Scott T. Hollenbeck

Surgical treatment and outcomes of patients with primary inferior vena cava leiomyosarcoma.

BACKGROUND The inferior vena cava (IVC) is a rare site for primary soft tissue sarcoma. There are limited data in the literature regarding surgical management of the IVC and longterm survival of these patients. STUDY DESIGN From 1982 to 2002, a total of 25 patients with primary IVC leiomyosarcoma was treated as inpatients and followed in a prospective database at Memorial Sloan-Kettering. Presenting symptoms, tumor characteristics, operative management, postoperative morbidity, and disease-specific survival were assessed for each patient. RESULTS The 25 patients with primary IVC leiomyosarcoma accounted for 0.5% of all adult patients with soft tissue sarcoma treated during this time. The median patient age was 56 years (range 41 to 79 years). The three most common presenting symptoms were abdominal pain (52%), distention (20%), and deep venous thrombosis (12%). Of the patients, 21 (84%) underwent complete resection of the tumor. The IVC was managed in one of three ways: ligation (n = 11), primary/patch repair (n = 8), and expanded polytetrafluoroethylene tube grafting (n = 2). Among patients undergoing IVC ligation and primary/patch repair (n = 19), 11% had severe postoperative edema and none had worsening renal function. Local recurrence occurred in 33% of patients and distant recurrence occurred in 48% of patients. Patients undergoing complete resection had 3-year and 5-year disease-specific survival rates of 76% and 33%, respectively. There were no 3-year survivors among patients with incomplete resections. CONCLUSIONS Complete resection of primary IVC leiomyosarcomas is feasible and associated with improved survival. The IVC can be managed by primary repair or ligation with a low risk of severe postoperative edema.

TGF-β through Smad3 signaling stimulates vascular smooth muscle cell proliferation and neointimal formation

The objective of this study was to better understand the role of transforming growth factor-beta (TGF-beta) and its primary signaling protein Smad3 in the development of intimal hyperplasia. Male Sprague-Dawley rats underwent left carotid balloon injury followed by intra-arterial infection with adenovirus-expressing Smad3 (AdSmad3). In uninfected injured arteries, endogenous Smad3 was upregulated with the expression peaking at 14 days. Moreover, in arteries infected with AdSmad3, we observed an enhancement of intimal hyperplasia and increased vascular smooth muscle cell (VSMC) proliferation. The novel finding, that TGF-beta/Smad3 stimulated rather than inhibited VSMC proliferation, was confirmed in cultured VSMCs infected with AdSmad3 and treated with TGF-beta. To identify the mechanism underlying TGF-beta/Smad3-mediated VSMC proliferation, we studied the cyclin-dependent kinase inhibitor p27. Although the upregulation of Smad3 in VSMCs had no significant effect on total p27 levels, Smad3 did stimulate the phosphorylation of p27 at serine-10 as well as the nuclear export of p27, events associated with cell proliferation. Furthermore, serine-10-phosphorylated p27 was also increased in AdSmad3-infected injured rat carotid arteries, demonstrating the existence of this same mechanism in vivo. In conclusion, our findings identify a novel mechanism for the effect of TGF-beta on intimal hyperplasia. In the presence of elevated levels of Smad3 that develop in response to injury, TGF-beta stimulates smooth muscle cell proliferation through a mechanism involving the phosphorylation and nuclear export of p27.

Factors Associated With Residual Breast Cancer After Re-excision for Close or Positive Margins

Background: Successful breast conservation surgery (BCS) requires complete tumor excision. Margin status of the initial specimen determines the need for additional surgery. We explored factors associated with residual cancer (RC) upon follow-up surgery in patients with close, positive, or undetermined margins following BCS.Methods: A retrospective analysis of 276 patients with initial close, positive, or undetermined margins who underwent re-excision (RE) or mastectomy was conducted. All initial excisions were intended as definitive procedures. Chi-square analysis was used to identify factors that may predict RC.Results: Of 276 patients, 87 had close, 168 had positive, and 21 had undetermined margins on initial excision. Of this group, 63% (175/276) had RC upon RE or mastectomy. Of positive-margin patients, 68% had RC, compared with 53% of close-margin and 67% of undetermined-margin patients (P = .006). Tumors ≥2 cm were more often associated with RC than smaller tumors (70.8% vs. 56.5%; P = .07). This association was strongest in positive-margin patients (P = .04). High tumor grade was associated with RC in all groups. RC linearly increased with the number of involved margins (P = .02). Specimen inking with multiple colors was associated with decreased risk of RC (P = .004).Conclusions: Over half of patients with involved or undetermined margins had RC upon RE or mastectomy. Positive and undetermined margins were more often associated with RC than close margins. Larger tumor size was associated with RC in patients with positive. Increasing tumor grade suggests a greater chance of detecting RC in all groups. Multiple involved margins led to a greater risk of RC.

Longitudinal Outcomes and Application of the Subunit Principle to 165 Foot and Ankle Free Tissue Transfers

Background: Free tissue transfer to the lower extremity has become a well-established reconstructive modality. The purpose of this study was to develop a “subunit” approach to patients undergoing free tissue transfer for foot and ankle wounds to help further define subunit-specific functional and aesthetic operative goals. Methods: The institutional review board approved this retrospective review of 161 patients who underwent free tissue transplantation for foot and ankle wounds between March 1, 1997, and February 28, 2007, at a single institution. Endpoints included flap-related complications, secondary surgery, time to ambulation, flap stability, and limb salvage. Results: The most common types of wounds treated were trauma-related [n = 120 (75 percent)], diabetes-related [n = 24 (15 percent)], and oncologic defects [n = 8 (5 percent)]. Ten different donor sites were used for reconstruction, with the latissimus dorsi flap being the most common. The mean follow-up time was 26.9 months (range, 0.5 to 130 months). Mean time to ambulation was 3.1 months (range, 0.75 to 14 months). Overall, 11 percent of patients required revision surgery for flap instability at a mean time of 25.3 months after flap surgery. Wounds located over the heel (subunit 5) were most likely to develop instability (Fishers exact test, p < 0.05). The overall 5-year limb salvage rate as determined by Kaplan-Meier analysis was 89 percent. Conclusions: The use of free tissue transplantation for treatment of foot and ankle wounds is associated with a high rate of limb salvage. Although a variety of flaps may be used, the application of the subunit principle can assist surgeons in designing flaps that will address subunit-specific functional and aesthetic concerns.

Areola-sparing mastectomy with immediate breast reconstruction.

Skin-sparing mastectomy with immediate breast reconstruction is a proved option for patients with early-stage breast cancer requiring mastectomy. Based on the authors’ recent pathologic analysis of mastectomy specimens showing less than 1% malignant involvement of the areola, they have begun to perform areola-sparing mastectomies (ASMs) on a select group of patients. They report their results from an ongoing study of ASM at their institution. During a 20-month period, 17 ASMs with immediate reconstruction were performed on 12 patients. Mastectomy was performed for breast cancer prophylaxis (n = 10), ductal carcinoma in situ (n = 4), and less than 2 cm of peripheral infiltrating carcinoma (n = 3). The most frequent incision performed was intraareola (n = 13). Thirteen patients were reconstructed with tissue expanders and 4 with pedicled transverse rectus abdominis musculocutaneous flaps. There was 1 postoperative complication, which consisted of a localized wound infection. Overall the authors found that ASM with immediate reconstruction provides excellent aesthetic results with infrequent complications.

Arterial gene transfer of the TGF-β signalling protein Smad3 induces adaptive remodelling following angioplasty: a role for CTGF

AIMS Although transforming growth factor-beta (TGF-beta) is believed to stimulate intimal hyperplasia after arterial injury, its role in remodelling remains unclear. We investigate whether Smad3, a TGF-beta signalling protein, might facilitate its effect on remodelling. METHODS AND RESULTS Using the rat carotid angioplasty model, we assess Smad3 expression following arterial injury. We then test the effect of arterial Smad3 overexpression on the response to injury, and use a conditioned media experimental design to confirm an Smad3-dependent soluble factor that mediates this response. We use small interfering RNA (siRNA) to identify this factor as connective tissue growth factor (CTGF). Finally, we attempt to replicate the effect of medial Smad3 overexpression through adventitial application of recombinant CTGF. Injury induced medial expression of Smad3; overexpression of Smad3 caused neointimal thickening and luminal expansion, suggesting adaptive remodelling. Smad3 overexpression, though exclusively medial, caused adventitial changes: myofibroblast transformation, proliferation, and collagen production, all of which are associated with adaptive remodelling. Supporting the hypothesis that Smad3 initiated remodelling and these adventitial changes via a secreted product of medial smooth muscle cells (SMCs), we found that media conditioned by Smad3-expressing recombinant adenoviral vector (AdSmad3)-infected SMCs stimulated adventitial fibroblast transformation, proliferation, and collagen production in vitro. This effect was attenuated by pre-treatment of SMCs with siRNA specific for CTGF, abundantly produced by AdSmad3-infected SMCs, and significantly up-regulated in Smad3-overexpressing arteries. Moreover, periadventitial administration of CTGF replicated the effect of medial Smad3 overexpression on adaptive remodelling and neointimal hyperplasia. CONCLUSION Medial gene transfer of Smad3 promotes adaptive remodelling by indirectly influencing the behaviour of adventitial fibroblasts. This arterial cell-cell communication is likely to be mediated by Smad3-dependent production of CTGF.

Perineal and lower extremity reconstruction.

Learning Objectives: After reading this article, the participant should be able to: 1. Perform a preoperative assessment of patients undergoing perineal and lower extremity reconstruction. 2. Describe the various tissue flaps used to perform these reconstructions and the advantages and disadvantages of each. 3. Provide appropriate postoperative care and interventions to maximize outcomes. Background: The lower extremity and perineum provide the foundation for upright posture and ambulation. These areas are made up of intricate contours with variable skin types and must withstand the functional demands of organ orifice support and weight-bearing forces. Successful reconstruction calls for careful preoperative planning and consideration of the site-specific demands. Methods: The authors reviewed literature regarding the most current treatment strategies for lower extremity and perineal reconstruction. Results: Perineal reconstruction is typically related to genitourinary or digestive tract abnormalities, mainly malignancies. Local and regional flaps are the mainstay of therapy, depending on their availability and the need for adjuvant therapy. Postoperatively, pressure reduction and closed-suction drainage are of major consideration. The lower extremities are prone to trauma, and these wounds often involve underlying and exposed bony abnormalities, and this must be considered in operative planning. Significant defects may be reconstructed with local or regional flaps and free-tissue transfer. The location of the wound and extent of surrounding tissue compromise are of major concern when determining flap coverage. Postoperatively, transition to ambulation and weight-bearing status is paramount. Conclusions: Reconstruction of the lower extremity and perineum requires recognition of the high functional demands of these areas. Local and regional flaps and free tissue transfer allow reconstruction of complex wounds in these areas. Selecting the correct flap and navigating the postoperative recovery to arrive at functional restoration remain a significant challenge.

Roux-en-Y Reconstruction After Pancreaticoduodenectomy

HYPOTHESIS Roux-en-Y reconstruction (RYR) is associated with a reduction in morbidity and mortality associated with pancreatic anastomotic failure after pancreaticoduodenectomy compared with conventional loop reconstruction (CLR). DESIGN Retrospective study of patients from 1991 to 2006. SETTING Tertiary care center. PATIENTS Records of patients undergoing CLR (n = 588) and patients undergoing RYR (n = 112) between February 1, 1991, and June 30, 2006, for pancreatic ductal adenocarcinoma at a single institution were retrospectively reviewed and compared. MAIN OUTCOME MEASURES Perioperative outcome and mortality were compared for patients who underwent RYR compared with those who underwent CLR. RESULTS Overall, both groups required a similar rate of postoperative interventional radiology procedures (CLR, 6.8%; RYR, 9.8%; P = .24) and subsequent operations (CLR, 6.9%; RYR, 9.1%; P = .62). No significant difference was found in the rate of overall postoperative mortality (CLR, 2.6%; RYR, 0.9%; P = .49). The overall rate of pancreatic anastomotic failure was 7.2%, and pancreatic anastomotic failure was associated with a 6% mortality rate. Among patients who developed pancreatic anastomotic failure, no significant difference was seen between CLR (n = 32) and RYR (n = 16) in length of hospital stay (18 vs 19 days; P = .98) or postoperative mortality (3 patients [9.4%] vs none [0%]; P = .54). CONCLUSION We found that RYR is not associated with a reduction in morbidity after pancreaticoduodenectomy for pancreatic adenocarcinoma compared with CLR, even among patients who develop pancreatic anastomotic failure.

Endoluminal recanalization in a patient with phlegmasia cerulea dolens using a multimodality approach-a case report.

Phlegmasia cerulea dolens is a limb-threatening form of deep venous thrombosis and should be treated aggressively. The authors report a patient who presented with iliocaval and femoral deep venous thrombosis and posed an additional therapeutic challenge based on a recent history of heparin-induced thrombocytopenia. Catheter-directed pharmacologic thrombolysis and balloon venoplasty were applied in treatment. The direct thrombin inhibitor argatroban was used in place of heparin for concurrent anticoagulation. This multimodality endovascular approach (chemical and mechanical interventions) was successful in relieving the venous occlusion and salvaging the limb, while maintaining appropriate treatment for heparin-induced thrombocytopenia.

Tissue engraftment of hypoxic‐preconditioned adipose‐derived stem cells improves flap viability

Adipose‐derived stem cells (ASCs) have the ability to release multiple growth factors in response to hypoxia. In this study, we investigated the potential of ASCs to prevent tissue ischemia. We found conditioned media from hypoxic ASCs had increased levels of vascular endothelial growth factor (VEGF) and enhanced endothelial cell tubule formation. To investigate the effect of injecting rat ASCs into ischemic flaps, 21 Lewis rats were divided into three groups: control, normal oxygen ASCs (106 cells), and hypoxic preconditioned ASCs (106 cells). At the time of flap elevation, the distal third of the flap was injected with the treatment group. At 7 days post flap elevation, flap viability was significantly improved with injection of hypoxic preconditioned ASCs. Cluster of differentiation‐31‐positive cells were more abundant along the margins of flaps injected with ASCs. Fluorescent labeled ASCs localized aside blood vessels or throughout the tissue, dependent on oxygen preconditioning status. Next, we evaluated the effect of hypoxic preconditioning on ASC migration and chemotaxis. Hypoxia did not affect ASC migration on scratch assay or chemotaxis to collagen and laminin. Thus, hypoxic preconditioning of injected ASCs improves flap viability likely through the effects of VEGF release. These effects are modest and represent the limitations of cellular and growth factor‐induced angiogenesis in the acute setting of ischemia.