-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Although the perioperative mortality from hepatic resection has improved considerably, this procedure is still associated with substantial morbidity and resource use. The goal of this investigation was to characterize the incidence, patterns, and risk factors for early reoperation and readmission after hepatectomy. STUDY DESIGN: Perioperative outcomes of 1,281 patients undergoing hepatic resection at an academic center from 1996 to 2009 were analyzed. The indications for early reoperation and readmission (90 days) were reviewed. Multivariate logistic regression analysis was performed to determine variables associated with reoperation and readmission. A scoring system was generated to predict the need for readmission after hepatectomy. RESULTS: Eighty-seven patients (6.8%) required reoperation. The perioperative mortality in patients requiring reoperation was significantly higher than for those not requiring reoperation (23.0% vs 3.4%; p < 0.001). Variables associated with reoperation included male sex, performance of concomitant major nonhepatic procedures, and greater intraoperative blood loss. One hundred and eighty-four patients (14.4%) required readmission. Variables associated with readmission included major hepatectomy, development of major postoperative complications, and index hospitalization >7 days. A Readmission Prediction Score ranging from 0 to 4 was generated and directly correlated with need for readmission. CONCLUSIONS: In the current era of hepatic surgery, early reoperation and readmission remain relatively frequent. As we care for patients who are increasingly receiving regionalized care far from home, we must be mindful of patients at increased risk for readmission. The development of strategies to minimize the complications that necessitate reoperation and readmission is critical to improving patient care.
Journal of the American College of Surgeons 03/2013; · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND:: A laparoscopic approach has been proposed to reduce the high morbidity and mortality associated with the Hartmann procedure for the emergency treatment of diverticulitis. OBJECTIVE:: The objective of our study was to determine whether a laparoscopic Hartmann procedure reduces early morbidity or mortality for patients undergoing an emergency operation for diverticulitis. DESIGN:: This is a comparative effectiveness study. A subset of the entire American College of Surgeons National Surgical Quality Improvement Program patient sample matched on propensity for undergoing their procedure with the laparoscopic approach were used to compare postoperative outcomes between laparoscopic and open groups. SETTING:: This study uses data from the American College of Surgeons National Surgical Quality Improvement Program Participant User Files from 2005 through 2009. PATIENTS:: All patients who underwent an emergency laparoscopic or open partial colectomy with end colostomy for colonic diverticulitis were reviewed. MAIN OUTCOME MEASURES:: The main outcome measures were 30-day mortality and morbidity. RESULTS:: Included in the analysis were 1186 patients undergoing emergency partial colectomy with end colostomy for diverticulitis. Among the entire cohort, the laparoscopic group had fewer overall complications (26% vs 41.7%, p = 0.008) and shorter mean length of hospitalization (8.9 vs 11.6 days, p = 0.0008). Operative times were not significantly different between groups. When controlling for potential confounders, a laparoscopic approach was not associated with a decrease in morbidity or mortality. In comparison with a propensity-match cohort, the laparoscopic approach did not reduce postoperative morbidity or mortality. LIMITATIONS:: This study is limited by its retrospective nature and the absence of pertinent variables such as postoperative pain indices, time for return of bowel function, and rates of readmission. CONCLUSIONS:: A laparoscopic approach to the Hartmann procedure for the emergency treatment of complicated diverticulitis does not significantly decrease postoperative morbidity or mortality in comparison with the open technique.
Diseases of the Colon & Rectum 01/2013; 56(1):72-82. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BACKGROUND: Although a concomitant diaphragm resection might be required at the time of hepatectomy to achieve tumor-free surgical margins, studies addressing its effect on postoperative morbidity and mortality have been inconclusive. The objective of this study was to determine whether the need for diaphragm resection at the time of hepatectomy truly increases 30-day morbidity or mortality using data from the American College of Surgeons National Surgical Quality Improvement Program. STUDY DESIGN: Data were obtained from the 2005-2010 American College of Surgeons National Surgical Quality Improvement Program Participant User Files based on CPT coding. All patients undergoing a simultaneous liver and diaphragm resection were propensity-matched to a subset of liver resection patients not undergoing a diaphragm resection. The main outcomes measures were 30-day mortality and morbidity. RESULTS: One hundred and ninety-two patients who underwent combined liver and diaphragm resection were matched to 192 patients treated with liver resection alone. The need for concomitant diaphragm resection was associated with a higher overall complication rate (38.54% vs 28.65%; p = 0.048), major complication rate (33.33% vs 23.44%; p = 0.030), and respiratory complication rate (14.06% vs 7.81%; p = 0.058). Postoperative mortality was similar between groups. Combined diaphragm and liver resection was also associated with longer operative times (median 311 minutes vs 247.5 minutes; p < 0.001), higher rates of intraoperative packed RBC transfusion (33.33% vs 23.44%; p = 0.037), and a longer length of hospitalization (median 7 vs 6 days; p = 0.002). CONCLUSIONS: The results of this study, when taken into account with those reported previously, suggest that the need for diaphragm resection at time of hepatectomy increases postoperative morbidity but not mortality.
Journal of the American College of Surgeons 12/2012; · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: INTRODUCTION: Our objective was to review our 10-year experience of surgical resection for acute ischemic colitis (IC) and to assess the predictive value of previously reported risk-stratification methods. METHODS: We retrospectively reviewed all adult patients at our institution undergoing colectomy for acute IC between 2000 and 2009. Descriptive statistics were calculated. Long-term survival was assessed using Kaplan-Meier methods and in-hospital mortality using multivariate logistic regression. Patients were risk-stratified based on previously reported methods, and discriminatory accuracy of predicting in-hospital mortality was evaluated by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. RESULTS: A total of 115 patients were included for analysis, of which 37 % (n = 43) died in-hospital. The median survival was 4.9 months for all patients and 43.6 months for patients surviving to discharge. Seventeen patients subsequently underwent end-ostomy reversal at our institution, with in-hospital mortality of 18 % (n = 3) and ICU admission for 35 % (n = 6). The discriminatory accuracy of risk stratification in predicting in-hospital mortality based on ROC AUC was 0.75. CONCLUSION: Acute IC continues to remain a very deadly disease. Patients who survive the initial acute IC insult can achieve long-term survival; however, we experienced high rates of death and complications following elective end-ostomy reversal. Risk stratification provides reasonable accuracy in predicting postoperative mortality.
Journal of Gastrointestinal Surgery 12/2012; · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The routine use of venous thromboembolism (VTE) chemoprophylaxis after hepatic surgery remains controversial due to the relatively low incidence of this complication and the significant risk of perioperative bleeding. The objective of our analysis was to identify perioperative predictors of postoperative VTE in patients undergoing resection.
All patients from the American College of Surgeons National Surgical Quality Improvement Program Participant User File from 2005 to 2009 who underwent hepatic resection were included for analysis. Forward stepwise multivariate logistic regression models were used to determine perioperative variables that are significantly associated with VTE after hepatic surgery.
The overall incidence of VTE after hepatic resection was 2.9 %. Significant predictors of VTE after hepatic resection included preoperative mechanical ventilation, male gender, operative time > 3 h, age ≥ 70 years, intraoperative transfusion, and extended hepatectomy. Several non-VTE postoperative complications were also associated with subsequent VTE, including prolonged mechanical ventilation, need for early reoperation, and postoperative bleeding.
Many perioperative factors, including extended hepatectomy as well as several postoperative non-VTE complications, are associated with an increased risk of VTE after hepatic resection. Knowledge of these factors may assist surgeons in deciding which patients merit more aggressive prophylaxis against this complication.
Journal of Gastrointestinal Surgery 06/2012; 16(9):1705-14. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: For colorectal cancer patients with liver metastases involving the hepatic dome or invading the diaphragm, a concomitant diaphragm resection is often required to achieve negative surgical margins. The purpose of this study is to determine whether diaphragm resection during partial hepatectomy for metastatic colorectal cancer influences short-term perioperative outcomes and overall survival.
Demographics, treatments, and outcomes of 442 patients who underwent hepatic resection for metastatic colorectal cancer from 1996 to 2010 at a high-volume center were reviewed. Recurrence and survival were measured from the date of metastectomy. Actuarial curves were generated using the Kaplan-Meier method and compared using log-ranks testing. Multivariate predictors of worse survival were compared using a Cox-proportional hazards model.
A total of 442 patients underwent hepatectomy for metastatic colorectal cancer. Of these, 34 required simultaneous diaphragm resection (DR) and 408 did not (LR). No significant differences existed in patient demographics or comorbidities. The DR group had longer median operative times (336 vs. 267 min, p = 0.0008) but had comparable rates of perioperative morbidity and mortality. Median overall survival was shorter in the DR group compared to the LR group (18.8 vs. 36 months, p = 0.0017). When controlling for potential cofounders, liver metastases size > 5 cm (HR 1.45 95 % CI (1.08-1.99), p = 0.015) and diaphragm resection (HR = 1.72 95 % CI (1.03-2.86), p = 0.038) predicted worse survival.
Simultaneous diaphragm resection during partial hepatectomy does not significantly influence perioperative morbidity or mortality despite longer operative times. However, patients who require diaphragm resection have less favorable survival rates as compared to those who do not.
Journal of Gastrointestinal Surgery 06/2012; 16(8):1508-15. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: BackgroundAlthough standard of care after most abdominal surgeries, post-operative pharmacologic thromboprophylaxis after major hepatectomy
is commonly withheld due to bleeding risks. The objective of this retrospective study is to evaluate the benefits and risks
of post-operative pharmacologic thromboprophylaxis after major hepatectomy at two high volume academic centers.
MethodsDemographics, clinicopathologic data, treatments, and post-operative outcomes from patients who underwent major hepatectomy
were reviewed.
ResultsFrom 2005 to 2010, 419 patients underwent major hepatectomy; 275 (65.6%) were treated with pharmacologicthromboprophylaxis
beginning a median of 1day after resection. Post-operative symptomatic venous thromboembolism (VTE) occurred in 15 (3.6%)
patients. Patients treated with pharmacologic thromboprophylaxis had lower rates of symptomatic VTE (2.2% vs. 6.3%, p = 0.03) and post-operative red blood cell (RBC) transfusion (16.7% vs. 26.4%, p = 0.02) with similar rates of overall RBC transfusion (35.0% vs. 30.6%, p = 0.36) compared to untreated patients. Specifically, isolated deep venous thrombosis (0% vs. 2.1%, p = 0.04) and pulmonary embolism (2.2% vs. 4.2%, p = 0.35) occurred less often in treated patients. Analysis of demographics, clinicopathologic data, and treatment factors
revealed that pharmacologic thromboprophylaxis was the only variable associated with post-operative VTE.
ConclusionsPost-operative pharmacologic thromboprophylaxis lowers the incidence of symptomatic VTE after major hepatectomy without increasing
the rate of RBC transfusion.
KeywordsLiver resection–Venous thromboembolism–Thromboprophylaxis
Journal of Gastrointestinal Surgery 04/2012; 15(9):1602-1610. · 2.83 Impact Factor
-
Ryan S Turley,
Kirk Peterson,
Andrew S Barbas,
Eugene P Ceppa,
Erik K Paulson,
Dan G Blazer,
Bryan M Clary,
Theodore N Pappas,
Douglas S Tyler,
Richard L McCann,
Rebekah R White
[show abstract]
[hide abstract]
ABSTRACT: Once thought to have unresectable disease, pancreatic cancer patients with portal venous involvement are now reported to have comparable survival after pancreaticoduodenectomy (PD) with vascular reconstruction (VR) as compared with patients without vascular involvement. We hypothesize that a multidisciplinary approach involving a vascular surgeon will minimize morbidity and improve patency of VRs.
We identified 204 patients who underwent PD for pancreatic adenocarcinoma from 1997 to 2008. Patients who underwent PD with VR (N = 42) were compared with those who underwent standard PD (N = 162). VRs were performed by a vascular surgeon and involved primary repair (N = 8), vein patch (N = 25), or interposition grafting (N = 9) with femoral or other venous conduit.
Patients undergoing PD with VR had larger tumors (3.0 cm vs. 2.5 cm, P < 0.01) but did not have different rates of tumor-free margins (73% vs. 72%, P = 0.84) or lymph nodes metastases (50% vs. 38%, P = 0.14). The VR group had higher median blood loss (875 mL vs. 550 mL, P = 0<0.01), but no differences in mortality, complication rates, length of stay, or readmission rates were found in a median follow-up of 29 months. Overall survival rates were similar. Predictors of mortality on multivariate analysis included increasing histological grade (P = 0.01), positive lymph nodes (P = 0.01), and increasing tumor size (P = 0.01), but not VR (P = 0.28). When evaluated by computed tomography scans within 6 months postoperatively, 97% of reconstructions remained patent.
The need for VR is not a contraindication to potentially curative resection in patients with pancreatic adenocarcinoma. Assistance of a vascular surgeon during VR may allow moderate-volume centers to achieve outcomes comparable with high-volume centers.
Annals of Vascular Surgery 02/2012; 26(5):685-92. · 1.03 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To compare outcomes and the use of multimodality therapy in young and elderly people with pancreatic cancer undergoing surgical resection.
Retrospective, single-institution study.
National Cancer Institute/National Comprehensive Cancer Network cancer center.
Two hundred three individuals who underwent pancreaticoduodenectomy for pancreatic adenocarcinoma at Duke University Medical Center comprised the study population. Participants were divided into three groups based on age (<65, n = 97; 65-74, n = 74; ≥75, N = 32).
Perioperative outcomes, the use of multimodality therapy, and overall survival of the different age groups were compared.
Similar rates of perioperative mortality and morbidity were observed in all age groups, but elderly adults were more likely to be discharged to a rehabilitation or skilled nursing facility. A similar proportion of participants received neoadjuvant therapy, but a smaller proportion of elderly participants received adjuvant therapy. Overall survival was similar between the age groups. Predictors of poorer overall survival included coronary artery disease, positive resection margin, and less-differentiated tumor histology. Treatment with neoadjuvant and adjuvant therapy were predictors of better overall survival.
Carefully selected elderly individuals experience similar perioperative outcomes and overall survival to those of younger individuals after resection of pancreatic cancer. There appears to be a significant disparity in the use of adjuvant therapy between young and elderly individuals.
Journal of the American Geriatrics Society 12/2011; 60(2):344-50. · 3.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recent studies have documented improved outcomes for patients undergoing colorectal cancer resection at NCI cancer centers compared to hospitals without this designation. Proposed contributory factors include a higher proportion of surgeons with specialty training in colorectal surgery and surgical oncology. The purpose of this study was to assess whether surgeon specialization is associated with differences in overall survival following colon cancer resection at an NCI cancer center.
We conducted a retrospective review of patients undergoing colectomy for colon cancer from 1994 to 2009 at Duke University Medical Center. Patients were divided into two groups based on specialization status of the attending surgeon, and several clinicopathologic variables were compared. A multivariate analysis was then performed examining variables influencing overall survival.
Total of 395 patients were included in the study, with 335 patients operated on by specialty-trained surgeons and 60 patients operated on by non-specialists. Overall, the two groups were similar with respect to demographic and pathologic variables. On multivariate analysis, surgeon specialization was found to be an independent predictor of improved overall survival [HR 0.43 (CI: 0.25-0.75), P = 0.003].
Surgeon specialization appears to be associated with improved overall survival in the setting of an NCI-designated cancer center.
Journal of Surgical Oncology 11/2011; 106(3):219-23. · 2.10 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Before the advent of tyrosine kinase inhibitors (TKIs), surgical resection was the primary treatment for hepatic gastrointestinal stromal tumor (GIST) metastases. Although TKIs have improved survival in the metastatic setting, outcomes after multimodal therapy comprised of hepatectomy and TKIs for GIST are unknown. The objective of this study was to determine whether combination therapy for hepatic GIST metastases is associated with improved overall survival compared with reported outcomes from surgery or TKI therapy alone.
Demographics, clinicopathologic tumor characteristics, treatments, and outcomes of patients who underwent hepatic resection at 3 high-volume centers from 1995 to 2010 were reviewed.
In total, 39 patients underwent hepatectomy for metastatic GISTs, and 27 patients received postoperative TKI therapy. At a median follow-up of 39.7 months, 23 patients (59%) experienced recurrence at a median of 18 months. The 1-year, 2-year, and 3-year overall survival rates were 96.7%, 76.8%, and 67.9%, respectively. Median survival was not reached at 5 years. The rates of severe complication and mortality were 10.2% (4 patients) and 2.5% (1 patient), respectively. When controlling for confounders, postoperative TKI therapy was associated with improved survival (hazard ratio, 0.04; 95% confidence interval, 0.01-0.50; P = .006), and extrahepatic disease was associated with worse survival (hazard ratio, 9.51; 95% confidence interval, 1.63-55.7; P = .012).
Overall survival after combination therapy exceeded previous reports for the treatment of metastatic GIST with hepatic resection or TKI therapy alone and was significantly enhanced by postoperative TKI therapy. The results from this study support findings that combination therapy for GIST liver metastases comprised of surgical resection and TKI therapy is more effective than surgery or TKI therapy alone.
Cancer 11/2011; 118(14):3571-8. · 4.77 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: While commonly used to describe liver resections at risk for post-operative complications, no standard definition of 'major hepatectomy' exists. The objective of the present retrospective study is to specify the extent of hepatic resection that should describe a major hepatectomy.
Demographics, diagnoses, surgical treatments and outcomes from patients who underwent a liver resection at two high-volume centres were reviewed.
From 2002 to 2009, 1670 patients underwent a hepatic resection. Post-operative mortality and severe, overall and hepatic-related morbidity occurred in 4.4%, 29.7%, 41.6% and 19.3% of all patients. Mortality (7.4% vs. 2.7% vs. 2.6%) and severe (36.7% vs. 24.7% vs. 24.1%), overall (49.3% vs. 40.6% vs. 35.9%) and hepatic-related (25.6% vs. 16.4% vs. 15.2%) morbidity were more common after resection of four or more liver segments compared with after three or after two or fewer segments (all P < 0.001). There were no significant differences in any post-operative outcome after resection of three and two or fewer segments (all P > 0.05). On multivariable analysis, resection of four or more liver segments was independently associated with post-operative mortality and severe, overall, and hepatic-related morbidity (all P < 0.01).
A major hepatectomy should be defined as resection of four or more liver segments.
HPB 07/2011; 13(7):494-502. · 1.60 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Although standard of care after most abdominal surgeries, post-operative pharmacologic thromboprophylaxis after major hepatectomy is commonly withheld due to bleeding risks. The objective of this retrospective study is to evaluate the benefits and risks of post-operative pharmacologic thromboprophylaxis after major hepatectomy at two high volume academic centers.
Demographics, clinicopathologic data, treatments, and post-operative outcomes from patients who underwent major hepatectomy were reviewed.
From 2005 to 2010, 419 patients underwent major hepatectomy; 275 (65.6%) were treated with pharmacologicthromboprophylaxis beginning a median of 1 day after resection. Post-operative symptomatic venous thromboembolism (VTE) occurred in 15 (3.6%) patients. Patients treated with pharmacologic thromboprophylaxis had lower rates of symptomatic VTE (2.2% vs. 6.3%, p = 0.03) and post-operative red blood cell (RBC) transfusion (16.7% vs. 26.4%, p = 0.02) with similar rates of overall RBC transfusion (35.0% vs. 30.6%, p = 0.36) compared to untreated patients. Specifically, isolated deep venous thrombosis (0% vs. 2.1%, p = 0.04) and pulmonary embolism (2.2% vs. 4.2%, p = 0.35) occurred less often in treated patients. Analysis of demographics, clinicopathologic data, and treatment factors revealed that pharmacologic thromboprophylaxis was the only variable associated with post-operative VTE.
Post-operative pharmacologic thromboprophylaxis lowers the incidence of symptomatic VTE after major hepatectomy without increasing the rate of RBC transfusion.
Journal of Gastrointestinal Surgery 06/2011; 15(9):1602-10. · 2.83 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Because of the aging United States population, increase in overall life expectancy, and rising incidence of hepatobiliary tumors, more elderly patients are considered for hepatic resection. The objective of this study was to assess the influence of age on postoperative outcomes after major hepatectomy among a contemporary cohort from 2 high volume centers.
Demographics, diagnoses, surgical treatments, and postoperative outcomes of patients who underwent major hepatic resection were reviewed.
There were 856 patients who underwent major hepatectomy (resection of 3 or more segments) from 2002 to 2009. Postoperative mortality and morbidity occurred in 53 (6.2%) and 403 (47.1%) patients, respectively. Increasing age was independently associated with postoperative mortality (p = 0.0345). Each 1-year and 10-year increase in age resulted in an odds ratio of mortality after major hepatic resection of 1.036 (95% CI [1.003-1.071]) and 1.426 (95% CI [1.026-1.982]), respectively. This relationship was independent of American Society of Anesthesiology (ASA) score. Increasing age was associated with postoperative sepsis (p = 0.0224, odds ratio for each year 1.025 [range 1.003 to 1.048]) after major hepatic resection, but not overall postoperative morbidity.
In the contemporary era, increasing age is independently associated with postoperative mortality after major hepatic resection at high volume academic centers.
Journal of the American College of Surgeons 03/2011; 212(5):787-95. · 4.55 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: For in-transit melanoma confined to the extremities, regional chemotherapy in the form of hyperthermic isolated limb perfusion and isolated limb infusion are effective treatment modalities carrying superior response rates to current standard systemic therapy. Despite high response rates, most patients will eventually recur, supporting the role for novel research aimed at improving durable responses and minimizing toxicity. Although the standard cytotoxic agent for regional chemotherapy is melphalan, alternative agents such as temozolomide are currently being tested, with promising preliminary results. Current strategies for improving chemosensitivity to regional chemotherapy are aimed at overcoming classic resistance mechanisms such as drug metabolism and DNA repair, increasing drug delivery, inhibiting tumor-specific angiogenesis, and decreasing the apoptotic threshold of melanoma cells. Concurrent with development and testing of these agents, genomic profiling and biomolecular analysis of acquired tumor tissue may define patterns of tumor resistance and sensitivity from which personalized treatment may be tailored to optimize efficacy. In this article rational strategies for treatment of in-transit melanoma are outlined, with special emphasis on current translational and clinical research efforts.
Surgical Oncology Clinics of North America 01/2011; 20(1):79-103. · 1.12 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To test the hypothesis that the association between prostate size and risk of Gleason grade upgrading varies as a function of sampling.
We examined the association between pathological prostate weight, prostate biopsy scheme and Gleason upgrading (Gleason > or =7 at radical prostatectomy, RP) among 646 men with biopsy Gleason 2-6 disease treated with RP between 1995 and 2007 within the Shared Equal Access Regional Cancer Hospital Database using logistic regression. In all, 204 and 442 men had a sextant (six or seven cores) or extended-core biopsy (eight or more cores), respectively. Analyses were adjusted for centre, age, surgery, preoperative prostate-specific antigen level, clinical stage, body mass index, race, and percentage of cores positive for cancer.
In all, 281 men (44%) were upgraded; a smaller prostate was positively associated with the risk of upgrading in men who had an extended-core biopsy (P < 0.001), but not among men who had a sextant biopsy (P = 0.22). The interaction between biopsy scheme and prostate size was significant (P interaction = 0.01).
These data support the hypothesis that the risk of upgrading is a function of two opposing contributions: (i) a more aggressive phenotype in smaller prostates and thus increased risk of upgrading; and (ii) more thorough sampling in smaller prostates and thus decreased risk of upgrading. When sampled more thoroughly, the phenotype association dominates and smaller prostates are linked with an increased risk of upgrading. In less thoroughly sampled prostates, these opposing factors nullify, resulting in no association between prostate size and risk of upgrading. These findings help to explain previously published disparate results of the importance of prostate size as a predictor of Gleason upgrading.
BJU International 10/2008; 102(9):1074-9. · 2.84 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The transforming growth factor-beta (TGF-beta) superfamily has essential roles in lung development, regulating cell proliferation, branching morphogenesis, differentiation and apoptosis. Although most lung cancers become resistant to the tumor suppressor effects of TGF-beta, and loss or mutation of one of the components of the TGF-beta signaling pathway, including TbetaRII, Smad2 and Smad4 have been reported, mutations are not common in non-small cell lung cancer (NSCLC). Here we demonstrate that the TGF-beta superfamily co-receptor, the type III TGF-beta receptor (TbetaRIII or betaglycan) is lost in the majority of NSCLC specimens at the mRNA and protein levels, with loss correlating with increased tumor grade and disease progression. Loss of heterozygosity at the TGFBR3 genomic locus occurs in 38.5% of NSCLC specimens and correlates with decreased TbetaRIII expression, suggesting loss of heterozygosity as one mechanism for TbetaRIII loss. In the H460 cell model of NSCLC, restoring TbetaRIII expression decreased colony formation in soft agar. In the A549 cell model of NSCLC, restoring TbetaRIII expression significantly decreased cellular migration and invasion through Matrigel, in the presence and absence of TGF-beta1, and decreased tumorigenicity in vivo. In a reciprocal manner, shRNA-mediated silencing of endogenous TbetaRIII expression enhanced invasion through Matrigel. Mechanistically, TbetaRIII functions, at least in part, through undergoing ectodomain shedding, generating soluble TbetaRIII, which is able to inhibit cellular invasiveness. Taken together, these results support TbetaRIII as a novel tumor suppressor gene that is commonly lost in NSCLC resulting in a functional increase in cellular migration, invasion and anchorage-independent growth of lung cancer cells.
Carcinogenesis 04/2008; 29(3):528-35. · 5.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Needle biopsy Gleason scores are often upgraded after pathological examination of the prostate following radical prostatectomy. It has been suggested that larger prostates would be associated with a greater risk of upgrading since a smaller percentage of the gland is sampled and, thus, the highest grade disease would more likely be missed, assuming an equal number of cores is taken from similar locations. We examined the likelihood of clinically relevant upgrading after radical prostatectomy as a function of transrectal ultrasound volume.
We examined the association between transrectal ultrasound volume and upgrading (higher Gleason score category in the radical prostatectomy specimen than in the biopsy) in 586 men treated with radical prostatectomy between 1995 and 2006 in the SEARCH database who underwent at least a sextant biopsy using multivariate logistic regression. Transrectal ultrasound volume was categorized as 20 or less (in 71), 21 to 40 (in 334), 41 to 60 (in 123) and greater than 60 cm(3) (in 58). Gleason score was examined as a categorical variable of 2-6, 3 + 4 and 4 + 3 or greater.
Overall 138 cases (24%) were upgraded, 80 (14%) were downgraded, and 368 (62%) had identical biopsy and pathological Gleason sum groups. Larger transrectal ultrasound volume was significantly associated with decreased likelihood of upgrading (p trend <0.001). For transrectal ultrasound volumes greater than 60, 41 to 60, 21 to 40 and 20 cm(3) or less, the estimated multivariate adjusted probability of upgrading was 12.6%, 27.5%, 36.4% and 45.5% for Gleason 2-6 tumors, and 6.1%, 8.5%, 18.9% and 20.9% for Gleason 3 + 4 tumors, respectively.
Larger transrectal ultrasound volumes were at decreased risk for clinically significant upgrading after radical prostatectomy. This fact should be kept in mind when deciding on treatment decisions for men with apparently low grade prostate cancer on biopsy.
The Journal of urology 03/2008; 179(2):523-7; discussion 527-8. · 4.02 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The transforming growth factor-beta (TGF-beta) signaling pathway has an important role in regulating normal prostate epithelium, inhibiting proliferation, differentiation, and both androgen deprivation-induced and androgen-independent apoptosis. During prostate cancer formation, most prostate cancer cells become resistant to these homeostatic effects of TGF-beta. Although the loss of expression of either the type I (TbetaRI) or type II (TbetaRII) TGF-beta receptor has been documented in approximately 30% of prostate cancers, most prostate cancers become TGF-beta resistant without mutation or deletion of TbetaRI, TbetaRII, or Smads2, 3, and 4, and thus, the mechanism of resistance remains to be defined. Here, we show that type III TGF-beta receptor (TbetaRIII or betaglycan) expression is decreased or lost in the majority of human prostate cancers as compared with benign prostate tissue at both the mRNA and protein level. Loss of TbetaRIII expression correlates with advancing tumor stage and a higher probability of prostate-specific antigen (PSA) recurrence, suggesting a role in prostate cancer progression. The loss of TbetaRIII expression is mediated by the loss of heterozygosity at the TGFBR3 genomic locus and epigenetic regulation of the TbetaRIII promoter. Functionally, restoring TbetaRIII expression in prostate cancer cells potently decreases cell motility and cell invasion through Matrigel in vitro and prostate tumorigenicity in vivo. Taken together, these studies define the loss of TbetaRIII expression as a common event in human prostate cancer and suggest that this loss is important for prostate cancer progression through effects on cell motility, invasiveness, and tumorigenicity.
Cancer Research 03/2007; 67(3):1090-8. · 7.86 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The transforming growth factor-β (TGF-β) superfamily has essential roles in lung development, regulating cell proliferation, branching morphogenesis, differentiation and apoptosis. Although most lung cancers become resistant to the tumor suppressor effects of TGF-β, and loss or mutation of one of the components of the TGF-β signaling pathway, including TβRII, Smad2 and Smad4 have been reported, mutations are not common in non-small cell lung cancer (NSCLC). Here we demonstrate that the TGF-β superfamily co-receptor, the type III TGF-β receptor (TβRIII or betaglycan) is lost in the majority of NSCLC specimens at the mRNA and protein levels, with loss correlating with increased tumor grade and disease progression. Loss of heterozygosity at the TGFBR3 genomic locus occurs in 38.5% of NSCLC specimens and correlates with decreased TβRIII expression, suggesting loss of heterozygosity as one mechanism for TβRIII loss. In the H460 cell model of NSCLC, restoring TβRIII expression decreased colony formation in soft agar. In the A549 cell model of NSCLC, restoring TβRIII expression significantly decreased cellular migration and invasion through Matrigel, in the presence and absence of TGF-β1, and decreased tumorigenicity in vivo. In a reciprocal manner, shRNA-mediated silencing of endogenous TβRIII expression enhanced invasion through Matrigel. Mechanistically, TβRIII functions, at least in part, through undergoing ectodomain shedding, generating soluble TβRIII, which is able to inhibit cellular invasiveness. Taken together, these results support TβRIII as a novel tumor suppressor gene that is commonly lost in NSCLC resulting in a functional increase in cellular migration, invasion and anchorage-independent growth of lung cancer cells.
