Tumor-specific T cells in head and neck cancer have rescuable functionality and can be identified through single-cell co-culture.

BACKGROUND: Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) remains a treatment-resistance disease with limited response to immunotherapy. While T cells in HNSCC are known to display phenotypic dysfunction, whether they retain rescuable functional capacity and tumor-killing capability remains unclear. METHODS: To investigate the functionality and tumor-specificity of tumor-infiltrating lymphocytes (TILs) across HNSCCs, malignant cell lines and TILs were derived from 31 HPV-negative HNSCCs at the time of standard surgical resection. T cell functional capacity was evaluated through ex vivo expansion, immunophenotyping, and IsoLight single-cell proteomics. Tumor-specificity was investigated through both bulk and single-cell tumor-TIL co-culture. RESULTS: TILs could be successfully generated from 24 patients (77%), including both previously untreated and radiation recurrent HNSCCs. We demonstrate that across HNSCCs, TILs express multiple exhaustion markers but maintain a predominantly effector memory phenotype. After ex vivo expansion, TILs retain immunogenic functionality even from radiation-resistant, exhausted, and T cell-depleted disease. We further demonstrate tumor-specificity of T cells across HNSCC patients through patient-matched malignant cell-T cell co-culture. Finally, we use optofluidic technology to establish an autologous single tumor cell-single T cell co-culture platform for HNSCC. Cells derived from three HNSCC patients underwent single-cell co-culture which enabled identification and visualization of individual tumor-killing TILs in real-time in all patients. CONCLUSIONS: These studies show that cancer-specific T cells exist across HNSCC patients with rescuable immunogenicity and can be identified on a single-cell level. These data lay the foundation for development of patient-specific T cell immunotherapies in HNSCC.

Functional considerations between flap and non-flap reconstruction in oral tongue cancer: A systematic review.

This systematic review aims to provide insight into the ideal reconstructive approach of the oral tongue in oral tongue cancer (OTC) by investigating the relationship between functional outcomes and the extent of tongue resection. A structured search was performed in Ovid MEDLINE, EMBASE, and Web of Science. Studies comparing patient-reported and objective measurements of the oral tongue function between flap vs. non-flap reconstruction were included. Functional outcomes of interest were speech production, deglutition efficiency, tongue mobility, overall quality of life, and postoperative complications. A total of nine studies were retrieved and critically appraised. Patients with 20 % or less of oral tongue resected had superior swallowing efficiency and speech intelligibility with a non-flap reconstruction while patients with a tongue defect of 40-50 % self-reported or demonstrated better swallowing function with a flap repair. The data in intermediate tongue defects (20-40 % tongue resected) was inconclusive, with several studies reporting comparable functional outcomes between approaches. A longitudinal multi-institutional prospective study that rigidly controls the extent of tongue resected and subsites involved is needed to determine the percentage of tongue resected at which a flap reconstruction yields a superior functional result in OTC.

Photoactivated HPPH-Liposomal therapy for the treatment of HPV-Negative head and neck cancer.

OBJECTIVES: Human Papillomavirus (HPV)-negative head and neck cancer (HNC) is an aggressive malignancy with a poor prognosis. To improve outcomes, we developed a novel liposomal targeting system embedded with 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a chlorin-based photosensitizer. Upon exposure to 660 nm light, HPPH phototriggering generates reactive oxygen species. The objective of this study was to evaluate biodistribution and test efficacy of HPPH-liposomal therapy in a patient-derived xenograft (PDX) model of chemoradioresistant HNC. MATERIALS AND METHODS: PDX models were developed from two surgically resected HNCs (P033 and P038) recurrent after chemoradiation. HPPH-liposomes were created including trace amounts of DiR (Ex/Em 785/830 nm), a near infrared lipid probe. Liposomes were injected via tail vein into PDX models. Biodistribution was assessed at serial timepoints in tumor and end-organs through in vivo DiR fluorescence. To evaluate efficacy, tumors were treated with a cw-diode 660 nm laser (90 mW/cm2, 5 min). This experimental arm was compared to appropriate controls, including HPPH-liposomes without laser or vehicle with laser alone. RESULTS: HPPH-liposomes delivered via tail vein exhibited selective tumor penetration, with a peak concentration at 4 h. No systemic toxicity was observed. Treatment with combined HPPH-liposomes and laser resulted in improved tumor control relative to either vehicle or laser alone. Histologically, this manifested as both increased cellular necrosis and decreased Ki-67 staining in the tumors treated with combined therapy. CONCLUSIONS: These data demonstrate tumor-specific anti-neoplastic efficacy of HPPH-liposomal treatment for HNC. Importantly, this platform can be leveraged in future studies for targeted delivery of immunotherapies which can be packaged within HPPH-liposomes.

Clinical Impact and Accuracy of Shave Biopsy for Initial Diagnosis of Cutaneous Melanoma.

INTRODUCTION: Effective treatment of malignant melanomas is dependent upon accurate histopathological staging of preoperative biopsy specimens. While narrow excision is the gold standard for melanoma diagnosis, superficial shave biopsies have become the preferred method by dermatologists but may transect the lesion and result in inaccurate Breslow thickness assessment. This is a retrospective cohort study evaluating an initial method of biopsy for diagnosis of cutaneous melanoma and indication for reoperation based on inaccurate initial T-staging. METHODS: We retrospectively analyzed consecutive patients referred to the Medical College of Wisconsin, a tertiary cancer center, with a diagnosis of primary cutaneous melanoma. Adult patients seen between 2015 and 2018 were included. Fisher's exact test was used to assess the association between method of initial biopsy and need for unplanned reoperation. RESULTS: Three hundred twenty three patients with cutaneous melanoma from the head and neck (H&N, n = 101, 31%), trunk (n = 90, 15%), upper extremity (n = 84, 26%), and lower extremity (n = 48, 28%) were analyzed. Median Breslow thickness was 0.54 mm (interquartile range = 0.65). Shave biopsy was the method of initial biopsy in 244 (76%), excision in 23 (7%), and punch biopsy in 56 (17%). Thirty nine (33%) shave biopsies had a positive deep margin, as did seven (23%) punch biopsies and 0 excisional biopsies. Residual melanoma at definitive excision was found in 131 (42.5%) of all surgical specimens: 95 (40.6%) shave biopsy patients, 32 (60.4%) punch biopsy patients, and four (19.0%) excision biopsy patients. Recommendations for excision margin or sentinel lymph node biopsy changed in 15 (6%) shave biopsy patients and five (9%) punch biopsy patients. CONCLUSIONS: Shave biopsy is the most frequent method of diagnosis of cutaneous melanoma in the modern era. While shave and punch biopsies may underestimate true T-stage, there was no difference in need for reoperation due to T-upstaging based on initial biopsy type, supporting current diagnostic practices. Partial biopsies can thus be used to guide appropriate treatment and definitive wide local excision when adjusting for understaging.

Multiple simultaneous free flaps for head and neck reconstruction: A multi-institutional cohort.

OBJECTIVES: To describe the experience of two tertiary academic centers with multiple, simultaneous free flaps for complex head and neck defect reconstruction. METHODS: Patients undergoing multiple, simultaneous free flaps from 2017 to 2022 were retrospectively reviewed. RESULTS: Seventy-one patients (64.8% male, median age 61 years) were identified and underwent 143 free flaps. The leading surgical indication was squamous cell carcinoma (n = 48, 67.6%). Defect sites included oral cavity, maxilla, pharynx, parotid, skull base, and scalp. The most common free flap combinations were fibula (FFF) with anterolateral thigh flap (n = 33, 46.5%), radial forearm (RFFF) with scapula (n = 11, 15.5%), and RFFF with FFF (n = 10, 14.1%). Median operative time was 12 h. Median length of hospitalization was 10 days. At last follow-up (median 6 months), 141 flaps (98.6%) survived without partial nor complete flap failure. CONCLUSION: Multiple, simultaneous free flaps are a rare, yet reliable option for head and neck reconstruction in select patients with defects involving several tissue types, multiple functional areas, or large volumes.

Free tissue reconstruction in the "vessel-depleted" neck: A multi-institutional cohort study.

OBJECTIVES: Much of the literature on free tissue reconstruction in the "vessel-depleted" neck is focused on identification of vessels outside the pretreated field and data on free flap outcomes when infield microvascular anastomosis is performed remain scarce. We aim to report on free flap outcomes and recipient vessel choice in a large cohort of patients with prior radiation and neck dissection (RTND) to the ipsilateral side of vessel anastomosis. METHODS: A retrospective review was performed including patients who received head and neck free tissue transfer following prior RTND to the ipsilateral side of vessel anastomosis. Pretreatment data, free flap type, defect site, and recipient vessel choice were reported. Recipient vessel choice was stratified according to neck dissection level and prior free flap. Primary outcome was free flap survival (total failure, partial failure, success) within 30 days after surgery. RESULTS: This study included 72 free flap cases in 68 patients. Free flap success was 94.4%; one case (1.4%) resulted in total flap loss and three cases (4%) had partial flap loss. The facial (35%), external carotid (ECA) (25%), and superior thyroid arteries (16%) were the most common recipient arteries. The external jugular (EJV) (38%), facial (30%), and internal jugular veins (IJV) (15%) were the most common recipient veins. The superior thyroid artery was used less frequently with a prior level 2-3/4 neck dissection compared to a prior level 1-3/4 neck dissection (6% vs. 17%, p = 0.83). The facial artery (7% vs. 67%, p < 0.01) and vein (13% vs. 46%, p = 0.04) were used less frequently when a prior free flap with ipsilateral anastomosis was performed. The superior thyroid, ECA, IJV, and EJV were more commonly used in this subgroup. CONCLUSION: Free tissue transfer with infield microvascular anastomosis in a neck with prior RTND can be safely done with comparable outcomes to surgically naïve, non-irradiated necks.

Infection Control With Topical Antimicrobial Prophylaxis for Mucosal Head and Neck Surgery: A Meta-analysis.

OBJECTIVE: To assess for differences in surgical site infection (SSI) rates and bacterial load after major mucosal head and neck surgery between patients who received topical antimicrobial prophylaxis and those who did not. DATA SOURCES: Ovid Medline, Embase, SCOPUS, Cochrane Library, and ClinicalTrials.gov from inception to May 20, 2021, with cross-referencing of retrieved studies per PRISMA guidelines. REVIEW METHODS: Inclusion criteria captured clinical trials, cohort studies, and case-control studies with infectious outcomes of adults who underwent major mucosal head and neck surgery and received perioperative topical antimicrobial therapy to the oral cavity and/or pharynx. Studies of dental procedures were excluded. The primary outcome was SSI rate, and the secondary outcome was bacterial load. Two blinded investigators screened each text. RESULTS: Of 265 unique citations, 9 studies of 470 total patients were included. Topical treatments included numerous antibiotics and antiseptics directly applied over mucosa. Pooled SSI rates of 252 patients in the intervention cohort and 218 in the control cohort were 8% (95% CI, 3%-14%; I 2 = 61.2%) and 29% (95% CI, 16%-43%; I 2 = 79.5%), respectively. A meta-analysis of 7 comparative studies totaling 192 patients receiving topical therapy and 218 control patients revealed a pooled relative risk of 0.44 (95% CI, 0.28-0.68; I 2 = 0.0%) in favor of the treatment group. The studies demonstrated a short-term decrease in bacterial counts after topical antimicrobial prophylaxis. CONCLUSION: Patients who underwent prophylactic topical antimicrobial therapy had less than half the risk of developing SSI after mucosal head and neck surgery when compared with those who received no topical prophylaxis.

Practice patterns in transoral robotic surgery: results of an American head and neck society survey.

To understand perioperative practices for transoral robotic surgery (TORS) among academic medical centers. An electronic cross-sectional survey was distributed to fellows and program directors participating in 49 American Head and Neck Society fellowships. Operative decisions, medical and swallowing management, and disposition planning were assessed. Thirty-eight responses were collected (77.6%). Twenty-three centers (60.5%) performed > 25 cases annually with the remainder performing fewer. The da Vinci Si was the most commonly used platform (n = 28, 73.7%). A majority of institutions advocated tailored resection to adequate margins (n = 27, 71.1%) over fixed subunit-based resection (n = 11, 28.9%). Most surgeons (n = 29, 76.3%) performed neck dissection concurrent with TORS, and 89.5% (n = 34) routinely ligated external carotid artery branches. A minority of institutions (n = 17, 45.9%) endorsed a standardized TORS care pathway. Antibiotic choices and duration varied, the most common choice being ampicillin/sulbactam (n = 21, 55.3%), and the most common duration being 24 h or less (n = 22, 57.9%). Multimodal analgesia was used at 36 centers (94.7%), steroids at 31 centers (81.6%), and pharmacologic venous thromboembolic prophylaxis at 29 centers (76.3%). Nasogastric feeding tubes were placed during surgery at 20 institutions (54.1%). Speech-language pathologists routinely performed postoperative swallow evaluations at 29 (78.4%) sites. Practice patterns are variable among institutions performing TORS. While certain surgical and postoperative practices were quite common, many institutions reported no standard TORS care pathway. Further understanding of the impact of individual practices on outcomes is necessary to develop evidence-based perioperative protocols for TORS.

Comparison of Absolute Expression and Turnover Number of COX-1 and COX-2 in Human and Rodent Cells and Tissues.

Objective: We aim to quantify the absolute protein expression of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) in various cells and tissues to determine the relative contribution of COX-1 and COX-2 to PGE2 production. Methods: An LC-MS method was developed and validated, then used for quantifying the absolute amounts of COX-1 and COX-2 in recombinant human COX-1 and COX-2, lysates from different cells, tissue microsomes of rodents and humans, Pirc rat colonic polyps, and biopsy specimens from squamous cell carcinoma (SCC) patients. The COX-1 and COX-2 turnover numbers were subsequently calculated based on apparent formation rates of PGE2. Results: A robust LC-MS method for quantification of COX-1 and COX-2 was developed and validated and then used to calculate their apparent turnover numbers. The results showed that COX-1 expression levels were much higher than that of COX-2 in all the tested tissues including the colonic epithelium of F344 (28-fold) and Pirc rats (20-fold), colonic polyps of Pirc rats (8-fold), and biopsy specimens of SCC patients (11-17-fold). In addition, both COX-1 and COX-2 were higher in polyps when compared to adjacent mucosa of Pirc rats. The turnover number of recombinant human COX-2 was 14-fold higher than that of recombinant human COX-1. LPS stimulation increased COX-2 protein expression in three cell lines (Raw 264.7, SCC9 and EOMA) as expected but unexpectedly increased COX-1 protein expression (13.8-fold) in EOMA cells. Conclusion: In human oral cancer tissues and cells as well as Pirc rat colon, COX-1 plays an unexpectedly but more important role than COX-2 in abnormal PGE2 production since COX-1 expression is much higher than COX-2. In addition, COX-1 expression levels are inducible in cells, and higher in polyps than surrounding mucosa in Pirc rat colon. These results indicate that targeted suppression of local COX-1 should be considered to reduce colon-specific PGE2-mediated inflammation.

A phase 2 trial of a topical antiseptic bundle in head and neck cancer surgery: Effects on surgical site infection and the oral microbiome.

BACKGROUND: Head and neck cancer (HNC) surgery remains an important component of management but is associated with a high rate of surgical site infection (SSI). We aimed to assess the safety and efficacy of a topical mucosal antiseptic bundle in preventing SSI and evaluate microbial predictors of infection through a genomic sequencing approach. METHODS: This study was an open-label, single-arm, single-center, phase 2 trial of a topical mucosal antiseptic bundle in patients with HNC undergoing aerodigestive tract resection and reconstruction. Patients underwent topical preparation of the oral mucosa with povidone-iodine (PI) and chlorhexidine gluconate (CHG) pre- and intra-operatively followed by oral tetracycline ointment every 6 hours for 2 days post-operatively. The primary outcome was change in bacterial bioburden at the oral surgical site. Secondary outcomes included safety, SSI, and microbial predictors of infection. FINDINGS: Of 27 patients screened between January 8, 2021, and May 14, 2021, 26 were enrolled and 25 completed the study. There were no antiseptic-related adverse events. The topical mucosal antiseptic bundle significantly decreased oral bacterial colony-forming units from pre-operative levels (log10 mean difference 4·03, 95%CI 3·13-4·;92). There were three SSI (12%) within 30 days. In correlative genomic studies, a distinct set of amplicon sequence variants in the post-operative microbiome was associated with SSI. Further, despite no instance of post-operative orocervical fistula, metagenomic sequence mapping revealed the oral cavity as the origin of the infectious organism in two of the three SSI. INTERPRETATION: The bacterial strains which subsequently caused SSI were frequently identified in the pre-operative oral cavity. Accordingly, a topical antiseptic bundle decreased oral bacterial bioburden throughout the peri-operative period and was associated with a low rate of SSI, supporting further study of topical antisepsis in HNC surgery. FUNDING: Alliance Oncology.

Free Flap Reconstruction of the Anterior Skull Base: A Systematic Review.

Objectives Given the limitations in the available literature, the precise indications, techniques, and outcomes of anterior skull base free flap reconstruction remain uncertain. The objective of this study was to perform a systematic review of published literature and evaluate indications, methods, and complications for anterior skull base free flap reconstruction. Methods A systematic review of the literature was performed using a set of search criteria to identify patients who underwent free flap reconstruction of the anterior skull base. Articles were reviewed for inclusion based on relevance, with the primary outcome being surgical complications. Results After a comprehensive search, 406 articles were obtained and 16 articles were ultimately found to be relevant to this review-79 patients undergoing free flap reconstruction were identified. Overall complication rates were 17.7% (95% confidence interval [CI]: 16.6-33.1%) for major complications and 19.0% (95% CI: 17.8-35.5%) for minor complications. Conclusion Microvascular reconstruction of the anterior skull base is feasible with high reliability reported in the literature.

Perioperative Topical Antisepsis and Surgical Site Infection in Patients Undergoing Upper Aerodigestive Tract Reconstruction.

Importance: Surgical site infections (SSIs) after vascularized reconstruction of the upper aerodigestive tract (UADT) are associated with considerable morbidity. The association between perioperative prophylaxis practices, particularly topical antisepsis, and SSIs remains uncertain. Objective: To assess the association between perioperative topical antisepsis and SSIs in patients undergoing vascularized reconstruction of the UADT. Design, Setting, and Participants: This cohort study included patients from 12 academic tertiary care centers over an 11-month period, from July 1, 2020, to June 1, 2021. Patients undergoing open surgical procedures requiring a communication between the UADT and cervical skin with a planned regional pedicled flap, free flap, or both were included. Patients with an active infection at the time of surgical procedure were excluded. Main Outcomes and Measures: The primary outcome measure was an SSI within 30 days of surgery. The association of demographic characteristics, perioperative antibiotic prophylaxis, surgical technique, and postoperative care with SSIs was assessed using univariable and multivariable analyses. The relative risk ratio and 95% CIs for developing SSI were calculated for each of the variables based on predetermined categories. Variables for which the relative risk 95% CI did not include the value of zero effect (relative risk = 1.00) were included in the multivariable model. Results: A total of 554 patients (median age, 64 years; range, 21-95 years; 367 men [66.2%]) were included. Cancer ablation was the most frequent reason for surgery (n = 480 [86.6%]). Overall, the SSI rate was 20.9% (n = 116), with most infections involving the head and neck surgical site only (91 [78.4%]). The median time to SSI diagnosis was 11 days (range, 1-28 days). Topical antisepsis mucosal preparation was performed preoperatively in 35.2% (195) and postoperatively in 52.2% (289) of cases. Ampicillin and sulbactam was the most common systemic antibiotic prophylaxis agent used (n = 367 [66.2%]), with 24 hours being the most common duration (n = 363 [65.5%]). On multivariable analysis, preoperative topical antisepsis mucosal preparation (odds ratio [OR], 0.49; 95% CI, 0.30-0.77) and systemic prophylaxis with piperacillin and tazobactam (OR, 0.42; 95% CI, 0.21-0.84) were associated with a decreased risk of a postoperative SSI. The use of an osseous vascularized flap was associated with an increased risk of postoperative SSI (OR, 1.76; 95% CI, 1.13-2.75). Conclusions and Relevance: Findings of this study suggest that preoperative topical antisepsis mucosal preparation was independently associated with a decreased risk of SSIs in a 12-center multi-institutional cohort. Further investigation of the association between individual perioperative practices and the incidence of postoperative SSIs is necessary to develop evidence-based protocols to reduce SSIs after UADT reconstruction.

Chronic stress promotes an immunologic inflammatory state and head and neck cancer growth in a humanized murine model.

BACKGROUND: Despite the importance of immune response and environmental stress on head and neck cancer (HNC) outcomes, no current pre-clinical stress model includes a humanized immune system. METHODS: We investigated the effects of chronic stress induced by social isolation on tumor growth and human immune response in subcutaneous HNC tumors grown in NSG-SGM3 mice engrafted with a human immune system. RESULTS: Tumor growth (p < 0.0001) and lung metastases (p = 0.035) were increased in socially isolated versus control animals. Chronic stress increased intra-tumoral CD4+ T-cell infiltrate (p = 0.005), plasma SDF-1 (p < 0.0001) expression, and led to tumor cell dedifferentiation toward a cancer stem cell phenotype (CD44+ /ALDHhigh , p = 0.025). CONCLUSIONS: Chronic stress induced immunophenotypic changes, increased tumor growth, and metastasis in HNC in a murine model with a humanized immune system. This model system may provide further insight into the immunologic and oncologic impact of chronic stress on patients with HNC.

Retrospective analysis of post-tracheostomy complications.

OBJECTIVE: To elucidate patient, disease, and surgical factors that are significantly associated with 90-day tracheostomy complications, readmissions, and mortality. STUDY DESIGN: Retrospective case series with chart review. SETTING: A single academic tertiary care center between 2011 and 2018. METHODS: Patients who underwent tracheostomy by any technique for any indication were included. Demographic, disease, and operative details were examined. Multivariable analysis was performed to determine factors associated with 90-day complications, 90-day readmissions, and overall mortality. RESULTS: 697 patients were included. 75% of patients had severe comorbidity (ACE-27 score of 3).1 Patients were intubated for 12 days prior to tracheostomy placement on average. The primary indication was ventilator dependence due to critical illness (85%). 74% were performed open and 26% percutaneous. 10% of patients had a tracheostomy-related complication within 90 days. Complications occurred at a median of post-operative day 11, and hemorrhage was most common (n = 35). 14 patients required immediate return to the operating room, and 3 patients died of their complication, all within 3 days of tracheostomy placement. 40% of patients undergoing tracheostomy died within 30 days. In multivariable analysis, only a documented difficult tracheostomy placement was significantly associated with a 90-day complication. CONCLUSIONS: While complications after tracheostomy are infrequent, they are often severe. A heightened level of preparedness to immediately manage accidental tracheostomy decannulation or hemorrhage is required for patients with a difficult tracheostomy placement. 30-day mortality is high, which reinforces the need for multi-disciplinary evaluation, including palliative care, to determine appropriate candidacy for tracheostomy.

Practice patterns of virtual surgical planning: Survey of the reconstructive section of the American Head and Neck Society.

PURPOSE: Virtual surgical planning (VSP), with custom made implants and guides represents a recent major advance. Nonetheless, knowledge related to practice patterns is limited. The purpose of this study was to provide data from the AHNS Reconstruction Section related to practice patterns, perceived value of VSP, as well as elucidate specific situations which represent high value for the application of VSP. MATERIALS AND METHODS: A multi-center web-based survey consisting of 30 questions regarding practice patterns related to VSP practices delivered via email to 203 members of the AHNS Reconstructive Surgery Section at institutions across North America. RESULTS: There was a 34% response rate (70/203). A majority of the respondents (96%) used VSP in approximately 50% of their mandibular reconstruction cases, and in 42% of maxillary cases. 46% reported using patient specific implants >75% of cases. Respondents estimated that ~17% of patients received dental implant reconstruction. The majority of respondents (71.0%) did not know the cost of VSP at their institution. The remaining respondents indicated the average cost was $6680 per case. VSP was felt to be necessary as a teaching tool by 55.9%. CONCLUSIONS: Our results demonstrate that a majority of respondents frequently utilize VSP in their practice for head and neck reconstruction. Complex, multi-unit reconstructions were felt to offer the greatest value when utilizing VSP. Future work should focus on increasing the rates of dental implant reconstruction in this population, optimizing value of VSP with careful case selection, and understanding the educational value and costs of these platforms.

Management of Flap Failure After Head and Neck Reconstruction: A Systematic Review and Meta-analysis.

OBJECTIVE: To systematically review management of flap loss in head and neck construction with free tissue transfer as compared with locoregional flap or conservative management. DATA SOURCES: Medline, Embase, Scopus, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and ClinicalTrials.gov were searched up to October 2019. REVIEW METHODS: Candidate articles were independently reviewed by 2 authors. Articles were considered eligible if they included adequate reporting of flap management after flap loss and outcomes for survival of reconstruction, length of hospitalization, and perioperative complications. RESULTS: A total of 429 patients had acute flap failure in the perioperative period. The overall success with a secondary free flap was 93% (95% CI, 0.89-0.97; n = 26 studies, I2 = 12.8%). There was no difference in hospitalization length after secondary reconstruction between free tissue transfer and locoregional flaps or conservative management (relative risk of hospitalization ≥2 weeks, 96%; 95% CI, 0.80-1.14; n = 3 studies, I2 = 0). The pooled relative risk of perioperative complications following free tissue transfer was 0.60 when compared with locoregional flap or conservative management (95% CI, 0.40-0.92; n = 5 studies, I2 = 0). CONCLUSION: Salvage reconstruction with free tissue transfer has a high success rate. Second free flaps following flap failure had a similar length of hospitalization and lower overall complication rate than locoregional reconstruction or conservative management. A second free tissue transfer, when feasible, is likely a more reliable and effective procedure for salvage reconstruction.