Single versus Double Drainage for Immediate Two-Stage Implant-Based Breast Reconstruction: A Propensity Score-Matched Analysis.

BACKGROUND: Reports evaluating plastic surgeons' practices indicate there are conflicting trends regarding the use of one or two drains for implant-based breast reconstruction (IBBR). Our study aimed to perform a matched cohort analysis to examine the postoperative outcomes and complications of immediate IBBR with tissue expander (TE) using two drains versus a single drain. METHODS: A propensity score-matched analysis (nearest neighbor, 1:1 matching) of immediate reconstructions using two versus one drain was conducted. Female patients undergoing immediate two-stage IBBR with TEs between January 2011 and May 2021 were included. The covariables were as follows: BMI, mastectomy weight, lymph node surgery, TE surface, plane of reconstruction, use of acellular dermal matrix products, fluorescence imaging use, and intraoperative TE volume. RESULTS: After matching using propensity scores, 192 reconstructions were included in the final analysis: 96 in each group. The rate of 30-day complications and overall complications during the first phase of IBBR were comparable between groups. The time for drain removal, time to initiate and finalize expansions, and time for TE-to-implant exchange were comparable between groups. Diabetes (OR 3.74, p = 0.025) and an increased estimated blood loss (OR 1.004, p = 0.01) were the only independent predictors for seroma formation. CONCLUSION: In this matched cohort analysis evaluating the role of one versus two drains for two-stage IBBR, we found a comparable rate of complications and surgical outcomes between the two cohorts. Using two drains for immediate IBBR needs to be tailored depending on intraoperative findings. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Predictors for Prolonged TE-to-Implant Exchange During Implant-Based Breast Reconstruction: A Single Institution Experience.

BACKGROUND: There is limited evidence regarding the factors causing a prolonged time for tissue expander (TE) exchange into a definitive implant using two-stage implant-based breast reconstruction (IBBR). This study aimed to review our experience with IBBR, focusing on the time for TE-to-implant exchange and determining which factors cause a prolonged time for exchange. METHODS: A retrospective review was performed to include women undergoing immediate two-stage IBBR with TEs after total mastectomy between January 2011 and May 2021. Reconstructions with irradiated TEs were excluded. Cases that had a prolonged time for TE-to-implant exchange were defined as those undergoing exchange longer than 232 days, which corresponds to the 75th percentile of the overall study group. RESULTS: We included 442 reconstructions in our analysis. The median age for our series was 51 years and the median body mass index was 26.43-kg/m2. The median time for TE-to-implant exchange was 155 days [IQR, 107-232]. Cases that had a prolonged time for TE-to-implant exchange were defined as those undergoing exchange on postoperative day 232 or afterward. Diabetes (OR 4.05, p = 0.006), neoadjuvant chemotherapy (OR 2.76, p = 0.006), an increased length of stay (OR 1.54, p = 0.013), and a lengthier time to complete outpatient expansions (OR 1.018, p < 0.001) were independently associated with a prolonged time for exchange. CONCLUSION: As evident from our analysis, the time for exchange is highly heterogeneous among patients. Although several factors affect the timing for TE-to-implant exchange, efforts must be directed to finalize outpatient expansions as soon as possible to expedite the transition into a definitive implant. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Simultaneous Fat Grafting During Tissue Expander-to-Implant Exchange: A Propensity Score-Matched Analysis.

BACKGROUND: Implant-based breast reconstruction (IBBR) is the most common technique for breast reconstruction. The primary resource for correcting deformities, once patients have achieved an adequate volume with two-stage IBBR, is autologous fat grafting. We compared the surgical outcomes of simultaneous fat grafting during TE-to-implant exchange (SFG + TtIE) versus no fat grafting during TE-to-implant exchange (No-FGX). METHODS: A retrospective review was performed of all consecutive patients undergoing two-stage implant-based breast reconstruction with TE from January 2011 to December 2020. Propensity score matching was implemented to optimize comparability. The control group did not receive fat grafting at the time of TE-to-implant exchange. RESULTS: After propensity score matching, 196 reconstructions were evaluated, 98 in each group. Reconstructions in the SFG + TtIE received larger implants during exchange in comparison with the No-FGX group (539 ± 135.1-cc versus 495.97 ± 148-cc, p=0.035). The mean volume of fat lipoinjected during TE-to-implant exchange in the SFG + TtIE group was 88.79 ± 41-ml. A higher proportion of reconstructions in the SFG + TtIE group underwent additional fat grafting after exchange versus the No-FGX group (19% versus 9%, p = 0.041). After propensity score matching, only the rate of fat necrosis after exchange was significantly higher in the SFG + TtIE group (10% versus 2%, p = 0.017). The rate of breast cancer recurrence (3% versus 5%, p = 1.00) was comparable between the groups. CONCLUSION: SFG + TtIE is a safe procedure to improve the envelope of reconstructed breasts during two-stage IBBR. SFG + TtIE does not increase the rate of periprosthetic infection or wound-related complication versus no fat grafting during TE-to-implant exchange, but increases the rate of fat necrosis. LEVEL OF EVIDENCE III: Therapeutic study. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Thinking Small: Small Molecules as Potential Synergistic Adjuncts to Checkpoint Inhibition in Melanoma.

Metastatic melanoma remains the deadliest form of skin cancer. Immune checkpoint inhibition (ICI) immunotherapy has defined a new age in melanoma treatment, but responses remain inconsistent and some patients develop treatment resistance. The myriad of newly developed small molecular (SM) inhibitors of specific effector targets now affords a plethora of opportunities to increase therapeutic responses, even in resistant melanoma. In this review, we will discuss the multitude of SM classes currently under investigation, current and prospective clinical combinations of ICI and SM therapies, and their potential for synergism in melanoma eradication based on established mechanisms of immunotherapy resistance.

Microspheres Encapsulating Immunotherapy Agents Target the Tumor-Draining Lymph Node in Pancreatic Ductal Adenocarcinoma.

INTRODUCTION: The tumor-draining lymph node (TDLN) plays a role in tumor immunity. Intratumorally administered microspheres (MS) that encapsulate immunomodulatory agents have emerged as a treatment strategy capable of causing profound changes in the tumor microenvironment (TME) and eliciting potent antitumor effects. We hypothesized that local delivery of MS to the TME may also drain to and therefore target the TDLN to initiate antitumor immune responses. METHODS: Fluorescent MS were injected into orthotopically implanted murine pancreatic tumors, and tissues were examined by whole-mount microscopy and imaging flow cytometry. The role of the TDLN was investigated for mice treated with intratumoral interleukin-12 (IL-12)-encapsulated MS in combination with stereotactic body radiotherapy (SBRT) by cytokine profile and TDLN ablation. RESULTS: Fluorescent AF-594 MS delivered intratumorally were detected in the tumor, peritumoral lymphatics, and the TDLN 2 h after injection. Phagocytic cells were observed with internalized fluorescent MS. SBRT + IL-12 MS-induced upregulation of Th1 and antitumor factors IL-12, IFN-γ, CXCL10, and granzyme B in the TDLN, and excision of the TDLN partially abrogated treatment efficacy. CONCLUSIONS: Our results demonstrate that intratumorally administered MS not only target the TME, but also drain to the TDLN. Furthermore, MS encapsulated with a potent antitumor cytokine, IL-12, induce an antitumor cytokine profile in the TDLN, which is essential for treatment efficacy.

Toxic epidermal necrolysis after radiotherapy for pleomorphic liposarcoma.

Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are life-threatening, cutaneous reactions often associated with culprit drugs. A growing body of knowledge has deepened our understanding of the pathophysiology and clarified mechanisms such as drug-specific cytotoxicity mediated by T-cells, genetic linkage with HLA and non-HLA genes, TCR restriction, and cytotoxicity mechanisms. Physicians should broadly consider the etiology of SJS/TEN in order to better understand treatment strategies as well as identify which patients may be at risk for developing this condition. Mechanisms for how radiotherapy and rare malignancies may contribute to the development of TEN and SJS have been proposed.

Neoadjuvant plus adjuvant dabrafenib and trametinib versus standard of care in patients with high-risk, surgically resectable melanoma: a single-centre, open-label, randomised, phase 2 trial.

BACKGROUND: Dual BRAF and MEK inhibition produces a response in a large number of patients with stage IV BRAF-mutant melanoma. The existing standard of care for patients with clinical stage III melanoma is upfront surgery and consideration for adjuvant therapy, which is insufficient to cure most patients. Neoadjuvant targeted therapy with BRAF and MEK inhibitors (such as dabrafenib and trametinib) might provide clinical benefit in this high-risk p opulation. METHODS: We undertook this single-centre, open-label, randomised phase 2 trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Eligible participants were adult patients (aged ≥18 years) with histologically or cytologically confirmed surgically resectable clinical stage III or oligometastatic stage IV BRAFV600E or BRAFV600K (ie, Val600Glu or Val600Lys)-mutated melanoma. Eligible patients had to have an Eastern Cooperative Oncology Group performance status of 0 or 1, a life expectancy of more than 3 years, and no previous exposure to BRAF or MEK inhibitors. Exclusion criteria included metastases to bone, brain, or other sites where complete surgical excision was in doubt. We randomly assigned patients (1:2) to either upfront surgery and consideration for adjuvant therapy (standard of care group) or neoadjuvant plus adjuvant dabrafenib and trametinib (8 weeks of neoadjuvant oral dabrafenib 150 mg twice per day and oral trametinib 2 mg per day followed by surgery, then up to 44 weeks of adjuvant dabrafenib plus trametinib starting 1 week after surgery for a total of 52 weeks of treatment). Randomisation was not masked and was implemented by the clinical trial conduct website maintained by the trial centre. Patients were stratified by disease stage. The primary endpoint was investigator-assessed event-free survival (ie, patients who were alive without disease progression) at 12 months in the intent-to-treat population. This trial is registered at ClinicalTrials.gov, number NCT02231775. FINDINGS: Between Oct 23, 2014, and April 13, 2016, we randomly assigned seven patients to standard of care, and 14 to neoadjuvant plus adjuvant dabrafenib and trametinib. The trial was stopped early after a prespecified interim safety analysis that occurred after a quarter of the participants had been accrued revealed significantly longer event-free survival with neoadjuvant plus adjuvant dabrafenib and trametinib than with standard of care. After a median follow-up of 18·6 months (IQR 14·6-23·1), significantly more patients receiving neoadjuvant plus adjuvant dabrafenib and trametinib were alive without disease progression than those receiving standard of care (ten [71%] of 14 patients vs none of seven in the standard of care group; median event-free survival was 19·7 months [16·2-not estimable] vs 2·9 months [95% CI 1·7-not estimable]; hazard ratio 0·016, 95% CI 0·00012-0·14, p<0·0001). Neoadjuvant plus adjuvant dabrafenib and trametinib were well tolerated with no occurrence of grade 4 adverse events or treatment-related deaths. The most common adverse events in the neoadjuvant plus adjuvant dabrafenib and trametinib group were expected grade 1-2 toxicities including chills (12 patients [92%]), headache (12 [92%]), and pyrexia (ten [77%]). The most common grade 3 adverse event was diarrhoea (two patients [15%]). INTERPRETATION: Neoadjuvant plus adjuvant dabrafenib and trametinib significantly improved event-free survival versus standard of care in patients with high-risk, surgically resectable, clinical stage III-IV melanoma. Although the trial finished early, limiting generalisability of the results, the findings provide proof-of-concept and support the rationale for further investigation of neoadjuvant approaches in this disease. This trial is currently continuing accrual as a single-arm study of neoadjuvant plus adjuvant dabrafenib and trametinib. FUNDING: Novartis Pharmaceuticals Corporation.

H-Scan Discrimination for Tumor Microenvironmental Heterogeneity in Melanoma.

OBJECTIVE: Melanoma is a form of malignant skin cancer that exhibits significant inter-tumoral differences in the tumor microenvironment (TME) secondary to genetic mutations. The heterogeneity may be subtle but can complicate the treatment of metastatic melanoma, contributing to a high mortality rate. Therefore, developing an accurate and non-invasive procedure to discriminate microenvironmental heterogeneity to facilitate therapy selection is an important goal. METHODS: In vivo murine melanoma models that recapitulate human disease using synchronous implanted YUMM 1.7 (Yale University Mouse Melanoma) and YUMMER 1.7 (Yale University Mouse Melanoma Exposed to Radiation) murine melanoma lines were investigated. Mice were treated with antibodies to modulate the immune response and longitudinally scanned with ultrasound (US). US radiofrequency data were processed using the H-scan analysis, attenuation estimation and B-mode processing to extract five US features. The measures were used to compare different TMEs (YUMMER vs. YUMM) and responses to immunomodulatory therapies with CD8 depletion or programmed cell death protein 1 (PD-1) inhibition. RESULTS: Multiparametric analysis produced a combined H-scan parameter, resolving significant differences (i) between untreated YUMMER and YUMM and (ii) between untreated, PD-1-treated and CD8-treated YUMMER. However, more importantly, the B-mode and attenuation measures failed to differentiate YUMMER and YUMM and to monitor treatment responses, indicating that H-scan is required to differentiate subtle differences within the TME. CONCLUSION: We anticipate that the H-scan analysis could discriminate heterogeneous melanoma metastases and guide diagnosis and treatment selection, potentially reducing the need for invasive biopsies or immunologic procedures.

Two-Stage Implant-Based Breast Reconstruction Using Intraoperative Fluorescence Imaging: A Propensity Score-Matched Analysis.

BACKGROUND: Limited comparability between study groups can generate significant selection and observer bias when evaluating the efficacy of the SPY system and fluorescence imaging for implant-based breast reconstruction. In this study, the authors compared the surgical outcomes and complications during the first stage of reconstruction between reconstructions evaluated intraoperatively with fluorescence imaging using the SPY system and clinical assessment using a matched analysis. METHODS: The authors conducted a retrospective review of patients undergoing total mastectomy and immediate two-stage implant-based breast reconstruction with TEs from January of 2011 to December of 2020. The rate of complication, time for TE-to-implant exchange, and time to start radiotherapy were compared between groups (intraoperative fluorescence imaging versus clinical assessment) using a propensity score-matched analysis. RESULTS: After propensity score matching, 198 reconstructions were evaluated. There were 99 reconstructions in each group. The median time for TE-to-implant exchange (140 days versus 185 days; P = 0.476) and time to initiate adjuvant radiotherapy (144 days versus 98 days; P = 0.199) were comparable between groups. The 30-day rate of wound-related complications (21% versus 9%; P = 0.017) and 30-day rate of wound-related unplanned interventions were significantly higher in reconstructions evaluated with clinical assessment when compared with the SPY system (16% versus 5%; P = 0.011). A higher 30-day rate of seroma (19% versus 14%; P = 0.041) and hematoma (8% versus 0%; P = 0.004) were found in reconstructions assessed intraoperatively with the SPY system. CONCLUSIONS: After matching, reconstructions evaluated with fluorescence imaging exhibited a lower incidence of early wound-related complications when compared with clinical evaluation alone. Nonetheless, the Wise pattern for mastectomy was found to be the only independent predictor associated with early wound-related complications. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Breast reconstruction with latissimus dorsi flap: a comprehensive review and case series.

The latissimus dorsi flap (LDF) has gained popularity given its versatile nature and broad applicability in breast reconstruction. Its resurgence has been attributed to its ability to be enhanced using implant or high-volume fat grafting, rendering it a primary option for selected patients. The aim of this review is to tackle current indications and subjects of controversy regarding use of complete-autologous and implant-enhanced LDF in breast reconstruction. Also, a case-series showcasing the authors' experience with this versatile reconstructive option is presented. A search across Web of Science and PubMed MEDLINE from inception through January 3, 2023, was conducted. Articles reporting postoperative outcomes of autologous breast reconstruction with LDF were included. Regarding the case series, electronic medical records of patients who underwent total mastectomy and autologous breast reconstruction with LDF from January 2011 to December 2021 were retrospectively reviewed. Data on demographic and oncologic characteristics, and surgical characteristics and outcomes were extracted. Our review suggests that LDF is suitable for patients who lack alternative donor site, have a history of abdominoplasty or no access to microsurgery, smokers or obese. Latissimus dorsi (LD) harvesting has almost complete shoulder function recovery in the long-term. Thoracodorsal nerve division does not cause volume loss or animation deformity. Multisite multilayer fat grafting, beveling the edges of the skin paddle and fat, folding the LD muscle and plicating the paddle allow adequate projection and contour achievement. Our case-series included 234 reconstructions. Almost half of the patients had immediate fat transfer during reconstruction (51.3%). The rate of recipient site hematoma was 3.0%, seroma was 7.7%, wound disruption 32.1%, wound disruption events requiring unplanned procedures was 13.7%, and surgical site infection (SSI) was 12.4%. The LDF is reliable and safe for immediate or delayed breast reconstruction or salvage after reconstruction failure. Its versatility, reliable anatomy, easy dissection, and relative low complication rate have revived this modality as valuable opportunity for breast reconstruction in this era.

Prepectoral versus subpectoral two-stage implant-based breast reconstruction: U.S. medical center experience and narrative review.

Background and Objective: With the incorporation of autologous fat grafting, acellular dermal matrix (ADM) products, and nipple-sparing mastectomy, prepectoral device placement has become more popular in selected patients when compared to partial submuscular (dual plane) or complete submuscular device placement. In this article, we aimed to present a review of the current state-of-the-art for implant-based breast reconstruction (IBBR) using expanders. Additionally, we present a case series of our experience with IBBR evaluating perioperative outcomes, complications, and patient-reported outcomes (PRO). Methods: For our series, we retrospectively evaluated adult female patients undergoing 2-stage immediate IBBR after total mastectomy between 2011 and 2021. We performed a systematic search across PubMed MEDLINE for articles evaluating outcomes of prepectoral versus subpectoral two-stage IBBR with expanders published from database inception through February 28th, 2023. Key Content and Findings: Both prepectoral and subpectoral are safe alternatives for two-stage IBBR. Due to current advancements in the field of breast reconstruction, prepectoral IBBR has gained popularity and has a comparable rate of complications compared to a subpectoral approach in selected patients according to high-quality articles. In patients with several comorbidities, current tobacco use, history of preoperative radiation, and limited perfusion of the mastectomy flaps, subpectoral device placement should be given special consideration as a layer of vascularized tissue can decrease the risk of major complications or unplanned procedures. As prepectoral device placement does not require dissection of the pectoral muscles, faster recovery, better implant position, decreased pain, and a shorter time to complete expansion is expected. The plane of reconstruction does not seem to significantly affect the time for expander-to-implant exchange or PRO for quality-of-life (QOL) according to most studies. Conclusions: Prepectoral and subpectoral IBBR demonstrated a comparable rate of complications in selected patients. Nonetheless, perioperative outcomes seem to be improved using a prepectoral approach in terms of reduced pain, reduced time to conclude outpatient expansions, and less animation deformity.

Subpectoral versus prepectoral two-stage breast reconstruction: A propensity score-matched analysis of 30-day morbidity and long-term outcomes.

BACKGROUND: Approximately 80% of patients undergoing total mastectomy in the US opt for implant-based breast reconstruction (IBBR). A two-stage reconstruction with tissue expander (TE) remains the most common technique. Since the implementation of ADMs, a prepectoral approach has gained popularity and is becoming the standard of care. Herein, we compared the surgical and postoperative outcomes of prepectoral versus subpectoral two-stage IBBR. METHODS: A retrospective chart review was performed between January 2011 and December 2020. We included female patients undergoing immediate two-stage IBBR. The primary outcomes of this study were to compare the 30-day morbidity and the overall rate of complications during the first and second stages of reconstruction, and to compare the time to initiate postmastectomy radiotherapy (PMRT). Propensity score matching was implemented. RESULTS: After matching, 154 reconstructions were analyzed, 77 in each group. The two matched groups exhibited comparable (p > 0.05) characteristics for all analyzed demographic and intraoperative independent variables. Reconstructions in the prepectoral group had a shortened median time for drain removal (13-days vs. 15-days, p = 0.001). The intraoperative expansion volumes were higher in the prepectoral group (300 ml versus 200 ml, p = 0.025). The 30-day morbidity and first- and second-stage complication rates were not significantly different between groups. The time to start postmastectomy radiation therapy (PMRT) was not significantly different between groups (134-days versus 126.5-days, p = 0.58). CONCLUSION: Prepectoral and subpectoral TE placement had comparable complication rates during the first and second stages of IBBR. Timing for TE-to-Implant exchange and initiation of PMRT were comparable between the two approaches.

Wise Pattern versus Transverse Pattern Mastectomy in Two-Stage Implant-Based Breast Reconstruction: A Propensity Score-Matched Analysis.

BACKGROUND: The Wise pattern adapted to mastectomy incisions has become a valuable asset for breast reconstruction in patients with large and ptotic breasts. The authors compared the time for exchange, time to initiate postmastectomy radiotherapy, and complication rates between Wise pattern and transverse incision pattern reconstructions. METHODS: Records of patients who underwent immediate, two-stage, implant-based breast reconstruction (IBBR) between January of 2011 and December of 2020 were retrospectively reviewed. Two cohorts were compared according to the incision pattern: Wise pattern versus transverse incision pattern. Complications were compared after propensity score matching. RESULTS: The authors initially analyzed 393 two-stage immediate IBBRs in 239 patients [91 IBBRs (23.2%) in the Wise pattern group and 302 (76.8%) in the transverse pattern group]. Expansion time (53 days versus 50 days, P = 0.9), time for tissue expander-to-implant exchange (154 versus 175 days, P = 0.547), and time to initiate postmastectomy radiotherapy (144 days versus 126 days, P = 0.616) were not different between groups. Before propensity score matching, the 30-day rate of wound-related complications (32% versus 10%, P < 0.001) and the 30-day rate of wound complications requiring excision/débridement and closure procedures (20% versus 7%, P < 0.001) were significantly higher in the Wise pattern group. After propensity score matching, the 30-day rate of wound complications was persistently higher (25% versus 10%, P = 0.03) in the Wise pattern group. CONCLUSIONS: The Wise pattern mastectomy independently increases the incidence of wound-related complications versus only transverse patterns during two-stage IBBR, even after propensity score matching. Delayed tissue expander placement may improve the safety profile of this procedure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Reconstruction of Pharyngolaryngeal Defects with the Ileocolon Free Flap: A Comprehensive Review and How to Optimize Outcomes.

Several reconstructive methods have been reported to restore the continuity of the aerodigestive tract following resection of pharyngeal and hypopharyngeal cancers. However, high complication rates have been reported after voice prosthesis insertion. In this setting, the ileocolon free flap (ICFF) offers a tubularized flap for reconstruction of the hypopharynx while providing a natural phonation tube. Herein, we systematically reviewed the current evidence on the use of the ICFF for reconstruction of the aerodigestive tract. A systematic literature search was conducted across PubMed MEDLINE, Web of Science, ScienceDirect, Scopus, and Ovid MEDLINE(R). Data on the technical considerations and surgical and functional outcomes were extracted. Twenty-one studies were included. The mean age and follow-up were 54.65 years and 24.72 months, respectively. An isoperistaltic or antiperistaltic standard ICFF, patch flap, or chimeric seromuscular-ICFF can be used depending on the patients' needs. The seromuscular chimeric flap is useful to augment the closure of the distal anastomotic site. The maximum phonation time, frequency, and sound pressure level (dB) were higher with ileal segments of 7 to 15 cm. The incidence of postoperative leakage ranged from 0 to 13.3%, and the majority was occurring at the coloesophageal junction. The revision rate of the microanastomosis ranged from 0 to 16.6%. The ICFF provides a reliable and versatile alternative for reconstruction of middle-size defects of the aerodigestive tract. Its three-dimensional configuration and functional anatomy encourage early speech and deglutition without a prosthetic valve and minimal donor-site morbidity.

Adoptive T Cell Therapy for Solid Tumors: Pathway to Personalized Standard of Care.

Adoptive cell therapy (ACT) with tumor-infiltrating T cells (TILs) has emerged as a promising therapy for the treatment of unresectable or metastatic solid tumors. One challenge to finding a universal anticancer treatment is the heterogeneity present between different tumors as a result of genetic instability associated with tumorigenesis. As the epitome of personalized medicine, TIL-ACT bypasses the issue of intertumoral heterogeneity by utilizing the patient's existing antitumor immune response. Despite being one of the few therapies capable of inducing durable, complete tumor regression, many patients fail to respond. Recent research has focused on increasing therapeutic efficacy by refining various aspects of the TIL protocol, which includes the isolation, ex vivo expansion, and subsequent infusion of tumor specific lymphocytes. This review will explore how the therapy has evolved with time by highlighting various resistance mechanisms to TIL therapy and the novel strategies to overcome them.

Intertumoral Genetic Heterogeneity Generates Distinct Tumor Microenvironments in a Novel Murine Synchronous Melanoma Model.

Metastatic melanoma portends a poor prognosis and patients may present with multiple, simultaneous tumors. Despite recent advances in systemic immunotherapy, a majority of patients fail to respond, or exhibit lesion-specific responses wherein some metastases respond as others progress within the same patient. While intertumoral heterogeneity has been clinically associated with these mixed lesion-specific therapeutic responses, no clear mechanism has been identified, largely due to the scarcity of preclinical models. We developed a novel murine synchronous melanoma model that recapitulates this intertumoral genetic and microenvironmental heterogeneity. We show that genetic differences between tumors are sufficient to generate distinct tumor immune microenvironments (TIME) simultaneously in the same mouse. Furthermore, these TIMEs lead to the independent regulation of PD-1/PD-L1 (programmed cell death protein 1/PD-1 ligand), a popular axis targeted by immune checkpoint therapy, in response to ongoing anti-tumor immunity and the presence of interferon-gamma. Currently, therapeutic selection for metastatic melanoma patients is guided by a single biopsy, which may not represent the immune status of all tumors. As a result, patients can display heterogeneous lesion-specific responses. Further investigations into this synchronous melanoma model will provide mechanistic insight into the effects of intertumoral heterogeneity and guide therapeutic selection in this challenging patient population.

Picomets: Assessing single and few cell metastases in melanoma sentinel lymph node biopsies.

BACKGROUND: Lymph node involvement is a significant prognostic factor for melanoma. Both number of positive nodes and disease burden within a lymph node affects survival. However, the significance of few tumor cells within a single node and subsequent optimal management remains without consensus. We investigated the implications of minimal nodal disease on clinical outcomes. METHODS: We reviewed 752 patients who underwent lymph node sampling at time of primary melanoma resection at our institution over 15 years. We deemed patients who had 1 node with 1 to 4 atypical cells staining positive for either Melan-A or Sox-10 as having "picomets." We examined the initial clinicopathological features, subsequent management, and outcomes. RESULTS: Thirty-three patients (4%) met criteria for having picomets. The most common number of positively staining atypical cells was 1 (n = 13). Nodal staging at initial pathology review varied, and overall stage ranged from IA to IIIC. Four patients underwent further therapy, none of whom had recurrent disease. Of the 29 patients undergoing observation/surveillance only, 5 had disease recurrence (17%). CONCLUSION: Although patients with picomets had better outcomes than historical stage matched cohorts, a small subset had recurrent disease. Staging patients with picomets as "N0" may not reflect the true negative prognostic significance of picomets. A larger population of patients meeting picomets criteria is needed to draw further conclusions.