Jonathan M. Winograd

Breast reconstruction following nipple-sparing mastectomy: predictors of complications, reconstruction outcomes, and 5-year trends.

Background: Nipple-sparing mastectomy is increasingly used for treatment and prevention of breast cancer. Few data exist on risk factors for complications and reconstruction outcomes. Methods: A single-institution retrospective review was performed between 2007 and 2012. Results: Two hundred eighty-five patients underwent 500 nipple-sparing mastectomy procedures for breast cancer (46 percent) or risk reduction (54 percent). The average body mass index was 24, and 6 percent were smokers. The mean follow-up was 2.17 years. Immediate breast reconstruction (reconstruction rate, 98.8 percent) was performed with direct-to-implant (59 percent), tissue expander/implant (38 percent), or autologous (2 percent) reconstruction. Acellular dermal matrix was used in 71 percent and mesh was used in 11 percent. Seventy-seven reconstructions had radiotherapy. Complications included infection (3.3 percent), skin necrosis (5.2 percent), nipple necrosis (4.4 percent), seroma (1.7 percent), hematoma (1.7 percent), and implant loss (1.9 percent). Positive predictors for total complications included smoking (OR, 3.3; 95 percent CI, 1.289 to 8.486) and periareolar incisions (OR, 3.63; 95 percent CI, 1.850 to 7.107). Increasing body mass index predicted skin necrosis (OR, 1.154; 95 percent CI, 1.036 to 1.286) and preoperative irradiation predicted nipple necrosis (OR, 4.86; 95 percent CI, 1.0197 to 23.169). An inframammary fold incision decreased complications (OR, 0.018; 95 percent CI, 0.0026 to 0.12089). Five-year trends showed increasing numbers of nipple-sparing mastectomy with immediate reconstruction and more single-stage versus two-stage reconstructions (p < 0.05). Conclusions: Nipple-sparing mastectomy reconstructions have a low number of complications. Smoking, body mass index, preoperative irradiation, and incision type were predictors of complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Infection following implant-based reconstruction in 1952 consecutive breast reconstructions: salvage rates and predictors of success.

Background: Few studies address salvage rates for infection in implant-based breast reconstruction. An understanding of success rates and clinical predictors of failure may help guide management. Method: A retrospective analysis of multisurgeon consecutive implant reconstructions from 2004 to 2010 was performed. Results: Immediate implant-based reconstructions (n = 1952) were performed in 1241 patients. Ninety-nine reconstruction patients (5.1 percent) were admitted for breast erythema and had a higher incidence of smoking (p = 0.007), chemotherapy (p = 0.007), radiation therapy (p = 0.001), and mastectomy skin necrosis (p < 0.0001). There was no difference in age, body mass index, or acellular dermal matrix usage. With intravenous antibiotics, 25 (25.3 percent) reconstruction patients cleared the infection, whereas 74 (74.7 percent) underwent attempted operative salvage (n = 18) or explantation (n = 56). Patients who failed to clear infection had a higher mean white blood cell count at admission (p < 0.0001). Of the attempted operative salvage group, 12 cleared the infection with immediate implant exchange and six eventually lost the implant. Patients who failed implant salvage were more likely to have methicillin-resistant Staphylococcus aureus (p = 0.004). The total explantation rate was 3.2 percent. Following explantation, 32 patients underwent attempted secondary tissue expander insertion. Twenty-six were successful and six had recurrent infection and implant loss. There were no differences in time interval to tissue expander insertion between successful and unsuccessful secondary operations. Conclusions: Salvage with intravenous antibiotics and implant exchange was successful in 37.3 percent of patients. Smoking, irradiation, chemotherapy, and mastectomy skin necrosis were predictors for developing infection. Patients with a higher white blood cell count at admission and methicillin-resistant S. aureus were more likely to fail implant salvage. There was no association with time interval to tissue expander insertion and secondary explantation.(Plast. Reconstr. Surg. 131: 1223, 2013.) CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

The neurotrophin receptor p75NTR in Schwann cells is implicated in remyelination and motor recovery after peripheral nerve injury

The function of the p75NTR neurotrophin receptor (p75NTR) in nervous system regeneration is still controversial. Part of that controversy may be due to the fact that p75NTR is expressed by both neuronal and glial cell types and may have very distinct and even contradictory roles in each population. In this study, to elucidate the in vivo function of p75NTR in Schwann cells during remyelination after peripheral nerve injury, we established a new animal model for p75NTR‐deficient Schwann cell transplantation in nude mice. We performed quantitative assessments of the functional, histological, and electrophysiological recovery after sciatic nerve injury, and compared them with those of the p75NTR(+/+) Schwann cell transplanted animals. At 7–10 weeks after injury, the motor recovery in the p75NTR(−/−) Schwann cell transplanted animals was significantly impaired compared with that in the p75NTR(+/+) Schwann cell transplanted animals. The lower number of the retrogradely labeled motoneurons and the hypomyelination in the p75NTR(−/−) Schwann cell transplanted animals were evident at 6 and 10 weeks after injury. At 10 weeks after injury, the radial growth in the axon caliber was also impaired in the p75NTR(−/−) Schwann cell transplanted animals. Measurement of the amount of myelin proteins and the nerve conduction velocity at 10 weeks after injury reflected these results. In summary, the p75NTR expression in Schwann cells is important for remyelination process, and the motor recovery after injury is impaired due to impaired axonal growth, remyelination, and radial growth in the axon calibers.

In vivo evaluation of demyelination and remyelination in a nerve crush injury model

Nerves of the peripheral nervous system have, to some extent, the ability to regenerate after injury, particularly in instances of crush or contusion injuries. After a controlled crush injury of the rat sciatic nerve, demyelination and remyelination are followed with functional assessments and imaged both ex vivo and in vivo over the course of 4 weeks with video-rate coherent anti-Stokes Raman scattering (CARS) microscopy. A new procedure compatible with live animal imaging is developed for performing histomorphometry of myelinated axons. This allows quantification of demyelination proximal and remyelination distal to the crush site ex vivo and in vivo respectively.

Augmenting peripheral nerve regeneration using stem cells: A review of current opinion

Outcomes following peripheral nerve injury remain frustratingly poor. The reasons for this are multifactorial, although maintaining a growth permissive environment in the distal nerve stump following repair is arguably the most important. The optimal environment for axonal regeneration relies on the synthesis and release of many biochemical mediators that are temporally and spatially regulated with a high level of incompletely understood complexity. The Schwann cell (SC) has emerged as a key player in this process. Prolonged periods of distal nerve stump denervation, characteristic of large gaps and proximal injuries, have been associated with a reduction in SC number and ability to support regenerating axons. Cell based therapy offers a potential therapy for the improvement of outcomes following peripheral nerve reconstruction. Stem cells have the potential to increase the number of SCs and prolong their ability to support regeneration. They may also have the ability to rescue and replenish populations of chromatolytic and apoptotic neurons following axotomy. Finally, they can be used in non-physiologic ways to preserve injured tissues such as denervated muscle while neuronal ingrowth has not yet occurred. Aside from stem cell type, careful consideration must be given to differentiation status, how stem cells are supported following transplantation and how they will be delivered to the site of injury. It is the aim of this article to review current opinions on the strategies of stem cell based therapy for the augmentation of peripheral nerve regeneration.

Rapid, effective, and long‐lasting behavioral recovery produced by microsutures, methylene blue, and polyethylene glycol after completely cutting rat sciatic nerves

Behavioral function lost in mammals (including humans) after peripheral nerve severance is slowly (weeks to years) and often poorly restored by 1–2‐mm/day, nonspecifically directed outgrowths from proximal axonal stumps. To survive, proximal stumps must quickly repair (seal) plasmalemmal damage. We report that, after complete cut‐ or crush‐severance of rat sciatic nerves, morphological continuity, action potential conduction, and behavioral functions can be consistently (>98% of trials), rapidly (minutes to days), dramatically (70–85% recovery), and chronically restored and some Wallerian degeneration prevented. We assess axoplasmic and axolemmal continuity by intra‐axonal dye diffusion and action potential conduction across the lesion site and amount of behavioral recovery by Sciatic Functional Index and Foot Fault tests. We apply well‐specified sequences of solutions containing FDA‐approved chemicals. First, severed axonal ends are opened and resealing is prevented by hypotonic Ca2+‐free saline containing antioxidants (especially methylene blue) that inhibit plasmalemmal sealing in sciatic nerves in vivo, ex vivo, and in rat B104 hippocampal cells in vitro. Second, a hypotonic solution of polyethylene glycol (PEG) is applied to open closely apposed (by microsutures, if cut) axonal ends to induce their membranes to flow rapidly into each other (PEG‐fusion), consistent with data showing that PEG rapidly seals (PEG‐seals) transected neurites of B104 cells, independently of any known endogenous sealing mechanism. Third, Ca2+‐containing isotonic saline is applied to induce sealing of any remaining plasmalemmal holes by Ca2+‐induced accumulation and fusion of vesicles. These and other data suggest that PEG‐sealing is neuroprotective, and our PEG‐fusion protocols that repair cut‐ and crush‐severed rat nerves might rapidly translate to clinical procedures.

Breast reconstruction outcomes after nipple-sparing mastectomy and radiation therapy.

Background: Few studies in the literature examine outcomes of immediate breast reconstruction after mastectomy with nipple preservation and radiation therapy. Methods: Retrospective analysis of multisurgeon consecutive implant-based reconstructions after nipple-sparing mastectomy from June of 2007 to December of 2012 was conducted at a single institution. Results: Six hundred five immediate breast reconstructions were performed following nipple-sparing mastectomy, of which 88 were treated with radiation therapy. There was a trend toward more complications in patients with radiation (19.3 percent versus 12.8 percent; p = 0.099) associated with a higher rate of implant loss (6.8 percent versus 1.0 percent; p = 0.001). Preoperative radiotherapy had a higher risk of total complications (p = 0.04; OR, 2.225; 95 percent CI, 1.040 to 4.758) and postoperative radiotherapy had a higher risk of explantation (p = 0.015; OR, 5.634; 95 percent CI, 1.405 to 22.603). There were no significant differences in nipple removal secondary to malposition or positive oncologic margins in patients with radiation compared to those without radiation. Patients with radiation did have a higher incidence of secondary procedures for capsular contracture (12.5 percent versus 2.3 percent; p < 0.001) and fat grafting (13.6 percent versus 3.9 percent; p < 0.001). The total nipple retention rate in patients with radiation therapy was 90 percent (79 of 88), and the reconstruction failure rate was 8 percent. Conclusions: Nipple-sparing mastectomy and immediate reconstruction in patients who had or will receive radiation therapy is associated with a higher incidence of complications and operative revisions compared with patients without radiation. However, most patients have successful reconstructions with nipple retention and no recurrences. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Real-time In Vivo Assessment of the Nerve Microenvironment with Coherent Anti–stokes Raman Scattering Microscopy

Background: Current analysis of nerve injury and repair relies largely on electrophysiologic and ex vivo histologic techniques. In vivo architectural assessment of a nerve without removal or destruction of the tissue would greatly assist in the grading of nerve injury and in the monitoring of nerve regeneration over time. Coherent anti–Stokes Raman scattering microscopy is an optical process with particular sensitivity for high-lipid-containing molecules such as myelin. This in vivo nonthermal technique offers high-resolution images that the authors aim to evaluate in both normal and injured nerves. Methods: A demyelinating crush injury was reproduced in the sciatic nerves of Sprague-Dawley rats (n = 12). Animals were randomized into groups, and coherent anti–Stokes Raman scattering microscopy was undertaken at day 1 and weekly up to 4 weeks after injury. Functional analysis was undertaken weekly and histomorphometry was completed after imaging. Results: All animals demonstrated loss of sciatic nerve function following injury. Recovery was documented, with functional data approaching normal at 3 and 4 weeks. Demyelination was confirmed in nerves up to 2 weeks after injury. Remyelination was observed in the 3-week group and beyond. Imaging of normal nerve revealed structured myelin bundles. These results were consistent with histologic findings that showed a statistically significant improvement in myelination over time. Conclusions: The authors conclude that coherent anti–Stokes Raman scattering microscopy has the ability to image the peripheral nerve following demyelinating crush injury. This technology, which permits in vivo, real-time microscopy of nerves at a resolution of 5 &mgr;m, could provide invaluable diagnostic and prognostic information regarding intraneural preservation and recovery following injury.

Improving electrophysiologic and histologic outcomes by photochemically sealing amnion to the peripheral nerve repair site

BACKGROUND The surgical approach used today in the repair of peripheral nerve injuries rarely achieves full functional recovery. This study determines whether isolation of the nerve repair site using photochemical tissue bonding (PTB) in combination with human amniotic membrane can improve both functional and histologic recovery. METHODS New Zealand white rabbits (n = 24) underwent transection of the right common peroneal nerve. Epineural nerve repair was performed using 10-0 nylon sutures. The repair site was then wrapped in a cuff of human amniotic membrane, which either was secured with sutures or sealed using PTB. Standard neurorrhaphy alone was assessed as a control group. Functional recovery was recorded at 30-day intervals postoperatively by electrophysiologic assessment. At 120 days, animals were killed humanely and nerves harvested for histomorphometry. RESULTS Nerves treated with amnion wraps and sealed with PTB demonstrated a statistically significant improvement across both functional and histologic parameters. Functional recovery, as measured by repeated electrophysiologic studies over time, revealed a 26.2% improvement over standard neurorrhaphy alone (P < .05). Nerves treated with PTB-sealed amnion wraps had significantly greater (P < .001) axon (5.08 +/- 1.06 microm) and fiber diameters (7.46 +/- 1.37 microm), as well as myelin thickness (2.39 +/- 0.7 microm) and the g ratio (axon diameter/fiber diameter ratio; 0.68 +/- 0.07) distal to the repair site compared to standard neurorrhaphy alone (4.98 +/- 1.81 microm, 6.77 +/- 1.94 microm, 1.79 +/- 0.42 microm, and 0.71 +/- 0.09, respectively). CONCLUSION Isolation of the repair site using a photochemically sealed amnion wrap improves electrophysiologic and histologic recovery compared to standard suture neurorrhaphy.

Photochemical sealing improves outcome following peripheral neurorrhaphy.

INTRODUCTION Peripheral nerve transection initiates a complex molecular response in the severed nerve endings, resulting in the release of neurotrophic and neurotropic factors that are central to axonal survival and regeneration. In this study we tested the hypothesis that sealing the neurorrhaphy site from the surrounding environment using a photochemically bonded nerve wrap would optimize the endoneural environment and enhance regeneration and nerve function recovery. MATERIALS AND METHODS Adult rats underwent unilateral sciatic nerve transection and standard epineural nerve repair. The repair site was wrapped with amniotic membrane or autologous vein and then was either sealed using photochemical tissue bonding (PTB) or secured with sutures. Photochemical sealing without a wrap was also carried out. Functional recovery was assessed at 2-wk intervals using walking track analysis and nerve histomorphometry was assessed at 12 wk. RESULTS Treating nerves with PTB-sealed amnion significantly improved functional recovery and increased distal axon and fiber diameters and myelin thickness compared to nerves treated with standard neurorrhaphy alone. Direct PTB sealing of the repair site also improved function. Neither amnion secured with sutures nor vein wraps exhibited improved functional or histological recovery compared to standard neurorrhaphy. CONCLUSIONS These results suggest that sealing the peripheral nerve repair site with amnion using a photochemical technique may lead to earlier restoration of neural homeostasis and consequent enhanced repair of nerve injury.