Learning curves in abdominal wall reconstruction with components separation: one step closer toward improving outcomes and reducing complications.

INTRODUCTION: Learning curves are characterized by incremental improvement of a process, through repetition and reduction in variability, but can be disrupted with the emergence of new techniques and technologies. Abdominal wall reconstruction continues to evolve, with the introduction of components separation in the 1990s and biologic mesh in the 2000s. As such, attempts at innovation may impact the success of reconstructive outcomes and yield a changing set of complications. The purpose of this project was to describe the paradigm shift that has occurred in abdominal wall reconstruction during the past 10 years, focusing on the incorporation of new materials and methods. METHODS: We reviewed 150 consecutive patients who underwent abdominal wall reconstruction of midline defects with components separation, from 2000 to 2010. Both univariate and multivariate logistic regression analyses were performed to identify risk factors for complications. Patients were stratified into the following periods: early (2000-2003), middle (2004-2006), and late (2007-2010). RESULTS: From 2000 to 2010, we performed 150 abdominal wall reconstructions with components separation [mean age, 50.2 years; body mass index (BMI), 30.4; size of defect, 357 cm; length of stay, 9.6 days; follow-up, 4.4 years]. Primary fascial closure was performed in 120 patients. Mesh was used in 114 patients in the following locations: overlay (n = 28), inlay (n = 30), underlay (n = 54), and unknown (n = 2). Complications occurred in a bimodal distribution, highest in 2001 (introduction of biologic mesh) and 2008 (conversion from underlay to overlay location). Age, sex, history of smoking, defect size, and length of stay were not associated with incidence of complications. Unadjusted risk factors for seroma (16.8%) were elevated BMI, of previous hernia repairs, use of overlay mesh, and late portion of the learning curve, with logistic regression supporting only late portion of the learning curve [odds ratio (OR), 4.3; 95% confidence interval (CI), 1.0-18.6] and BMI (OR, 1.17; 95% CI, 1.06-1.29). The only unadjusted risk factor for recurrence was location of mesh. Logistic regression, comparing underlay, inlay, and overlay mesh to no mesh, revealed that the use of underlay mesh predicted recurrence (OR, 3.0; 95% CI, 1.04-8.64). All P values were less than 0.05. CONCLUSIONS: The overall learning curve for a specific procedure, such as abdominal wall reconstruction, can be quite volatile, especially as innovative techniques and new technologies are introduced and incorporated into the surgeon's practice. Our current practice includes primary repair myofascial flap of the components separation and the use of biologic mesh as an overlay graft, anchored to the external oblique. This process of outcome improvement is not gradual but is often punctuated by periods of failure and redemption.

Racial differences in ischemic complications of pedicled versus free abdominal flaps for breast reconstruction.

PURPOSE: This study aims to determine the relationship between race and ischemic complications in women undergoing breast reconstruction with pedicled TRAM (pTRAM) and perforator flaps (DIEP). PATIENTS AND METHODS: A retrospective, cross-sectional study of women who underwent breast reconstruction utilizing either pTRAM or DIEP flaps from March 1, 2002 to September 1, 2012 was performed. Clinical and demographic variables, including race and ischemic complications (mastectomy flap necrosis, fat necrosis, partial abdominal flap necrosis, vascular compromise requiring reoperation), were examined. Fat necrosis was graded using a previously established scale (grade I = radiologically visible, II = palpable, III = palpable and visible, IV = symptomatic). RESULTS: Over the 10-year study period, adequate follow-up was available for 138 women (94 Caucasian, 36 African American) who underwent pTRAM or DIEP. Fat necrosis occurred more frequently in the pTRAM group (53.5% vs. 17.4%, P < 0.001). There was no statistically significant difference in partial flap necrosis or mastectomy flap necrosis between the 2 groups. The DIEP group had a higher rate of vascular compromise requiring reoperation (13% vs. 0, P = 0.003). In the pTRAM group, there was a higher rate of fat necrosis (77% vs. 45.6%, P < 0.001) and grade IV fat necrosis in African Americans (42.8% vs. 9.5%, P = 0.005). Rates of other ischemic complications were comparable between the 2 racial groups. In the DIEP group, ischemic complications were comparable between the 2 racial groups. After stratifying by flap type and race, we saw no differences in mastectomy flap necrosis (P = 0.0182). DISCUSSION: African Americans undergoing pTRAM flap are at higher risk for grade IV fat necrosis but not mastectomy flap necrosis or partial flap necrosis. This may be due to difficulty using physical examination to judge the vascular status of a pedicle flap that is known to undergo significant changes in vascular physiology following transfer. Intraoperative assessment of perfusion using new technologies may be useful in these higher risk patients.

Incidence and management of adverse events after the use of laser therapies for the treatment of hypertrophic burn scars.

INTRODUCTION: Hypertrophic burn scars may generate significant morbidity, due to intense pruritus, persistent dysesthesias, and contracture. Although treatment with pulsed dye laser and fractional CO2 laser may improve symptoms, incidence of secondary wound complications is not well known. We examined the adverse event profile of laser therapies for the treatment of hypertrophic burn scars. METHODS: We performed a descriptive, retrospective, 6-month study of all patients who underwent laser therapies, at an accredited regional burn center, to improve the vascularity, texture, thickness, and stiffness of symptomatic burn scars. Data regarding skin type, mechanism, area treated, and laser parameters were collected. Main outcome measures included pigmentation changes, blistering, rash, infection. χ analysis and Student t test were used to evaluate associations between variables. RESULTS: A total of 95 patients underwent 163 treatment sessions (mean, 2.7 sessions/patient) with pulsed dye laser (71%), CO2 laser (22%), and other lasers (7%). Forty-one adverse events were recorded: hyperpigmentation (2%), hypopigmentation (12%), mild blistering (27%), pain (37%), rash (7%), fever (10%), and infection (2%). Patients with scald burns were more likely to develop blistering, rash, and fever after treatment (all P < 0.05). Higher Fitzpatrick skin type was associated with hypopigmentation and blistering, whereas CO2 laser was associated with increased postoperative pain (all P < 0.05) CONCLUSIONS: Despite the frequent occurrence of pain and mild blistering after laser treatment of hypertrophic burn scars, major adverse effects were exceedingly rare, with improvement noted in all patients. Patients with higher Fitzpatrick skin types must be handled with care, to avoid complications of blistering and hypopigmentation.

Once is not enough: withholding postoperative prophylactic antibiotics in prosthetic breast reconstruction is associated with an increased risk of infection.

BACKGROUND: There has been a trend toward limiting perioperative prophylactic antibiotics, based on research not conducted in plastic surgery patients. The authors' university hospital instituted antibiotic prescribing guidelines based on the Surgical Care Improvement Project. An increased rate of surgical-site infections was noted in breast reconstruction patients. The authors sought to determine whether the change in antibiotic prophylaxis regimen affected rates of surgical-site infections. METHODS: A retrospective study compared patients undergoing breast reconstruction who received preoperative and postoperative prophylactic antibiotics with a group who received only a single dose of preoperative antibiotic. Type of reconstruction and known risk factors for implant infection were noted. RESULTS: Two hundred fifty patients were included: 116 in the pre-Surgical Care Improvement Project group and 134 in the Surgical Care Improvement Project group. The overall rate of surgical-site infections increased from 18.1 percent to 34.3 percent (p = 0.004). Infections requiring reoperation increased from 4.3 percent to 16.4 percent (p = 0.002). Multivariate logistic regression demonstrated that patients in the Surgical Care Improvement group were 4.74 times more likely to develop a surgical-site infection requiring reoperation (95 percent CI, 1.69 to 13.80). Obesity, history of radiation therapy, and reconstruction with tissue expanders were associated with increased rates of surgical-site infection requiring reoperation. CONCLUSIONS: Withholding postoperative prophylactic antibiotics in prosthetic breast reconstruction is associated with an increased risk of surgical-site infection, reoperation, and thus reconstructive failure. The optimal duration of postoperative prophylactic antibiotic use is the subject of future study.

The volume-outcome relationship for immediate breast reconstruction.

BACKGROUND: Efforts to improve the quality of surgical care in the United States have led many organizations to advocate the use of high-volume hospitals for complex surgical procedures and/or comprehensive multidisciplinary care. The benefits, if any, of selective referral to high-volume hospitals for immediate breast reconstruction are relatively unknown. It is this gap in knowledge that forms the basis for the current study. METHODS: Using California's Office of Statewide Health Planning and Development discharge database, all patients undergoing immediate breast reconstruction from January 1, 1998, to December 31, 1999, were identified. Information regarding demographic, comorbidity, complication, and hospital volume characteristics was obtained. Patient comorbidity was graded using a modified version of the Charlson score. Annual hospital volume was categorized into patient quartiles. Multivariate logistic regression was performed to identify predictors of surgical complications. RESULTS: A total of 2691 patients were included: 1271 had immediate autogenous tissue reconstruction and 1420 had immediate tissue expander placement. The complication rate was 11.6 percent among patients undergoing autogenous reconstruction and 2.4 percent among patients receiving tissue expanders. For autogenous reconstruction, complications were more likely in patients with comorbidities (odds ratio, 2.24) and in patients receiving care at very-low-volume (less than eight) and medium-volume (20 to 41) hospitals (odds ratio,1.81 and 1.90, respectively). For tissue expander reconstruction, patient comorbidity (odds ratio, 2.42) was the only significant predictor of complications. CONCLUSIONS: Hospital volume appears to be an important predictor of patient outcome with regard to autogenous reconstruction but not tissue expander reconstruction. Patient comorbidity predicts complications for both autogenous and tissue expander reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Risk factors for cervical spine injury.

INTRODUCTION: The early recognition of cervical spine injury remains a top priority of acute trauma care. Missed diagnoses can lead to exacerbation of an existing injury and potentially devastating consequences. We sought to identify predictors of cervical spine injury. METHODS: Trauma registry records for blunt trauma patients cared for at a Level I Trauma Centre from 1997 to 2002 were examined. Cervical spine injury included all cervical dislocations, fractures, fractures with spinal cord injury, and isolated spinal cord injuries. Univariate and adjusted odds ratios (ORs) were calculated to identify potential risk factors. Variables and two-way interaction terms were subjected to multivariate analysis using backward conditional stepwise logistic regression. RESULTS: Data from 18,644 patients, with 55,609 injuries, were examined. A total of 1255 individuals (6.7%) had cervical spine injuries. Motor Vehicle Collision (MVC) (odds ratio (OR) of 1.61 (1.26, 2.06)), fall (OR of 2.14 (1.63, 2.79)), age <40 (OR of 1.75 (1.38-2.17)), pelvic fracture (OR of 9.18 (6.96, 12.11)), Injury Severity Score (ISS) >15 (OR of 7.55 (6.16-9.25)), were all significant individual predictors of cervical spine injury. Neither facial fracture nor head injury alone were associated with an increased risk of cervical spine injury. Significant interactions between pelvic fracture and fall and pelvic fracture and head injury were associated with a markedly increased risk of cervical spine (OR 19.6 (13.1, 28.8)) and (OR 27.2 (10.0-51.3)). CONCLUSIONS: MVC and falls were independently associated with cervical spine injury. Pelvic fracture and fall and pelvic fracture and head injury, had a greater than multiplicative interaction and high risk for cervical spine injury, warranting increased vigilance in the evaluation of patients with this combination of injuries.

Comparison of implant-based immediate breast reconstruction with and without acellular dermal matrix.

BACKGROUND: Acellular dermal matrix is frequently used in implant-based breast reconstruction to cover the inferior aspect of the breast pocket. Its performance profile remains equivocal. The authors studied whether adding it in implant-based immediate breast reconstruction improved outcomes when compared with non-acellular dermal matrix reconstruction. METHODS: Patients undergoing implant-based immediate breast reconstruction at a single academic medical center were evaluated. Aesthetic outcomes and postoperative complications were assessed and direct comparisons were made between acellular dermal matrix and non-acellular dermal matrix cohorts. RESULTS: A total of 203 patients underwent 337 immediate expander-based breast reconstructions [with acellular dermal matrix, n=208 (61.7 percent); without, n=129 (38.3 percent)]. Patient characteristics, including age at time of reconstruction (mean, 49±11 versus 47±10 years) and body mass index (mean, 23±5 versus 23±3 kg/m) were similar between groups (p>0.05). Complications occurred in one-third of patients (33.5 percent). In univariate analyses, acellular dermal matrix use had fewer overall complications (odds ratio, 0.61; 95 percent CI, 0.38 to 0.97). The incidences of seroma/hematoma (p=0.59), infection (p=0.31), and wound complications (p=0.26) did not differ. Aesthetic outcomes were higher in the acellular dermal matrix group. In multivariate logistic regression, acellular dermal matrix use was associated with less capsular contracture (odds ratio, 0.18; 95 percent CI, 0.08 to 0.43) and mechanical shift (odds ratio, 0.23; 95 percent CI, 0.06 to 0.78). CONCLUSIONS: Optimizing the inframammary fold with acellular dermal matrix creates a superior aesthetic result. Its use appears safe and is associated with less capsular contracture and mechanical shift and improvement in the inframammary fold appearance, without increasing postoperative complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Risk factors for recurrence after repair of enterocutaneous fistula.

OBJECTIVES: To assess outcomes after repair of enterocutaneous fistulae (ECF) and identify factors that predict mortality and recurrence. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: One hundred thirty-five patients undergoing ECF repair between 1989 and 2005. MAIN OUTCOME MEASURES: Mortality and recurrence of ECF. RESULTS: Definitive operation for ECF was attempted in 135 patients. Mortality was 8%, recurrence was 17%, and 84% of patients eventually survived with a closed fistula. The primary determinant of mortality was ECF recurrence (odds ratio [OR], 6.7; 95% confidence interval [CI], 1.9-23.4). Factors independently associated with ECF recurrence by multivariate logistic regression included the presence of inflammatory bowel disease (OR, 4.9; 95% CI, 1.5-16.1), interval between diagnosis and operation of 36 weeks or longer (OR, 5.4; 95% CI, 1.8-16.4), location of fistulae in the small intestine (OR, 9.8; 95% CI, 1.7-57.6), and resection with stapled anastomosis (OR, 4.1; 95% CI, 1.3-13.2). Recurrence of ECF was 35% with resection and stapled anastomosis, 22% with simple oversew, and 11% with resection and hand-sewn anastomosis. Recurrence of ECF was 12% when operation was performed prior to 36 weeks from diagnosis, compared with 36% if performed at or beyond 36 weeks. CONCLUSIONS: The primary determinant of mortality after ECF repair is a failed operation leading to recurrence of the fistula. Risk factors for ECF recurrence include inflammatory bowel disease, fistula located in the small intestine, an interval of 36 weeks or longer between diagnosis and operation, and resection with stapled anastomosis.

Pelvic fractures in children.

Although rare, pelvic fractures in children have significant morbidity and mortality. No specific guidelines have been developed for the management of these injuries. We reviewed all trauma patients of age 16 years or younger with pelvic fractures treated at our Level I trauma center over the past 12 years. Of 1008 patients with pelvic fractures, 74 were children. Early hemodynamic instability was seen in 14 per cent of cases. Blood transfusions were required in 26 per cent of cases, angiography in 3 per cent of cases, operations for associated injuries in 46 per cent of cases, operative pelvic fracture fixation in 18 per cent of cases, and intensive care unit care in 58 per cent of cases. Mortality was 5 per cent, mostly from hemorrhage and multiple complex injuries. We conclude that pelvic fractures in children are associated with a high frequency of pelvic bleeding and associated injuries that often require operative interventions and intensive care unit care.

High body mass index and short- and long-term renal allograft survival in adults.

BACKGROUND: The effect of recipient obesity on kidney allograft survival remains enigmatic. The purpose of this study was to evaluate the effect of donor and recipient body mass index on graft survival. METHODS: Retrospective study of 193 consecutive, adult renal transplants, with at least six months follow-up (mean 24+/-14.1 months). Patients were divided into two groups based upon body mass index (BMI), [weight (kg)/height (m)]: normal (<30.0, n=137) and obese (> or =30.0, n=56). Endpoints were graft loss, defined as either total loss of graft function (return to dialysis) or patient death with a functional graft. Unadjusted and adjusted multivariate analysis techniques, including Kaplan-Meier and Cox proportional hazards regression were used. RESULTS.: Individuals with a BMI > or =30 were not more likely to experience graft loss (O.R. 0.93, 95% C.I. 0.50, 1.72). Rates of acute rejection were not increased in obese recipients. While mortality was not increased in the BMI > 30 group, morbidity, especially surgical, had an increased incidence. The ratio of recipient to donor BMI did not influence graft survival. CONCLUSION: Obese recipients (BMI > or =30.0) were not at increased risk for graft failure. Additionally, matching donor and recipient BMI's would not appear to substantially improve transplant outcome. Obese recipients do have increased posttransplant morbidity and risk all the known health consequences associated with obesity. Careful evaluation and clinical management of obese patients allows for successful kidney transplantation with results equivalent to normal BMI patients.

Multicenter construct validity for southwestern laparoscopic videotrainer stations.

BACKGROUND: The "Southwestern" videotrainer stations have demonstrated concurrent validity (transferability to the operating room). The purpose of this study was to evaluate the Southwestern stations for construct validity (the ability to discriminate between subjects at different levels of experience). MATERIALS AND METHODS: From two surgical training programs, Institutional Review Board approved protocol data were collected from 142 subjects, including novice (medical students and R1, n = 66), intermediate (R2-R4, n = 67), and advanced (R5 and expert surgeons, n = 9) groups. All participants performed three repetitions on each of five stations. Completion time was scored for each task. Laparoscopic experience was determined from residency case log databases and from expert surgeon personal case logs. Results for the three groups were compared using one-way ANOVA, including relevant pair-wise comparisons. Correlations between number of laparoscopic cases performed and task scores were determined by Pearson's and Spearman's rho-correlation coefficients. RESULTS: The mean number of laparoscopic cases performed prior to completing the five tasks was 0 for novices, 9 for intermediates, and 431 for the advanced group. Significant differences (P < 0.001) were noted between groups for all five tasks and composite score. Task scores and composite scores significantly correlated with laparoscopic experience (P < 0.01). CONCLUSION: These data suggest that differences in laparoscopic ability are detected by performance on the videotrainer; thus, construct validity is demonstrated. Moreover, scores accurately reflect laparoscopic experience. Further validation may allow such simulators to be used for testing and credentialing purposes.

Clinical outcomes and disease progression among patients coinfected with HIV and human T lymphotropic virus types 1 and 2.

The goal of this study was to investigate clinical outcomes and survival probabilities among persons coinfected with human immunodeficiency virus (HIV) and human T lymphotropic viruses types 1 and 2 (HTLV-I/II). A nonconcurrent cohort study of 1033 HIV-infected individuals was also conducted. Sixty-two patients were coinfected with HTLV-I, and 141 patients were coinfected with HTLV-II. HTLV-I/II coinfection was highly associated with African-American race/ethnicity, age of >36 years, higher CD4(+) T cell count at baseline and over time, and history of injection drug use. Coinfected patients were more likely to have neurologic complications, thrombocytopenia, respiratory and urinary tract infections, and hepatitis C. Despite having higher CD4(+) T cell counts over time, there was no difference in the incidence of opportunistic infections. Progression to both acquired immunodeficiency syndrome (AIDS; adjusted hazard ratio [aHR], 0.50; 95% confidence interval [CI], 0.25-0.98) and death (aHR, 0.57, 95% CI, 0.37-0.89) were slower among HTLV-II-coinfected patients, compared with time-entry- and CD4(+) T cell count-matched control subjects. In conclusion, HIV-HTLV-I/II coinfection may result in improved survival and delayed progression to AIDS, but this happens at the expense of an increased frequency of other of clinical complications.

Regulation of estrogen-mediated cell survival and proliferation by p160 coactivators.

BACKGROUND: Estrogen receptor (ER) activity is dependent on coactivator (CoA) proteins. The role of CoA-ER interactions in breast cancer apoptosis remains unexplored. METHODS: Expression vectors for the p160 CoA genes NCOA-1, NCOA-2, or NCOA-3 were transiently transfected into MCF-7 cells. Cell survival was determined by viability and clonogenic survival assays. Effects of CoA expression on estrogen (E2) signaling were determined by estrogen response element (ERE)-luciferase reporter-gene assay. Clonogenic and reporter-gene survival assays were used to examine the molecular inhibition of CoA function (dominant inhibitory [DI]-decoy-CoA) on cell survival. Statistical significance was established at the P < .05 level. RESULTS: Overexpression of NCOA-1, NCOA-2, and NCOA-3 enhanced E2-mediated gene expression by 3.17 +/- 0.51-, 2.33 +/- 0.8-, and 3.65 +/- 0.65-fold, respectively, and enhanced cell survival by suppressing tumor necrosis factor alpha (TNF-alpha)-induced cell death from 80.23% +/- 2.66% viability to 101.5% +/- 8.9%, 86.9% +/- 9.9%, and 95.7% +/- 8.5% viability, respectively. NCOA-1 enhancement of cell survival occurred via suppression of TNF-alpha-induced apoptosis as confirmed by viability and morphologic evaluation. Clonogenic survival and E2-stimulated colony formation in MCF-7 cells were suppressed by expression of DI-decoy-NCOA-1 and DI-decoy-NCOA-3 to 34.4% +/- 7.4% and 54% +/- 5.4% of vector control, but not DI-decoy-NCOA-2. CONCLUSIONS: Overexpression of NCOA-1 and NCOA-3 exerted potent survival effects in breast carcinoma cells. Use of DI-CoA constructs enhanced TNF-alpha-induced cell death and abrogated E2-induced survival. Inhibition of CoA proteins represents a mechanism for enhancing sensitivity therapies in breast carcinoma.

Sensitization of apoptotically-resistant breast carcinoma cells to TNF and TRAIL by inhibition of p38 mitogen-activated protein kinase signaling.

The mitogen-activated protein kinase (MAPK) cascade is a critical component in the regulation of cell survival and proliferation decisions. In breast carcinoma cells, activation of the p38-MAPK member of this family occurs in response to pro-inflammatory cytokines and cellular stress. The involvement of p38-MAPK in the activation of the transcription factor, NF-kappaB, suggests a potential role and mechanism for regulation of cell survival and drug resistance. Generation of the resistant MCF-7 variant (MCF-7TN-R) was achieved by prolonged exposure of MCF-7N cells to increasing concentrations of TNF. Differences in MAPK activation and function in the MCF-7 cell variants were determined. The role of the p38-MAPK pathway in regulation of resistance was determined using pharmacological (SB 203580) or molecular [Dominant Inhibitory (DI)-p38] inhibition. The effect of p38 inhibition on NF-kappaB transcriptional activation was analyzed. As compared to the sensitive MCF-7N parent cell line, the MCF-7TN-R cell line displayed significant resistance to TNF- and TRAIL-induced cell death. Analysis of the expression and phosphorylation of members of the MAPK family revealed an increased basal activation of p38 in the MCF-7TN-R variant. The p38-mediated phosphorylation and transcriptional activity were suppressed by pharmacologic inhibition with SB 230580. Treatment of MCF-7TN-R cells with SB partially restored sensitivity to TNF-induced cell death. In addition, use of a DI-p38 construct with or without the addition to TNF induced cell death, thus restoring TNF-sensitivity to these cells. The ability of p38 inhibition to restore apoptotic sensitivity was correlated with suppression of the TNF-induced cell survival pathway, NF-kappaB. The increased activation of p38-MAPK in MCF-7TN-R cells demonstrates that this signaling pathway through activation of NF-kappaB is an important route for control of resistance to cell death in breast carcinoma. Molecular and pharmacological inhibition of p38-MAPK signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens and restoration of apoptotic signaling.

Identification of mitogen-activated protein kinase kinase as a chemoresistant pathway in MCF-7 cells by using gene expression microarray.

BACKGROUND: Components of the mitogen-activated protein kinase (MAPK) cascade have been implicated in apoptotic regulation. This study used gene expression profiling analysis to identify and implicate mitogen-activated protein kinase kinase (MEK5)-BMK1 (big mitogen-activated kinase-1)/extracellular signal related protein kinase (ERK5) pathway as a novel target involved in chemoresistance. METHODS: Differential gene expression between apoptotically sensitive (APO+) and apoptotically resistant (APO-) MCF-7 cell variants was determined by using microarray and confirmed by reverse transcriptase- polymerase chain reaction (RT-PCR). An apoptotic/viability reporter gene assay was used to deter-mine the effects of the transfection of a dominant-negative mutant of BMK1 (BMK1/DN) in conjunction with apoptotic-inducing agents (etoposide, tumor necrosis factor-alpha [TNF], or TNF-related apoptosis-inducing ligand [TRAIL]), with or without phorbol ester (PMA). RESULTS: Of the 1186 genes detected through microarray analysis, MEK5 was increased 22-fold in APO- cells. Overexpression of MEK5 was confirmed by using RT-PCR analysis. Expression of BMK1/DN alone resulted in a dose-dependent increase in cell death versus control (P <.05). In addition, BMK1/DN enhanced the sensitivity of MCF-7 cells to treatment-induced cell death (P <.05). The ability of PMA to partially suppress TRAIL- and TNF-induced cell death was inhibited by BMK1/DN. However, only TRAIL-induced activity suppression reached statistical significance (P <.05). CONCLUSIONS: The overexpression of MEK5 in APO- MCF-7 breast carcinoma cells shows that this MAPK signaling protein represents a potent survival molecule. Molecular inhibition of MEK5 signaling may represent a mechanism for sensitizing cancer cells to chemotherapeutic regimens.

Detection of human papillomavirus DNA in urine specimens from human immunodeficiency virus-positive women.

Human immunodeficiency virus (HIV)-positive women may represent one of the fastest-growing populations at risk for acquiring cervical cancer and thus require frequent screening. The purpose of the present studies was to validate a PCR-based urine assay by comparing detection and genotyping of human papillomavirus (HPV) DNA in urine samples and matching cervical swab specimens of HIV-positive women. Despite a difference in amplifiability, the prevalence of any HPV genotype (58% for the cervical swab specimens and 48% for the urine specimens) was not significantly different in this population. The levels of concordance were 70, 71, and 78% for detection of any HPV type, any high-risk HPV type, or any low-risk HPV type in the two specimen types, respectively. While instances of discordant detection were greater for the cervical swab specimens than for the urine specimens, this was not statistically significant. The distributions of HPV genotypes were similar in the cervix and the urine for the majority of types examined. Importantly, detection of HPV DNA in urine was associated with an abnormal Papanicolaou smear to the same extent that detection of HPV DNA in a cervical swab specimen was. These data provide preliminary support for the proposal to use urine testing as a primary or secondary screening tool for cervical cancer in HIV-positive women or as an epidemiological tool. Additional studies with larger sample sizes must be conducted in order to further verify these findings.

Morphologic and clinical significance of multifocal prostate cancers in radical prostatectomy specimens.

OBJECTIVES: To examine the histologic details of small, independent cancers compared with the largest (index) tumor and their impact on prostate-specific antigen (PSA) failure in 486 men treated only by radical retropubic prostatectomy (RRP). METHODS: The tumor volume and percentage of Gleason grade 4/5 carcinoma were recorded in 3-mm step sections. Univariate statistics were calculated for the largest, total (largest plus smaller cancers), and smaller tumor volumes, number of independent foci, patient age, and follow-up. Cox hazards model determined the relative importance of all variables in relation to failure. RESULTS: The mean index tumor volume was 4.16 cm3; smaller cancer volumes averaged 0.63 cm3. The index cancer volume was gaussian in distribution; smaller tumor volumes were highly skewed toward 234 carcinomas less than 0.5 cm3. Only 17% of all cases had one carcinoma. The Cox model showed similar hazard rates of PSA failure for both the index (3.43) and the total cancer (3.74) volumes. The hazard rate for the presence of any Gleason grade 4/5 carcinoma was 6.5. As the numbers of smaller tumors increased, the PSA cure rates improved. CONCLUSIONS: The PSA failure rates (hazard ratios) were similar for the index tumor and the index plus smaller cancers, confirming that predictive estimates only need to measure the largest carcinoma. The greater the number of lesser cancers, the smaller the size of the index cancer. The extraordinary multiplicity of these small independent cancers in 3-mm step sections may explain the poor correlation between six or more biopsies with the index cancer in radical prostatectomy specimens.

Older partners not associated with recurrence among female teenagers infected with Chlamydia trachomatis.

BACKGROUND: Chlamydia trachomatis-infected female teenagers with older partners may be less likely to discuss the infection with their partner(s) and to use condoms and therefore may be more likely to get reinfected. GOAL: To determine if C trachomatis-infected female teenagers with older partners were more likely to be reinfected than those with same-aged partners. STUDY DESIGN: Females aged 14 years to 18 years who had uncomplicated chlamydial infection, were nonpregnant, attended clinics in five United States cities from June 1995 to May 1997, completed treatment, and resumed sexual activity were observed at 1 and 4 months for interim history and retesting. RESULTS: Of 225 women studied, 73.3% were black, 34.5% had at least one partner who was 3 or more years older during follow-up, 51.6% reported using a condom at the last sex act with all partners, 13.8% had a recurrent infection, and 47.4% reported they were certain that all of their baseline partners were treated. Partner age was not associated with condom use, certainty of partners' taking medication, or recurrent infections after adjustment for visit. CONCLUSIONS: Older partners, accounting for approximately one third of all partners, did not increase the risk of reinfection. Given the high risk for recurrence, follow-up testing and enhanced efforts to ensure partner treatment are appropriate for all young women with chlamydial infections.