%–19.5%; P < .0001). TP was associated with significantly higher early mortality (odds ratio, 2.6; 95% confidence interval, 1.6 to 4.1; P < .0001), but late survival did not differ significantly between TP, PPPD, and PD (P = .69). Significant variation was also seen in the number of LN assessed (range across SEER regions, 7.3–13.5; P < .0001). Decreased LN assessment reduced the odds of diagnosing a patient as node positive and was associated with worse late survival. Conclusions In this population-based study, we found marked clinically important variability in the surgical treatment of adenocarcinoma of the pancreatic head, with respect to the use of TP, PPPD, or PD, and the extent of LN assessment. Further research is warranted to elucidate the underlying reasons, and to clarify the role of adequate lymphadenectomy.