Influence of Closed-incision Negative Pressure Wound Therapy on Abdominal Site Complications in Autologous Breast Reconstruction.

Background: Closed-incision negative pressure wound therapy (ciNPWT) has shown promise in reducing surgical wound complications. Among its numerous benefits, it allows for exudate management and tension offloading from wound edges. The purpose of this systematic review and meta-analysis was to assess the efficacy of prophylactic ciNPWT versus conventional dressings on abdominal donor site complications in microsurgical breast reconstruction (MR). Methods: A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in January 2023. PubMed and Embase were searched to identify all relevant studies. Data collected included rates of total wound complications, wound dehiscence, infection, seroma, and length of hospital stay. Results: A total of 202 articles were screened, and eight studies (1009 patients) met the inclusion criteria. Use of ciNPWT was associated with a significantly lower rate of wound dehiscence (OR, 0.53; 95% confidence interval, 0.33-0.85; P = 0.0085, I2 = 0%). There was no significant difference in the rate of total wound complications [odds ratio (OR), 0.63; 95% CI, 0.35-1.14; P = 0.12, I2 = 69%], donor site infection (OR, 0.91; 95% CI, 0.42-1.50; P = 0.47, I2 = 13%), seroma (OR, 0.74; 95% CI, 0.22-2.49; P = 0.63, I2 = 57%), or length of hospital stay (SMD, 0.089; 95% CI, -0.13-0.35; P = 0.37, I2 = 29%). Conclusions: Although exudate management by ciNPWT fails to reduce surgical site infection, seroma formation, and overall length of stay, ciNPWT tension offloading properties seem to be associated with lower rates of wound dehiscence when compared with conventional dressings in abdominal-based autologous breast reconstruction.

A New Measure of Posterior Morphology in Sagittal Craniosynostosis: The Occipital Bullet Index.

INTRODUCTION: Sagittal craniosynostosis (SC) is associated with scaphocephaly, an elongated narrow head shape. Assessment of regional severity in the scaphocephalic head is limited by the use of serial computed tomographic (CT) imaging or complex computer programing. Three-dimensional measurements of cranial surface morphology provide a radiation-free alternative for assessing cranial shape. This study describes the creation of an occipital bulleting index (OBI), a novel tool using surface morphology to assess the regional severity in patients with SC. METHODS: Surface imaging from CT scans or 3D photographs of 360 individuals with SC and 221 normocephalic individuals were compared to identify differences in morphology. Cartesian grids were created on each individual's surface mesh using equidistant axial and sagittal planes. Area under the curve (AUC) analyses were performed to identify trends in regional morphology and create measures capturing population differences. RESULTS: The largest differences were located in the medial regions posteriorly. Using these population trends, a measure was created to maximize AUC. The OBI has an AUC of 0.72 with a sensitivity of 74% and a specificity of 61%. When the frontal bossing index is applied in tandem, the two have a sensitivity of 94.7% and a specificity of 93.1%. Correlation between the two scores in individuals with SC was found to be negligible with an intraclass correlation coefficient of 0.018. Severity was found to be independent of age under 24 months, sex, and imaging modality. CONCLUSIONS: This index creates a tool for differentiating control head shapes from those with SC and has the potential to allow for objective evaluation of the regional severity, outcomes of different surgical techniques, and tracking shape changes in individuals over time, without the need for radiation.

Postoperative Day 1 Discharge in Deep Inferior Epigastric Artery Perforator Flap Breast Reconstruction.

With high success rates of autologous breast reconstruction, the focus has shifted from flap survival to improved patient outcomes. Historically, a criticism of autologous breast reconstruction has been the length of hospital stay. Our institution has progressively shortened the length of stay after deep inferior epigastric artery perforator (DIEP) flap reconstruction and began discharging select patients on postoperative day 1 (POD1). The purpose of this study was to document our experience with POD1 discharges and to identify preoperative and intraoperative factors that may identify patients as candidates for earlier discharge. Methods: An institutional review board-approved, retrospective chart review of patients undergoing DIEP flap breast reconstruction from January 2019 to March 2022 at Atrium Health was completed, consisting of 510 patients and 846 DIEP flaps. Patient demographics, medical history, operative course, and postoperative complications were collected. Results: Twenty-three patients totaling 33 DIEP flaps were discharged on POD1. The POD1 group and the group of all other patients (POD2+) had no difference in age, ASA score, or comorbidities. BMI was significantly lower in the POD1 group (P = 0.039). Overall operative time was significantly lower in the POD1 group, and this remained true when differentiating into unilateral operations (P = 0.023) and bilateral operations (P = 0.01). No major complications occurred in those discharged on POD1. Conclusions: POD1 discharge after DIEP flap breast reconstruction is safe for select patients. Lower BMI and shorter operative times may be predictive in identifying patients as candidates for earlier discharge.

"Creation of the Scaphocephalic Index: Measurement of Global and Regional Severity in Scaphocephaly".

INTRODUCTION: The recently described frontal bossing index (FBI) and occipital bullet index (OBI) allow for quantification of scaphocephaly. A similar index examining biparietal narrowing has not been described. Addition of such an index measuring width would allow for direct evaluation of the primary growth restriction in sagittal craniosynostosis (SC) and the formation of an optimized global Width/Length measure. METHODS: CT scans and 3D photos were used to recreate scalp surface anatomy. Equidistant axial, sagittal, and coronal planes were overlaid creating a Cartesian grid. Points of intersection were analyzed for population trends in biparietal width. Using the most descriptive point coupled with the sellion's protrusion to control for head size, the vertex narrowing index (VNI) is formed. By combining this index with the FBI and OBI, the Scaphocephalic Index (SCI) is created as a tailored W/L measure. RESULTS: Using 221 control and 360 individuals with sagittal craniosynostosis, the greatest difference occurred superiorly and posteriorly at a point 70% of the head's height and 60% of the head's length. This point had an area under the curve (AUC) of 0.97 and sensitivity and specificity of 91.2% and 92.2% respectively. The SCI has an AUC of 0.9997, sensitivity and specificity >99%, and interrater reliability of 0.995. The correlation coefficients between the CT imaging and 3D photography was 0.96. CONCLUSION: The VNI, FBI, and OBI evaluate regional severity while the SCI is able to describe global morphology in patients with sagittal craniosynostosis. These allow for superior diagnosis, surgical planning, and outcome assessment, independent of radiation.

The Need for Additional Surgery after Passive versus Active Approaches to Syndromic Craniosynostosis: A Meta-analysis.

Endoscopically assisted craniofacial surgery (EACS) has numerous advantages over traditional, open approaches, such as fronto-orbital advancement in treating nonsyndromic craniosynostosis. However, several articles report high reoperation rates in syndromic patients treated with EACS. This meta-analysis and review examines undesirable outcome rates (UORs), defined as reoperation or Whitaker category III/IV, in syndromic patients undergoing primary EACS compared with procedures that actively expand the cranial vault. Methods: PubMed and Embase were searched in June 2022 to identify all articles reporting primary reoperation or Whitaker outcomes for syndromic patients undergoing cranial vault expanding surgery or suturectomy. A meta-analysis of proportions was performed comparing UORs, and a trim-and-fill adjustment method was used to validate sensitivity and assess publication bias. Results: A total of 721 articles were screened. Five EACS articles (83 patients) and 22 active approach articles (478 patients) met inclusion criteria. Average UORs for EACS and active approaches were 26% (14%-38%) and 20% (13%-28%), respectively (P = 0.18). Reoperation occurred earlier in EACS patients (13.7 months postprimary surgery versus 37.1 months for active approaches, P = 0.003). Relapse presentations and reason for reoperation were also reviewed. Subjectively, EACS UORs were higher in all syndromes except Apert, and Saethre-Chotzen patients had the highest UOR for both approaches. Conclusions: There was no statistically significant increase in UORs among syndromic patients treated with EACS compared with traditional approaches, although EACS patients required revision significantly sooner. Uncertainties regarding the long-term efficacy of EACS in children with syndromic craniosynostosis should be revisited as more data become available.

"Primary Correction of the Cleft Nasal Septum: A Systematic Review".

Patients affected by cleft lip and palate have a characteristic nasal deformity; however, the treatment timeline varies amongst providers. There has been a shift from a more conservative approach to earlier intervention in order to allow for more normal development of the nose. Form, function, and future development all must be considered. For this reason, this investigation was undertaken to present the current literature available on the effects to all aspects of primary septoplasty in the cleft nasal deformity.An initial list of 222 papers was identified, and it was determined that 16 papers fit the inclusion criteria. Studies were included in which the initial age of operation for the majority of patients was between 3 and 12 months and in which patients underwent septal repositioning at the time of cleft lip repair. These papers were all reviewed by a single author initially, and the results recorded. All results were then verified by a second author for accuracy and completeness.Symmetry was found to be improved by primary septoplasty. Growth was not found to be impaired in any study; data was insufficient to indicate that growth was improved. Obstruction was improved as determined both by imaging, endoscopy, and patient survey. Finally, reoperation rates occurred at an acceptable rate not exceeding that of primary rhinoplasty without septoplasty.Primary septoplasty leads to better aesthetic symmetry and function of the cleft nose without impairing growth. This change is maintained into adulthood often without the need for revisionary surgery.

Rigid External Distractors in Midface Fractures: A Review of Relevant and Related Literature.

INTRODUCTION: Literature discussing the use of rigid external distraction devices in midfacial trauma is limited. Rigid external distraction devices have been described for use in craniofacial surgery, allowing for distraction and stabilization of bony segments. In complex facial trauma, bony fragments are often comminuted and unstable, making traditional approaches with internal fixation difficult. Moreover, these approaches require subperiosteal dissection, limiting blood supply that is important for bone healing. OBJECTIVE: The goal of this study was to evaluate the role of rigid external distraction devices for the treatment of complex facial trauma. METHODS: We performed a literature review of rigid external distraction devices, as relevant both for facial trauma and for other craniofacial indications, to better elucidate their use and efficacy in complex facial fractures. RESULTS: The review revealed only 2 articles explicitly describing rigid external distraction devices for facial trauma, while 6 other articles describing its use for other craniofacial cases. An important benefit associated with the use of rigid external distraction devices is their ability to provide controlled traction of bony segments while also allowing for movement as needed for fracture reduction. Various articles describe performing internal fixation following rigid external distraction device usage, while others emphasize that internal fixation is not necessarily indicated if the rigid external distraction device is left intact long enough to ensure bony healing. One potential setback described is unfamiliarity with using the rigid external distraction device, which can preclude its use by many surgeons. In addition, the literature review did not provide any uniform guidelines or recommendations about how long rigid external distraction devices should remain intact. CONCLUSION: Based on relevant literature, rigid external distraction devices have been shown to be useful in the stabilization and treatment of complex facial fractures. Further studies should be conducted to better elucidate the specific indications for rigid external distraction devices in complex facial trauma.

Biologics in Acute Burn Injury.

There have been significant advances in the care of burns over the past decade. As a result of the improved survival of burn patients, attention has shifted to the optimized management of their wounds. Traditionally, autografts have been described as the gold standard treatment in cases of deep second- and third-degree burn wounds; however, they are limited especially in large surface area burns. As such, advancements have been made in the development of biologic dressings, which attempt to mimic the function of the lost epidermis and/or dermis. The ideal biologic dressing is nontoxic, lacks antigenicity, is immunologically compatible, and is sterile. Additionally, easy storage conditions, long shelf lives, and reasonable costs are key determinants of whether biologic dressings may truly be widely used in the clinical setting. Biologic dressings serve an important role as skin substitutes in the setting of acute burn injury. This review aims to summarize the multitude of available biologic dressings and their applications. METHODS: The PubMed and Google Scholar databases were searched for the following terms either alone or in combination: "burn injury," "biologic membrane," "skin substitutes," "biosynthetic dressings," and "acellular membrane."

Amniotic Membrane Adjuncts and Clinical Applications in Wound Healing: A Review of the Literature.

INTRODUCTION: Recent advances in the preservation and processing of amnion/chorion tissue have dramatically increased the bioavailability of these wound healing factors as well as the shelf life of their related tissue products, allowing for a surge in clinical use. Many studies, including basic science, clinical trials, and randomized controlled trials, have emerged examining the biologic properties of amnion/chorion membrane products and their efficacy in wound healing. OBJECTIVE: A literature review was conducted regarding the safety and efficacy of amniotic membrane adjuncts. METHODS: The PubMed and MEDLINE databases were queried and sorted based on clinical trials with publication dates ranging from 2013 to 2017. Only studies pertaining to human subjects were included for review. RESULTS: Amnion/chorion membranes have been studied in the treatment of burns, diabetic foot ulcers, fistulas, ocular defects, and venous leg ulcers, among other wounds. Amnion/chorion allografts were found to be beneficial in the setting of difficult-to-heal fistulas and were effective in treating diabetic and venous ulcers when combined with standard therapy. CONCLUSIONS: Overall, clinical trials have demonstrated that patients treated with amniotic membrane products have increased rates of wound healing compared with the standard of care. Additional trials are needed to examine more amnion/chorion membrane products.

Zinc Metallochaperones Reactivate Mutant p53 Using an ON/OFF Switch Mechanism: A New Paradigm in Cancer Therapeutics.

Purpose: Zinc metallochaperones (ZMC) are a new class of anticancer drugs that reactivate zinc-deficient mutant p53 by raising and buffering intracellular zinc levels sufficiently to restore zinc binding. In vitro pharmacodynamics of ZMCs indicate that p53-mutant activity is ON by 4-6 hours and is OFF by 24. We sought to understand the mechanism of this regulation and to translate these findings preclinically. We further sought to innovate the formulation of ZMCs to improve efficacy.Experimental Design: We performed in vitro mechanistic studies to determine the role of cellular zinc homeostatic mechanisms in the transient pharmacodynamics of ZMCs. We conducted preclinical pharmacokinetic, pharmacodynamic, and efficacy studies using a genetically engineered murine pancreatic cancer model (KPC) to translate these mechanistic findings and investigate a novel ZMC formulation.Results:In vitro, cellular zinc homeostatic mechanisms that restore zinc to its physiologic levels function as the OFF switch in ZMC pharmacodynamics. In vivo pharmacokinetic studies indicate that ZMCs have a short half-life (< 30 minutes), which is sufficient to significantly improve survival in mice expressing a zinc-deficient allele (p53R172H) while having no effect in mice expressing a non-zinc-deficient allele (p53R270H). We synthesized a novel formulation of the drug in complex with zinc and demonstrate this significantly improves survival over ZMC1.Conclusions: Cellular zinc homeostatic mechanisms function as an OFF switch in ZMC pharmacodynamics, indicating that a brief period of p53-mutant reactivation is sufficient for on-target efficacy. ZMCs synthesized in complex with zinc are an improved formulation. Clin Cancer Res; 24(18); 4505-17. ©2018 AACR.

Zinc Metallochaperones as Mutant p53 Reactivators: A New Paradigm in Cancer Therapeutics.

Restoration of wild-type structure and function to mutant p53 with a small molecule (hereafter referred to as "reactivating" mutant p53) is one of the holy grails in cancer therapeutics. The majority of TP53 mutations are missense which generate a defective protein that is targetable. We are currently developing a new class of mutant p53 reactivators called zinc metallochaperones (ZMCs) and, here, we review our current understanding of them. The p53 protein requires the binding of a single zinc ion, coordinated by four amino acids in the DNA binding domain, for proper structure and function. Loss of the wild-type structure by impairing zinc binding is a common mechanism of inactivating p53. ZMCs reactivate mutant p53 using a novel two-part mechanism that involves restoring the wild-type structure by reestablishing zinc binding and activating p53 through post-translational modifications induced by cellular reactive oxygen species (ROS). The former causes a wild-type conformation change, the later induces a p53-mediated apoptotic program to kill the cancer cell. ZMCs are small molecule metal ion chelators that bind zinc and other divalent metal ions strong enough to remove zinc from serum albumin, but weak enough to donate it to mutant p53. Recently we have extended our understanding of the mechanism of ZMCs to the role of cells' response to this zinc surge. We found that cellular zinc homeostatic mechanisms, which normally function to maintain free intracellular zinc levels in the picomolar range, are induced by ZMCs. By normalizing zinc levels, they function as an OFF switch to ZMCs because zinc levels are no longer sufficiently high to maintain a wild-type structure. This on/off switch leads to a transient nature to the mechanism of ZMCs in which mutant p53 activity comes on in a few hours and then is turned off. This finding has important implications for the translation of ZMCs to the clinic because it indicates that ZMC concentrations need not be maintained at high levels for their activity. Indeed, we found that short exposures (as little as 15 min) were adequate to observe the mutant p53 reactivating activity. This switch mechanism imparts an advantage over other targeted therapeutics in that efficacy can be accomplished with minimal exposure which minimizes toxicity and maximizes the therapeutic window. This on/off switch mechanism is unique in targeted cancer therapeutics and will impact the design of human clinical trials.

Palliative Endovascular Techniques for Management of Peripheral Vascular Blowout Syndrome in End-Stage Malignancies.

Vascular blowout syndrome (VBOS) secondary to neoplastic erosion is a dreadful complication of advanced stage malignancies that can compromise quality of life and overall prognosis in a fragile patient population. Endovascular therapy can offer minimally invasive, life-saving maneuvers both acutely and prophylactically. Four patients with end-stage malignancies eroding into various peripheral vascular beds with impending, threatened, and acute VBOS underwent successful endovascular management. Technical success was achieved in all patients with no perioperative morbidity or mortality. In all patients, endovascular intervention controlled life-threatening hemorrhage and facilitated adjunctive therapeutic modalities such as surgical tumor debulking and/or chemoradiation. In conclusion, our small case series demonstrates that endovascular therapy can offer safe and effective palliation of peripheral VBOS secondary to neoplastic erosion.

Zinc and Wound Healing: A Review of Zinc Physiology and Clinical Applications.

Our understanding of the role of zinc in normal human physiology is constantly expanding, yet there are major gaps in our knowledge with regard to the function of zinc in wound healing. This review aims to provide the clinician with sufficient understanding of zinc biology and an up-to-date perspective on the role of zinc in wound healing. Zinc is an essential ion that is crucial for maintenance of normal physiology, and zinc deficiency has many manifestations ranging from delayed wound healing to immune dysfunction and impairment of multiple sensory systems. While consensus has been reached regarding the detrimental effects of zinc deficiency on wound healing, there is considerable discord in the literature on the optimal methods and true benefits of zinc supplementation.

U1 Adaptors Suppress the KRAS-MYC Oncogenic Axis in Human Pancreatic Cancer Xenografts.

Targeting KRAS and MYC has been a tremendous challenge in cancer drug development. Genetic studies in mouse models have validated the efficacy of silencing expression of both KRAS and MYC in mutant KRAS-driven tumors. We investigated the therapeutic potential of a new oligonucleotide-mediated gene silencing technology (U1 Adaptor) targeting KRAS and MYC in pancreatic cancer. Nanoparticles in complex with anti-KRAS U1 Adaptors (U1-KRAS) showed remarkable inhibition of KRAS in different human pancreatic cancer cell lines in vitro and in vivo As a nanoparticle-free approach is far easier to develop into a drug, we refined the formulation of U1 Adaptors by conjugating them to tumor-targeting peptides (iRGD and cRGD). Peptides coupled to fluorescently tagged U1 Adaptors showed selective tumor localization in vivo Efficacy experiments in pancreatic cancer xenograft models showed highly potent (>90%) antitumor activity of both iRGD and (cRGD)2-KRAS Adaptors. U1 Adaptors targeting MYC inhibited pancreatic cancer cell proliferation caused by apoptosis in vitro (40%-70%) and tumor regressions in vivo Comparison of iRGD-conjugated U1 KRAS and U1 MYC Adaptors in vivo revealed a significantly greater degree of cleaved caspase-3 staining and decreased Ki67 staining as compared with controls. There was no significant difference in efficacy between the U1 KRAS and U1 MYC Adaptor groups. Our results validate the value in targeting both KRAS and MYC in pancreatic cancer therapeutics and provide evidence that the U1 Adaptor technology can be successfully translated using a nanoparticle-free delivery system to target two undruggable genes in cancer. Mol Cancer Ther; 16(8); 1445-55. ©2017 AACR.

Pharmacological targeting of mutant p53.

TP53 is the most commonly mutated gene in cancer, with over half of all human cancers harboring a mutation in the gene. The p53 protein is a transcription factor that functions as a tumor suppressor, and a subset of its numerous roles include the arrest of proliferation, promotion of DNA repair, and induction of apoptosis in cells with severe DNA damage or stress. The vast majority of p53 mutations are single amino acid substitutions within the DNA binding domain, which either directly impede the protein's ability to bind DNA or destabilize the structure, resulting in misfolding. These missense mutant proteins are found at high levels due to loss of the MDM2 mediated regulation, and consequently serve as potential drug targets. Numerous pharmacological approaches have been investigated to restore wild type p53 function to these mutants (so-called reactivating mutant p53) with some entering in clinical trials while most have failed in early development. Recently, the field of cancer drug development has produced a number of new compounds that continue to advance this field, each with a different mechanism of action. Here we sought to review these compounds and approaches to reactivating mutant p53. Given the large number of patients with missense mutant p53 mutations, reactivating mutant p53 remains a highly sought after goal in developmental therapeutics.

Multimodal endovascular palliation for femoral arterial blowout in the setting of metastatic vulvar carcinoma.

BACKGROUND: Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes. METHODS: Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity. RESULTS: Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation. CONCLUSION: We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation.

Accuracy of transpulmonary thermodilution versus gravimetric measurement of extravascular lung water.

OBJECTIVE: Pulmonary edema is a severe and often life-threatening condition. The diagnosis of pulmonary edema and its quantification have great clinical significance and yet can be difficult. A new technique based on thermodilution measurement using a single indicator has recently been developed (PiCCO, Pulsion Medical Systems, AG Germany). This method allows the measurement of extravascular lung water and thus can quantify degree of pulmonary edema. The technique has not been compared with a gold standard, gravimetric measurement of extravascular lung water. Therefore, the objective of this study was to determine the ability of extravascular lung water measurement with the PiCCO to reflect the extravascular lung water as measured with a gravimetric technique in a dog model of pulmonary edema. DESIGN: Prospective, randomized animal study. SETTING: A university animal research laboratory. SUBJECTS: Fifteen mongrel dogs (n = 5/group) weighing 20-30 kg. INTERVENTIONS: The dogs were anesthetized and mechanically ventilated. Five dogs served as controls; in five dogs hydrostatic pulmonary edema was induced using inflation of a left atrial balloon combined with fluid administration to maintain a high pulmonary artery occlusion pressure; and in five dogs pulmonary edema was induced by intravenous injection of oleic acid. After a period of stabilization in a state of pulmonary edema, extravascular lung water was measured with the PiCCO monitor. The animals were then killed, and extravascular lung water was measured using a gravimetric technique. MEASUREMENTS AND MAIN RESULTS: There was a very close (r =.967, p <.001) relationship between transpulmonary thermodilution and gravimetric measurements. The measurement with the PiCCO was consistently higher, by 3.01 +/- 1.34 mL/kg, than the gravimetric measurement. CONCLUSIONS: Measurement of extravascular lung water using transpulmonary thermodilution with a single indicator is very closely correlated with gravimetric measurement of lung water in both increased permeability and hydrostatic pulmonary edema.