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Prepectoral implant-based breast reconstruction (IBR) has recently become the standard of care for many reconstructive surgeons and is often supplemented with coverage using acellular dermal matrix(ADM). However, more clinical data examining the use of ADM in breast reconstruction are needed. The present study compares complications and patient-reported outcomes(PROs) between three different types of ADM used in IBR.We performed a retrospective review of consecutive patients who underwent immediate prepectoral IBR from January 2018 through December 2019. Surgical outcomes and PROs (using the BREAST-Q) were compared between the Alloderm, Surgimend, and Dermacell ADMs.Overall, 557 breasts (383 patients) were included (78.6% Alloderm, 14% Surgimend, and 7.4% Dermacell). Patients in the Dermacell group were older (p=0.001) and more likely to have diabetes mellitus (p=0.001) compared to Alloderm and Surgimend patients. Other patient characteristics were similar between the three groups. The overall complication rate was equivalent between the three ADM groups (Alloderm 27% vs. Surgimend 33% vs. Dermacell 39%; p=0.209). Multivariable frailty models demonstrated that the type of ADM was not significantly associated with overall complications, infection, major complications, or device explantation. BREAST-Q satisfaction with the breast, psychosocial well-being, and sexual well-being were also similar between the three ADM groups (p=0.109, p=0.439, p=0.152, respectively).We found that three of the most commonly used ADMs in the United States have similar surgical outcomes and PROs when used for prepectoral IBR. No significant differences in infection, overall complication, and device removal rates were identified between Alloderm, Surgimend, and Dermacell.

Background With the increased use of acellular dermal matrix (ADM) in breast reconstruction, the number of available materials has increased. There is a relative paucity of high-quality outcomes data for use of different ADMs. Objectives The goal of this study was to compare the outcomes between a human (HADM) and a bovine ADM (BADM) in implant-based breast reconstruction. Methods A prospective, single-blinded, randomized controlled trial was conducted to evaluate differences in outcomes between HADM and BADM for patients undergoing immediate tissue expander breast reconstruction. Patients with prior radiation to the index breast were excluded. Patient and surgical characteristics were collected and analyzed. Results From April 2011 to June 2016, a total of 90 patients were randomized to a mesh group, with 68 patients (HADM, 36 patients/55 breasts; BADM, 32 patients/48 breasts) included in the final analysis. Baseline characteristics were similar between the 2 groups. No significant differences in overall complication rates were identified between HADM (n = 14, 25%) and BADM (n = 13, 27%) (P = 0.85). Similar trends were identified for major complications and complications requiring reoperation. Tissue expander loss was identified in 7% of HADM patients (n = 4) and 17% of BADM patients (n = 8) (P = 0.14). Conclusions Similar complication and implant loss rates were found among patients undergoing immediate tissue expander breast reconstruction with HADM or BADM. Regardless of what material is used, careful patient selection and counseling, and cost consideration, help to improve outcomes and sustainability in immediate breast reconstruction. Level of Evidence: 2

Muscle flaps must have a strong vascular network to support a large tissue volume and ensure successful engraftment. We developed porcine stomach musculofascial flap matrix (PDSF) comprising extracellular matrix (ECM) and intact vasculature. PDSF had a dominant vascular pedicle, microcirculatory vessels, a nerve network, well-retained 3-dimensional (3D) nanofibrous ECM structures, and no allo- or xenoantigenicity. In-depth proteomic analysis demonstrated that PDSF was composed of core matrisome proteins (e.g., collagens, glycoproteins, proteoglycans, and ECM regulators) that, as shown by Gene Ontology term enrichment analysis, are functionally related to musculofascial biological processes. Moreover, PDSF-human adipose-derived stem cell (hASC) synergy not only induced monocytes towards IL-10-producing M2 macrophage polarization through the enhancement of hASCs' paracrine effect but also promoted the proliferation and interconnection of both human skeletal muscle myoblasts (HSMMs) and human umbilical vein endothelial cells (HUVECs) in static triculture conditions. Furthermore, PDSF was successfully prevascularized through a dynamic perfusion coculture of hASCs and HUVECs, which integrated with PDSF and induced the maturation of vascular networks

Background Type 1 internal hemipelvectomies and total sacrectomies cause significant biomechanical instability, demanding pelvic ring reconstruction for ambulation and torso support. Previously described methods include autografts, allografts, and implants, commonly with poor long-term outcomes. The authors hypothesized that the free fibula flap for spinopelvic reconstruction is safe and effective, and associated with a high bony union rate and superior functional outcomes. Methods The authors performed a retrospective review of all patients who underwent free fibula flap surgery after internal hemipelvectomy or total sacrectomy at M. D. Anderson Cancer Center from 2003 to 2018. The primary outcome was radiographic evidence of bony union. Secondary outcomes included surgical-site occurrence and lower extremity function. Univariate and multivariate logistic regression analyses were performed. Results Forty-seven patients were included (internal hemipelvectomy, n = 38; total sacrectomy, n = 9). The mean follow-up was 3.3 years and the most common abnormality was chondrosarcoma (30.4 percent). The nonunion rate was 9.7 percent and the surgical-site occurrence rate was 34 percent; there were no flap losses. Greater age was significantly associated with nonunion (OR, 1.1; 95 percent CI, 1 to 1.2; p = 0.003), whereas obesity was the only independent predictor of surgical-site occurrence (OR, 9.2; 95 percent CI, 1.2 to 71.3; p = 0.03). Functional metrics approached those of adult norms by 3 years postoperatively. Compared to internal hemipelvectomy patients, patients undergoing total sacrectomy had more comorbidities, a higher complication rate, and a worse functional outcome. Conclusion The free fibula flap for spinopelvic reconstruction is safe and effective, and is associated with a high bony union rate and superior functional outcomes. Clinical question/level of evidence Risk, III.

Objective To summarize the multi-specialty strategy and initial guidelines of a Case Review Committee in triaging oncologic surgery procedures in a large Comprehensive Cancer Center and to outline current steps moving forward after the initial wave. Summary of background data The impetus for strategic rescheduling of operations is multifactorial and includes our societal responsibility to minimize COVID-19 exposure risk and propagation among patients, the healthcare workforce, and our community at large. Strategic rescheduling is also driven by the need to preserve limited resources. As many states have already or are considering to re-open and relax stay-at-home orders, there remains a continued need for careful surgical scheduling because we must face the reality that we will need to co-exist with COVID-19 for months, if not years. Methods The quality officers, chairs, and leadership of the 9 surgical departments in our Division of Surgery provide specialty-specific approaches to appropriately triage patients. Results We present the strategic approach for surgical rescheduling during and immediately after the COVID-19 first wave for the 9 departments in the Division of Surgery at The University of Texas MD Anderson Cancer Center in Houston, Texas. Conclusions Cancer surgeons should continue to use their oncologic knowledge to determine the window of opportunity for each surgical procedure, based on tumor biology, preoperative treatment sequencing, and response to systemic therapy, to safely guide patients through this cautious recovery phase.

BACKGROUND Locally advanced malignancies of the upper torso and shoulder girdle (UT-SG) necessitate extensive resection and complex reconstruction. Due to the infrequent nature of these operations, a global reconstructive algorithm has not been defined. METHODS A retrospective review of all patients who received reconstructive surgery following malignant tumor extirpation in the UT-SG from 2008 to 2018 at the University of Texas MD Anderson Cancer Center. Factors predicting the need for flap reconstruction and risk for postoperative complications were evaluated. RESULTS In total, 252 procedures met inclusion criteria. The most common pathology was sarcoma (76%) and 52% were primary tumors. The median defect area was 112 cm2 (range 4-1350 cm2 ). Reconstructive techniques included pedicled flaps (46%), local tissue rearrangement (38%), and free flaps (16%). On univariate analysis, the probability of needing a free flap increased 39% when the defect size increased by 100 cm2 . The strongest independent predictors of requiring a free flap were major vessel exposure (adjusted odds ratio [OR] = 4.92, 95% confidence interval [CI], 1.36-17.84, P = .015) and major peripheral nerve exposure (adjusted OR = 3.2, 95% CI, 1.1-9.2, P = .031). CONCLUSION Despite the aggressive nature of their malignancies, patients requiring an UT-SG resection demonstrate high survival rates and therefore demand a durable reconstruction. Exposed critical structures and defect size were predictive of free tissue transfer.

Background Oncologic resections involving both the spine and chest wall commonly require immediate soft tissue reconstruction to eliminate dead space and protect spinal instrumentation and vital neurovascular structures. We hypothesized that reconstructions of composite resections involving both the thoracic spine and chest wall would have a higher complication rate than reconstructions for resections limited to the thoracic spine alone. Methods We performed a retrospective analysis of all consecutive patients who underwent a thoracic vertebrectomy and soft tissue reconstruction from 2002 to 2017. Patients were divided into two groups: those whose defect was limited to the thoracic spine (TS) and those who also required chest wall resection (TS+CW). Results One hundred patients were included (TS: n=53 vs TS+CW: n=47). TS+CW patients had larger resections, as indicated by a greater incidences of multi-level vertebrectomies (70.2% vs. 17%; p=0.001) and instrumentation of more than 6 vertebral levels (76.6% vs. 26.4%; p=0.001). TS patients were older (58.2 α 10.4 vs 48.6 α 13.9 years; p 1 comorbidity (96.2% vs. 74.5%; p=0.002), and had a greater incidence of metastatic disease (88.7% versus 38.3%; p=0.001). Univariate and multivariate logistic regression analyses demonstrated that composite resections were not significantly associated with a higher rate of surgical, medical, or overall complications. Multivariate logistic regression analysis of the TS+CW subgroup demonstrated that flap separation of the spinal cord from the intrapleural space was protective against complications (odds ratio [OR]=0.22, 95% CI 0.05-0.81; p=0.03). Conclusions Despite the large defect size in TS+CW patients, there was no increase in complications compared to TS patients. In TS+CW patients, separating the exposed spinal cord from the intrapleural space with well-vascularized soft tissue was protective against complications.

Navigating the rapidly evolving field of materials for soft tissue reinforcement is challenging given the volume of clinically available options. Additionally, the current generally accepted classifications of these mesh materials confound the understanding of their utility by grouping disparate materials that have attributes overlapping category boundaries and that do not fully consider their clinically functionality. This review article highlights, from a materials science perspective, the most important attributes of these materials to improve the clinical decision-making process in the selection of the most appropriate features and design for the patient, surgery and clinical need. These characteristics include the physical attributes that directly impact the surgical procedure and immediate postoperative mechanical requirements as well as the post-implantation properties such as an adequate reinforcement time, strength of the resulting tissue and infection risk profile.

Introduction Tumors involving the lacrimal drainage apparatus can be effectively treated with oncologic eye-sparing resection, immediate reconstruction, and adjuvant radiation. The extirpative technique is well described, whereas the reconstructive approach and outcomes are limited and largely anecdotal. The present study describes the largest series in the literature evaluating outcomes after reconstruction after globe-preserving oncologic resection. Methods A retrospective review was performed for all patients undergoing reconstruction after resection of lacrimal gland tumors from 2008 to 2019. Reconstruction and ophthalmologic outcomes were assessed. Results Of the 17 patients included, 2 underwent complex repair, 6 were reconstructed with a locoregional flap, and 9 underwent free flap reconstruction. All patients were treated with adjuvant radiation therapy. The median follow-up was 19 months (range, 5-126 months). Defects reconstructed with free flaps had lower rates of wound dehiscence and fistula formation compared with those reconstructed with other techniques (11% vs 25%, P = 0.45). Patients undergoing reconstruction with free tissue transfer also tended to have lower rates of ectropion, keratopathy and decreased visual acuity compared with those undergoing nonmicrosurgical reconstruction (33% vs 50%, P = 0.48; 11% vs 38%, P = 0.20; 56% vs 75%, P = 0.40, respectively). These differences were not statistically significant. Conclusions This is the first study to compare reconstructive and functional outcomes of nonmicrosurgical reconstruction and microsurgical free tissue transfer in the setting of eye-sparing surgery for tumors of the lacrimal drainage apparatus. Although various reconstructive options are feasible, microsurgical free tissue transfer is often used at our center and is associated with reliable outcomes.

Background With the current focus on value-based outcomes and reimbursement models, perioperative risk adjustment is essential. Specialty surgical outcomes are not well predicted by the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP); the Head and Neck-Reconstructive Surgery NSQIP was created as a specialty-specific platform for patients undergoing head and neck surgery with flap reconstruction. This study aims to investigate risk prediction models in these patients. Methods The Head and Neck-Reconstructive Surgery NSQIP collected data on patients undergoing head and neck surgery with flap reconstruction from August 1, 2012 to October 20, 2016. Multivariable logistic regression models were created for 9 outcomes (postoperative ventilator dependence, pneumonia, superficial recipient surgical site infection, presence of tracheostomy/nasoenteric (NE)/gastrostomy/gastrojejunostomy(G/GJ) tube 30 days postoperatively, conversion from NE to G/GJ tube, unplanned return to the operating room, length of stay > 7 days). External validation was completed with a more contemporary cohort. Results A total of 1095 patients were included in the modelling cohort and 407 in the validation cohort. Models performed well predicting tracheostomy, NE, G/GJ tube presence at 30 days postoperatively and conversion from NE to G/GJ tube (c-indices = 0.75–0.91). Models for postoperative pneumonia, superficial recipient surgical site infection, ventilator dependence > 48 h, and length of stay > 7 days were fair (concordance [c]-indices = 0.63–0.69). The predictive model for unplanned return to the operating room was poor (c-index = 0.58). Conclusions and relevance Reliable and discriminant risk prediction models were able to be created for postoperative outcomes using the specialty-specific Head and Neck-Reconstructive Surgery Specific NSQIP.

BACKGROUND Nonvascular bone grafts larger than 4 cm have a 50 percent nonunion rate in spine surgery. Vascular bone flaps are one potential solution; however, their utility in spine surgery has not been fully elucidated. The authors hypothesized that the addition of a free fibula flap after oncologic vertebrectomy would safely potentiate bone union. METHODS The authors performed a retrospective analysis, including all patients who underwent oncologic vertebrectomy for a primary bone tumor at their institution from 2002 to 2017. Patients were divided into two groups: those who underwent spinal reconstruction with nonvascularized bone graft and an alloplastic cage (control) and those whose reconstruction was augmented with a free fibula flap. RESULTS Forty patients were included (free fibula flap, n = 16; control, n = 24). Adjuvant therapies and medical comorbidities were similar between the two groups. Chordoma was the most common abnormality in both groups. The median number of vertebrae resected in the free fibula flap group was two, compared to one in the cage group (p = 0.08). Despite the smaller mean resection size, there were significantly more nonunions (41.7 percent versus 6.3 percent; p = 0.02), instrumentation complications (33.3 percent versus 6.3 percent; p = 0.04), and neurologic complications (25 percent versus 0 percent; p = 0.03) in the control group. Multivariate logistic regression revealed a control reconstruction significantly predictive of nonunion (OR, 57.04; 95 percent CI, 1.17 to 2773; p = 0.04). Free fibula flap patients demonstrated evidence of bony union at a mean of 4.8 months versus 22.4 months in the control group (p < 0.001). CONCLUSIONS Free fibula flap surgery in spinal reconstruction after oncologic vertebrectomy is safe and effective. Free fibula flap surgery is independently protective against nonunion and is associated with more rapid union compared with the control. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, III.

Background Reconstruction of partial breast defects in low-volume, nonptotic breasts can be challenging. The authors hypothesized that use of the latissimus dorsi flap in partial breast reconstruction is safe and associated with low complication and high patient satisfaction rates. Methods All patients who underwent breast-conserving therapy and latissimus dorsi flap reconstruction from January 1, 2006, to December 31, 2016, were identified in a prospectively maintained database. Patient demographics, tumor characteristics, and complications were recorded. Patient-reported outcomes were assessed with the BREAST-Q breast-conserving therapy module. A group of plastic surgeons and laypersons used a five-point Likert scale to evaluate aesthetic outcomes in representative patients. Results Forty-seven patients met the inclusion criteria. Median follow-up was 5.4 years. Most patients (93.6 percent) underwent immediate reconstruction. The mean resection volume was 219.5 cc (range, 70 to 877 cc). The overall complication rate was 8.5 percent. Grade 2 or 3 ptosis (OR, 1.21; 95 percent CI, 1.0 to 1.46; p = 0.03), smoking (OR, 13.1; 95 percent CI, 1.2 to 143.2; p = 0.03), and multicentric tumor (OR, 1.23; 95 percent CI, 1.04 to 1.64; p = 0.02) were associated with a higher complication rate. Ductal carcinoma in situ was associated with reoperation for positive margins (OR, 14.4; 95 percent CI, 2.1 to 100; p = 0.009). Of particular interest, patient-reported outcomes were favorable, with the highest rated domains being Satisfaction with Breasts (61; interquartile range, 37 to 77), Psychosocial Well-being (87; interquartile range, 63 to 100), and Physical Well-being (87; interquartile range, 81 to 100). The median aesthetic score was 4 (of 5). Conclusions This is the first study to date using the BREAST-Q to assess patient-reported outcomes associated with the latissimus dorsi flap for partial breast reconstruction. The flap is safe and effective for reconstruction in the setting of breast-conserving therapy, providing aesthetically pleasing results with high patient satisfaction. Clinical question/level of evidence Therapeutic, IV.

Pharyngo-esophageal and tracheostomal defects pose a challenge in head and neck reconstruction whenever microanastomosis is extremely difficult in hostile neck that is previously dissected and irradiated. The deltopectoral (DP) flap was initially described as a pedicled flap for such reconstruction with acceptable postoperative results. A major drawback is still that the DP flap is based on 3 perforator vessels leading to a decreased arc of rotation. The DP flap also left contour deformities in the donor site. The internal mammary artery perforator flap was described as a refinement of the deltopectoral flap. It is a pedicled fasciocutaneous flap based on a single perforator, with comparable and reliable blood supply compared with the DP flap, giving it the benefit of having a wide arc of rotation. It is both thin and pliable, with good skin color match and texture. The donor site can be closed primarily with no esthetic deformity and minimal morbidity. The procedure is relatively simple and does not require microvascular expertise. In this report, the authors describe a patient in whom bilateral internal mammary artery perforator flaps were used for subtotal pharyngo-esophageal reconstruction and neck resurfacing. The flaps healed uneventfully bilaterally with no postoperative complications.

Background: The clinical results with extracellular matrix biomaterials are confounded by expectations of material response based on years of experience with permanent or degradable synthetic polymers. However, the remodeling or assimilation of extracellular matrix biomaterials is dictated by cell-mediated processes rather than fibrous encapsulation or hydrolytic degradation. Previously, we found that tissue adherence and revascularization were dictated by proximity with de-epithelialized host tissue. We now investigate the effects of polymer and fixation type on attachment strength and rate of cell repopulation in an intra-abdominal implant model. Methods: An intra-abdominal implant model in rats was used to probe assimilation properties at 4 weeks and 12 weeks with permanent and degradable suture types as well a combination of suture and biologic attachment (mesothelial abrasion). The mechanical strength of the attachment was measured by peel testing and the repopulation by automated cell counting of histologic sections. Results: The intensity of the biologic response was greater with degradable polymers than permanent polypropylene. Tissue attachment strength ranged from 2 to 15 N but changed in elasticity with time. The magnitude and distribution of cell repopulation was highly variable by suture type but ultimately did not affect the long-term strength of the soft tissue attachment. Conclusions: The tissue approximating polymer sutures were stretchy and of similar strength regardless of degradation rate or polymer type. The strongest attachment, most rapid repopulation of the deep matrix regions, and most uniform distribution of cells were found with the addition of biologic attachment.

Despite advances in surgical training, microsurgery is still based on an apprenticeship model. To evaluate skill acquisition and apply targeted feedback to improve their training model, the authors applied the Structured Assessment of Microsurgery Skills to the training of microsurgical fellows. They hypothesized that subjects would demonstrate measurable improvement in performance throughout the study period and consistently across evaluators.Seven fellows were evaluated during 118 microsurgical cases by 16 evaluators over three 1-month evaluation periods in 1 year (2010 to 2011). Evaluators used the Structured Assessment of Microsurgery Skills questionnaire, which measures dexterity, visuospatial ability, operative flow, and judgment. To validate the data, microsurgical anastomoses in rodents performed by the fellows in a laboratory at the beginning and end of the study period were evaluated by five blinded plastic surgeons using the same questionnaire. Primary outcomes were change in scores between evaluation periods and interevaluator reliability.Between the first two evaluation periods, all skill areas and overall performance improved significantly. Between the second two periods, most skill areas improved, but only a few improved significantly. Operative errors decreased significantly between the first and subsequent periods (81 versus 36; p0.05). In the laboratory study, all skills were significantly (p0.05) or marginally (0.05 ≤ p0.10) improved between time points. The overall interevaluator reliability of the questionnaire was acceptable (α = 0.67).The Structured Assessment of Microsurgery Skills questionnaire is a valid instrument for assessing microsurgical skill, providing individualized feedback with acceptable interevaluator reliability. Use of the questionnaire is anticipated to enhance microsurgical training.

The purpose of this study was to determine the optimal timing of delayed abdominal free flap breast reconstruction following postmastectomy radiation therapy. The authors evaluated the association between timing of delayed abdominal free flap breast reconstruction following postmastectomy radiation therapy and postoperative complications.The authors reviewed a prospectively maintained database of delayed abdominal free flap breast reconstruction performed between July of 2005 and December of 2009. Data regarding demographics, operative variables, and clinical outcomes were collected. Patients were classified as having undergone reconstruction less than 12 months after postmastectomy radiation therapy (group I) or 12 months or more after postmastectomy radiation therapy (group II). Complications were compared between groups, including microvascular thrombosis, flap loss, reoperation, wound dehiscence, and fat necrosis.One hundred eighty-nine patients were identified, 82 (43.4 percent) in group I and 107 (56.6 percent) in group II. The total flap loss rate was 2.6 percent, with all flap losses occurring in group I (p = 0.014). The reoperation rate was higher in group I (14.6 percent versus 4.7 percent; p = 0.022). In addition, group I patients trended toward a higher incidence of microvascular thrombosis, infection, and wound dehiscence.Patients who underwent delayed abdominal free flap breast reconstruction after 12 months from the completion of postmastectomy radiation therapy developed fewer complications, including microvascular thrombosis and total flap loss, than those who underwent delayed abdominal free flap breast reconstruction within 12 months of completing postmastectomy radiation therapy. Allowing an interval of 12 months between the completion of postmastectomy radiation therapy and delayed abdominal free flap breast reconstruction will likely minimize complications and optimize outcomes in free flap breast reconstruction in patients receiving postmastectomy radiation.

240 Background: With increasing health care costs, risk-adjusted quality outcomes are essential. The American College of Surgeons – National Surgical Quality Improvement Program (ACS-NSQIP) is a robust perioperative risk-adjustment platform, but lacks capture of oncologic- and specialty-specific variables and has limited utility for risk adjustment in head and neck oncologic surgery. This study uses the specialty-specific Head and Neck-Reconstructive Surgery (HNSR) NSQIP to develop risk-adjusted models for patients undergoing head and neck oncologic surgery with reconstruction. Methods: Multiple logistic regression modelling using data from patients in the HNSR NSQIP between 8/2012-10/2016 identified predictors of postoperative morbidity. Final models were validated using a cohort of patients treated between 10/2016-12/2017. The concordance index (c-index) was used to evaluate the model performance. Results: The modelling cohort included 1095 patients and the validation cohort included 407. Models were created to predict probability of postoperative complications (presence of fistula, ventilator dependence > 48 hours, pneumonia, deep/superficial surgical site infection); presence of gastrostomy-jejunostomy (GJ), nasoenteric (NE), or tracheostomy tube at 30 days postoperatively; conversion from NE to GJ tube; unplanned return to the operating room; and length of stay > 7 days. Most discriminant models were those predicting presence of GJ tube (model c-index [MCI] = 0.91; validation c-index[VCI] = 0.93), NE tube (MCI= 0.83; VCI= 0.84), and conversion from NE to GJ tube (MCI= 0.86; VCI= 0.80). Prediction models were least discriminant for ventilator dependence (MCI= 0.63; VCI= 0.45), fistula (MCI= 0.58; VCI= 0.54), and unplanned return to the operating room (MCI= 0.59; VCI= 0.51). Conclusions: Reliable and discriminant risk prediction models were able to be created for a variety of perioperative complications incorporating oncologic- and specialty-specific variables in the HNSR NSQIP. These models help inform risk stratification strategies for patients undergoing head and neck reconstructive surgery and the development of a specialty-specific preoperative risk calculators.

Chest wall resection is indicated most often for primary chest wall tumors but may also be required for solitary metastases, infection, or for resection of devitalized tissue following radiation. Whether the chest wall defect is reconstructed with prosthetic material or not depends on its size and location. Resections >25 cm2 or resection of four or more ribs generally require some sort of rigid or flexible or prosthetic material in order to preserve chest wall mechanics. In most instances, it is ideal to cover any prosthetic material with healthy, well-vascularized tissue, which mitigates severe consequences if wound separation, breakdown, or infection were to occur. There are a variety of pedicled muscle flaps that can be rotated to cover most chest wall defects, of which the most commonly used are the pectoralis major and the latissimus dorsi. Both are easily harvested by general thoracic surgeons. Lesser used muscle flaps such as the rectus abdominis, external oblique and trapezius or flaps that require free tissue transfer usually require the expertise of a reconstructive surgeon. Thus, it is ideal to manage larger chest wall reconstructions in a multidisciplinary approach. Though frequently used for intrathoracic translocation, the omentum is less utilized for chest wall coverage, however, it can be a useful second option in cases where rotational muscle flaps are not available or have failed. This review will describe the flaps commonly used for chest wall reconstruction.

Placental development initially occurs in a low-oxygen (O2) or hypoxic environment. In this report we show that two hypoxia-inducible factors (HIFs), HIF1 and HIF2, are essential for determining murine placental cell fates. HIF is a heterodimer composed of HIF and HIF (ARNT) subunits. Placentas from Arnt / and Hif1 / Hif2 / embryos exhibit defective placental vascularization and aberrant cell fate adoption. HIF regulation of Mash2 promotes spongiotrophoblast differentiation, a prerequisite for trophoblast giant cell differentiation. In the absence of Arnt or Hif, trophoblast stem cells fail to generate these cell types and become labyrinthine trophoblasts instead. Therefore, HIF mediates placental morphogenesis, angiogenesis, and cell fate decisions, demonstrating that O2 tension is a critical regulator of trophoblast lineage determination. This novel genetic approach provides new insights into the role of O2 tension in the development of life-threatening pregnancy-related diseases such as preeclampsia. Defective placentation is implicated as one of the causes of preeclampsia, a pregnancy-associated disease that affects 4 to 5% of all births and a major cause of maternal and neonatal mortality (49). Women with preeclampsia suffer from edema, hypertension, and proteinuria. Preeclamptic placentas display shallow invasion of cytotrophoblasts (trophectoderm derivatives of the placenta) into the uterus, fewer numbers of invasive cytotrophoblasts, and maternal spiral arteries that have not been converted into enlarged vessels. These pathologies lead to reduced placental blood flow and placental hypoxia (16, 49). Physiological hypoxia may also play an important role in directing placental development. Therefore, delineating the role of O2 tension in trophoblast differentiation during placentation will enable us to better understand and treat pregnancyrelated diseases. Furthermore, mouse models of preeclampsia resulting in intrauterine growth retardation will allow us to genetically define pathways that are involved in both placental development and pathologies. Murine placental development is similar to that of human embryos. The three layers of the chorioallantoic placenta form between embryonic day 9.0 (E9.0) and E10.0. The layer closest to the embryo, the labyrinthine layer, develops when fetal blood vessels from the allantoic mesoderm invade the chorion (Fig. 1A). Fetal blood vessel invasion instructs chorionic trophoblast precursors to differentiate by fusion into syncytiotrophoblasts (38). Labyrinthine fetal and maternal blood vessels become interdigitated in order to facilitate O2, nutrient, and waste exchange (14). Trophoblasts from the polar trophecto

The ubiquitously expressed basic helix–loop–helix (bHLH)-PAS protein ARNT ( a rylhydrocarbon r eceptor n uclear t ransporter) forms transcriptionally active heterodimers with a variety of other bHLH-PAS proteins, including HIF-1α ( h ypoxia- i nducible f actor-1α) and AHR ( a ryl h ydrocarbon r eceptor). These complexes regulate gene expression in response to hypoxia and xenobiotics, respectively, and mutation of the murine Arnt locus results in embryonic death by day 10.5 associated with placental, vascular, and hematopoietic defects. The closely related protein ARNT2 is highly expressed in the central nervous system and kidney and also forms complexes with HIF-1α and AHR. To assess unique roles for ARNT2 in development, and reveal potential functional overlap with ARNT, we generated a targeted null mutation of the murine Arnt2 locus. Arnt2 −/− embryos die perinatally and exhibit impaired hypothalamic development, phenotypes previously observed for a targeted mutation in the murine bHLH-PAS gene Sim1 (Single-minded 1), and consistent with the recent proposal that ARNT2 and SIM1 form an essential heterodimer in vivo [Michaud, J. L., DeRossi, C., May, N. R., Holdener, B. C. & Fan, C. (2000) Mech. Dev. 90, 253–261]. In addition, cultured Arnt2 −/− neurons display decreased hypoxic induction of HIF-1 target genes, demonstrating formally that ARNT2/HIF-1α complexes regulate oxygen-responsive genes. Finally, a strong genetic interaction between Arnt and Arnt2 mutations was observed, indicating that either gene can fulfill essential functions in a dose-dependent manner before embryonic day 8.5. These results demonstrate that Arnt and Arnt2 have both unique and overlapping essential functions in embryonic development.

A two-fold difference in X chromosome dosage distinguishes males (XO) and hermaphrodites (XX) of the nematode Caenorhabditis elegans at the beginning of embryogenesis. As adults, individuals of the two sexes differ in size, anatomy, and behavior. About one-third of their somatic cells express sex-specific characteristics. How the X chromosome to autosome (X : A) ratio determines sex has been the subject of detailed genetic investigation (for review, see Meyer 1997). These studies have defined a regulatory pathway that transduces information about the X : A ratio to a gene known as tra-1. In all somatic tissues, tra-1 activity is necessary and sufficient to promote female differentiation (Hodgkin 1987). Inhibition of tra-1 activity results in male development. The tra-1 gene encodes a zinc finger transcription factor, TRA-1A, that is related to Drosophila Ci and the Gli proteins of vertebrates (Zarkower and Hodgkin 1992). Few targets of TRA-1A have been identified, but in at least two cell types, TRA-1A represses genes that would otherwise cause adoption of male-specific fates. The survival of the HSN neurons, which are required for egg laying in hermaphrodites, depends on the repression of the egl-1 gene by TRA-1A (Conradt and Horvitz 1999). Similarly, vitellogenin synthesis by intestinal cells in the hermaphrodite requires that TRA-1A repress the mab-3 gene (Yi et al. 2000). The role of tra-1 in the germ line is less well understood. Mutants lacking tra-1 activity, whether XX or XO, often exhibit limited spermatogenesis followed by oogenesis, suggesting that tra-1 is needed to sustain spermatogenesis (Schedl et al. 1989). On the other hand, strong gain-of-function alleles of tra-1 completely feminize the germ line, indicating that unregulated tra-1 activity can suppress spermatogenesis (Hodgkin 1980; 1987). Recent observations suggesting that TRA-1A may serve as both an activator and a repressor of the fog-3 gene, which is required for spermatogenesis, reinforce the idea that the function of tra-1 in the germ line is complex (Chen and Ellis 2000). Negative regulation plays a prominent role in C. elegans sex determination (Fig. ​(Fig.1A).1A). Thus, male development in XO animals requires the inhibition of tra-1 activity by three fem genes (Doniach and Hodgkin 1984; Kimble et al. 1984; Hodgkin 1986). In XX animals, the tra-2 and tra-3 genes indirectly activate tra-1 by inhibiting fem activity. Support for this model comes from the observation that mutational inactivation of any of the fem genes renders tra-2 and tra-3 dispensable for female development. For example, both fem-1 mutants and tra-2; fem-1 double mutants develop as true females as a result of unregulated tra-1 activity (Doniach and Hodgkin 1984). Figure 1 Model of somatic sex determination in C. elegans. (A) Genetic pathway regulating somatic sex determination. Barred lines indicate negative interactions, and arrows indicate positive interactions. The X/A ratio controls X chromosome dosage compensation ... The major product of tra-2 is a large membrane protein known as TRA-2A (Fig. ​(Fig.1B)1B) (Kuwabara et al. 1992). A direct interaction between the intracellular domain of TRA-2A and FEM-3 inhibits the masculinizing activity of the FEM proteins, and although the mechanism of inhibition remains to be determined, this interaction would seem sufficient to explain the feminizing role of TRA-2A (Mehra et al. 1999). In support of this idea, overproduction of the intracellular domain of TRA-2A as a soluble protein in the somatic tissues of XO animals is strongly feminizing (Kuwabara and Kimble 1995; Mehra et al. 1999). A 1.8 kb mRNA specific to the hermaphrodite germ line can encode a second TRA-2 protein known as TRA-2B, which is equivalent to the intracellular domain of TRA-2A (Okkema and Kimble 1991; Kuwabara et al. 1998). Genetic evidence suggests that TRA-2B may limit the extent of spermatogenesis in the hermaphrodite. Because TRA-2B includes the entire FEM-3-binding domain of TRA-2A, it is reasonable to expect that TRA-2B might also act by binding to and inhibiting FEM-3. Although the mRNA encoding TRA-2B is restricted to the hermaphrodite germ line, a similar soluble protein might be produced in other tissues by cleavage of TRA-2A. The tra-3 gene, which acts at the same level in the sex-determining pathway as tra-2, encodes an atypical calpain protease (Barnes and Hodgkin 1996). When the two proteins are expressed together in insect cells, TRA-3 can cleave TRA-2A to release a fragment that includes part of the intracellular domain of TRA-2A (Sokol and Kuwabara 2000). This observation led to a suggestion that tra-3 might fulfill its role in sex determination by producing a soluble, FEM-3-binding fragment of TRA-2A. In this paper, we will use TRA-2c to refer to the intracellular domain of TRA-2A, whether it originates as part of TRA-2A or as TRA-2B. Interaction with FEM-3 is the only effector function of TRA-2 that has been defined to date. FEM-3 binding does not require the C-terminal 200 amino acids of TRA-2c, but genetic evidence suggests that this region is nevertheless important for TRA-2 activity. Doniach (1986) identified tra-2 alleles that cause germ line feminization, a phenotype associated with increased tra-2 activity. Some of these alleles, now known as tra-2(mx) alleles, are unusual in that although they feminize the XX germ line, they appear to reduce tra-2 activity in somatic tissues. All of the tra-2(mx) alleles carry missense mutations that alter the sequence of a 22-amino acid region near the C-terminal of TRA-2c, outside the FEM-3-binding domain (Kuwabara et al. 1998). It has been suggested that this “MX region” might represent a domain required for interaction with a negative regulator of tra-2 in the germ line. Here we report that TRA-2 directly interacts with TRA-1A and that the MX region of TRA-2 is critical for the interaction. The somatic effects of tra-2(mx) mutations and the results of overexpression experiments lead us to suggest that TRA-2 may promote somatic female development not only by inhibiting FEM-3, but also by directly stimulating the activity of TRA-1A. Mutations that alter either TRA-2 or TRA-1A so as to disrupt their interaction feminize the germ line. This observation raises the conundrum of why an interaction that enhances the feminizing activity of both proteins in somatic tissues should appear to have a role in hermaphrodite spermatogenesis.

Background Abdominal wall reconstruction with bioprosthetic mesh is associated with lower rates of mesh infection, fistula formation, and mesh explantation than reconstruction with synthetic mesh. The authors directly compared commonly used bioprosthetic meshes in terms of clinical outcomes and complications. Methods A database of consecutive patients who underwent abdominal wall reconstruction with porcine or bovine acellular dermal matrix and midline musculofascial closure at their institution between January of 2008 and March of 2011 was reviewed. Surgical outcomes were compared. Results One hundred twenty patients were identified who underwent a nonbridged, inlay abdominal wall reconstruction with porcine [69 patients (57.5 percent)] or bovine acellular dermal matrix (51 patients (42.5 percent)]. The mean follow-up time was 21.0 ± 9.9 months. The overall complication rate was 36.6 percent; the porcine matrix group had a significantly higher complication rate (44.9 percent) than the bovine matrix group (25.5 percent; p = 0.04) and statistically equivalent surgical complications (29.2 percent versus 21.6 percent; p = 0.34). There were no significant differences in rates of recurrent hernia (2.9 percent versus 3.9 percent; p = 0.99) or bulge (7.2 percent versus 0 percent; p = 0.07). However, the rate of intraoperative adverse events in the porcine matrix group [seven events (10.1 percent)] was significantly higher than that in the bovine matrix group (0 percent; p = 0.02). Conclusions In patients who undergo complex abdominal wall reconstruction, both bovine and porcine acellular dermal matrix are associated with similar rates of postoperative surgical complications and appear to result in similar outcomes. Porcine acellular dermal matrix may be prone to intraoperative device failure. Clinical question/level of evidence Therapeutic, III.

We examine the role of the conformational restriction imposed by constrained ends of a protein loop on the determination of a strained loop conformation. The Lys 116-Pro 117 peptide bond of staphylococcal nuclease A exists in equilibrium between the cis and trans isomers. The folded protein favors the strained cis isomer with an occupancy of 90%. This peptide bond is contained in a solvent-exposed, flexible loop of residues 112-117 whose ends are anchored by Val 111 and Asn 118. Asn 118 is constrained by 2 side-chain hydrogen bonds. We investigate the importance of this constraint by replacing Asn 118 with aspartate, alanine, and glycine. We found that removing 1 or more of the hydrogen bonds observed in Asn 118 stabilizes the trans configuration over the cis configuration. By protonating the Asp 118 side chain of N118D through decreased pH, the hydrogen bonding character of Asp 118 approached that of Asn 118 in nuclease A, and the cis configuration was stabilized relative to the trans configuration. These data suggest that the rigid anchoring of the loop end is important in establishing the strained cis conformation. The segment of residues 112-117 in nuclease A provides a promising model system for study of the basic principles that determine polypeptide conformations. Such studies could be useful in the rational design or redesign of protein molecules.

Proapoptotic Bcl-2 family members have been proposed to play a central role in regulating apoptosis. However, mice lacking bax display limited phenotypic abnormalities. As presented here, bak −/− mice were found to be developmentally normal and reproductively fit and failed to develop any age-related disorders. However, when Bak-deficient mice were mated to Bax-deficient mice to create mice lacking both genes, the majority of bax −/− bak −/− animals died perinatally with fewer than 10% surviving into adulthood. bax −/− bak −/− mice displayed multiple developmental defects, including persistence of interdigital webs, an imperforate vaginal canal, and accumulation of excess cells within both the central nervous and hematopoietic systems. Thus, Bax and Bak have overlapping roles in the regulation of apoptosis during mammalian development and tissue homeostasis.

Although most cells undergo growth arrest during hypoxia, endothelial cells and placental cytotrophoblasts proliferate in response to low O(2). We demonstrate that proliferation of embryonic multilineage hematopoietic progenitors is also regulated by a hypoxia-mediated signaling pathway. This pathway requires HIF-1 (HIF-1alpha/ARNT heterodimers) because Arnt(-/-) embryoid bodies fail to exhibit hypoxia-mediated progenitor proliferation. Furthermore, Arnt(-/-) embryos exhibit decreased numbers of yolk sac hematopoietic progenitors. This defect is cell extrinsic, is accompanied by a decrease in ARNT-dependent VEGF expression, and is rescued by exogenous VEGF. Therefore, "physiologic hypoxia" encountered by embryos is essential for the proliferation or survival of hematopoietic precursors during development.

Summary Hypoxia inducible factors (HIFs) regulate adaptive responses to changes in oxygen (O 2 ) tension during embryogenesis, tissue ischemia, and tumorigenesis. Because HIF-deficient embryos exhibit a number of developmental defects, the precise role of HIF in early vascular morphogenesis has been uncertain. Using para-aortic splanchnopleural (P-Sp) explant cultures, we show that deletion of the HIF-β subunit (ARNT) results in defective hematopoiesis and the inhibition of both vasculogenesis and angiogenesis. These defects are rescued upon the addition of wild-type Sca-1 + hematopoietic cells or recombinant VEGF. Arnt −/− embryos exhibit reduced levels of VEGF protein and increased numbers of apoptotic hematopoietic cells. These results suggest that HIF coordinates early endothelial cell emergence and vessel development by promoting hematopoietic cell survival and paracrine growth factor production.